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Query Topic: EGFR

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EGFR transcription in non-small-cell lung cancer tumours can be revealed in ctDNA by cell-free chromatin immunoprecipitation (cfChIP).
Determination of tumour-specific transcription based on liquid biopsies possesses a large diagnostic and prognostic potential in non-small cell lung cancer (NSCLC). Cell-free DNA (cfDNA) packed in nucleosomes mirrors the histone modification profiles present in the cells of origin. H3 lysine 36 trimethylation (H3K36me3)-modified nucleosomes are associated with active genes and, therefore, cell-free chromatin immunoprecipitation (cfChIP) of H3K36me3-associated cfDNA has the potential to delineate whether transcription of a particular gene is occurring in the cells from which its cfDNA originates. We hypothesized that cfChIP can delineate transcriptional status of genes harbouring somatic cancer mutations and analysed the recurrently observed EGFR-L858R mutation as an example. In representative NSCLC cell lines, the relationship between wild type (WT) and mutated EGFR transcriptional activity and mRNA expression levels was analysed using H3K36me3 ChIP and EGFR mRNA reverse transcription quantitative PCR (RT-qPCR), respectively. The ChIP analysis showed that both WT and mutated EGFR are transcribed, and that mRNA is similarly expressed per EGFR copy. Based on this observation, we proceeded with EGFR cfChIP using blood plasma from NSCLC patients harbouring the EGFR-L858R mutation. EGFR-WT fragments can originate from both non-tumour cells with no or low EGFR transcription and tumour cells with active EGFR transcription, whereas EGFR-L858R fragments must specifically originate from tumour cells. H3K36me3 cfChIP followed by droplet digital PCR (ddPCR) revealed significantly higher enrichment of EGFR-L858R compared to EGFR-WT fragments. This is in alignment with EGFR-L858R being actively transcribed in the NSCLC tumour cells. This study is proof-of-principle that cfChIP can be used to identify tumour-specific transcriptional activity of mutated alleles, which can expand the utility of liquid-biopsy-based cfDNA analyses to enhance tumour diagnostics and therapeutics.
Publication Date: 2021-08-29
Journal: Molecular oncology


Clinical and molecular characteristics of epidermal growth factor receptor exon 20 insertion mutations in non-small-cell lung cancer.
To evaluate the genomic and immune characteristics of non-small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) exon 20 insertion (ex20ins) mutations from a retrospective dataset with molecular spectrum, tumor mutational burden (TMB), and programmed death-ligand 1 (PD-L1) expression, as well as to evaluate the efficacy of immune checkpoint inhibitors (ICIs). A total of 283 patients with EGFR ex20ins mutations who were diagnosed with NSCLC at our hospital from August 2013 to September 2020 were enrolled in this single-center retrospective study. Among the 283 patients with EGFR ex20ins mutations, 182 patients received next-generation sequencing (NGS) test, and 51 different subtypes of insertion variants were recorded. The most common mutations were A767_V769dup (21.4%), S768_D770dup (19.2%) and A763_Y764insFQEA (7.1%). The most common co-occurring mutations were EGFR amplification (37.9%), TP53 mutation (35.0%) and PIK3CA mutation (8.7%). PD-L1 status was available for 141 patients, and 75.9% (107/141) of these samples showed negative PD-L1 expression. In the 36 cases with TMB tested by NGS, the median TMB was 4.6 mutations/Mb. Then 12 patients received ICIs monotherapy or combination therapy. No severe adverse events were observed. Low PD-L1 expression and TMB were observed in NSCLC patients harboring EGFR ex20ins mutations. Further investigations are needed to confirm the therapeutic sensitivity of ICIs in this subgroup of EGFR mutations.
Publication Date: 2021-08-29
Journal: Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico

tyrosine kinase(367)

The predictive and prognostic effects of PD-L1 expression on TKI treatment and survival of EGFR-mutant NSCLC: A meta-analysis.
Whether programmed death-ligand 1 (PD-L1) expression could predict the outcome of tyrosine kinase inhibitor (TKI) treatment and prognosis of epidermal growth factor receptor (EGFR)-mutant nonsmall cell lung cancer (NSCLC) is remaining controversial.Potential studies were search from PubMed, Embase, and Web of Science databases. Pooled odds ratio of objective response rate was used to describe the relationship between PD-L1 expression and primary resistance to EGFR-TKIs. Pooled hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS) were included to assess the effects of PD-L1 status on the outcome of EGFR-TKI treatment and survival of EGFR-mutant NSCLCs.Eighteen eligible studies (1986 EGFR-mutant NSCLCs) were included in this meta-analysis. Positive PD-L1 expression correlated with lower objective response rate of EGFR-TKI treatment (odds ratio [95% confidence interval {CI}] = 0.52 [0.28-0.98], P = .043), while PFS (adjusted HR [95% CI] = 1.49 [0.96-1.89], P = .332) and OS (HR [95% CI] = 1.24 [0.70-2.20], P = .456) of EGFR-TKI treatment did not correlated with PD-L1 status. Furthermore, PD-L1 expression was not a predictive biomarker for the OS (HR [95% CI] = 1.43 [0.98-2.08], P = .062) in overall EGFR-mutant cohort.Positive PD-L1 expression indicated a higher incidence of primary resistance, but did not correlate with the PFS or OS of EGFR-TKI therapy. In addition, PD-L1 expression was unlikely a predictive biomarker for prognosis of EGFR-mutant NSCLCs.
Publication Date: 2021-08-28
Journal: Medicine


Disruption of Cytosolic Folate Integrity Aggravates Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors and Modulates Metastatic Properties in Non-Small-Cell Lung Cancer Cells.
Patients with advanced-stage non-small-cell lung cancer (NSCLC) are susceptible to malnutrition and develop folate deficiency (FD). We previously found that folate deprivation induces drug resistance in hepatocellular carcinoma; here, we assessed whether disrupted cytoplasmic folate metabolism could mimic FD-induced metastasis and affect the sensitivity of NSCLC cells to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). We examined whether cytosolic folate metabolism in NSCLC cells was disrupted by FD or the folate metabolism blocker pemetrexed for 1-4 weeks. Our results revealed an increase in NF-κB overexpression-mediated epithelial-mesenchymal transition biomarkers: N-cadherin, vimentin, matrix metalloproteinases (MMPs), SOX9, and SLUG. This finding suggests that the disruption of folate metabolism can drastically enhance the metastatic properties of NSCLC cells. Cytosolic FD also affected EGFR-TKI cytotoxicity toward NSCLC cells. Because SLUG and N-cadherin are resistance effectors against gefitinib, the effects of SLUG knockdown in folate antagonist-treated CL1-0 cells were evaluated. SLUG knockdown prevented SLUG/NF-κB/SOX9-mediated invasiveness and erlotinib resistance acquisition and significantly reduced pemetrexed-induced gelatinase activity and MMP gene expression. To summarize, our data reveal two unprecedented adverse effects of folate metabolism disruption in NSCLC cells. Thus, the folic acid status of patients with NSCLC under treatment can considerably influence their prognosis.
Publication Date: 2021-08-28
Journal: International journal of molecular sciences


Elastography ultrasound with machine learning improves the diagnostic performance of traditional ultrasound in predicting kidney fibrosis.
Noninvasively predicting kidney tubulointerstitial fibrosis is important because it's closely correlated with the development and prognosis of chronic kidney disease (CKD). Most studies of shear wave elastography (SWE) in CKD were limited to non-linear statistical dependencies and didn't fully consider variables' interactions. Therefore, support vector machine (SVM) of machine learning was used to assess the prediction value of SWE and traditional ultrasound techniques in kidney fibrosis. We consecutively recruited 117 CKD patients with kidney biopsy. SWE, B-mode, color Doppler flow imaging ultrasound and hematological exams were performed on the day of kidney biopsy. Kidney tubulointerstitial fibrosis was graded by semi-quantification of Masson staining. The diagnostic performances were accessed by ROC analysis. Tubulointerstitial fibrosis area was significantly correlated with eGFR among CKD patients (R = 0.450, P < 0.001). AUC of SWE, combined with B-mode and blood flow ultrasound by SVM, was 0.8303 (sensitivity, 77.19%; specificity, 71.67%) for diagnosing tubulointerstitial fibrosis (>10%), higher than either traditional ultrasound, or SWE (AUC, 0.6735 [sensitivity, 67.74%; specificity, 65.45%]; 0.5391 [sensitivity, 55.56%; specificity, 53.33%] respectively. Delong test, p < 0.05); For diagnosing different grades of tubulointerstitial fibrosis, SWE combined with traditional ultrasound by SVM, had AUCs of 0.6429 for mild tubulointerstitial fibrosis (11%-25%), and 0.9431 for moderate to severe tubulointerstitial fibrosis (>50%), higher than other methods (Delong test, p < 0.05). SWE with SVM modeling could improve the diagnostic performance of traditional kidney ultrasound in predicting different kidney tubulointerstitial fibrosis grades among CKD patients.
Publication Date: 2021-08-29
Journal: Journal of the Formosan Medical Association = Taiwan yi zhi


Sodium-glucose cotransporter 2 inhibitors as the first universal treatment of chronic kidney disease.
In the last five years, the medical community was astonishingly surprised by the sequential large outcome trials that displayed the renal effects of sodium glucose co-transporter inhibitors (SGLT2Is) in type 2 diabetes mellitus (T2DM) patients with or without chronic kidney disease (CKD). This favorable effect was later disclosed in non-diabetic CKD patients. The EMPA-REG OUTCOME trial was the first trial that showed a reduction for the need for dialysis in patients suffering diabetic kidney disease (DKD) by 55%. This figure is double the score achieved by the angiotensin receptor blocker, Losartan, in RENAAL trial. The need for dialysis in DAPA-CKD trial was reduced in diabetic and non-diabetic CKD patients by 33%. The renal-specific composite outcome was reduced by 39% in EMPA-REG trial, 40% in CANVAS study, 47% in DECLARE-TIMI 58 study, 34% in CREDENCE trial, and 44% in DAPA-CKD trial. The greater surprise is the significant favorable effect of SGLT2Is on overall mortality in CKD patients with or without T2DM. Similar survival benefit was not previously encountered with any of the medications used in CKD patients with or without diabetes. In this review, we disclose the results of the DAPA-CKD trial, the CREDENCE trial and those of several cardiovascular outcome trials (CVOT) that used different SGLT2Is and showed that patients with lower eGFR levels may have greater benefit with respect to cardiovascular morbidity than patients with normal kidney function. In addition, we discuss the different mechanisms of action that explain the renal beneficial effects of SGLT2Is.
Publication Date: 2021-08-29
Journal: Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia


Relationship of the Intake of Water and Other Beverages With Renal Endpoints: Cross-Sectional and Longitudinal Data-Observational, Population-Based Study.
The relationship of water intake with kidney function in the population is uncertain. This study investigated cross-sectionally and longitudinally the relationship of the intake of water and other beverages with kidney function within an adult Italian population sample. In 4,554 Gubbio Study examinees (54.4% women, age 18-95 years), data collection at baseline included demographics, anthropometry, questionnaires on habitual intakes of water and other beverages (non-water fluids), a timed overnight urine collection, estimated glomerular filtration rate (eGFR), decreased eGFR (<60 mL/minute/1.73 m In multivariable analyses, higher water intake is independently related to higher urine flow (beta = 0.163, P < .001), lower urine osmolality (beta = 0.184, P < .001), lower eGFR (beta = 0.030, P = .002), and higher prevalence of decreased eGFR (logistic coefficient ± standard error = 1.13 ± 0.32, P < .001). Water intake did not relate to kidney function change over time. Intake of non-water fluids did not independently relate to urinary indices nor to kidney function. In the general population, water intake relates cross-sectionally to urine flow, urine concentration, and kidney function but it does not relate to kidney function change over time. The intake of other beverages does not relate to urinary indices or kidney function. Results do not support a role of water intake in kidney function decline over time in the population.
Publication Date: 2021-08-29
Journal: Journal of renal nutrition : the official journal of the Council on Renal Nutrition of the National Kidney Foundation


Effects of Bivalirudin and Unfractionated Heparin on Liver and Renal Function in Chinese Patients with Coronary Artery Disease Undergoing Coronary Angiography with/without Percutaneous Coronary Intervention.
Unfractionated heparin (UFH) and bivalirudin are widely used as anticoagulants in cardiovascular medicine, including for thrombosis prevention during coronary angiography (CAG) and percutaneous coronary intervention (PCI). Little is known of the effects of UFH and bivalirudin on liver and kidney function in patients subjected to these procedures. This study compared the effects of bivalirudin and UFH on liver/renal function in patients with coronary artery disease who underwent CAG, with or without PCI. The study comprised 134 consecutive patients (40-89 years-old), who underwent CAG (or CAG and PCI); among them, 66 and 68 patients were subject to, respectively, bivalirudin or UFH. The following indicators of liver/renal function were measured before and after the procedures: plasma alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen, estimated glomerular filtration rate (eGFR), creatinine clearance, and serum creatinine. Patients were further stratified by severity of chronic kidney disease (CKD), based on original eGFR. Relative to baseline, in the bivalirudin group, ALT and AST were higher after CAG ( Relative to UFH, bivalirudin may better safeguard the renal function of patients with coronary artery disease who undergo CAG, especially patients with moderate-to-severe renal insufficiency. UFH may cause less liver damage than bivalirudin.
Publication Date: 2021-08-28
Journal: Journal of clinical and translational hepatology


The potential targeted drugs for fusion genes including NRG1 in pancreatic cancer.
Pancreatic cancer (PC) remains an incurable disease with few treatment options Recently, promising targets have been identified and novel therapeutic drugs are currently under development in KRAS wild-type PC. It has been reported that KRAS wild-type PC has the genomic alterations such as oncogenic derivers and kinase fusions. NRG1 fusion, which encodes the neuregulin 1 and is the main ligands for ERRB3, has been identified in approximately half of younger patients with PC with KRAS -wild-type tumors by RNA sequencing. There are several promising targeted therapies for NRG1 fusion-positive tumors, such as EGFR-tyrosine kinase inhibitor,HER3, HER2 antibodies. BRAF, NTRK, and ALK fusion are also potentially actionable alterations in KRAS -wild-type PC and novel therapies targeting certain aberrations have shown activity in clinical trials.
Publication Date: 2021-08-29
Journal: Critical reviews in oncology/hematology


Expression of Cancer Stem Cell Markers EpCAM and CD90 Is Correlated with Anti- and Pro-Oncogenic EphA2 Signaling in Hepatocellular Carcinoma.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Additionally, the efficacy of targeted molecular therapies with multiple tyrosine kinase inhibitors is limited. In this study, we focused on the cellular signaling pathways common to diverse HCC cells and used quantitative reverse phase protein array (RPPA) and statistical analyses to elucidate the molecular mechanisms determining its malignancy. We examined the heterogeneity of 17 liver cancer cell lines by performing cluster analysis of their expression of CD90 and EpCAM cancer stem cell markers. Gaussian mixture model clustering identified three dominant clusters: CD90-positive and EpCAM-negative (CD90+), EpCAM-positive and CD90-negative (EpCAM+) and EpCAM-negative and CD90-negative (Neutral). A multivariate analysis by partial least squares revealed that the former two cell populations showed distinct patterns of protein expression and phosphorylation in the EGFR and EphA2 signaling pathways. The CD90+ cells exhibited higher abundance of AKT, EphA2 and its phosphorylated form at Ser
Publication Date: 2021-08-28
Journal: International journal of molecular sciences


Urinary phthalate metabolites mixture, serum cytokines and renal function in children: A panel study.
Epidemiological evidence regarded the relations of phthalates with children's renal function and its underlying mechanism were largely unknown. We conducted a panel study using 287 paired urine-blood samples by repeated measurements of 103 children (4-13 years) across 3 seasons to explore effects of urinary phthalate metabolites on estimated glomerular filtration rate (eGFR) and the potential role of multiple cytokines. We found that mono-ethyl phthalate (MEP), monobutyl phthalate (MBP), mono-benzyl phthalate (MBzP) and mono-n-octyl phthalate (MOP) were significantly associated with eGFR reduction. Compared with the lowest quartile, MBP, MBzP and MEP in the third and fourth quartiles exhibited a graded decrease in eGFR. Meanwhile, weighted quantile sum regression analyses showed an inverse association of metabolites mixture with eGFR, to which MEP, MBzP, MOP were the major contributors. MEP also remained robust in multiple-phthalate model. Age and weight status might modify such relationships with significant interactions. Furthermore, eGFR related phthalate metabolites were associated with increased multiple cytokines, and CCL27, CXCL1 might be potential mediators between MEP and eGFR with mild mediated proportions. Accordingly, urinary phthalate metabolites were related to eGFR reduction in dose-response manner and multiple cytokines elevation, of which CCL27 and CXCL1 might partly mediate phthalate-associated decreased renal function among children.
Publication Date: 2021-08-28
Journal: Journal of hazardous materials

cell lung cancer(306)

The Prognostic Role of PORT and EGFR Mutation Status in Completely Resected Stage IIIA/N2 Non-Small Cell Lung Cancer Patients with Postoperative Chemotherapy.
Publication Date: 2021-08-28
Journal: Pathology oncology research : POR

ml min 1 73(302)

Associations between nutritional factors and excessive daytime sleepiness in older patients with chronic kidney disease.
Excessive daytime sleepiness (EDS) is prevalent in not only older adults, but also patients with chronic kidney disease (CKD), and is associated with higher risks of morbidity and mortality. The aim of the present study is to determine associations between EDS and nutritional status and serum nutrient levels in older patients with CKD. This cross-sectional study included 367 patients (aged ≥ 65 years) with CKD (eGFR < 60 ml/min/1.73 m The mean age was 81 ± 7 years, and 248 (67%) were female. EDS was seen in 99 (26.9%) patients. Those with EDS had significantly lower MNA scores and more frequent malnutrition than those without EDS (p < 0.05). In multivariable analysis adjusted for age, sex, cerebrovascular disease, dementia, number of drugs, and number of urinations at night, and the Charlson Comorbidity Index the relationship between malnutrition and EDS persisted (OR 2.58, 95% CI 1.38-4.83, p = 0.003). There was no significant difference between the presence of EDS and serum levels or deficiencies of vitamin D, vitamin B EDS is associated with malnutrition in older patients with CKD. Therefore, EDS and nutritional status should be evaluated together in clinical practice. However, future studies are needed to determine the direction of the association between malnutrition and EDS and to evaluate if dietary intervention can improve EDS.
Publication Date: 2021-08-28
Journal: Aging clinical and experimental research

cancer nsclc(292)

EphB4 as a Novel Target for the EGFR-Independent Suppressive Effects of Osimertinib on Cell Cycle Progression in Non-Small Cell Lung Cancer.
Osimertinib is the latest generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor used for patients with EGFR-mutated non-small cell lung cancer (NSCLC). We aimed to explore the novel mechanisms of osimertinib by particularly focusing on EGFR-independent effects, which have not been well characterized. We explored the EGFR-independent effects of osimertinib on cell proliferation using NSCLC cell lines, an antibody array analysis, and the association between the action of osimertinib and the ephrin receptor B4 (EphB4). We also studied the clinicopathological significance of EphB4 in 84 lung adenocarcinoma patients. Osimertinib exerted significant inhibitory effects on cell growth and cell cycle progression by promoting the phosphorylation of p53 and p21 and decreasing cyclin D1 expression independently of EGFR. EphB4 was significantly suppressed by osimertinib and promoted cell growth and sensitivity to osimertinib. The EphB4 status in carcinoma cells was positively correlated with tumor size, T factor, and Ki-67 labeling index in all patients and was associated with poor relapse-free survival in EGFR mutation-positive patients. EphB4 is associated with the EGFR-independent suppressive effects of osimertinib on cell cycle and with a poor clinical outcome. Osimertinib can exert significant growth inhibitory effects in EGFR-mutated NSCLC patients with a high EphB4 status.
Publication Date: 2021-08-28
Journal: International journal of molecular sciences

lung cancer nsclc(289)

Diagnostic Performance of Electromagnetic Navigation Bronchoscopy-Guided Biopsy for Lung Nodules in the Era of Molecular Testing.
Electromagnetic navigation bronchoscopy (ENB) is an emerging technique used to evaluate peripheral lung lesions. The aim of this study was to determine the diagnostic yield, safety profile, and adequacy of specimens obtained using ENB for molecular testing. This single-center, prospective pilot study recruited patients with peripheral pulmonary nodules that were not suitable for biopsy via percutaneous transthoracic needle biopsy methods. The possibility of molecular testing, including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and programmed death ligand 1 (PD-L1), was identified with non-small cell lung cancer (NSCLC) tissue obtained using ENB. ENB-guided biopsy was performed on 30 pulmonary nodules in 30 patients. ENB-guided biopsy was successfully performed in 96.6% (29/30) of cases, but one case failed to approach the target lesion. The diagnostic accuracy of ENB-guided biopsy was 68.0% (17/25). Biopsy-related pneumothorax occurred in one patient and there was no major bleeding or deaths related to the procedure. Among 13 patients diagnosed with NSCLC, molecular testing was successfully performed in 92.3% (12/13). ENB-guided biopsy demonstrated acceptable accuracy and excellent sample adequacy, with a high possibility of achieving molecular testing and a good safety profile to evaluate peripheral pulmonary nodules, even when the percutaneous approach was difficult and/or dangerous.
Publication Date: 2021-08-28
Journal: Diagnostics (Basel, Switzerland)


Nephrotoxic Metal Mixtures and Preadolescent Kidney Function.
Exposure to metals including lead (Pb), cadmium (Cd), and arsenic (As), may impair kidney function as individual toxicants or in mixtures. However, no single medium is ideal to study multiple metals simultaneously. We hypothesized that multi-media biomarkers (MMBs), integrated indices combining information across biomarkers, are informative of adverse kidney function. Levels of Pb, Cd, and As were quantified in blood and urine in 4-6-year-old Mexican children (n = 300) in the PROGRESS longitudinal cohort study. We estimated the mixture effects of these metals, using weighted quantile sum regression (WQS) applied to urine biomarkers (Umix), blood biomarkers (Bmix), and MMBs, on the cystatin C-based estimated glomerular filtration rate (eGFR) and serum cystatin C assessed at 8-10 years of age, adjusted for covariates. Quartile increases in Umix and the MMB mixture were associated with 2.5% (95%CI: 0.1, 5.0) and 3.0% (95%CI: 0.2, 5.7) increased eGFR and -2.6% (95% CI: -5.1%, -0.1%) and -3.3% (95% CI: -6.5%, -0.1%) decreased cystatin C, respectively. Weights indicate that the strongest contributors to the associations with eGFR and serum cystatin C were Cd and Pb, respectively. MMBs detected mixture effects distinct from associations with individual metals or media-type, highlighting the benefits of incorporating information from multiple exposure media in mixtures analyses.
Publication Date: 2021-08-28
Journal: Children (Basel, Switzerland)


Ticagrelor or Prasugrel in Patients With Acute Coronary Syndrome in Relation to Estimated Glomerular Filtration Rate.
The aim of this study was to assess the safety and efficacy of ticagrelor versus prasugrel for patients with acute coronary syndrome (ACS) according to their estimated glomerular filtration rates (eGFRs). The outcomes of ticagrelor versus prasugrel in patients with ACS according to eGFR have not been defined. Patients (n = 4,012) were categorized into 3 groups: low eGFR (<60 mL/min/1.73 m Patients with low eGFRs had a higher risk for the primary endpoint compared with patients with intermediate eGFRs (adjusted hazard ratio [HR]: 1.89; 95% confidence interval [CI]: 1.46-2.46]) and those with high eGFRs (adjusted HR: 2.33; 95% CI: 1.57-3.46). A risk excess for low eGFR was also observed for bleeding (adjusted HR: 1.55 [95% CI: 1.12-2.13] vs intermediate eGFR; adjusted HR: 1.59 [95% CI: 1.01-2.50] vs high eGFR). However, eGFR did not affect the relative efficacy and safety of ticagrelor versus prasugrel. In patients with low eGFR, the primary endpoint occurred in 20.5% with ticagrelor and in 14.7% with prasugrel (HR: 1.47; 95% CI: 1.04-2.08; P = 0.029); there was no significant difference in bleeding. These results show that among patients with ACS, reduction of eGFR is associated with increased risk for ischemic and bleeding events but has no significant impact on the relative efficacy and safety of ticagrelor versus prasugrel. (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome [ISAR-REACT 5]; NCT01944800).
Publication Date: 2021-08-28
Journal: JACC. Cardiovascular interventions

kinase inhibitors(264)

Synergistic Antitumor Activity of SH003 and Docetaxel via EGFR Signaling Inhibition in Non-Small Cell Lung Cancer.
Epidermal growth factor receptor (EGFR) is overexpressed in lung cancer patients. Despite treatment with various EGFR tyrosine kinase inhibitors, recurrence and metastasis of lung cancer are inevitable. Docetaxel (DTX) is an effective conventional drug that is used to treat various cancers. Several researchers have studied the use of traditional herbal medicine in combination with docetaxel, to improve lung cancer treatment. SH003, a novel herbal mixture, exerts anticancer effects in different cancer cell types. Here, we aimed to investigate the apoptotic and anticancer effects of SH003 in combination with DTX, in human non-small-cell lung cancer (NSCLC). SH003, with DTX, induced apoptotic cell death, with increased expression of cleaved caspases and cleaved poly (ADP-ribose) polymerase in NSCLC cells. Moreover, SH003 and DTX induced the apoptosis of H460 cells via the suppression of the EGFR and signal transducer and activator of transcription 3 (STAT3) signaling pathways. In H460 tumor xenograft models, the administration of SH003 or docetaxel alone diminished tumor growth, and their combination effectively killed cancer cells, with increased expression of apoptotic markers and decreased expression of p-EGFR and p-STAT3. Collectively, the combination of SH003 and DTX may be a novel anticancer strategy to overcome the challenges that are associated with conventional lung cancer therapy.
Publication Date: 2021-08-28
Journal: International journal of molecular sciences


Liquid Biopsy for Disease Monitoring in Non-Small Cell Lung Cancer: The Link between Biology and the Clinic.
Cell-free DNA (cfDNA) analysis offers a non-invasive method to identify sensitising and resistance mutations in advanced Non-Small Cell Lung Cancer (NSCLC) patients. Next-generation sequencing (NGS) of circulating free DNA (cfDNA) is a valuable tool for mutations detection and disease's clonal monitoring. An amplicon-based targeted gene NGS panel was used to analyse 101 plasma samples of advanced non-small cell lung cancer (NSCLC) patients with known oncogenic mutations, mostly EGFR mutations, serially collected at different clinically relevant time points of the disease. The variant allelic frequency (VAF) monitoring in consecutive plasma samples demonstrated different molecular response and progression patterns. The decrease in or the clearance of the mutant alleles was associated with response and the increase in or the emergence of novel alterations with progression. At the best response, the median VAF was 0% (0.0% to 3.62%), lower than that at baseline, with a median of 0.53% (0.0% to 9.9%) ( The targeted NGS of circulating tumour DNA (ctDNA) has clinical utility to monitor treatment response in patients with advanced lung adenocarcinoma.
Publication Date: 2021-08-28
Journal: Cells


Absence of renal remission portends poor long-term kidney outcome in lupus nephritis.
The very long-term consequences of absence of remission in lupus nephritis (LN) remain understudied. In this retrospective analysis, we studied a selected cohort of 128 patients with biopsy-proven class III, IV or V incident LN followed for a median period of 134 months (minimum 25). Remission was defined as a urine protein to creatinine (uP:C) ratio <0.5 g/g and a serum creatinine value <120% of baseline. Renal relapse was defined as the reappearance of a uP:C >1 g/g, leading to a repeat kidney biopsy and treatment change. Poor long-term renal outcome was defined as the presence of chronic kidney disease (CKD). Twenty per cent of patients never achieved renal remission. Their baseline characteristics did not differ from those who did. Absence of renal remission was associated with a threefold higher risk of CKD (48% vs 16%) and a 10-fold higher risk of end-stage renal disease (20% vs 2%). Patients achieving early remission had significantly higher estimated glomerular filtration rate (eGFR) at last follow-up compared with late remitters. Accordingly, patients with CKD at last follow-up had statistically longer time to remission. Among patients who achieved remission, 32% relapsed, with a negative impact on renal outcome, that is, lower eGFR values and higher proportion of CKD (33% vs 8%). Early remission should be achieved to better preserve long-term renal function.
Publication Date: 2021-08-28
Journal: Lupus science & medicine


Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes.
Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favorable effects on cardiorenal outcomes in patients with predominantly stage 3 or 4 chronic kidney disease (CKD) with severely elevated albuminuria and type 2 diabetes. The use of finerenone in patients with type 2 diabetes and a wider range of CKD is unclear. In this double-blind trial, we randomly assigned patients with CKD and type 2 diabetes to receive finerenone or placebo. Eligible patients had a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 30 to less than 300 and an estimated glomerular filtration rate (eGFR) of 25 to 90 ml per minute per 1.73 m A total of 7437 patients underwent randomization. Among the patients included in the analysis, during a median follow-up of 3.4 years, a primary outcome event occurred in 458 of 3686 patients (12.4%) in the finerenone group and in 519 of 3666 (14.2%) in the placebo group (hazard ratio, 0.87; 95% confidence interval [CI], 0.76 to 0.98; P = 0.03), with the benefit driven primarily by a lower incidence of hospitalization for heart failure (hazard ratio, 0.71; 95% CI, 0.56 to 0.90). The secondary composite outcome occurred in 350 patients (9.5%) in the finerenone group and in 395 (10.8%) in the placebo group (hazard ratio, 0.87; 95% CI, 0.76 to 1.01). The overall frequency of adverse events did not differ substantially between groups. The incidence of hyperkalemia-related discontinuation of the trial regimen was higher with finerenone (1.2%) than with placebo (0.4%). Among patients with type 2 diabetes and stage 2 to 4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria, finerenone therapy improved cardiovascular outcomes as compared with placebo. (Funded by Bayer; FIGARO-DKD number, NCT02545049.).
Publication Date: 2021-08-28
Journal: The New England journal of medicine


Low Albumin, Low Bilirubin, and High Alfa-Fetoprotein Are Associated with a Rapid Renal Function Decline in a Large Population Follow-Up Study.
A rapid decline in renal function is associated with high cardiovascular morbidity and mortality, and therefore it is important to identify those at high-risk of rapid renal function decline. The relationship between liver function and renal function is unclear. Therefore, in this longitudinal study, we aimed to investigate associations between liver function and rapid renal function decline. A total of 27,116 participants were enrolled from the Taiwan Biobank and followed for 3.8 years. A rapid decline in renal function was defined as a decline in estimated glomerular filtration rate (eGFR) of ≥25%. Binary logistic regression analysis was used to identify associations between liver function parameters (glutamic-oxalacetic transaminase, glutamic-pyruvic transaminase, albumin, α-fetoprotein [AFP], total bilirubin, and gamma-glutamyl transpeptidase) and eGFR decline ≥ 25%. The rate of eGFR decline of ≥25% was 4.7%. Multivariable analysis showed that low albumin (odds ratio [OR], 0.173;
Publication Date: 2021-08-28
Journal: Journal of personalized medicine


Angiotensin II-Induced Vasoconstriction via Rho Kinase Activation in Pressure-Overloaded Rat Thoracic Aortas.
Angiotensin II (Ang II) induces vasoconstriction through myosin light chain (MLC) kinase activation and MLC phosphatase inactivation via phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) by Rho kinase. However, the detailed mechanism underlying Rho kinase activation by Ang II is still unknown. We investigated the mechanism of Ang II-induced vasoconstriction mediated by Rho kinase in pressure-overloaded rat thoracic aortas. Pressure-overloaded rats were produced by coarctation of the suprarenal abdominal aorta in four-week-old male Wistar rats. The contractile response to Ang II was significantly enhanced in the pressure-overloaded rats. Ang II-induced vasoconstriction was attenuated by inhibitors of Rho kinase, extracellular signal-regulated kinase 1 and 2 (Erk1/2), and epidermal growth factor receptor (EGFR) in both the sham-operated and pressure-overloaded rats. The Ang II-induced vasoconstriction was attenuated by a Janus kinase 2 (JAK2) inhibitor in only the pressure-overloaded rats. The protein levels of MYPT1 and JAK2 increased only in the pressure-overloaded rat thoracic aortas. These results suggested that Ang II-induced contraction is mediated by Rho kinase activation via EGFR, Erk1/2, and JAK2 in pressure-overloaded rat thoracic aortas. Moreover, Ang II-induced contraction was enhanced in pressure-overloaded rats probably because the protein levels of MYPT1 and JAK2 increased in the thoracic aortas.
Publication Date: 2021-08-28
Journal: Biomolecules


Clinical Mass Spectrometry Discovered Human IgG Sialylation as a Potential Biosignature for Kidney Function.
Immunoglobulin G (IgG) N-glycosylation was discovered to have an association with inflammation status, which has the potential to be a novel biomarker for kidney diseases. In this study, we applied an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) method to plasma and urine samples from 57 individuals with different levels of kidney function. Natural abundances of total IgG, IgG1, IgG2, and IgG3 subclasses in plasma showed positive correlations to the estimated glomerular filtration rates (eGFRs). Eighteen IgG glycopeptides also showed positive correlations. In contrast, higher IgG amounts were found in urine samples from participants with lower eGFR values. After normalizing IgG glycopeptides from plasma to their respective protein amounts, H4N4F1S1-IgG1 (
Publication Date: 2021-08-28
Journal: Journal of personalized medicine


Neutrophil gelatinase-associated lipocalin partly reflects the dynamic changes of renal function among chronic hepatitis C patients receiving direct-acting antivirals.
Changes in renal function in chronic hepatitis C (CHC) patients receiving direct-acting antivirals (DAAs) are controversial. The evolution of neutrophil gelatinase-associated lipocalin (NGAL) in these patients remains unclear. A total of 232 CHC patients receiving DAA at Dalin Tzu Chi Hospital from May 2016 to February 2019, were enrolled in this retrospective study. Grade 2/3 renal function deterioration, defined as a decrease in eGFR between 10% and 50% from baseline (BL) to 12 weeks after the end of treatment (P12), was investigated for its association with BL characteristics. The changes in renal function and NGAL levels were also analyzed at the SOF-base or nonSOF-base DAA. Sixty-two patients (26.7%) had grade 2/3 renal function deterioration at P12 after DAA therapy. Univariate analysis showed that it was associated with age (P = 0.038). Multivariate analysis indicated that age (OR = 1.033, 95% CI: 1.004-1.064, P = 0.027), sex (male; OR = 2.039, 95% CI: 1.093-3.804, P = 0.025), ACEI/ARB use (OR = 2.493, 95% CI: 1.016-6.119, P = 0.046), and BL NGAL (OR = 1.033, 95% CI: 1.001-1.067, P = 0.046) positively correlated with grade 2/3 renal function deterioration. Furthermore, eGFR was decreased (P = 0.009) and NGAL was increased (P = 0.004) from BL to P12 in CHC patients receiving SOF-based DAA. Of the CHC patients receiving DAA therapy, 26.7% had grade 2/3 renal function deterioration at P12, and it was associated with older age, gender being male, ACEI/ARB use, and higher BL NGAL levels. In addition, NGAL might be a biomarker of nephrotoxicity at P12 in patients receiving SOF-based DAA.
Publication Date: 2021-08-27
Journal: PloS one


EGFR DNA Methylation Correlates With EGFR Expression, Immune Cell Infiltration, and Overall Survival in Lung Adenocarcinoma.
The epidermal growth factor receptor (EGFR) is a primary target of molecular targeted therapy for lung adenocarcinoma (LUAD). The mechanisms that lead to epigenetic abnormalities of EGFR in LUAD are still unclear. The purpose of our study was to evaluate the abnormal methylation of EGFR CpG sites as potential biomarkers for LUAD. To assess the differentially methylation CpG sites of EGFR in LUAD, we used an integrative study of Illumina HumanMethylation450K and RNA-seq data from The Cancer Genome Atlas (TCGA). We evaluated and compared EGFR multiple-omics data to explore the role of CpG sites located in EGFR promoter regions and gene body regions and the association with transcripts, protein expression levels, mutations, and somatic copy number variation. We calculated the correlation coefficients between CpG sites of EGFR and immune infiltration fraction (by MCPcounter and ESTIMATE) and immune-related pathways in LUAD. Finally, we validated the differential methylation of clinically and prognostically relevant CpG sites using quantitative methylation-specific PCR (qMSP). We found that the methylation level of many EGFR CpGs in the promoter region was negatively correlated with the transcription level, protein expression, and SCNV, while the methylation at the gene body region was positively correlated with these features. The methylation level of EGFR CpGs in the promoter region was positively correlated with the level of immune infiltration and IFN-γ signature, while the opposite was found for methylation of the gene body region. The qMSP results showed that cg02316066 had a high methylation level, while cg02166842 had a low methylation level in LUAD. There was a high degree of co-methylation between cg02316066 and cg03046247. Our data indicate that EGFR is an epigenetic regulator in LUAD acting through DNA methylation. Our research provides a theoretical basis for the further detection of EGFR DNA methylation as a predictive biomarker for LUAD survival and immunotherapy.
Publication Date: 2021-08-28
Journal: Frontiers in oncology


Interaction between SCP3 and JAB1 Confers Cancer Therapeutic Resistance and Stem-like Properties through EGF Expression.
Synaptonemal complex protein 3 (SCP3), a member of the Cor1 family, has been implicated in cancer progression, and therapeutic resistance, as well as cancer stem cell (CSC)-like properties. Previously, we demonstrated that SCP3 promotes these aggressive phenotypes via hyperactivation of the AKT signaling pathway; however, the underlying mechanisms responsible for SCP3-induced AKT activation remain to be elucidated. In this study, we demonstrated that the EGF-EGFR axis is the primary route through which SCP3 acts to activate AKT signaling. SCP3 triggers the EGFR-AKT pathway through transcriptional activation of EGF. Notably, neutralization of secreted EGF by its specific monoclonal antibody reversed SCP3-mediated aggressive phenotypes with a concomitant reversal of EGFR-AKT activation. In an effort to elucidate the molecular mechanisms underlying SCP3-induced transcriptional activation of EGF, we identified Jun activation domain-binding protein 1 (JAB1) as a binding partner of SCP3 using a yeast two-hybrid (Y2H) assay system, and we demonstrated that SCP3 induces EGF transcription through physical interaction with JAB1. Thus, our findings establish a firm molecular link among SCP3, EGFR, and AKT by identifying the novel roles of SCP3 in transcriptional regulation. We believe that these findings hold important implications for controlling SCP3
Publication Date: 2021-08-28
Journal: International journal of molecular sciences


Use of SGLT-2 Inhibitors in Patients with Chronic Kidney Disease.
• Chronic kidney disease (CKD) is common, occurring in 1 of 7 adults in the United States. • 9 out of 10 adults with CKD are unaware of it. • People with CKD have the same risk for cardiovascular (CV) death as people with known atherosclerotic heart disease. • The risk for CV events and death increases with worsening albuminuria and estimated glomerular filtration rate (eGFR). • Patients with risk factors for CKD (hypertension, diabetes, family history of CKD, or advancing age) should be screened by measuring both eGFR and urinary albuminto-creatinine ratio. • Sodium-glucose cotransporter-2 inhibitors are first-line agents for treatment of patients with type 2 diabetes mellitus and CKD or a history of atherosclerotic CV disease. • Dapagliflozin has demonstrated equivalent efficacy for reducing kidney events in patients with CKD irrespective of diabetes status, and a similar, ongoing trial with empagliflozin may provide potential confirmation.
Publication Date: 2021-08-26
Journal: The Journal of family practice

tyrosine kinase inhibitors(199)

Transformation From Adenocarcinoma to Pleomorphic Carcinoma as an Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors.
Pulmonary pleomorphic carcinoma is a very rare histological type of primary lung cancer, and usually provides aggressive clinical courses. A 65-year-old Japanese woman was diagnosed by transbronchial biopsy of the primary tumor as c-stage IV (cT4N3M1b) of adenocarcinoma harboring L858R point mutation in the exon 21 of epidermal growth factor receptor (EGFR). She received EGFR tyrosine kinase inhibitors (TKIs) (gefitinib and erlotinib) and subsequently cytotoxic chemotherapies. Gefitinib achieved partial response, but was switched to erlotinib due to elevated serum aspartate transaminase. After resistance to EGFR-TKIs, the second transbronchial re-biopsy revealed pulmonary pleomorphic carcinoma. Both carcinomatous and sarcomatous components retained the L858R mutation, but did not acquire T790M mutation. This case suggested that the histological transformation to pulmonary pleomorphic carcinoma may be one of mechanisms of drug resistance to EGFR-TKIs.
Publication Date: 2021-08-27
Journal: Journal of medical cases


Association of EGFR Tyrosine Kinase Inhibitor Treatment With Progression-Free Survival Among Taiwanese Patients With Advanced Lung Adenocarcinoma and EGFR Mutation.
Publication Date: 2021-08-27
Journal: Frontiers in pharmacology


The Association of Annexin A1 and Chemosensitivity to Osimertinib in Lung Cancer Cells.
Annexin A1 (ANXA1) has been reported to promote tumor growth and resistance to chemotherapy drugs in lung cancer cells. In this study, we focused on the association of ANXA1 and chemosensitivity with a third generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), Osimertinib, in lung cancer cells with EGFR mutations. The overexpression of ANXA1 was observed in the lung cancer cells studied. The downregulation of ANXA1 with small interference RNA (siRNA) decreased the growth of lung cancer cells. In lung cancer cells with EGFR mutations, the knockdown of ANXA1 increased the chemosensitivity to Osimertinib, and decreased the tumorigenesis, invasion and migration of lung cancer cells. Further study showed that the knockdown of ANXA1 inhibited the phosphorylation of EGFR and down-stream Akt pathways and promoted apoptosis in lung cancer cells treated with Osimertinib. A mice xenograft lung cancer model was established in our study and showed that ANXA1 siRNA enhanced the effects of Osimertinib in vivo. Our study results showed that ANXA1 plays critical roles in chemosensitivity to EGFR-TKI in lung cancer cells with the EGFR mutation. Our efforts may be used in the development of lung cancer treatment strategies in the future.
Publication Date: 2021-08-28
Journal: Cancers


Stronger Association of Albuminuria with the Risk of Vascular Complications than Estimated Glomerular Filtration Rate in Type 2 Diabetes.
Albuminuria is a risk factor for macro- and microvascular complications of type 2 diabetes (T2D).With an increasing trend of normoalbuminuria, however, of the 2 predictors - estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR) - which one is a better predictor of vascular complications of T2D is not clear. This study aimed to compare the impacts of albuminuria and eGFR on patients with T2D associated with micro- and macrovascular complications. This retrospective study recruited 4,715 patients with T2D and grouped them based on the values of UACR (high UACR: ≥30 mg/g, low UACR: <30 mg/g) and eGFR (mL/[min × 1.73 m2]) (G1: eGFR ≥ 90; G2: eGFR = 60-89; G3-5: eGFR < 60) from April 2008 to November 2018. Logistic regression analysis was carried out for risk factors in patients with diabetic retinopathy (DR), diabetic peripheral neuropathy (DPN), peripheral arterial disease (PAD), left ventricular remodeling, diastolic disorders, and carotid atherosclerotic plaque in 6 different groups: low UACR + G1 (control group), low UACR + G2, low UACR + G3-5, high UACR + G1, high UACR + G2, and high UACR + G3-5. Patients were grouped according to the change in the UACR value (UACR-decreased group: ≤-30%, UACR-stable group: -30 to 30%, and UACR-increased group ≥30%), eGFR value (eGFR-decreased group: >3%, and eGFR-stable group: ≤3%) and followed up. Compared with the control group, patients with higher albuminuria and lower eGFR had higher adjusted odds ratio (OR) trends of complications, especially in the high UACR + G3-5 group. The OR of 2.010, 3.444, 1.633, 2.742, and 3.014 were obtained for DR, DPN, PAD, left ventricular remodeling, and diastolic disorders, respectively. No statistically significant difference was found in the risk of complications within each one of 2 phenotypes, regardless of the change in the eGFR. After grouping by eGFR, the regression analysis of the urinary protein level in each stage revealed that a majority of complications had a statistically significant difference, except for DR and PAD in the high UACR + G3-5 group. DR in the follow-up study had a higher risk in the UACR-stable/increased group than the UACR-decreased group (UACR stable: OR = 2.568; 95% confidence interval (CI): 1.128-5.849; p = 0.025; UACR increased: OR = 2.489; 95% CI: 1.140-5.433; p = 0.022). UACR is a more predictive risk factor for diabetic complications compared with a reduced eGFR.
Publication Date: 2021-08-25
Journal: Kidney & blood pressure research

95 ci(175)

Clinical significance of the N-terminal pro-brain natriuretic peptide and B-type natriuretic peptide ratio in the acute phase of acute heart failure.
Serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and B-type natriuretic peptide (BNP) levels are rarely evaluated simultaneously in the acute phase of acute heart failure (AHF). A total of 1207 AHF patients were enrolled, and 1002 patients were analysed. Blood samples were collected within 15 min of admission. Patients were divided into two groups according to the median value of the NT-proBNP/BNP ratio [low-NT-proBNP/BNP group (Group L) vs. high-NT-proBNP/BNP group (Group H)]. A multivariate logistic regression model showed that the C-reactive protein level (per 1-mg/dL increase), Controlling Nutrition Status score (per 1-point increase), and estimated glomerular filtration rate (eGFR, per 10-mL/min/1.73 m2 increase) were independently associated with Group H [odds ratio (OR) 1.049, 95% confidence interval (CI) 1.009-1.090, OR 1.219, 95% CI 1.140-1.304, and OR 1.543, 95% CI 1.401-1.698, respectively]. A Kaplan-Meier curve analysis showed that the prognosis was significantly poorer in Group H than in Group L, and a multivariate Cox regression model revealed Group H to be an independent predictor of 180-day mortality [hazard ratio (HR) 3.084, 95% CI 1.838-5.175] and HF events (HR 1.963, 95% CI 1.340-2.876). The same trend in the prognostic impact was significantly observed in the low-BNP (<810 pg/mL, n = 501), high-BNP (≥810 pg/mL, n = 501), and low-eGFR (<60 mL/min/1.73 m2, n = 765) cohorts, and tended to be observed in normal-eGFR (≥60 mL/min/1.73 m2, n = 237) cohort. A high NT-proBNP/BNP ratio was associated with a non-cardiac condition (e.g. inflammatory reaction, nutritional status, and renal dysfunction) and is independently associated with adverse outcomes in AHF.
Publication Date: 2021-08-26
Journal: European heart journal. Acute cardiovascular care

egfr mutations(173)

EGFR-plasma mutations in prognosis for non-small cell lung cancer treated with EGFR TKIs: A meta-analysis.
The plasma-based epidermal growth factor receptor (EGFR) mutation testing is approved recently to use in clinical practice. However, it has not been used as a prognostic marker yet because of contradictory results. This meta-analysis aims to clarify the role of the EGFR-plasma test in prognosis for non-small cell lung cancer (NSCLC) who have mutant tumors and receive EGFR tyrosine kinase inhibitors (TKIs). The PubMed/MEDLINE, Web of Science, Cochrane Library, and Google Scholar databases were searched for relevant studies by April 10, 2021. The hazard ratio (HR) from reports was extracted and used to assess the correlation of EGFR-plasma status with progression-free survival (PFS) and overall survival (OS). A total of 35 eligible studies with 4106 patients were enrolled in the final analysis. Patients with concurrent EGFR mutations in pretreatment plasma have shorter PFS (HR = 2.00, 95% confidence interval [CI]: 1.73-2.31, p < .001) and OS time (HR = 2.31, 95% CI: 1.89-2.83, p < .001) compared to the tumor-only mutation cases. Besides, the persistence of EGFR-activating mutations in post-treatment plasma is associated with worse PFS (HR = 3.84, 95% CI: 2.96-4.99, p < .001) and OS outcome (HR = 3.22, 95% CI: 2.35-4.42, p < .001) compared to others. Notably, the prognostic value of the EGFR-plasma test is also validated in treatment with third-generation EGFR TKI and significance regardless of different detection methods. The presence of EGFR-plasma mutations at pretreatment and after EGFR TKI initiation is the worse prognostic factor for PFS and OS in NSCLC.
Publication Date: 2021-08-25
Journal: Cancer reports (Hoboken, N.J.)


Renal function trajectories in hepatitis C infection: differences between renal healthy and chronic kidney disease individuals.
Associations between hepatitis C virus (HCV) and chronic kidney disease (CKD) have been reported; however, differences of renal progression between general and CKD population remain to be elucidated in prospective studies. A total of 1179 participants, who have tested for anti-HCV antibody, were enrolled and prospectively followed for 3 years. The risks associated with HCV infection, in terms of incidence of CKD, annual estimated glomerular filtration rate (eGFR) changes and 50% decline of eGFR at 3-year from baseline, were compared between normal renal function subjects and CKD patients. Overall, 111 of 233 (47.6%) CKD patients and 167 of 946 (17.7%) non-CKD subjects had HCV infection. The crude incidence rates of CKD were 226.9 per 1000 person-years and 14.8 per 1000 person-years in in HCV and non-HCV infected patients, respectively. The adjusted hazard ratio of HCV infection for incident CKD was 7.9 (95% CI 5-12.7). The HCV-infected normal renal function subjects were independently associated with increased risks of eGFR decline in the 1-year, 2-year and 3-year, respectively. The risk associations remained significant in 50% decline of eGFR at 3 years models and in different subgroup analyses. The increases of risks of eGFR decline were also notorious among overall HCV-infected CKD patients. However, the risk associations were less prominent in subgroup analyses (elderly, women and diabetic patients). The findings highlighted the importance of viral diagnosis with not only prognostic but also public health implications for preserving kidney function.
Publication Date: 2021-08-27
Journal: Scientific reports


Osimertinib Holds Its Own in NSCLC.
An updated, final analysis from the phase III FLAURA study showed that compared with older EGFR inhibitors, the third-generation drug osimertinib was better tolerated and significantly improved overall survival among patients newly diagnosed with
Publication Date: 2019-12-01
Journal: Cancer discovery


A phase II study of osimertinib for radiotherapy-naïve CNS metastasis from non-small cell lung cancer: Results for the T790M cohort of the OCEAN study (LOGIK1603/WJOG9116L).
Osimertinib has been reported to be effective against central nervous system (CNS) metastasis from activating epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, the true antitumor effects of osimertinib alone for CNS metastasis are unclear because the aforementioned studies included previously irradiated cases, in which tumor shrinkage can occur later due to the effects of radiotherapy. This study aimed to evaluate the efficacy of osimertinib against radiotherapy-naïve CNS metastasis from sensitizing EGFR mutation-positive NSCLC. The OCEAN study was a two-cohort trial, involving 66 patients (the T790M cohort [n=40] and 1st-line cohort [n=26]) with radiotherapy-naïve CNS metastasis from sensitizing EGFR mutation-positive NSCLC. The patients were treated once daily with 80 mg osimertinib. The primary endpoint was the brain metastasis response rate (BMRR) according to the PAREXEL criteria. In this report, we present the results for the T790M cohort with drug concentrations and plasma ctDNA analysis. The patients' median age was 69, and 30% of the patients were male. Eight patients (20%) were symptomatic, and most had multiple CNS metastases (78%). Among the eligible 39 patients, the BMRR (PAREXEL criteria), median brain metastasis-related progression-free survival (PFS), median overall survival, overall response rate, and median PFS were 66.7% (90%CI, 54.3-79.1%), 25.2 months, 19.8 months, 40.5%, and 7.1 months, respectively. The BMRR according to the RECIST criteria was 70.0% (n=20). The brain metastasis-related PFS of patients with EGFR exon 19 deletion was significantly longer than that of exon 21 L858R (median 31.8 vs. 8.3 months; log-rank p=0.032). The treatment-related pneumonitis was observed in 4 (10%) patients. On or after day 22, the median trough blood and cerebrospinal fluid (CSF) concentrations of osimertinib were 568 nM and 4.10 nM, respectively, and those of its metabolite AZ5104 were 68.0 nM and 0.260 nM, respectively. The median blood to CSF penetration rates of osimertinib and AZ5104 were 0.79 % and 0.53%, respectively. The blood trough concentration at day 22 was not correlated with the efficacy of osimertinib against CNS metastasis. Plasma T790M and C797S mutations were detected in 83% and 3% of patients before treatment, 11% and 3% patients on day 22, and 39% and 22% of patients at the detection of progressive disease, respectively. This study assessed the efficacy of osimertinib against radiotherapy-naïve CNS metastasis from T790M-positive NSCLC. The primary endpoint was met, and the results demonstrated the efficacy of osimertinib in patients with CNS metastasis harboring EGFR T790M mutations especially for EGFR-sensitizing mutation of exon 19 deletion.
Publication Date: 2021-08-23
Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer


Clinical Characteristics and Outcomes of Adults with Nephrotic Syndrome Due to Minimal Change Disease.
Minimal change disease (MCD) is considered a relatively benign glomerulopathy, as it rarely progresses to end-stage kidney disease. The aim of this study was to describe the characteristics and outcomes of adults with MCD and identify potential risk factors for relapse. We retrospectively studied a cohort of adults with biopsy-proven MCD in terms of clinical features and treatment outcomes. Baseline characteristics and outcomes were recorded and predictors of relapse were analyzed using logistic regression multivariate analysis. 59 patients with adult-onset primary MCD with nephrotic syndrome were included. Mean serum creatinine at diagnosis was 0.8 mg/dL (±2.5) and estimated GFR (eGFR) was 87 mL/min/1.73 m In this series of patients, almost 46% of adult-onset nephrotic MCD patients experienced a relapse, although their renal progression was rare. Younger onset age was an independent risk factor for relapse in adult-onset MCD patients.
Publication Date: 2021-08-28
Journal: Journal of clinical medicine

lung adenocarcinoma(151)

Effect of aerobic exercise on acquired gefitinib resistance in lung adenocarcinoma.
Lung adenocarcinoma patients with epidermal growth factor receptor (EGFR)-activating mutations respond well to tyrosine kinase inhibitors but typically develop resistance. Current therapies mainly target differentiated cells, not cancer stem cells (CSCs), but CSCs affect the occurrence, invasion, metastasis and treatment sensitivity of malignant tumours. Recently, aerobic exercise has emerged as adjuvant therapy for cancer. Aerobic exercise can accelerate blood circulation, improve tissue oxygen supply, reduce the stress level of patients, improve the antioxidant capacity of the body, and facilitate the degradation of hypoxia-inducible factor-1 (HIF-1) in tumour tissues, thus weakening its maintenance effect on CSCs. In this study, we successfully established lung adenocarcinoma cell lines with gefitinib resistance. Long-term gefitinib induction could increase the level of oxidative stress in lung adenocarcinoma cells and reduce the antioxidant capacity, resulting in the high expression of HIF-1 and ALDH1 and leading to the enrichment of CSCs, and a decreased response to gefitinib. This may be one of the important reasons for gefitinib-acquired resistance in lung adenocarcinoma. In the case of drug resistance, effective aerobic exercise could reduce ROS, activate SOD, inhibit HIF-1 and ALDH1, and cause a reduction in CSCs to sensitise cells to gefitinib again and ultimately inhibit the malignant proliferation of tumours. Therefore, in the treatment of lung adenocarcinoma, the inhibitory effect of aerobic exercise on oxidative stress can enhance the response of drug-resistant cells to gefitinib and can be used as an effective adjunct measure in the treatment of lung adenocarcinoma.
Publication Date: 2021-08-24
Journal: Translational oncology


Kidney Biopsy Chronicity Grading in Antineutrophil Cytoplasmic Antibody Associated Vasculitis.
Kidney biopsy is valuable for prognostic assessment of renal outcomes in antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) with glomerulonephritis (AAV-GN) but the impact of chronic changes is not determined. A retrospective cohort study of MPO- or PR3-ANCA positive patients with AAV and active renal disease. We applied the Mayo Clinic Chronicity Score (MCCS), validated and evaluated its implications on outcome prediction in AAV-GN. We analyzed 329 patients with kidney biopsies available to score. The extent of chronicity was graded by MCCS as (i) minimal - 102 (31.0%), (ii) mild - 106 (32.2%), (iii) moderate - 86 (26.1%), and (iv) severe - 35 (10.6%). The MCCS grades correlated with the degree of renal function impairment at presentation (mean eGFR: 48.3 vs. 29.2 vs. 23.7 vs. 18.5 mL/min/1.73 m2, p < 0.0001). Higher degrees of the individual components of the MCCS (glomerulosclerosis, interstitial fibrosis, tubular atrophy and arteriosclerosis) were associated with lower median eGFR (p < 0.0001) and decreased event free (kidney failure (KF) and death) survival (p = 0.002, p < 0.0001, p < 0.0001 and p = 0.017, respectively). Patients with lower MCCS grades recovered renal function more frequently (p < 0.0001). Increasing MCCS grades were associated with decreased renal recovery (p = 0.001), more frequent events and shorter time to KF (p < 0.0001), KF and death (p < 0.0001), and death (p = 0.042), independently of remission-induction treatment used (CYC or RTX). The MCCS stratified renal outcomes for each MCCS grade and can be used in clinical practice as a cut-off for KF prediction (MCCS≥4). Chronic changes on kidney histology independently predict renal function, outcomes and response to treatment in AAV-GN.
Publication Date: 2021-08-27
Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association


Molecular Engineering of Curcumin, an Active Constituent of
Cancer is the world's second leading cause of death, accounting for nearly 10 million deaths and 19.3 million new cases in 2020. Curcumin analogs are gaining popularity as anticancer agents currently. We reported herein the isolation, molecular engineering, molecular docking, antiproliferative, and anti-epidermal growth factor receptor (anti-EGFR) activities of curcumin analogs. Three curcumin analogs were prepared and docked against the epidermal growth factor receptor (EGFR), revealing efficient binding. Antiproliferative activity against 60 NCI cancer cell lines was assessed using National Cancer Institute (NCI US) protocols. The compound
Publication Date: 2021-08-29
Journal: Plants (Basel, Switzerland)


Urinary CXCL10 Measurement in Late Renal Allograft Biopsies Predicts Outcome Even in Histologically Quiescent Patients.
CXCL10 is a promising early noninvasive diagnostic marker for allograft rejection and predictive for long-term outcomes. However, its value when measured later in the posttransplant course has not yet been accurately analyzed. We investigated urinary CXCL10 in 141 patients from a prospective, observational renal transplant cohort with 182 clinically indicated allograft biopsies performed >12 months posttransplant and corresponding urines. Urinary CXCL10 was retrospectively quantified on stored urines using the MSD V-Plex Chemokine Panel 1 sandwich immunoassay (Meso Scale Discovery). The primary outcome was a composite of allograft loss/renal function decline (>30% estimated glomerular filtration rate [eGFR]-decrease between index biopsy and last follow-up). Seventy-two patients (51%) reached the primary outcome, and their urinary CXCL10 levels were significantly higher at the time of their biopsy compared with patients with stable allograft function (median 9.3 ng/mmol vs 3.3 ng/mmol, P < .0001). Time-to-endpoint analyses according to high/low urinary CXCL10 demonstrated that low urinary CXCL10 (≤7.0 ng/mmol) was associated with 73% 5-year event-free graft survival compared with 48% with high urinary CXCL10 (>7.0 ng/mmol; P = .0001). Even in histologically quiescent patients, high urinary CXCL10 was associated with inferior endpoint-free graft survival (P = .003), and it was an independent predictor of the primary outcome (P = .03). This study demonstrates that urinary CXCL10 has a promising diagnostic performance for detection of late allograft rejection and is an independent predictor of long-term renal allograft outcomes, even in histologically quiescent patients.
Publication Date: 2021-08-23
Journal: Transplantation proceedings


Cytoplasmic P120ctn Promotes Gefitinib Resistance in Lung Cancer Cells by Activating PAK1 and ERK Pathway.
Our previous studies indicated that cytoplasmic p120ctn mediated epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKI) resistance in lung cancer. In the present study, we aim to further explore the underlying molecular mechanisms. Immunohistochemistry detected PAK1, Cdc42, and Rac1 expression in lung cancer with cytoplasmic p120ctn. Immunoblotting, protein activity analysis, and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide evaluated p120ctn location, PAK1, Cdc42/Rac1, and extracellular signal-regulated kinase (ERK) activity in response to TKI treatment in HCC827 and PC9 cell lines, as well as the cell sensitivity to Gefitinib. Most non-small cell lung cancer patients with cytoplasmic p120ctn showed enhanced PAK1 and Cdc42/Rac1. When Gefitinib resistance was induced, cytoplasmic p120ctn is accompanied with increasing PAK1 and Cdc42/Rac1. Cytoplasmic p120ctn activated ERK via PAK1, while PAK1 downregulation attenuated ERK activation by cytoplasmic p120ctn. After Cdc42/Rac1 inhibition, cytoplasmic p120ctn could not activate PAK1. Cytoplasmic p120ctn activates PAK1 via Cdc42/Rac1 activation, constitutively activates ERK in the EGFR downstream signaling, and promotes EGFR-TKI resistance in lung cancer cells. The current study will aid to screen the subpopulation patients who would benefit from therapy with first-generation EGFR-TKIs.
Publication Date: 2021-08-20
Journal: Applied immunohistochemistry & molecular morphology : AIMM


Phase 1 study of M2698, a p70S6K/AKT dual inhibitor, in patients with advanced cancer.
The PI3K/AKT/mTOR (PAM) pathway is a key regulator of tumor therapy resistance. We investigated M2698, an oral p70S6K/AKT dual inhibitor, in patients with advanced cancer who failed standard therapies. M2698 was administered as monotherapy (escalation, 15-380 mg daily; food effect cohort, 240-320 mg daily) and combined with trastuzumab or tamoxifen. Overall, 101 patients were treated (M2698, n = 62; M2698/trastuzumab, n = 13; M2698/tamoxifen, n = 26). Patients were predominantly aged < 65 years, were female, had performance status 1 and were heavily pretreated. There was a dose- and concentration-dependent inhibition of pS6 levels in peripheral blood mononuclear cells and tumor tissue. M2698 was well tolerated; the most common treatment-emergent adverse events were gastrointestinal, abnormal dreams and fatigue (serious, attributed to M2698: monotherapy, 8.1%; M2698/trastuzumab, 7.7%; M2698/tamoxifen, 11.5% of patients). The recommended phase 2 doses of M2698 were 240 mg QD (monotherapy), 160 mg QD (M2698/trastuzumab) and 160 mg QD/240 mg intermittent regimen (M2698/tamoxifen). In the monotherapy cohort, 27.4% of patients had stable disease at 12 weeks; no objective response was noted. The median progression-free survival (PFS) durations in patients with PAM pathway alterations with and without confounding markers (KRAS, EGFR, AKT2) were 1.4 months and 2.8 months, respectively. Two patients with breast cancer (M2698/trastuzumab, n = 1; M2698/tamoxifen, n = 1) had partial response; their PFS durations were 31 months and 2.7 months, respectively. M2698 was well tolerated. Combined with trastuzumab or tamoxifen, M2698 demonstrated antitumor activity in patients with advanced breast cancer resistant to multiple standard therapies, suggesting that it could overcome treatment resistance. Trial registration, NCT01971515. Registered October 23, 2013.
Publication Date: 2021-08-20
Journal: Journal of hematology & oncology


Technical Evaluation of the COBAS EGFR Semiquantitative Index (SQI) for Plasma cfDNA Testing in NSCLC Patients with EGFR Exon 19 Deletions.
The cobas
Publication Date: 2021-08-28
Journal: Diagnostics (Basel, Switzerland)

nsclc patients(129)

Real-world efficacy of osimertinib in previously EGFR-TKI treated NSCLC patients without identification of T790M mutation.
The efficacy of osimertinib in previously EGFR-TKI-treated NSCLC without identification of T790M mutational status remains unclear in real-world practice. 417 patients had stage III-IV NSCLC harboring EGFR mutation and 154 out of 417 patients receiving osimertinib as ≥ second-line EGFR-TKI were identified. The time to treatment failure and risk of death were analyzed. Higher risk of death was found in EGFR-mutant patients with age ≥ 65 years, non-adenocarcinoma, no surgery or radiation, non-exon 19 deletion/exon 21 L858R, higher ECOG PS (2-4), PD-L1 expression ≥ 50%, and bone/liver/adrenal metastasis (all p < 0.05). Osimertinib as ≥ second-line TKI in patients with/without identification of T790M revealed lower risk of death compared to first-line first/second generation TKI without subsequent osimertinib (p = 0.0002; 0.0232, respectively). However, osimertinib-treated patients with T790M did not have superior survival than those without (p = 0.2803). A higher risk of treatment failure for osimertinib was found in males, patients with first-line TKI duration ≤ 12 months, BMI drop > 10%, and PD-L1 expression ≥ 50% (All p < 0.05). Nonetheless, osimertinib as ≥ second-line TKI in patients without identification of 790 M did not have higher risk of treatment failure than those with T790M (p = 0.1236). This study demonstrates that osimertinib as second line or subsequent TKI in EGFR-TKI-treated patients without identification of T790M revealed lower risk of death compared to first-line first/second generation TKI without subsequent osimertinib, in real-world practice. Additionally, EGFR-mutant patients with PD-L1 expression ≥ 50% had a higher risk of treatment failure for osimertinib and worse overall survival than those with PD-L1 expression < 50%. These results suggest that osimertinib as second line or subsequent TKI may be a potential alternative option for the treatment of patients without identification of T790M and PD-L1 expression ≥ 50% is associated with a significantly poor outcome in patients receiving osimertinib.
Publication Date: 2021-08-27
Journal: Journal of cancer research and clinical oncology


Associations of Estimated Glomerular Filtration Rate with All-Cause Mortality and Cardiovascular Mortality in Patients with Diabetic Foot Osteomyelitis.
The purpose of this study was to explore the association between estimated glomerular filtration rate (eGFR) and clinical outcomes in patients with diabetic foot osteomyelitis (DFO). This was a retrospective observational study. A total of 199 patients with DFO were recruited and divided into three groups by eGFR: normal kidney function group (eGFR ≥ 90), mildly decreased kidney function group (eGFR 60-89) and moderately to severely decreased kidney function group (eGFR < 60). The patients were followed-up for a median of 36 months, and the study outcomes were all-cause mortality and major cardiovascular adverse events (MACE). Cox proportional hazard models were used to assess the association between eGFR and the outcomes, and a stratified analysis by sex was conducted. During follow-up, all-cause mortality occurred in 51 (25.63%) patients among 199 participants, 54 (28.72%) had MACE in 188 participants and 26 (48.15%) of them died. After fully adjusting for potential confounders, compared to eGFR < 90 mL/min/1.73 m In conclusion, decreased eGFR is a risk factor for all-cause mortality and MACE in individuals with DFO. Additionally, male with decreased eGFR had a higher risk of all-cause mortality and MACE, but female did not.
Publication Date: 2021-08-26
Journal: International journal of general medicine


Active or Attractive? Oral Antiangiogenesis Therapy Plus EGFR Tyrosine Kinase Inhibitor in EGFR-Mutant NSCLC.
Publication Date: 2021-08-25
Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer


Association between autophagy and KRAS mutation with clinicopathological variables in colorectal cancer patients.
Autophagy is a host defensive mechanism responsible for eliminating harmful cellular components through lysosomal degradation. Autophagy has been known to either promote or suppress various cancers including colorectal cancer (CRC). KRAS mutation serves as an important predictive marker for epidermal growth factor receptor (EGFR)-targeted therapies in CRC. However, the relationship between autophagy and KRAS mutation in CRC is not well-studied. In this single-centre study, 92 formalin-fixed paraffin-embedded (FFPE) tissues of CRC patients (42 Malaysian Chinese and 50 Indonesian) were collected and KRAS mutational status was determined by quantitative PCR (qPCR) (n=92) while the expression of autophagy effector (p62, LC3A and LC3B) was examined by immunohistochemistry (IHC) (n=48). The outcomes of each were then associated with the clinicopathological variables (n=48). Our findings demonstrated that the female CRC patients have a higher tendency in developing KRAS mutation in the Malaysian Chinese population (p<0.05). Expression of autophagy effector LC3A was highly associated with the tumour grade in CRC (p<0.001) but not with other clinicopathological parameters. Lastly, the survival analysis did not yield a statistically significant outcome. Overall, this small cohort study concluded that KRAS mutation and autophagy effectors are not good prognostic markers for CRC patients.
Publication Date: 2021-08-28
Journal: The Malaysian journal of pathology

serum creatinine(123)

Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of randomised trials.
GLP-1 receptor agonists reduce major adverse cardiovascular events (MACE) in patients with type 2 diabetes. However, uncertainty regarding kidney outcomes persists and whether benefits extend to exendin-4-based GLP-1 receptor remains uncertain. We aimed to meta-analyse the most up-to-date evidence on the cardiovascular benefits and risks of GLP-1 receptor agonists from outcome trials in patients with type 2 diabetes. We did a meta-analysis, including new data from AMPLITUDE-O, using a random effects model to estimate overall hazard ratio (HR) for MACE; its components; all-cause mortality; hospital admission for heart failure; a composite kidney outcome consisting of development of macroalbuminuria, doubling of serum creatinine, or at least 40% decline in estimated glomerular filtration rate (eGFR), kidney replacement therapy, or death due to kidney disease; worsening of kidney function, based on eGFR change; and odds ratios for key safety outcomes (severe hypoglycaemia, retinopathy, pancreatitis, and pancreatic cancer). We also examined MACE outcome in patient subgroups on the basis of MACE incidence rates in the placebo group, presence or absence of cardiovascular disease, HbA Of 98 articles screened, eight trials comprising 60 080 patients fulfilled the prespecified criteria and were included. Overall, GLP-1 receptor agonists reduced MACE by 14% (HR 0·86 [95% CI 0·80-0·93]; p<0·0001), with no significant heterogeneity across GLP-1 receptor agonist structural homology or eight other examined subgroups (all p GLP-1 receptor agonists, regardless of structural homology, reduced the risk of individual MACE components, all-cause mortality, hospital admission for heart failure, and worsening kidney function in patients with type 2 diabetes. None.
Publication Date: 2021-08-24
Journal: The lancet. Diabetes & endocrinology


Local ablative therapy in oncogenic-driven oligometastatic non-small cell lung cancer: present and ongoing strategies-a narrative review.
Oligometastatic (OM) disease is defined by a low metastatic tumor spread. OM non-small cell lung cancer (NSCLC) treatment aims to improve the patient's prognosis and quality of life, in an attempt-to-cure objective. Oncogenic-driven metastatic NSCLC accounts for about 20-25% of NSCLCs, with an ever-increasing number of potentially druggable molecular alterations. Due to specific targeted therapy, the care and prognosis of mutated NSCLC is quite different from non-oncogenic-driven NSCLC. However, OM-NSCLC treatment guidelines do not specifically discuss oncogenic-driven OM-NSCLC patients. We conducted a narrative review regarding retrospective and prospective studies published from inception to May 2020 dealing with oncogenic-driven OM-NSCLC in order to: (I) describe the specific patterns of metastatic spread of oncogenic-driven NSCLC (i.e., bone and pleural tropism in EGFR mutated NSCLC and serous and brain metastases in ALK NSCLC); (II) review the low level of current evidence for local ablative therapy (LAT) strategies in patients with oncogenic-driven OM-NSCLC, focusing on the benefit/risk of tyrosine kinase inhibitors (TKI) and LATs combination and (III) present strategies to help to select the best candidate for an attempt-to-cure approach. Finally, the optimal strategy may be to introduce a targeted therapy, then treat all tumor sites with LAT, and finally continue TKI for unknown prolonged duration in an attempt to prolong progression free survival in most patients, improve overall survival for some patients, and potentially lead to a cancer cure for a few patients.
Publication Date: 2021-08-26
Journal: Translational lung cancer research

chronic kidney disease(120)

Normocalcaemic Primary Hyperparathyroidism: Is nephrolithiasis more common than osteoporosis?
Normocalcaemic primary hyperparathyroidism(NPHPT) is often underrecognised in clinical practice. To determine the prevalence and clinical significance of NPHPT in an unselected sample in an acute hospital setting. Patients aged over 18 years who measured an elevated serum parathyroid hormone(PTH ≥7 pmol/L) during 12 months from 1 January 2017 to 31 December 2017 were retrospectively studied. NPHPT was defined by the presence of elevated serum PTH with normal albumin-corrected serum calcium on two or more occasions after excluding secondary causes. Patients were followed for two years. Relevant data were collected by review of electronic medical records. Of the 2593 patients who had PTH measured during the study period, 1278 had serum PTH ≥7 pmol/L. Hypercalcaemic primary hyperparathyroidism(PHPT) was diagnosed in 174. Secondary causes for elevated serum PTH were identified in 993: 815(chronic kidney disease - eGFR <60 mL/min/1.73m The findings give further credence to the diagnosis of NPHPT as a clinical entity. Nephrolithiasis may be a greater problem than osteoporosis in NPHPT as compared with PHPT. This needs prospective evaluation. This article is protected by copyright. All rights reserved.
Publication Date: 2021-08-27
Journal: Internal medicine journal


Risk of Renal Dysfunction Following Heart Transplantation in Patients Bridged with a Left Ventricular Assist Device.
Acute renal failure (ARF) and chronic kidney disease (CKD) are associated with short- and long-term morbidity and mortality following heart transplantation (HT). We investigated the incidence and risk factors for developing ARF requiring hemodialysis (HD) and CKD following HT specifically in patients with a left ventricular assist device (LVAD). We examined the International Society for Heart and Lung Transplantation (ISHLT) Thoracic Transplant Registry for heart transplant patients between January 2000 and June 2015. We compared patients bridged with durable continuous-flow LVAD to those without LVAD support. Primary outcomes were ARF requiring HD before discharge following HT and CKD (defined as creatinine >2.5 mg/dl, permanent dialysis, or renal transplant) within 3 years. There were 18,738 patients, with 4,535 (24%) bridged with LVAD support. Left ventricular assist device patients had higher incidence of ARF requiring HD and CKD at 1 year, but no significant difference in CKD at 3 years compared to non-LVAD patients. Among LVAD patients, body mass index (BMI) (odds ratio [OR] = 1.79, p < 0.001), baseline estimated glomerular filtration rate (eGFR) (OR = 0.43, p < 0.001), and ischemic time (OR = 1.28, p = 0.014) were significantly associated with ARF requiring HD. Similarly, BMI (hazard ratio [HR] = 1.49, p < 0.001), baseline eGFR (HR = 0.41, p < 0.001), pre-HT diabetes mellitus (DM) (HR = 1.37, p = 0.011), and post-HT dialysis before discharge (HR = 3.93, p < 0.001) were significantly associated with CKD. Left ventricular assist device patients have a higher incidence of ARF requiring HD and CKD at 1 year after HT compared with non-LVAD patients, but incidence of CKD is similar by 3 years. Baseline renal function, BMI, ischemic time, and DM can help identify LVAD patients at risk of ARF requiring HD or CKD following HT.
Publication Date: 2021-08-23
Journal: ASAIO journal (American Society for Artificial Internal Organs : 1992)

tyrosine kinase inhibitor(119)

EGFR exon 20 Insertion NSCLC and Response to Platinum-Based Chemotherapy.
In classical EGFR mutant non-small-cell lung cancer (NSCLC), EGFR tyrosine kinase inhibitor (TKI) therapy yields better outcomes than platinum-based chemotherapy. However, EGFR exon 20 insertion (ex20ins) NSCLC is relatively resistant to currently available EGFR TKIs. Though platinum-based chemotherapy is the frontline standard of care for EGFR ex20ins NSCLC, its efficacy is not fully described. A retrospective, single-center, case series METHODS: Patients were identified through an electronic research database at a single institution and included if they had advanced EGFR ex20ins NSCLC, received platinum-based chemotherapy for metastatic disease, and had scans evaluable for response. Each patient's demographics, tumor characteristics, and clinical course were recorded. Treatment response was evaluated using RECIST v1.1 criteria, and the PFS was calculated by the Kaplan-Meier method. Among 27 patients identified with EGFR ex20ins NSCLC at our institution, 18 (67%) received platinum-based chemotherapy for metastatic disease and had scans evaluable for response. These patients received platinum-based chemotherapy in the first-line (N = 17, 94%) and second-line settings (N = 1, 6%). The objective response rate (ORR) to platinum-based chemotherapy was 39% (7 of 18 patients; 95% confidence interval [CI] 16-61). The median PFS with platinum-based chemotherapy was 7.1 months (95% CI, 6.3 -13.7), and the median overall survival was 3.2 years (95% CI, 1.92 - NR). The efficacy of platinum-based chemotherapy in EGFR ex20ins NSCLC is similar to that expected for TKI sensitive EGFR mutant NSCLC. Novel agents designed to specifically target ex20ins mutant EGFR should additionally improve outcomes.
Publication Date: 2021-08-16
Journal: Clinical lung cancer


Repurposing FDA Drug Compounds against Breast Cancer by Targeting EGFR/HER2.
Repurposing studies have identified several FDA-approved compounds as potential inhibitors of the intracellular domain of epidermal growth factor receptor 1 (EGFR) and human epidermal receptor 2 (HER2). EGFR and HER2 represent important targets for the design of new drugs against different types of cancer, and recently, differences in affinity depending on active or inactive states of EGFR or HER2 have been identified. In this study, we first identified FDA-approved compounds with similar structures in the DrugBank to lapatinib and gefitinib, two known inhibitors of EGFR and HER2. The selected compounds were submitted to docking and molecular dynamics MD simulations with the molecular mechanics generalized Born surface area approach to discover the conformational and thermodynamic basis for the recognition of these compounds on EGFR and HER2. These theoretical studies showed that compounds reached the ligand-binding site of EGFR and HER2, and some of the repurposed compounds did not interact with residues involved in drug resistance. An in vitro assay performed on two different breast cancer cell lines, MCF-7, and MDA-MB-23, showed growth inhibitory activity for these repurposed compounds on tumorigenic cells at micromolar concentrations. These repurposed compounds open up the possibility of generating new anticancer treatments by targeting HER2 and EGFR.
Publication Date: 2021-08-29
Journal: Pharmaceuticals (Basel, Switzerland)

ml min(114)

Technetium-99m-MAG3 and Technetium-99m-DTPA: Renal clearance measured by the constant infusion technique - old news?
Accurate, precise and straightforward methods for measuring glomerular filtration rate (GFR) and/or renal plasma flow (RPF) are still in demand today. The time-consuming constant infusion technique (CIT) is the gold standard and preferred for research, whereas the simple, but less precise, single injection technique (SIT) is used in clinical settings. This study investigated the use of 14 healthy subjects received All participants had an eGFR above 60 ml/min and none had fluid retention. CIT with fixed primer and infusion rate using
Publication Date: 2021-08-22
Journal: Clinical physiology and functional imaging


Interleukin 6 and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Chronic Coronary Syndrome.
Inflammation promotes cardiovascular disease and anti-inflammatory treatment reduces cardiovascular events in patients with chronic coronary syndrome. Chronic kidney disease (CKD) is a risk factor for cardiovascular disease. It is unclear how inflammation mediated by interleukin 6 (IL-6) in patients with CKD is linked to cardiovascular disease. To investigate associations between IL-6 and cardiovascular outcomes in patients with chronic coronary syndrome in association with kidney function. This multicenter cohort study included patients enrolled at 663 centers in 39 countries with chronic coronary syndrome who were included in the Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy (STABILITY) trial. Patients were enrolled between December 2008 and April 2010 and were followed up for a median length of 3.7 years. Analysis in this substudy began September 2020. Exposures were IL-6 and creatinine estimated glomerular filtration rates (eGFR), which were collected at baseline. Associations between continuous and categorical levels (<2.0 ng/L vs ≥2.0 ng/L) of IL-6 and cardiovascular outcomes were tested in association with eGFR cutoffs (normal eGFR level [≥90 mL/min/1.73 m2], mildly decreased eGFR level [60-90 mL/min/1.73 m2], and moderately to severely decreased eGFR level [<60 mL/min/1.73 m2]). Main outcome was major adverse cardiovascular events (MACE), a composite of cardiovascular death, myocardial infarction, and stroke. This substudy of the STABILITY trial included 14 611 patients with available IL-6 levels at baseline. The median (interquartile range) age was 65 (59-71) years, and 2700 (18.5%) were female. During follow-up, MACE occurred in 1459 individuals (10.0%). Higher levels of IL-6 were in continuous models independently associated with risk of MACE (P < .001) in all CKD strata. Using predefined strata, elevated IL-6 level (≥2.0 vs <2.0 ng/L) was associated with increased risk of MACE at normal kidney function (2.9% vs 1.9% events/y [hazard ratio, 1.35; 95% CI, 1.02-1.78]), mild CKD (3.3% vs 1.9% [hazard ratio, 1.57; 95% CI, 1.35-1.83]), and moderate to severe CKD (5.0% vs 2.9% [hazard ratio, 1.60; 95% CI, 1.28-1.99]). In patients with chronic coronary syndrome, elevated levels of IL-6 were associated with risk of MACE in all CKD strata. Thus, IL-6 and CKD stage may help when identifying patients with chronic coronary syndrome for anti-inflammatory treatment.
Publication Date: 2021-08-26
Journal: JAMA cardiology

non-small-cell lung cancer(110)

Nuclear Pyruvate Kinase M2 (PKM2) Contributes to Phosphoserine Aminotransferase 1 (PSAT1)-Mediated Cell Migration in EGFR-Activated Lung Cancer Cells.
An elevated expression of phosphoserine aminotransferase 1 (PSAT1) has been observed in multiple tumor types and is associated with poorer clinical outcomes. Although PSAT1 is postulated to promote tumor growth through its enzymatic function within the serine synthesis pathway (SSP), its role in cancer progression has not been fully characterized. Here, we explore a putative non-canonical function of PSAT1 that contributes to lung tumor progression. Biochemical studies found that PSAT1 selectively interacts with pyruvate kinase M2 (PKM2). Amino acid mutations within a PKM2-unique region significantly reduced this interaction. While PSAT1 loss had no effect on cellular pyruvate kinase activity and PKM2 expression in non-small-cell lung cancer (NSCLC) cells, fractionation studies demonstrated that the silencing of PSAT1 in epidermal growth factor receptor (EGFR)-mutant PC9 or EGF-stimulated A549 cells decreased PKM2 nuclear translocation. Further, PSAT1 suppression abrogated cell migration in these two cell types whereas PSAT1 restoration or overexpression induced cell migration along with an elevated nuclear PKM2 expression. Lastly, the nuclear re-expression of the acetyl-mimetic mutant of PKM2 (K433Q), but not the wild-type, partially restored cell migration in PSAT1-silenced cells. Therefore, we conclude that, in response to EGFR activation, PSAT1 contributes to lung cancer cell migration, in part, by promoting nuclear PKM2 translocation.
Publication Date: 2021-08-28
Journal: Cancers


EGFR analysis on scrapings from cytology smears in lung carcinoma, an effective alternative to testing on trucut biopsies.
Lung carcinomas are a leading cause of cancer morbidity and mortality. Many cases present at an advanced stage of disease where definitive treatment by surgical resection is not feasible. Molecular testing using materials derived from minimally invasive procedures aid in targeted therapy with least iatrogenic burden to the patient. Cases diagnosed as non-small cell lung carcinoma (NSCLC) on cytology were included in the study. Scrapings from the smears with adequate tumor cell load were submitted for molecular testing. The DNA was extracted and quantified. Mutations in exons 18, 19, 20, and 21 of the EGFR gene were detected using Sanger sequencing. DNA quantity and EGFR mutation status on equal number of consecutive trucut biopsy specimens were also analyzed. Seventy cases of NSCLC tested for EGFR mutation had a median DNA concentration of 40.2 ng/μl and 31% cases showed mutation. Majority of mutations (14/21, 66.66%) were identified in exon 19. Among 70 trucut biopsy samples, DNA concentration was 41.42 ng/μl and 30% cases showed mutation. No significant difference was seen in DNA quantity and EGFR mutation between cytology smears and trucut biopsies. EGFR testing on cytology smears provides adequate DNA yield with minimal invasiveness and is equally effective as biopsies. Testing on samples like pleural effusion allows for concomitant diagnosis, staging, and molecular testing in one procedure. Tests done on the smears rather than on cell block or trucut biopsies ensures superior quality DNA from the tumor cells as they are unexposed to cross linking formalin fixative.
Publication Date: 2021-08-26
Journal: Diagnostic cytopathology

p 0 001(102)

Calculated plasma osmolality at hospital admission correlates well with eGFR and D-Dimer, a simple outcome predictor and guiding tool for management of severe COVID-19 patients.
To evaluate calculated total plasma osmolality as a marker of outcome prediction, fluid and metabolic balance, thrombotic risk in severe COVID-19 patients. Retrospective data of RT-PCR confirmed hospitalized severe COVID-19 patients (total: n = 175 patients, including diabetic subset: n = 102) were analyzed. Clinically applicable cut-offs were derived using receiver operating characteristic (ROC) curve analysis for calculated total osmolality, eGFR, and D-dimer, and their correlations were studied. Among 175 severe COVID-19 patients, a significant association with mortality was seen with respect to calculated total osmolality (p < 0.001), eGFR (p < 0.001), and D-dimer (p < 0.001). In the total cohort, applicable cut-offs based on ROC curve in predicting outcome were, for total osmolality 299 mosm/kg (area under the curve (AUC)-0.773, odds ratio (OR)-1.09), eGFR 61.5 ml/min/m2 (AUC-0.789, OR-0.96), D-dimer 5.13 (AUC-0.814, OR-2.65) respectively. In diabetic subset, the cut-offs for total osmolality were 298 mosm/kg (AUC-0.794, OR-1.12), eGFR 44.9 ml/min/m2 (AUC-0.774, OR-0.96) and D-dimer 1.59 (AUC-0.769, OR-1.52) respectively. Applicable cut-offs for calculated total plasma osmolality, eGFR, and D-dimer predicts clinical outcome in severe COVID-19 with and without diabetes. Correlation studies validated calculated total osmolality as a marker of the combined effect of fluid and metabolic imbalance, compromised renal function and hypercoagulability.
Publication Date: 2021-08-18
Journal: Diabetes & metabolic syndrome


Triplet Succeeds in Colorectal Cancer.
A drug trio consisting of BRAF, MEK, and EGFR inhibitors may become the new standard of care in
Publication Date: 2019-12-01
Journal: Cancer discovery

kinase inhibitors tkis(90)

Targeting AXL in NSCLC.
State-of-the-art cancer precision medicine approaches involve targeted inactivation of chemically and immunologically addressable vulnerabilities that often yield impressive initial anti-tumor responses in patients. Nonetheless, these responses are overshadowed by therapy resistance that follows. AXL, a receptor tyrosine kinase with bona fide oncogenic capacity, has been associated with the emergence of resistance in an array of cancers with varying pathophysiology and cellular origins, including in non-small-cell lung cancers (NSCLCs). Here in this review, we summarize AXL biology during normal homeostasis, oncogenic development and therapy resistance with a focus on NSCLC. In the context of NSCLC therapy resistance, we delineate AXL's role in mediating resistance to tyrosine kinase inhibitors (TKIs) deployed against epidermal growth factor receptor (EGFR) as well as other notable oncogenes and to chemotherapeutics. We also discuss the current understanding of AXL's role in mediating cell-biological variables that function as important modifiers of therapy resistance such as epithelial to mesenchymal transition (EMT), the tumor microenvironment and tumor heterogeneity. We also catalog and discuss a set of effective pharmacologic tools that are emerging to strategically perturb AXL mediated resistance programs in NSCLC. Finally, we enumerate ongoing and future exciting precision medicine approaches targeting AXL as well as challenges in this regard. We highlight that a holistic understanding of AXL biology in NSCLC may allow us to predict and improve targeted therapeutic strategies, such as through polytherapy approaches, potentially against a broad spectrum of NSCLC sub-types to forestall tumor evolution and drug resistance.
Publication Date: 2021-08-20
Journal: Lung Cancer (Auckland, N.Z.)


Cyclophosphamide induction dose and outcomes in ANCA-associated vasculitis with renal involvement: A comparative cohort study.
Treatment of ANCA-associated vasculitis (AAV) improved over the last decades but disease-unspecific agents such as cyclophosphamide are still associated with serious adverse events, including high rates of infectious complications and malignancy with increased mortality.In this comparative cohort study, we included 121 AAV patients with renal involvement from 2 German vasculitis centers. Patients were separated into subsequent groups: 2.5 to 3 g vs >3 g cumulative cyclophosphamide induction dose. We investigated if a cyclophosphamide induction dose of 2.5 to 3 g could maintain efficacy while minimizing adverse events in AAV patients with renal involvement.Patients with 2.5 to 3 g vs >3 g cumulative cyclophosphamide (median 3.0 g vs 5.5 g, P < .001) had a comparable time to remission (median 4.0 vs 3.8 months, log-rank P = .87) with 90.6% and 91.5% achieving remission after 12 months. Refractory disease was low in both groups (median 3.6% vs 6.2%, P = .68) and relapse rate did not differ (median 36% vs 42%, log-rank P = .51). Kidney function was comparable at disease onset in both groups (eGFR, mean ± SD 29 ± 20 mL/min/1.73 m2 vs 35 ± 26 mL/min/1.73 m2, P = .34) and improved after 2 years irrespective of the cyclophosphamide dose (ΔeGFR, mean ± SD +8.9 ± 1.4 mL/min/1.73 m2 vs +6.0 ± 1.1 mL/min/1.73 m2, P = .33). The 2.5-3 g group had a lower rate of leukopenia (HR = 2.73 [95% CI, 1.2-6.3], P = .014) and less infectious episodes per patient (median 1.2 vs 0.7, P = .012), especially urinary tract infections (HR = 2.15 [95% CI, 1.1-4.5], P = .032).A cyclophosphamide induction dose of 2.5 to 3 g was able to induce remission and prevent from relapses with fewer cases of leukopenia and less infectious episodes during follow-up. Especially elderly AAV patients who are particularly susceptible to infectious complications could benefit from minimizing dosing regimens with maintained efficacy to control disease activity.
Publication Date: 2021-08-17
Journal: Medicine


Effects of Sex and Seasonal Climatic Changes on the Risk of Incidence of Anti-EGFR Therapy-Induced Rash in Cancer Patients: A Retrospective Study.
Publication Date: 2021-08-28
Journal: Medicina (Kaunas, Lithuania)

cancer cells(77)

Inhibition of STAT3 enhances sensitivity to tamoxifen in tamoxifen-resistant breast cancer cells.
The mechanisms of endocrine resistance are complex, and deregulation of several oncogenic signalling pathways has been proposed. We aimed to investigate the role of the EGFR and Src-mediated STAT3 signalling pathway in tamoxifen-resistant breast cancer cells. The ER-positive luminal breast cancer cell lines, MCF-7 and T47D, were used. We have established an MCF-7-derived tamoxifen-resistant cell line (TamR) by long-term culture of MCF-7 cells with 4-hydroxytamoxifen. Cell viability was determined using an MTT assay, and protein expression levels were determined using western blot. Cell cycle and annexin V staining were analysed using flow cytometry. TamR cells showed decreased expression of estrogen receptor and increased expression of EGFR. TamR cells showed an acceleration of the G1 to S phase transition. The protein expression levels of phosphorylated Src, EGFR (Y845), and STAT3 was increased in TamR cells, while phosphorylated Akt was decreased. The expression of p-STAT3 was enhanced according to exposure time of tamoxifen in T47D cells, suggesting that activation of STAT3 can cause tamoxifen resistance in ER-positive breast cancer cells. Both dasatinib (Src inhibitor) and stattic (STAT3 inhibitor) inhibited cell proliferation and induced apoptosis in TamR cells. However, stattic showed a much stronger effect than dasatinib. Knockdown of STAT3 expression by siRNA had no effect on sensitivity to tamoxifen in MCF-7 cells, while that enhanced sensitivity to tamoxifen in TamR cells. There was not a significant synergistic effect of dasatinib and stattic on cell survival. TamR cells have low nuclear p21(Cip1) expression compared to MCF-7 cells and inhibition of STAT3 increased the expression of nuclear p21(Cip1) in TamR cells. The EGFR and Src-mediated STAT3 signalling pathway is activated in TamR cells, and inhibition of STAT3 may be a potential target in tamoxifen-resistant breast cancer. An increase in nuclear p21(Cip1) may be a key step in STAT3 inhibitor-induced cell death in TamR cells.
Publication Date: 2021-08-20
Journal: BMC cancer

baseline egfr(75)

Tolvaptan in ADPKD Patients With Very Low Kidney Function.
Tolvaptan slowed estimated glomerular filtration rate (eGFR) decline in subjects with autosomal dominant polycystic kidney disease (ADPKD) in TEMPO 3:4 and REPRISE trials. Tolvaptan effects in subjects with eGFR 15 to 24 ml/min per 1.73 m One data subset comprised subjects with OLE baseline eGFR 15 to 29 ml/min per 1.73 m Mean annualized eGFR slopes (ml/min per 1.73 m Initiating or maintaining tolvaptan therapy significantly delayed eGFR decline in subjects with baseline eGFR 15 to 24 and 25 to 29 ml/min per 1.73 m
Publication Date: 2021-08-14
Journal: Kidney international reports


CHIP/STUB1 Ubiquitin Ligase Functions as a Negative Regulator of ErbB2 by Promoting Its Early Post-Biosynthesis Degradation.
Overexpression of the epidermal growth factor receptor (EGFR) family member ErbB2 (HER2) drives oncogenesis in up to 25% of invasive breast cancers. ErbB2 expression at the cell surface is required for oncogenesis but mechanisms that ensure the optimal cell surface display of overexpressed ErbB2 following its biosynthesis in the endoplasmic reticulum are poorly understood. ErbB2 is dependent on continuous association with HSP90 molecular chaperone for its stability and function as an oncogenic driver. Here, we use knockdown and overexpression studies to show that the HSP90/HSC70-interacting negative co-chaperone CHIP (C-terminus of HSC70-Interacting protein)/STUB1 (STIP1-homologous U-Box containing protein 1) targets the newly synthesized, HSP90/HSC70-associated, ErbB2 for ubiquitin/proteasome-dependent degradation in the endoplasmic reticulum and Golgi, thus identifying a novel mechanism that negatively regulates cell surface ErbB2 levels in breast cancer cells, consistent with frequent loss of CHIP expression previously reported in ErbB2-overexpressing breast cancers. ErbB2-overexpressing breast cancer cells with low CHIP expression exhibited higher endoplasmic reticulum stress inducibility. Accordingly, the endoplasmic reticulum stress-inducing anticancer drug Bortezomib combined with ErbB2-targeted humanized antibody Trastuzumab showed synergistic inhibition of ErbB2-overexpressing breast cancer cell proliferation. Our findings reveal new insights into mechanisms that control the surface expression of overexpressed ErbB2 and suggest that reduced CHIP expression may specify ErbB2-overexpressing breast cancers suitable for combined treatment with Trastuzumab and ER stress inducing agents.
Publication Date: 2021-08-28
Journal: Cancers


Multiplexed electrokinetic sensor for detection and therapy monitoring of extracellular vesicles from liquid biopsies of non-small-cell lung cancer patients.
Liquid biopsies based on extracellular vesicles (EVs) represent a promising tool for treatment monitoring of tumors, including non-small-cell lung cancers (NSCLC). In this study, we report on a multiplexed electrokinetic sensor for surface protein profiling of EVs from clinical samples. The method detects the difference in the streaming current generated by EV binding to the surface of a functionalized microcapillary, thereby estimating the expression level of a marker. Using multiple microchannels functionalized with different antibodies in a parallel fluidic connection, we first demonstrate the capacity for simultaneous detection of multiple surface markers in small EVs (sEVs) from NSCLC cells. To investigate the prospects of liquid biopsies based on EVs, we then apply the method to profile sEVs isolated from the pleural effusion (PE) fluids of five NSCLC patients with different genomic alterations (ALK, KRAS or EGFR) and applied treatments (chemotherapy, EGFR- or ALK-tyrosine kinase inhibitors). The vesicles were targeted against CD9, as well as EGFR and PD-L1, two treatment targets in NSCLC. The electrokinetic signals show detection of these markers on sEVs, highlighting distinct interpatient differences, e.g., increased EGFR levels in sEVs from a patient with EGFR mutation as compared to an ALK-fusion one. The sensors also detect differences in PD-L1 expressions. The analysis of sEVs from a patient prior and post ALK-TKI crizotinib treatment reveals significant increases in the expressions of some markers (EGFR and PD-L1). These results hold promise for the application of the method for tumor treatment monitoring based on sEVs from patient liquid biopsies.
Publication Date: 2021-08-25
Journal: Biosensors & bioelectronics

95 confidence(72)

Predicting 10-year stroke mortality: development and validation of a nomogram.
Predicting long-term stroke mortality is a clinically important and unmet need. We aimed to develop and internally validate a 10-year ischaemic stroke mortality prediction score. In this UK cohort study, 10,366 patients with first-ever ischaemic stroke between January 2003 and December 2016 were followed up for a median (interquartile range) of 5.47 (2.96-9.15) years. A Cox proportional-hazards model was used to predict 10-year post-admission mortality. The predictors associated with 10-year mortality included age, sex, Oxfordshire Community Stroke Project classification, estimated glomerular filtration rate (eGFR), pre-stroke modified Rankin Score, admission haemoglobin, sodium, white blood cell count and comorbidities (atrial fibrillation, coronary heart disease, heart failure, cancer, hypertension, chronic obstructive pulmonary disease, liver disease and peripheral vascular disease). The model was internally validated using bootstrap resampling to assess optimism in discrimination and calibration. A nomogram was created to facilitate application of the score at the point of care. Mean age (SD) was 78.5 ± 10.9 years, 52% female. Most strokes were partial anterior circulation syndromes (38%). 10-year mortality predictors were: total anterior circulation stroke (hazard ratio, 95% confidence intervals) (2.87, 2.62-3.14), eGFR < 15 (1.97, 1.55-2.52), 1-year increment in age (1.04, 1.04-1.05), liver disease (1.50, 1.20-1.87), peripheral vascular disease (1.39, 1.23-1.57), cancers (1.37, 1.27-1.47), heart failure (1.24, 1.15-1.34), 1-point increment in pre-stroke mRS (1.20, 1.17-1.22), atrial fibrillation (1.17, 1.10-1.24), coronary heart disease (1.09, 1.02-1.16), chronic obstructive pulmonary disease (1.13, 1.03-1.25) and hypertension (0.77, 0.72-0.82). Upon internal validation, the optimism-adjusted c-statistic was 0.76 and calibration slope was 0.98. Our 10-year mortality model uses routinely collected point-of-care information. It is the first 10-year mortality score in stroke. While the model was internally validated, further external validation is also warranted.
Publication Date: 2021-08-19
Journal: Acta neurologica Belgica

egfr exon(72)

Durable response to immunotherapy plus chemotherapy in a patient with untreated, brain-metastatic, EGFR exon 20 insertion mutation lung adenocarcinoma: A case report.
Epidermal growth factor receptor (EGFR) 20 exon insertion is the second most common EGFR aberrations in non-small cell lung cancer (NSCLC). Despite some novel EGFR inhibitors, clinically obtainable management for this subset of patients remains an unmet need. there are no previous reports of upfront combination therapy with immunotherapy and chemotherapy for lung adenocarcinoma with brain metastasis harboring EGFR 20 insertion. A 56-year-old man who sought care for dry cough was diagnosed with lung adenocarcinoma with brain metastases indicating a poor prognosis. Next-generation sequencing of lung biopsied tissue revealed an EGFR exon 20 in-frame insertion (P772_H773insYNP+H773Y). The patient started treatment of pemetrexed and carboplatin plus programmed cell death-1 inhibitor sintilimab in November 2019. The patient achieved partial responses both intra- and extra-cranially. After 6 cycles of treatment, the patient accepted sintilimab plus pemetrexed every 3 weeks as maintenance therapy, which was well-tolerated without any toxicity and is still ongoing after 18 months since initiation of 1st-line treatment. This is the first case report of the clinical benefit of upfront immune checkpoint inhibitors (ICIs) plus chemotherapy for a brain metastatic NSCLC patient harboring EGFR exon 20 insertion mutation. Further study is needed to validate the predictor involved in responders to ICIs-based therapy with EGFR mutations.
Publication Date: 2021-08-17
Journal: Medicine

60 ml min 1 73(71)

Metabolic Differences Between Unilateral and Bilateral Renal Stones and Their Association with Markers of Kidney Injury.
Urinary stone disease (USD) has been associated with an increased risk for chronic kidney disease (CKD) and end-stage renal disease (ESRD) in Western populations. However, the metabolic disorders associated with unilateral and bilateral renal stones and the association of these types of stones with CKD and kidney tubular injury markers, such as urine N-acetyl-ß-D-glucosaminidase (NAG) and alpha-1-microglobulin (α1-MG), have not been fully examined. We performed a cross-sectional study of 10,281 participants in rural China in 2014. All the subjects underwent renal ultrasound to detect USD; stone formers were divided into groups with unilateral or bilateral renal stones by ultrasound exams. CKD was defined as a decreased estimated glomerular filtration rate (eGFR, <60 mL/min/1.73 m Among all the participants, 4.9% (n=507) had unilateral renal stones, and 0.7% (n=75) had bilateral renal stones. The proportion of CKD in the non-stone, unilateral and bilateral renal stone formers was 11.0%, 19.2%, and 29.7%, respectively (p for trend <0.001). Individuals with bilateral renal stones had the highest proportion of metabolic components, such as elevated blood pressure and serum glucose. In multivariate analyses after adjustment for multiple confounders, bilateral renal stones were significantly associated with an increased risk of decreased eGFR (odds ratio (OR) 3.38; 95% CI 1.05-10.90), albuminuria (OR 3.01; 95% CI 1.76-5.13), CKD (OR 3.18; 95% CI 1.88-5.36), increased urine NAG/Cr (OR 1.95; 95% CI 1.21-3.16) and α1-MG/Cr levels (OR 2.54; 95% CI 1.56-4.12) compared with the lack of stones. Bilateral renal stones were associated with a higher risk of CKD and higher levels of kidney tubular injury markers. Clinicians should pay attention to metabolic disorders in bilateral renal stone formers.
Publication Date: 2021-08-26
Journal: The Journal of urology


Clinicians' Attitude to Doublet Plus Anti-EGFR Versus Triplet Plus Bevacizumab as First-line Treatment in Left-Sided RAS and BRAF Wild-Type Metastatic Colorectal Cancer Patients: A Multicenter, "Real-Life", Case-Control Study.
Doublets plus antiepidermal growth factor receptors monoclonal antibodies (EGFRi) are widely considered the preferable first-line regimen in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC), resulting superior in terms of activity and efficacy compared to doublets plus bevacizumab. However, data comparing doublet plus EGFRi and triplet plus bevacizumab are lacking, and the relative benefit of an intensive regimen plus an antiangiogenic backbone in this population is debated. This multicenter, retrospective study aimed at evaluating clinicians' attitude to triplet-bevacizumab and doublet-EGFRi as first-line regimen in patients with left-sided RAS/BRAF wild-type mCRC treated in clinical practice at 22 Oncology Units from March 2012 to October 2020. A random case-control matching was performed to compare activity (ORR), and effectiveness (PFS, OS, secondary resection rate of metastases with curative intent) between triplet-bevacizumab and doublet-EGFRi, on the basis of ECOG-PS, age, gender, and burden of disease. A total of 718 patients were consecutively treated with doublet-EGFRi (686, 95.5%) or triplet-bevacizumab (32, 4.5%). After case-control matching, median PFS was 13.6 (95% CI, 8.9-31.7) and 16.1 (95% CI, 12.1-36.8) months (P= .621), while median OS was 30.2 (95% CI, 14.4-69.5) and 38.1 (95% CI, 33.1-101.1) months (P= .0283) in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. The ORR was 65.6% and 90.6% (P= .016), while the secondary resection rate was 18.8% and 46.9% (P= .016), in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. Triplet-bevacizumab was associated with a higher incidence of G3/G4 neutropenia (25.0% vs. 12.5%, P= .041). Although a doublet-EGFRi remains the recommended upfront regimen in patients with left-sided RAS and BRAF wild-type mCRC, our real life data suggest a triplet-bevacizumab might be at least equally active and effective in properly selected cases.
Publication Date: 2021-08-13
Journal: Clinical colorectal cancer

inhibitors egfr-tkis(68)

Novel, selective acrylamide linked quinazolines for the treatment of double mutant EGFR-L858R/T790M Non-Small-Cell lung cancer (NSCLC).
T790M mutation is the most common mechanism of acquired resistance to first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). To overcome this resistance, 4-anilinoquinazoline-based irreversible inhibitors afatinib, dacomitinib has been developed. However, the clinical application of these irreversible inhibitors is limited due to its narrow selectivity against L858R/T790M mutant EGFR. In an attempt to develop potent and selective EGFR T790M inhibitors, we have designed and synthesized two series of novel acrylamide linked quinazolines. Among them, compounds 2i (IC
Publication Date: 2021-08-17
Journal: Bioorganic chemistry

ml min 1 73 m2(67)

Rationale, design, demographics, and baseline characteristics of the randomised, controlled, phase 2b SAPPHIRE study of verinurad plus allopurinol in patients with chronic kidney disease and hyperuricaemia.
Verinurad is a human uric acid transporter (URAT1) inhibitor known to decrease serum uric acid (sUA) levels and may reduce albuminuria. In a Phase 2a study (NCT03118739), treatment with verinurad + febuxostat lowered urine albumin-to-creatinine ratio (UACR) at 12 weeks by 39% (90% confidence interval: 4%, 62%) among patients with type 2 diabetes mellitus, hyperuricaemia and albuminuria. The Phase 2 b, randomised, placebo-controlled Study of verinurAd and alloPurinol in Patients with cHronic kIdney disease and hyperuRicaEmia (SAPPHIRE; NCT03990363) will examine the effect of verinurad + allopurinol on albuminuria and estimated glomerular filtration rate (eGFR) slope among patients with chronic kidney disease (CKD) and hyperuricaemia. Adults (≥18 years of age) with CKD, eGFR ≥25 mL/min/1.73 m2, UACR 30-5000 mg/g and sUA ≥6.0 mg/dL will be enrolled. Approximately 725 patients will be randomised 1:1:1:1:1 to 12, 7.5 or 3 mg verinurad + allopurinol, allopurinol or placebo. An 8-week dose-titration period will precede a 12-month treatment period; verinurad dose will be increased to 24 mg at month 9 in a subset of patients in the 3 mg verinurad + allopurinol arm. The primary efficacy endpoint is change from baseline in UACR at 6 months. Secondary efficacy endpoints include changes in UACR, eGFR and sUA from baseline at 6 and 12 months. This study will assess the combined clinical effect of verinurad + allopurinol on kidney function in patients with CKD, hyperuricaemia and albuminuria, and whether this combination confers renoprotection beyond standard-of-care.
Publication Date: 2021-08-13
Journal: Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association


Dramatic response to osimertinib combined with crizotinib in EGFR T790 M mutation only in blood and Met amplification only in tumor tissue expressive non-small cell lung cancer: A case report.
Besides the T790 M mutation, it may coexist with bypass pathway activation in real clinical cases for patients with EGFR mutations who resisted to the first- and second-generation tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). There are limited clinical trial data describing the efficacy of osimertinib combined with MET inhibition in EGFR T790M-mutant NSCLC patients with Met amplification. A non-smoking 53-year-old male patient with lung adenocarcinoma underwent gefitinib, afatinib, and osimertinib combined with crizotinib treatment and developed different EGFR resistance mutations. The patient was diagnosed with lung adenocarcinoma (stage cT4N2M0, IIIB). After resistance to the therapy targeting EGFR exon 21 L858R point mutation, T790 M mutation was detected in liquid biopsy and Met amplification was detected via tissue biopsy by next-generation sequencing (NGS). The patient received systemic treatments, including chemotherapy, gefitinib, afatinib, and osimertinib combined with crizotinib. The patient died of multisystem organ failure and had an overall survival of 24 months. Although osimertinib combined with crizotinib therapy showed dramatic tumor shrinkage in both the primary tumor and bone metastasis to an EGFR T790M-mutant NSCLC patient with MET amplification, the progression-free survival (PFS) was only two months.
Publication Date: 2021-08-17
Journal: Medicine


Risk of incident heart failure in individuals with early-onset type 2 diabetes.
Early-onset diabetes has been associated with unfavourable cardiovascular risk but data on heart failure (HF) in this subpopulation are scarce. To study the risk of, and risk factors for incident HF in individuals with early- onset type 2 diabetes. 606 individuals with type 2 diabetes diagnosed before 40 years old (early-onset) and 1258 counterparts with diabetes diagnosed between 41 to 65 years old (usual-onset) with no HF history were followed for a median of 7.1 years in a regional hospital. Incident HF by European Cardiology Society criteria. 62 and 108 HF events were identified in early- and usual- onset group (1.55 and 1.29 per 100 patient- years), respectively. As compared to usual-onset counterparts, individuals with early-onset diabetes had 1.20 (95% CI 0.88-1.63, P=0.26) folds unadjusted and 1.91 (95% CI 1.37-2.66, P<0.001) folds age- adjusted hazards for incident HF. Adjustment for traditional cardio-metabolic risk factors only moderately mitigated the hazards (adjusted HR 1.69, 95% CI 1.19-2.40, P=0.003). However, additional adjustment for eGFR and albuminuria markedly attenuated the association of early-onset age with incident HF (adjusted HR 1.24, 95% CI 0.87-1.77, P=0.24). Noteworthy, a long diabetes duration was not significantly associated with HF risk after accounting for kidney measures. Individuals with early- onset diabetes have at least the same absolute risk and 2-fold age- adjusted relative risk for incident HF. Excess cardio-renal risk factors but not a long diabetes duration are main drivers for HF development in this diabetic population.
Publication Date: 2021-08-21
Journal: The Journal of clinical endocrinology and metabolism

confidence interval(65)

Association of community socioeconomic deprivation with evidence of reduced kidney function at time of type 2 diabetes diagnosis.
While there are known individual-level risk factors for kidney disease at time of type 2 diabetes diagnosis, little is known regarding the role of community context. We evaluated the association of community socioeconomic deprivation (CSD) and community type with estimated glomerular filtration rate (eGFR) when type 2 diabetes is diagnosed. This was a retrospective cohort study of 13,144 adults with newly diagnosed type 2 diabetes in Pennsylvania. The outcome was the closest eGFR measurement within one year prior to and two weeks after type 2 diabetes diagnosis, calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-Epi) equation. We used adjusted multinomial regression models to estimate associations of CSD (quartile 1, least deprivation) and community type (township, borough, city) with eGFR and used adjusted generalized estimating equation models to evaluate whether community features were associated with the absence of diabetes screening in the years prior to type 2 diabetes diagnosis. Of the participants, 1279 (9.7%) had hyperfiltration and 1377 (10.5%) had reduced eGFR. Women were less likely to have hyperfiltration and more likely to have reduced eGFR. Black (versus White) race was positively associated with hyperfiltration when the eGFR calculation was corrected for race but inversely associated without the correction. Medical Assistance (ever versus never) was positively associated with reduced eGFR. Higher CSD and living in a city were each positively associated (odds ratio [95% confidence interval]) with reduced eGFR (CSD quartiles 3 and 4 versus quartile 1, 1.23 [1.04, 1.46], 1.32 [1.11, 1.58], respectively; city versus township, 1.38 [1.15, 1.65]). These features were also positively associated with the absence of a type 2 diabetes screening measure. In a population-based sample, more than twenty percent had hyperfiltration or reduced eGFR at time of type 2 diabetes diagnosis. Individual- and community-level factors were associated with these outcomes.
Publication Date: 2021-08-12
Journal: SSM - population health


Muscle mass and grip strength in relation to carotid intima-media thickness and plaque score in patients with type 2 diabetes.
In this study, we examined the relationships of appendicular skeletal muscle mass (ASM) and grip strength (GS) with carotid intima-media thickness (CIMT) and plaque score (PS) in patients with type 2 diabetes. A total of 1185 patients were recruited. High CIMT and high PS were defined as ≥ 75 percentile of maximal CIMT of each sex and PS ≥ 3. Patients in the lowest ASM/body mass index (BMI) or GS/BMI tertile were older and had lower HDL cholesterol, and eGFR, but higher BMI, waist circumference (WC), HOMA-IR, and C-reactive protein than those in the highest tertile. Meanwhile, individuals in the lowest ASM or GS tertile group had lower BMI and WC than those in the highest one. CIMT and PS and the prevalence of high CIMT, carotid plaques, and high PS gradually increased with decreasing tertiles of ASM, ASM/BMI, GS, and GS/BMI (p < 0.001). After adjusting for age and sex, odds ratios (ORs) and 95% confidence intervals (CIs) for high CIMT and high PS were 0.98 (0.68-1.42), 1.64 (1.14-2.36), 2.000 (1.33-3.01), and 1.77 (1.22-2.58) and 1.63 (1.16-2.30), 1.78 (1.28-2.54), 1.91 (1.33-2.75), and 1.61 (1.13-2.28) in the lowest tertile of ASM, ASM/BMI, GS, and GS/BMI, respectively. After further adjusting for potential confounders, ORs and 95% CI for high CIMT and high PS remained significant in the lowest tertile group. Low ASM and low GS may be independent risk factors for high CIMT and high PS in patients with type 2 diabetes.
Publication Date: 2021-08-24
Journal: Nutrition, metabolism, and cardiovascular diseases : NMCD


Population Epidemiology of Hyperkalemia: Cardiac and Kidney Long-term Health Outcomes.
The population burden and long-term implications of hyperkalemia have not been comprehensively studied. We studied how often and where hyperkalemia occurs as well as its independent association with survival and long-term cardiac and kidney health. Population-based cohort study of adults residents of Grampian, UK (adult population 468,594). Among the 468,594 adult residents, 2012-2014, 302,630 people with at least one blood test were followed until 2019. Hyperkalemia was defined as serum potassium ≥5.5 mmol/L. Adjustment for comorbidities, demographics, KDIGO measures of acute and chronic kidney function, and medications prescribed prior to measurement of serum potassium. All-cause mortality, cardiac events and kidney failure. Description of the annual incidence of hyperkalemia and the characteristics associated with its occurrence. Adjusted Cox proportional hazards (PH) analysis to evaluate the independent long-term association of hyperkalemia with all-cause mortality among people who survived >90-days after blood testing. Cause-specific PH models were fit to evaluate the association of hyperkalemia with cardiac events/death, non-cardiac death, and kidney failure. Effect modification by level of eGFR at the time of blood testing was explored. The annual population incidence of hyperkalemia was 0.96 per 100 person-years. This represented 2.3%, 2.1%, and 1.9% of people with at least one blood test in 2012, 2013 and 2014, respectively. Two-thirds of episodes of hyperkalemia occurred in the community. The hyperkalemia rate was two-fold higher for each 10-year greater age. Those with hyperkalemia were 20 times more likely to have concurrent AKI, and 17 times more likely to have eGFR <30 ml/min/1.73m The observational nature of this study limits evaluation of causal relationships. There is a substantial burden of hyperkalemia in the general population. Hyperkalemia is associated with poorer long-term health outcomes, especially kidney outcomes, that are independent of other established risk factors.
Publication Date: 2021-08-23
Journal: American journal of kidney diseases : the official journal of the National Kidney Foundation

nsclc patients(58)

Elevated exosome-derived miRNAs predict osimertinib resistance in non-small cell lung cancer.
Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations will inevitably develop drug resistance after being treated with the third-generation EGFR-tyrosine kinase inhibitor (TKI), osimertinib. Recently, the drug resistance information transmitted by exosomal miRNAs has attracted much attention. However, the mechanism of exosome-derived miRNAs in osimertinib resistance remains unexplored. We extracted and sequenced exosomes from the supernatant of the osimertinib-resistant cell line, H1975-OR, and the sensitive cell line, H1975. The results were compared with plasma exosome sequencing before and after the appearance of drug resistance in three NSCLC clinical patients treated with oral osimertinib. Exosome-derived miRNAs that had significantly increased expression levels after osimertinib resistance were screened for expanded validation in other 64 NSCLC patients. Cluster analysis of the target genes revealed that exosomal miRNAs participate in osimertinib resistance mechanisms through the activation of bypass pathways (RAS-MAPK pathway abnormality and PI3K pathway activation). Exosome-derived miR-184 and miR-3913-5p expression levels increased significantly after the onset of osimertinib resistance. Exosomal miR-3913-5p was associated with TNM stage, platelet count, tumor marker carcinoembryonic antigen, and distant metastases. In patients with EGFR exon 21 L858R mutation, the increased expression levels of miR-184 and miR-3913-5p derived from serum exosomes indicated osimertinib resistance. Similarly, for T790M-positive patients, the level of exosome-derived miR-3913-5p can be used as a predictive marker for osimertinib resistance. The expression levels of miR-184 and miR-3913-5p derived from exosomes in the peripheral blood of NSCLC patients could be used as biomarkers to indicate osimertinib resistance.
Publication Date: 2021-08-16
Journal: Cancer cell international

disease ckd(56)

Meta-Analysis of Transradial Versus Transfemoral Access for Percutaneous Coronary Intervention in Patients With Chronic Kidney Disease.
Data comparing outcomes of transradial (TR) versus transfemoral (TF) access for percutaneous coronary intervention (PCI) in chronic kidney disease (CKD) including patients with eGFR< 30 ml/min/1.73m
Publication Date: 2021-08-15
Journal: The American journal of cardiology

blood pressure(52)

Data driven evaluation of healthy volunteer characteristics at screening for phase I clinical trials to inform on study design and optimize screening processes.
Protocols for clinical trials describe inclusion and exclusion criteria based on general and compound-specific considerations to ensure subject safety and data quality. In phase I clinical trials, healthy volunteers (HVs) are screened against these criteria that often specify predefined eligibility ranges for vital signs, electrocardiogram, and laboratory tests. HVs are excluded if baseline parameters deviate from these ranges even though this may not indicate underlying pathology, which could delay trial execution. Data from 3365 HVs participating in 9670 screening visits for 94 phase I HV trials, conducted between December 2008 and May 2019 at the Janssen Clinical Pharmacology Unit, were retrospectively analyzed. Commonly predefined protocol ranges were overlaid with HV data to estimate predicted screen failure rates (SFRs). Of the overall population, 91% was White and 64% were men with mean age of 42.8 ± 12.5 years. High predicted SFRs are related to cardiovascular/metabolic (body mass index, heart rate [HR], blood pressure [BP], and corrected QT Fridericia's formula [QTcF]), renal (estimated glomerular filtration rate [eGFR]), liver (alanine aminotransferase [ALT], and total bilirubin), and coagulation (prothrombin time [PT]) parameters. Predicted SFRs increased with age for high systolic and diastolic BP, QTcF interval, and eGFR. In contrast, lower SFRs in the older age groups were seen for low diastolic BP, liver function test, ALT, PT, and total bilirubin. This analysis can be used to inform on study design, protocol inclusion and exclusion criteria, and to optimize the screening process. Data-driven critical appraisal of proposed inclusion and exclusion criteria using a risk-based approach may significantly reduce screen failure rates without compromising subjects' safety.
Publication Date: 2021-08-12
Journal: Clinical and translational science

interval ci(46)

Plasma Homocysteine Is a Predictive Factor for Accelerated Renal Function Decline and Chronic Kidney Disease in a Community-Dwelling Population.
Whether elevated plasma total homocysteine (tHcy) is a risk factor for the progression of kidney disease in general population has not been well established. The purpose of this study was to investigate the prognostic properties of plasma tHcy for renal function decrement and early chronic kidney disease (CKD) in community-dwelling populations with normal renal function at baseline. A total of 1,426 participants were enrolled and followed for a median of 4.8 years (interquartile range, 4.5-5.2), and estimated glomerular filtration rate (eGFR) was evaluated. One main outcome was the rapid eGFR decline defined as a decline in eGFR of >3 mL/min per 1.73 m2 per year; the other was the new incidence of CKD. At the end of follow-up, the incidence of rapid eGFR decline and new-onset CKD was 20.7 and 5.6%, respectively. In multivariate linear regression analysis, age, central pulse pressure, fasting blood glucose, and concentration of tHcy were independent determinants of the change in eGFR. There was a graded association between tHcy quartiles and eGFR decline. Compared with participants with the lowest quartile of tHcy levels, those with the highest quartile had significantly increased risk for rapid eGFR decline (adjusted odds ratio [aOR] = 1.81; 95% confidence interval [CI]: 1.25-2.94) and new onset of CKD (adjusted hazard ratio = 4.29; 95% CI: 1.42-12.99) after adjusting for various confounders. Similarly, significant associations were also found when baseline tHcy was classified as hyperhomocysteinemia (>15 μmol/L) versus normal tHcy level (≤15 μmol/L). However, there was only association between the change in tHcy levels and new occurrence of CKD but not with rapid eGFR decline (aOR = 0.99, p = 0.613). In this prospective cohort of individuals from community-based population, elevated plasma tHcy emerged as an independent predictor of renal function decline and incident CKD, which might support selection of at-risk individuals.
Publication Date: 2021-08-09
Journal: Kidney & blood pressure research

inhibitor egfr-tki(46)

The positive role of traditional Chinese medicine as an adjunctive therapy for cancer.
Traditional Chinese medicine (TCM), especially Chinese herbal medicines and acupuncture, has been traditionally used to treat patients with cancers in China and other East Asian countries. Numerous studies have indicated that TCM not only alleviates the symptoms (e.g., fatigue, chronic pain, anorexia/cachexia, and insomnia) of patients with cancer and improves their quality of life (QOL) but also diminishes adverse reactions and complications caused by chemotherapy, radiotherapy, or targeted-therapy. Therefore, Chinese herbal medicines and acupuncture and other alternative therapies need to be understood by TCM physicians and other health care providers. This review mainly summarizes the experimental results and conclusions from literature published since 2010, and a search of the literature as been performed in the PubMed, MEDLINE, Web of Science, Scopus, Springer, ScienceDirect, and China Hospital Knowledge Database (CHKD) databases. Some Chinese herbal medicines (e.g., Panax ginseng, Panax quinquefolius, Astragali radix, Bu-zhong-yi-qi-tang (TJ-41), Liu-jun-zi-tang (TJ-43), Shi-quan-da-bu-tang (TJ-48), and Ban-xia-xie-xin-tang (TJ-14)) and some acupuncture points (e.g., Zusanli (ST36), Zhongwan (CV12), Neiguan (PC6) and Baihui (GV20)) that are commonly used to treat cancer-related symptoms and/or to reduce the toxicity of chemotherapy, radiotherapy, or targeted-therapy are highlighted and summarized. Through a review of literature, we conclude that TCM can effectively alleviate adverse gastrointestinal reactions (including diarrhea, nausea, and vomiting) to these anti-cancer therapies, decrease the incidence of bone marrow suppression, alleviate cardiotoxicity, and protect against chemotherapy-induced peripheral neuropathy and radiation-induced pneumonitis. Moreover, TCM can alleviate epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-related acneiform eruptions, diarrhea, and other adverse reactions. The hope is that this review can contribute to an understanding of TCM as an adjuvant therapy for cancer and that it can provide useful information for the development of more effective anti-cancer therapies. However, more rigorously designed trials involving cancer treatment must be conducted in the future, including complete quality control and standardized models at the cellular, organic, animal and clinical levels, in order to study TCM in multiple forms and at multiple levels.
Publication Date: 2021-08-24
Journal: Bioscience trends

confidence interval ci(45)

MRI-based radiomics analysis for predicting the EGFR mutation based on thoracic spinal metastases in lung adenocarcinoma patients.
This study aims to develop and evaluate multi-parametric MRI-based radiomics for preoperative identification of epidermal growth factor receptor (EGFR) mutation, which is important in treatment planning for patients with thoracic spinal metastases from primary lung adenocarcinoma. A total of 110 patients were enrolled between January 2016 and March 2019 as a primary cohort. A time-independent validation cohort was conducted containing 52 patients consecutively enrolled from July 2019 to April 2021. The patients were pathologically diagnosed with thoracic spinal metastases from primary lung adenocarcinoma; all underwent T1-weighted (T1W), T2-weighted (T2W), and T2-weighted fat-suppressed (T2FS) MRI scans of the thoracic spinal. Handcrafted and deep learning-based features were extracted and selected from each MRI modality, and used to build the radiomics signature. Various machine learning classifiers were developed and compared. A clinical-radiomics nomogram integrating the combined rad signature and the most important clinical factor was constructed with receiver operating characteristic (ROC), calibration, and decision curves analysis (DCA) to evaluate the prediction performance. The combined radiomics signature derived from the joint of three modalities can effectively classify EGFR mutation and EGFR wild-type patients, with an area under the ROC curve (AUC) of 0.886 (95% confidence interval [CI]: 0.826-0.947, SEN =0.935, SPE =0.688) in the training group and 0.803 (95% CI: 0.682-0.924, SEN = 0.700, SPE = 0.818) in the time-independent validation group. The nomogram incorporating the combined radiomics signature and smoking status achieved the best prediction performance in the training (AUC = 0.888, 95% CI: 0.849-0.958, SEN = 0.839, SPE = 0.792) and time-independent validation (AUC = 0.821, 95% CI: 0.692-0.929, SEN = 0.667, SPE = 0.909) cohorts. The DCA confirmed potential clinical usefulness of our nomogram. Our study demonstrated the potential of multi-parametric MRI-based radiomics on preoperatively predicting the EGFR mutation. The proposed nomogram model can be considered as a new biomarker to guide the selection of individual treatment strategies for patients with thoracic spinal metastases from primary lung adenocarcinoma.
Publication Date: 2021-07-29
Journal: Medical physics

p 0 05(44)

Evaluation of acute and chronic nephrotoxicity in patients received cisplatin-based chemotherapy: has anything changed over time?
The aim of this study was to determine the frequency and the risk factors of acute and chronic nephrotoxicity in patients who received cisplatin due to malignancy. Medical records of all patients who received cisplatin-based chemotherapy regimen between January 2013 and July 2019 were retrospectively evaluated. The data of 203 patients who met the study criteria were examined. The patients were evaluated for acute nephrotoxicity at 48 h and late nephrotoxicity at 3rd month after first course of cisplatin. Early and late nephrotoxicity were defined by NCI CTCAE Version 4.0 criteria. The mean age of the study patients was 56.44 ± 12.69 years, 78.8% were males and 21.2% were females. It is revealed that the incidence of cisplatin-induced acute nephrotoxicity was 9.2% and chronic nephrotoxicity was 37.9%. While the development of acute nephrotoxicity was associated with female gender, history of diabetes mellitus, history of ischemic heart disease and use of antiplatelet drug, the development of chronic nephrotoxicity was associated with older age, female gender and using of diuretics. High serum creatinine, urea and low eGFR value before treatment were found to be associated with both early and late nephrotoxicity (p < 0.05). There was no statistically significant relationship between acute or chronic nephrotoxicity and cumulative dose of cisplatin, hydration or intravenous magnesium supplementation. High initial serum creatinine value and low initial eGFR are the most important determinants of both early and late nephrotoxicity.
Publication Date: 2021-08-15
Journal: International urology and nephrology

egfr mutation(43)

Identification of predictors for brain metastasis in newly diagnosed non-small cell lung cancer: a single-center cohort study.
To identify clinical and staging chest CT characteristics predictive of brain metastasis in patients with newly diagnosed NSCLC dichotomized according to resectability. Patients newly diagnosed with NSCLC of clinical stages II-IV between November 2017 and October 2018 were enrolled and classified into resectable (stage II+IIIA) and unresectable stages (stage IIIB/C+IV) according to chest CT. Associations of clinicopathological characteristics and CT findings with brain metastasis were analyzed using logistic regression. Predictive models were evaluated using receiver operating characteristics curve analysis. A subgroup analysis for unresectable-stage patients with known epidermal growth factor receptor gene (EGFR) mutation status was performed. This study included 911 NSCLC patients (mean age, 65 ± 11 years; 620 men), 194 of whom were diagnosed with brain metastasis. For resectable stages, independent predictors for brain metastasis were N2-stage (13 of 25 patients), absence of air-bronchogram/bubble lucency (23 of 25 patients), and presence of spiculation (15 of 25 patients), with a model combining the two imaging features showing an AUC of 0.723. In unresectable stages, independent predictors of brain metastasis were younger age, female sex, extrathoracic metastasis, and adenocarcinoma, with models combining these showing AUCs of 0.675-0.766. In the subgroup with known EGFR-mutation status, extrathoracic metastasis and positive EGFR mutation were independent predictors of brain metastasis, with the model showing AUCs of 0.641-0.732. CT-derived imaging features, clinical stages, lung cancer subtype, and EGFR mutation were associated with brain metastasis in patients with newly diagnosed NSCLC. The predictors were completely different between resectable and unresectable stages. • In resectable stages of NSCLC, two imaging features (absence of air-bronchogram/bubble lucency and presence of spiculation) and N2 stage were independent predictors of brain metastasis. • In unresectable stages of NSCLC, younger age, female sex, extrathoracic metastasis, and adenocarcinoma were associated with brain metastasis. • In the subgroup of NSCLC with known EGFR-mutation status, extrathoracic metastasis and positive EGFR mutation were independent predictors of brain metastasis.
Publication Date: 2021-08-12
Journal: European radiology


Response to: The Role of Dual Inhibition of EGFR and Vascular EGF(R) in the Treatment of NSCLC With EGFR Mutation.
Publication Date: 2021-08-25
Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

odds ratio(39)

Pharmacovigilance analysis of cardiac toxicities associated with targeted therapies for metastatic non-small cell lung carcinoma.
Targeted therapies have transformed treatment of driver-mutated metastatic non-small cell lung carcinoma (NSCLC). We compared cardiovascular adverse events between and within targeted therapy classes. We used WHO pharmacovigilance database VigiBase to compare odds of heart failure, conduction disease, QT prolongation, supraventricular tachycardia (SVT), and ventricular arrhythmias between inhibitors of EGFR (erlotinib, gefitinib, afatinib, osimertinib), BRAF (dabrafenib), MEK (trametinib), and ALK ± ROS1 (alectinib, brigatinib, ceritinib, crizotinib, lorlatinib). Of 98,765 adverse reactions reported with NSCLC targeted therapies, 1,783 (1.8%) were arrhythmias and 1,146 (1.2%) were heart failure. ALK/ROS1 inhibitors were associated with increased odds of conduction disease (reporting odds ratio [ROR] 12.95, 99% CI: 10.14-16.55) and QT prolongation (ROR 5.16, 99% CI: 3.92-6.81) relative to BRAF and EGFR inhibitors. Among ALK/ROS1 inhibitors, crizotinib had highest odds of conduction disease (ROR 1.75, 99% CI: 1.30-2.36) and QT prolongation (ROR 1.91, 99% CI: 1.22-3.00). Dabrafenib (ROR 2.24, 99% CI: 1.86-2.70) and trametinib (ROR 2.44, 99% CI: 2.03-2.92) had higher odds of heart failure than other targeted therapies. Osimertinib was strongly associated with QT prolongation (ROR 6.13, 99% CI: 4.43-8.48), heart failure (ROR 3.64, 99% CI: 2.94-4.50), and SVT (ROR 1.90, 99% CI: 1.26-2.86) relative to other targeted therapies. ALK/ROS1 inhibitors are associated with higher odds of conduction disease and QT prolongation than other targeted therapies. Osimertinib is strongly associated with QT prolongation, SVT, and heart failure relative to other EGFR inhibitors and targeted therapies. Monitoring for heart failure and arrhythmias should be considered with NSCLC targeted therapies, especially osimertinib.
Publication Date: 2021-08-22
Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

kinase alk(38)

A case of synchronous multiple primary lung adenocarcinomas harboring epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement successfully treated with combination of osimertinib and alectinib.
Synchronous multiple primary lung cancers (SMPLC) should be distinguished from intrapulmonary metastasis to define the optimal treatment approach. Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are typically mutually exclusive and the co-existence of both mutations is relatively rare. Herein, we report a case of SMPLC harboring each EGFR mutation and ALK rearrangement successfully treated with combination of osimertinib and alectinib. A combination of EGFR- and ALK-tyrosine kinase inhibitors could be an effective and tolerable therapeutic option for SMPLC with EGFR mutations and ALK rearrangement.
Publication Date: 2021-08-18
Journal: Respiratory medicine case reports


Clonal myelopoiesis promotes adverse outcomes in chronic kidney disease.
We sought to determine the relationship between age-related clonal hematopoiesis (CH) and chronic kidney disease (CKD). CH, defined as mosaic chromosome abnormalities (mCA) and/or driver mutations was identified in 5449 (2.9%) eligible UK Biobank participants (n = 190,487 median age = 58 years). CH was negatively associated with glomerular filtration rate estimated from cystatin-C (eGFR.cys; β = -0.75, P = 2.37 × 10
Publication Date: 2021-08-21
Journal: Leukemia

egfr tyrosine(36)

Triple therapy with osimertinib, bevacizumab and cetuximab in EGFR-mutant lung cancer with HIF-1α/TGF-α expression.
Osimertinib, a third generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, is the standard treatment for patients with lung cancer harboring EGFR T790M; however, acquired resistance is inevitable due to genetic and epigenetic changes in cancer cells. In addition, a recent randomized clinical trial revealed that the combination of osimertinib and bevacizumab failed to exhibit superior progression-free survival compared with osimertinib alone. The present study aimed to investigate the effect of triple therapy with osimertinib, bevacizumab and cetuximab in xenograft tumors with different initial tumor volumes (conventional model, 200 mm
Publication Date: 2021-08-14
Journal: Oncology letters

age sex(34)

Association of autosomal dominant polycystic kidney disease with cerebral small vessel disease.
Cilia dysfunction in autosomal-dominant polycystic kidney disease (ADPKD) may impair the integrity of glymphatic system and be implicated in the progression of cerebral small vessel disease (SVD), although the link between the two diseases has not been investigated. We evaluated the association of ADPKD pathology with SVD pattern and severity. Overall, 304 individuals in an ADPKD (chronic kidney disease stage ≤4 and age ≥50 years) cohort and their age, sex, and estimated glomerular filtration rate (eGFR)-matched controls were retrospectively included. ADPKD severity was classified into 1 A-B, 1 C, and 1 D-E, according to age and height-adjusted total kidney volume. SVD parameters included white-matter hyperintensity (WMH) severity scale, enlarged perivascular space (ePVS) score, and degree of lacunes or cerebral microbleeds (CMBs). After adjustments for age, sex, eGFR, and cerebrovascular risk factor parameters, ADPKD was associated with higher ePVS scores (
Publication Date: 2021-08-21
Journal: Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

0 01(26)

Prevalence and risk of chronic kidney disease in oral lichen planus: a large cross-sectional study from eastern China.
Oral lichen planus (OLP) is a chronic inflammatory mucocutaneous disease which is frequently associated with comorbidities such as diabetes and cardiovascular diseases. However, little is known about the association of OLP with impaired kidney function. To elucidate the possible association of chronic kidney disease (CKD) with OLP and its severity, this study investigated the prevalence of CKD as well as its risk factors in patients with OLP. A large prospective cross-sectional study of 1,021 patients with OLP was carried out using questionnaires and laboratory tests available from an oral medicine clinic at a university in eastern China. According to the Kidney Disease: Improving Global Outcomes (KDIGO) diagnostic guideline, CKD was classified based on the estimated glomerular filtration rate (eGFR, <60 mL/min/1.73 m The prevalence of CKD in the patients with OLP in this study was 14.3% (95% CI, 12.3-16.6%), which was higher than that in the general Chinese population (10.8%; 95% CI, 10.2-11.3%). The mean values of serum creatinine, eGFR, UACR, and urine N-acetyl-β-D-glucosidase in patients with CKD were significantly higher than those in patients without CKD (all P<0.01). Pearson's correlation analysis revealed that CKD stage and UACR were positively correlated with the severity of OLP (both P<0.001). Importantly, multivariate regression analysis revealed that age ≥58 years old, female sex, and hypertension were independent risk factors for incident CKD and abnormal UACR (>30 mg/g) in patients with OLP (all P<0.01). This study has reported for the first time that CKD is a comorbidity in patients with OLP. The occurrence and staging of incident CKD are associated with OLP and its severity.
Publication Date: 2021-08-24
Journal: Annals of translational medicine

p 0 0001(23)

Radiomic Feature-Based Nomogram: A Novel Technique to Predict EGFR-Activating Mutations for EGFR Tyrosin Kinase Inhibitor Therapy.
To develop and validate a radiomic feature-based nomogram for preoperative discriminating the epidermal growth factor receptor (EGFR) activating mutation from wild-type EGFR in non-small cell lung cancer (NSCLC) patients. A group of 301 NSCLC patients were retrospectively reviewed. The EGFR mutation status was determined by ARMS PCR analysis. All patients underwent nonenhanced CT before surgery. Radiomic features were extracted (GE healthcare). The maximum relevance minimum redundancy (mRMR) and LASSO, were used to select features. We incorporated the independent clinical features into the radiomic feature model and formed a joint model (i.e., the radiomic feature-based nomogram). The performance of the joint model was compared with that of the other two models. In total, 396 radiomic features were extracted. A radiomic signature model comprising 9 selected features was established for discriminating patients with EGFR-activating mutations from wild-type EGFR. The radiomic score (Radscore) in the two groups was significantly different between patients with wild-type EGFR and EGFR-activating mutations (training cohort: P<0.0001; validation cohort: P=0.0061). Five clinical features were retained and contributed as the clinical feature model. Compared to the radiomic feature model alone, the nomogram incorporating the clinical features and Radscore exhibited improved sensitivity and discrimination for predicting EGFR-activating mutations (sensitivity: training cohort: 0.84, validation cohort: 0.76; AUC: training cohort: 0.81, validation cohort: 0.75). Decision curve analysis demonstrated that the nomogram was clinically useful and surpassed traditional clinical and radiomic features. The joint model showed favorable performance in the individualized, noninvasive prediction of EGFR-activating mutations in NSCLC patients.
Publication Date: 2021-08-24
Journal: Frontiers in oncology

p 0 01(21)

The Impact of Cold Ischaemia Time On Outcomes of Living Donor Kidney Transplantation in the UK Living Kidney Sharing Scheme.
To assess the impact of cold ischaemia time (CIT) on living donor kidney transplantation (LDKT) outcomes in the UK living kidney sharing scheme (UKLKSS) versus outside the scheme. LDKT provides the best treatment option for end-stage kidney disease (ESKD) patients. ESKD patients with an incompatible living donor still have an opportunity to be transplanted through Kidney Exchange Programmes (KEP). In KEPs where kidneys travel rather than donors, CIT can be prolonged. Data from all UK adult LDKT between 2007 and 2018 were analysed. 9969 LDKT were performed during this period, of which 1396 (14%) were transplanted through the UKLKSS, which we refer to as KEP. Median CIT was significantly different for KEP versus non-KEP (339 versus 182 minutes, p < 0.001). KEP LDKT had a higher incidence of delayed graft function (DGF) (4.08% versus 6.97%, p < 0.0001), lower 1-year (eGFR 57.90 versus 55.25 ml/min, p = 0.04) and 5-year graft function (eGFR 55.62 versus 53.09 ml/min, p = 0.01) compared to the non-KEP group, but 1- and 5-year graft survival were similar. Within KEP, a prolonged CIT was associated with more DGF (9.26% versus 4.80%, p = 0.03), and lower graft function at 1-year and 5-years (eGFR = 55 vs 50 ml/min, p = 0.02), but had no impact on graft survival. Whilst CIT was longer in KEP, associated with more DGF and lower graft function, excellent 5-year graft survival similar to non-KEP was found.
Publication Date: 2021-08-03
Journal: Annals of surgery

60 ml min 1 73 m2(19)

Risk factor analysis of acute kidney injury after one-stop hybrid coronary revascularization.
One-stop hybrid coronary revascularization (HCR) combines coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) procedures simultaneously. Acute kidney injury (AKI) is a common complication after CABG or PCI. This study explored the risk factors for developing AKI after one-stop HCR. A total of 123 consecutive patients who underwent one-stop HCR between April 2018 and November 2020 were included in this single-center retrospective study. Postoperative AKI was observed in 11 patients (the AKI group), and 112 patients did not develop postoperative AKI (the non-AKI group). Baseline characteristics and perioperative variables were extracted from the electronic medical records and statistically analyzed. Postoperative AKI occurred in 11 (8.9%) patients. Compared to patients who did not develop AKI, patients in the AKI group were older (71.0±9.5 vs. 64.1±9.2 years, P=0.019), had higher preoperative creatinine levels (92.6±16.8 vs. 69.8±14.4 mmol/L, P<0.001), experienced a greater volume of postoperative drainage on the first day {850 mL [410, 1,500] vs. 500 mL [321, 700], P=0.045}, had a higher proportion of chronic renal insufficiency (eGFR <60 mL/min/1.73 m2) (36.4% vs. 7.1%, P=0.012), and had more perioperative transfusions (63.6% vs. 22.3%, P=0.007). Multivariate logistics analyses revealed that advanced age [odds ratio (OR) 5.44, P=0.014] and perioperative transfusions (OR 4.62, P=0.028) were independent risk factors for developing AKI after one-stop HCR. One-stop HCR did not increase the incidence of postoperative AKI in our center. Advanced age (≥75 years) and perioperative transfusions were independent risk factors for developing AKI after one-stop HCR. Further studies need to be conducted to confirm the risk factors of AKI after HCR procedures.
Publication Date: 2021-07-16
Journal: Annals of palliative medicine

p 0 002(14)

Multigene Combined Detection by RT-qPCR Using Cytological Specimens.
The aim of the study was to investigate the mutation status of multiple driver genes by RT-qPCR and their significance in advanced lung adenocarcinoma using cytological specimens. 155 cytological specimens that had been diagnosed with lung adenocarcinoma in the Fourth Hospital of Hebei Medical University were selected from April to November 2019. The cytological specimens included serous cavity effusion and fine-needle aspiration biopsies. Among cytological specimens, 108 cases were processed by using the cell block method (CBM), and 47 cases were processed by the disposable membrane cell collector method (MCM) before DNA/RNA extraction. Ten drive genes of EGFR, ALK, ROS1, BRAF, KRAS, NRAS, HER2, RET, PIK3CA, and MET were combined detected at one step by the amplification refractory mutation system and ABI 7500 RT-qPCR. The purity of RNA (p = 0.005) and DNA (p = 0.001) extracted by using the MCM was both significantly higher than that extracted by using the CBM. Forty-seven cases of fresh cell specimens processed by the MCM all succeeded in multigene detections, while of 108 specimens processed by the CBM, 6 cases failed in multigene detections. Among 149 specimens, single-gene mutation rates of EGFR, ALK, ROS1, RET, HER2, MET, KRAS, NRAS, BRAF, and PIK3CA mutations were 57.71%, 6.04%, 3.36%, 2.68%, 2.01%, 2.01%, 1.34%, 0.67%, 0% and 0% respectively, and 6 cases including 2 coexistence mutations. We found that mutation status was correlated with gender (p = 0.047), but not correlated with age (p = 0.141) and smoking status (p = 0.083). We found that the EGFR mutation status was correlated with gender (p = 0.003), age (p = 0.015) and smoking habits (p = 0.007), and ALK mutation status was correlated with age (p = 0.002). Compared with the CBM, the MCM can improve the efficiency of DNA/RNA extraction and PCR amplification by removing impurities and enriching tumor cells. And we speculate that the successful detection rate of fresh cytological specimens was higher than that of paraffin-embedded specimens. EGFR, ALK, and ROS1 mutations were the main driver mutations in patients with advanced lung adenocarcinoma. We speculate that EGFR and ALK are more prone to concomitant mutations, respectively. Targeted therapies for patients with coexisting mutations need further study.
Publication Date: 2021-08-04
Journal: Acta cytologica

p 001(9)

Driver and novel genes correlated with metastasis of non-small cell lung cancer: A comprehensive analysis.
Although mutations of genes are crucial events in tumorigenesis and development, the association between gene mutations and lung cancer metastasis is still largely unknown. The goal of this study is to identify driver and novel genes associated with non-small cell lung cancer (NSCLC) metastasis. Candidate genes were identified using a novel comprehensive analysis, which was based on bioinformatics technology and meta-analysis. Firstly, EGFR, KRAS, ALK, TP53, BRAF and PIK3CA were identified as candidate driver genes. Further meta-analysis identified that EGFR (Pooled OR 1.33, 95% CI 1.19, 1.50; P < .001) and ALK (Pooled OR 1.52, 95% CI 1.22, 1.89; P < .001) mutations were associated with distant metastasis of NSCLC. Besides, ALK (Pooled OR 2.40, 95% CI 1.71, 3.38; P < .001) mutation was associated with lymph node metastasis of NSCLC. In addition, thirteen novel gene mutations were identified to be correlated with NSCLC metastasis, including SMARCA1, GGCX, KIF24, LRRK1, LILRA4, OR2T10, EDNRB, NR1H4, ARID4A, PRKCI, PABPC5, ACAN and TLN1. Furthermore, elevated mRNA expression level of SMARCA1 and EDNRB was associated with poor overall survival in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), respectively. Additionally, pathway and protein-protein interactions network analyses found the two genes were correlated with epithelial-mesenchymal transition process. In conclusion, mutations of EGFR and ALK were significantly correlated with NSCLC metastasis. In addition, thirteen novel genes were identified to be associated with NSCLC metastasis, especially SMARCA1 in LUAD and EDNRB in LUSC.
Publication Date: 2021-07-24
Journal: Pathology, research and practice

months 95(9)

Combination atezolizumab, bevacizumab, pemetrexed and carboplatin for metastatic EGFR mutated NSCLC after TKI failure.
Acquired resistance to TKI is an important unmet need in the management of EGFR mutated lung cancer. Recent clinical trial IMPower150 suggested that combination approach with VEGF inhibitor, check point inhibitor immunotherapy and platinum-based chemotherapy was effective in oncogene driven lung cancer. The current trial examined the efficacy of a modified regimen in an EGFR mutated cohort. An open-labelled, single arm, phase II study was conducted in patients with EGFR mutated NSCLC who had progressed on at least one EGFR TKI. For those with T790M mutation, radiological progression on osimertinib was required for enrolment. Patients were treated with combination atezolizumab (1200 mg), bevacizumab (7.5 mg/kg), pemetrexed (500 mg/m2) and carboplatin (AUC 5) given once every 3 weeks until progression. Forty patients were enrolled. Median age was 62 (range 45-76) years. More than one half (23/40, 57.5%) had progressed on osimertinib. PD-L1 expression was < 1% in 52.5%. Median follow-up time was 17.8 months. ORR was 62.5%. Median PFS was 9.4 months (95% CI: 7.6 - 12.1). One year OS was 72.5% (95% CI: 0.56-0.83). Treatment related grade 3 or above adverse events (AE) occurred in 37.5% (15/40). Immune-related AE occurred in 32.5% (13/40) patients. Quality of life measures of function and symptoms did not change significantly throughout the course of treatments. Post-trial rechallenge with EGFR TKI containing regimen resulted in PFS of 5.8 months (95% CI 3.9-10.0 months). Combination approach of atezolizumab, bevacizumab, pemetrexed and carboplatin achieved promising efficacy in metastatic EGFR mutated NSCLC after TKI failure. The results were comparable with taxane based regimen of IMPower150 while toxicity profile was improved.
Publication Date: 2021-07-25
Journal: Lung cancer (Amsterdam, Netherlands)

3 6(6)

AI-supported modified risk staging for multiple myeloma cancer useful in real-world scenario.
An efficient readily employable risk prognostication method is desirable for MM in settings where genomics tests cannot be performed owing to geographical/economical constraints. In this work, a new Modified Risk Staging (MRS) has been proposed for newly diagnosed Multiple Myeloma (NDMM) that exploits six easy-to-acquire clinical parameters i.e. age, albumin, β2-microglobulin (β2M), calcium, estimated glomerular filtration rate (eGFR) and hemoglobin. MRS was designed using a training cohort of 716 NDMM patients of our inhouse MM Indian (MMIn) cohort and validated on MMIn (n=354) cohort and MMRF (n=900) cohort. K-adaptive partitioning (KAP) was used to find new thresholds for the parameters. Risk staging rules, obtained via training a J48 classifier, were used to build MRS. New thresholds were identified for albumin (3.6 g/dL), β2M (4.8 mg/L), calcium (11.13 mg/dL), eGFR (48.1 mL/min), and hemoglobin (12.3 g/dL) using KAP on the MMIn dataset. On the MMIn dataset, MRS outperformed ISS for OS prediction in terms of C-index, hazard ratios, and its corresponding p-values, but performs comparable in prediction of PFS. On both MMIn and MMRF datasets, MRS performed better than RISS in terms of C-index and p-values. A simple online tool was also designed to allow automated calculation of MRS based on the values of the parameters. Our proposed ML-derived yet simple staging system, MRS, although does not employ genetic features, outperforms RISS as confirmed by better separability in KM survival curves and higher values of C-index on both MMIn and MMRF datasets. Grant: BT/MED/30/SP11006/2015 (Department of Biotechnology, Govt. of India), Grant: DST/ICPS/CPS-Individual/2018/279(G) (Department of Science and Technology, Govt. of India), UGC-Senior Research Fellowship.
Publication Date: 2021-07-12
Journal: Translational oncology

p 0 00001(3)

Risk factors for brain metastases in patients with non-small cell lung cancer: a meta-analysis of 43 studies.
Lung cancer is a leading cause of cancer-related mortality worldwide. The purpose of our meta-analysis was to assess the risk factors for brain metastases (BM) in patients with non-small cell lung cancer (NSCLC). Multiple databases, including PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang, were systematically searched to recruit relevant studies investigating the risk factors for BM in NSCLC patients. The Newcastle-Ottawa Scale was used to evaluate literature quality, and the meta-analysis was performed using the Review Manager 5.3. Evidence quality evaluation was carried out according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) standard. The estimated odds ratio (OR) and 95% confidence intervals (CIs) were set as effect measures. Funnel plots and sensitivity analyses were used to assess publication bias and the robustness and reliability of the combined results, respectively. A total of 43 studies with 11,415 participants were included in this meta-analysis. The results indicated that the following factors were significantly associated with an increased risk of BM in NSCLC patients (P<0.05): (I) gender (female) (OR =1.32, 95% CI: 1.17-1.49, P<0.00001); (II) adenocarcinoma (OR =2.34, 95% CI: 1.76-3.11, P<0.00001) or non-squamous cell carcinoma (OR =0.63, 95% CI: 0.42-0.94, P=0.02); (III) advanced tumor stage (OR =1.48, 95% CI: 1.01-2.17, P=0.04); (IV) node stage (OR =2.19, 95% CI: 1.39-3.45, P=0.0007); (V) lymphatic metastasis (OR =2.43, 95% CI: 1.76-3.36, P<0.00001); (VI) epidermal growth factor receptor (EGFR) gene mutation (OR =1.88, 95% CI: 1.26-2.80, P=0.002); (VII) kirsten rat sarcoma viral oncogene (KRAS) gene mutation (OR =2.99, 95% CI: 1.82-4.91, P<0.00001); (VIII) higher levels of carcinoembryonic antigen (P<0.00001), carbohydrate antigen 199 (P<0.0001), cytokeratin-19 fragment (P=0.04), neuron-specific enolase (P<0.00001), and carbohydrate antigen 125 (P=0.0005). This meta-analysis demonstrated that NSCLC patients with BM have more aggressive clinical features.
Publication Date: 2021-04-10
Journal: Annals of palliative medicine