Pretreatment Neutrophil-to-Lymphocyte Ratio and Smoking History as Prognostic Factors in Advanced Non-Small Cell Lung Cancer Patients Treated with Osimertinib.

BACKGROUND: The remarkable efficacy of osimertinib in non‒small cell lung cancer (NSCLC) with acquired T790M mutation has been widely documented in clinical trials and real-world practice. However, some patients show primary resistance to this drug. Even patients who initially show a favorable response have inconsistent clinical outcomes later. Therefore, the aim of this study was to identify additional clinical predictive factors for osimertinib efficacy. METHODS: A prospective cohort of patients with acquired T790M positive stage IV lung adenocarcinoma treated with osimertinib salvage therapy in Hallym University Medical Center were analyzed. RESULTS: Sixty-one eligible patients were analyzed, including 38 (62%) women and 39 (64%) who never smoked. Their mean age was 63.3 years. The median follow-up after treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) was 36.0 months (interquartile range, 24.7-50.2 months). The majority (n=45, 74%) of patients were deceased. Based on univariate analysis, low baseline neutrophil-to-lymphocyte ratios (NLR), age ≥50 years, never-smoking history, stage IVA at osimertinib initiation, and prolonged response to previous TKIs (≥10 months) were associated with a significantly longer progression-free survival (PFS). Multivariate analysis showed that never-smoking status (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.30-0.98; p=0.041) and a baseline NLR less than or equal to 3.5 (HR, 0.23; 95% CI, 0.12-0.45; p-lt;0.001) were independently associated with a prolonged PFS with osimertinib. CONCLUSION: Smoking history and high NLR were independent negative predictors of osimertinib PFS in patients with advanced NSCLC developing EGFR T790M resistance after the initial EGFR-TKI treatment.

Neoadjuvant Therapy of Cyclin-Dependent Kinase 4/6 Inhibitors Combined with Endocrine Therapy in HR+/HER2- Breast Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Cyclin-dependent kinase (CDK) 4/6 inhibitors have been advocated for adjuvant therapy of metastatic hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)- breast cancer (BC). However, the efficiency of adding CDK 4/6 inhibitors to neoadjuvant therapy was not unequivocal. OBJECTIVE: The aim of the study was to evaluate the efficiency and toxicity of neoadjuvant CDK 4/6 inhibitors + endocrine therapy (ET) versus neoadjuvant endocrine monotherapy or standard neoadjuvant chemotherapy in HR+/HER2- BC. METHOD: We searched PubMed, the Cochrane Library, Web of Science, and Embase online databases for randomized controlled trials and single-arm studies written in English until April 2021. RESULTS: Five studies comparing CDK 4/6 inhibitors + ET as neoadjuvant treatments to ET alone and 2 studies comparing neoadjuvant CDK 4/6 inhibitors + ET to neoadjuvant chemotherapy were analysed. Neoadjuvant CDK 4/6 inhibitors + ET improved the rate of complete cell cycle arrest (CCCA: central Ki67 < 2.7%, odds ratio [OR] = 7.91, 95% confidence interval [CI] = 4.81-13.03, p < 0.001), increased the risk of adverse events (AEs; especially ≥3 AEs; AEs of all grades: OR = 9.10, 95% CI = 2.39-34.58, p = 0.001; AEs ≥3: OR = 12.24, 95% CI = 4.17-35.88, p < 0.001), led to no significant differences in pathological complete response (pCR) in patients with BC (OR = 0.34, 95% CI = 0.04-2.85, p = 0.318) compared to endocrine monotherapy. Moreover, subgroup analysis showed that the 3 types of CDK 4/6 inhibitors all improved the rate of CCCA (ribociclib: OR = 10.31, 95% CI = 3.59-29.61, p < 0.001; palbociclib: OR = 7.39, 95% CI = 1.26-43.40, p = 0.027, and abemaciclib: OR = 8.28, 95% CI = 3.41-20.11, p < 0.001). Compared to neoadjuvant chemotherapy, neoadjuvant CDK 4/6 inhibitors plus ET decreased the risk of AEs ≥3 (OR = 0.50, 95% CI = 0.29-0.87, p = 0.015) and showed similar ability to reach pCR (OR = 0.50, 95% CI = 0.12-2.07, p = 0.342) and reduce the residual cancer burden (RCB, RCB 0-1: OR = 0.47, 95% CI = 0.18-1.22, p = 0.121; RCB 2-3: OR = 2.30, 95% CI = 0.89-5.91, p = 0.084). CONCLUSIONS: The results suggested that combination therapy had increased efficacy and toxicity compared to endocrine monotherapy and showed similar efficacy to and better safety than neoadjuvant chemotherapy.

[Phase â ¢ randomized controlled, multicenter, prospective study of recombinant anti-HER2 humanized monoclonal antibody (Cipterbin) combined with vinorelbine in patients with HER2 positive metastatic breast cancer: the HOPES Study].

Objective: To evaluate the clinical efficacy and safety of recombinant anti-HER2 humanized monoclonal antibody (Cipterbin) combined with vinorelbine in patients with HER2 positive metastatic breast cancer. Methods: Patients were randomized 2∶1 to test group and control group. Patients in test group received Cipterbin (4 mg/kg loading dose and 2 mg/kg maintenance dose each week, IV) combined with vinorelbine (25 mg/m(2) on days 1,8 and 15 of each 28 days, IV). Patients in control group received vinorelbine (25 mg/m(2) on days 1,8 and 15 of each 28 days, IV).The primary end point was progression free survival (PFS). Results: A total of 315 patients were enrolled from Jan 2009 to Jan 2013 (212 in test group and 103 in control group). The median PFS of test group was significantly longer than that of control group, 39.1 weeks vs 14.0 weeks (HR=0.24; 95%CI, 0.16-0.36; P<0.000 1). The objective response rate (ORR) and disease control rate (DCR) in test group were significantly higher than those in control group, ORR was 46.7% vs 18.45% (P<0.000 1) and DCR was 79.72% vs 45.63% (P<0.000 1). The incidence of neutropenia, leucopenia and erythrocytopenia were higher in both groups, but there was no significant difference between two groups.The most common adverse events associated with Cipterbin were infusion reactions. Left ventricular ejection fraction reduced to less than 50% in 5 patients, which were recovered. No serious cardiotoxicity. Conclusion: The recombinant anti-HER2 humanized monoclonal antibody (Cipterbin) combined with vinorelbine has significant efficacy and good safety. It is the optimized therapy regime for patients with taxane-pretreated HER2 positive metastatic breast cancer, which provides more targeted therapy opportunities for HER2 positive breast cancer patients in China.

Advances in targeting acquired resistance mechanisms to epidermal growth factor receptor tyrosine kinase inhibitors.

Next-generation sequencing (NGS) of tumor samples and circulating tumor DNA has revolutionized diagnostic and therapeutic strategies in lung cancer. The identification of the epidermal growth factor receptor (EGFR) oncogenic driver has translated into successful therapy of advanced lung cancer using EGFR tyrosine kinase inhibitors (TKI). Unfortunately, responses are limited by acquired mechanisms of resistance. We review herein the current landscape of acquired resistance mechanisms to EGFR-TKI therapy and recent advances in therapeutic strategies to overcome acquired resistance.

[The (18)F-FDG positron emission tomography integrated computed tomography associate with intravoxel incoherent motion in prediction of EGFR expression in lung cancer].

Objective: To discuss the diagnostic value potential of (18)F-FDG PET/CT and intravoxel incoherent motion (IVIM) in genotype EGFR of lung cancer. Methods: A total of 116 cases proved pathologically pulmonary space occupying lesions (72 males, 44 females; age range was 31-85 years; 37 cases of high differentiation; 53 cases of middle differentiation, 26 cases of low differentiation) were prospectively collected from August 2017 to March 2019 in Henan Provincial People's Hospital. EGFR gene detection was performed in 50 patients (wild type 20 cases, mutant 30 cases). Whole body PET/CT and lung MR-imaging were performed before treatment in all patients. Comparison of PET/CT, IVIM semi-quantitative parameters between positive and negative of EGFR by Student-t test or Mann-Whitney U test. Evaluation diagnostic efficacy of each parameter to EGFR by drawing ROC curves. The optimum diagnostic threshold, specificity, sensitivity, positive predictive value, negative predictive value and the diagnostic accuracy were calculated. The diagnostic accuracy of (18)F-FDG PET/CT combined with IVIM was calculated. Results: The quantitative parameters standard intake(SUV), apparent diffusion coefficient (ADC), true diffusion coefficient (D), pseudo-diffusion coefficient (D(*)), perfusion fraction (f) were 8.7±3.5, (1.59±0.26) ×10(-3) mm(2)/s, (1.04±0.12)×10(-3) mm(2)/s, (3.9±3.0)×10(-2) mm(2)/s, 0.43±0.16 and the above parameters of the wild group were 14.3±3.3, (1.34±0.26)×10(-3) mm(2)/s, (0.89±0.12)×10(-3) mm(2)/s, (3.5±2.5)×10(-2) mm(2)/s, 0.40±0.11, respectively. The difference of quantitative parameters SUV (t=4.196, P=0.0001), ADC (t=2.502, P=0.0018), D (t=3.158, P=0.006) between the EGFR mutant group and the wild group was statistically significant. The difference of quantitative parameters D(*) (t=0.361, P=0.721), f (t=0.627, P=0.536) was not statistically significant. ROC curve was drawn and the area under the curves for diagnosis of EGFR mutations by SUV, ADC, D, D(*), f was 0.880, 0.755, 0.820, 0.575, 0.550. The diagnostic accuracy of these parameters above mentioned was 80.0%, 76.7%, 73.3%, 66.7%, 53.3% respectively. The diagnostic accuracy of SUV combined with ADC, D values was 83.3% and 80.0%. Conclusion: PET/CT and IVIM have certain diagnostic value for EGFR typing of lung cancer gene.

[The value of CT radiomics in the prediction of EGFR mutation in lung cancer].

Objective: To explore the value of CT radiomics quantitative features in the prediction of epidermal growth factor receptor (EGFR) mutation in lung cancer. Methods: The data of 144 patients, 75 males, 69 females, median age 54 (25-68 years), with EGFR gene test results in lung cancers diagnosed in the First Affiliated Hospital of Soochow University were retrospectively analyzed, including 81 patients, 39 males, 42 females, median age 52 (25-64)years old, with EGFR mutations and 63 patients,36 males,27 females,median age 56(32-68) years old,with EGFR wild types. According to a ratio of 2︰1, patients were randomly assigned to the training group and validation group. MaZda software was used to extract radiomics features including the gray level histogram (GLH), absolute gradient (GRA), gray-level co-occurrence matrix (GLCM), gray-level run-length matrix (GLRLM), auto-regressive model (ARM) and wavelets transform (WAV), and so on. Fisher coefficients (Fisher), classification error probability combined average correlation coefficients (POE+ACC) and mutual information (MI) were used to select 10 optimal features making up the optimal feature subsets. The optimal feature subsets were analyzed by using linear discriminant analysis (LDA) and nonlinear discriminant analysis (NDA) to calculate the accuracy, sensitivity and specificity in the differential diagnosis of EGFR mutant types and wild types in lung cancers. The prediction model was established using the optimal feature subsets with the highest accuracy in the training group with artificial neural network (ANN). The established prediction model was used to differentiate EGFR mutant types from wild types in the validation group. Results: MaZda software extracted a total of 301 quantitative features in the CT images for the patients with EGFR mutant types and EGFR wild types in the training group. The optimal feature subsets obtained from Fisher-NDA and (POE+ACC)-NDA had the highest accuracy of 93.8%, in the differential diagnosis of the EGFR mutant types and EGFR wild types of lung cancer in the training group. The optimal feature subset prediction model obtained from Fisher-NDA had the accuracy, sensitivity and specificity of 83.3%, 86.7% and 77.8%, respectively, in the differential diagnosis of the EGFR mutant types and EGFR wild types of lung cancer in the validation group. Conclusion: The optimal subset of CT radiomics features has high accuracy in predicting EGFR mutations in lung cancer, providing a new method for predicting gene expression of lung cancer.

[Clinical research on the expression of three vascular regulatory factors in different morphological regions of Marjolin ulcer and their relationship with angiogenesis].

Objective: To investigate the expressions of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1 alpha (HIF-1α), and epidermal growth factor receptor (EGFR) in different morphological regions of Marjolin ulcer and their clinical relationship with angiogenesis. Methods: From January 2012 to December 2017, the patients admitted to our hospital who met the inclusion criteria were selected, including 92 patients with Marjolin ulcer [56 males and 36 females, aged (55±15) years], 100 patients with chronic non-cancerous skin ulcer [59 males and 41 females, aged (51±16) years], and 100 patients performed with other skin-related surgery [58 males and 42 females, aged (52±15) years], and they were enrolled into Marjolin ulcer group (MU), chronic non-cancerous ulcer group (CNU), and other skin surgery group (OSS) respectively. The etiology, pathogenic site, ulcer diameter, and course of patients in group MU were retrospectively analyzed. Ulcer tissue specimens from patients of group MU and group CNU and specimens of normal skin tissue attached to the tissue resected during operation from patients of group OSS were collected. The expressions of VEGF, HIF-1α, EGFR, and CD34 in the above-mentioned tissue and the surrounding normal skin, ulcer, epitheliomatous hyperplasia, and canceration areas in Marjolin ulcer tissue were detected by immunohistochemical method, and the positive expression rate and protein expression level were calculated. Data were processed with Pearson chi-square test, Mann-Whitney U test, Bonferroni method, and Bonferroni correction, and Spearman correlation analysis was used to analyze the relationship among the total protein expression levels. Results: In group MU, burns accounted for 91.3% (84/92) of the causes of patients, 44.6% (41/92) of the patients had tumors in the lower extremities, 62.0% (57/92) of the patients had skin ulcer diameter of 2.1-5.0 cm, and 75.0% (69/92) of the patients had a course of disease of more than 20 years. The positive rates of VEGF, HIF-1α, and EGFR in ulcer tissue of patients in group CNU were 41.0% (41/100), 77.0% (77/100), and 83.0% (83/100), respectively, significantly higher than those of normal skin tissue of patients in group OSS [12.0% (12/100), 45.0% (45/100), and 67.0% (67/100), χ(2)=21.589, 21.522, 6.827, P<0.01]. The positive rates of VEGF, HIF-1α, and EGFR in ulcer tissue of patients in group MU were 91.3% (84/92), 100.0% (92/92), and 100.0% (92/92), respectively, which were significantly higher than those in corresponding tissue of patients in group CNU and group OSS (χ(2)=53.372, 24.772, 17.159; 120.543, 72.777, 36.661, P<0.01). In ulcer tissue of patients in group MU, the positive expression rates of VEGF in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than the rate in surrounding normal skin area (χ(2)=87.120, 42.368, 89.624, P<0.01); the positive expression rates of VEGF in canceration and ulcer areas were significantly higher than the rate in epitheliomatous hyperplasia area (χ(2)=22.586, 16.060, P<0.01). In ulcer tissue of patients in group MU, the positive expression rates of EGFR in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than the rate in surrounding normal skin area (χ(2)=21.679, 27.600, 27.600, P<0.01), but the positive expression rates of HIF-1α in four morphological areas were similar (χ(2)=3.008, P>0.05). In ulcer tissue of patients in group MU, the protein expression levels of VEGF and CD34 in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than those in surrounding normal skin area (Z=-6.765, -6.819; -6.765, -6.640; -6.765, -6.819, P<0.01), the protein expression levels of VEGF and CD34 in epitheliomatous hyperplasia area were significantly lower than those in ulcer area (Z=-4.484, -5.266, P<0.01), and the protein expression levels of VEGF and CD34 in canceration area were significantly higher than those in ulcer area (Z=-6.427, -6.723, P<0.01) and epitheliomatous hyperplasia area (Z=-6.427, -6.462, P<0.01). In ulcer tissue of patients in group MU, the protein expression levels of HIF-1α and EGFR in ulcer, epitheliomatous hyperplasia, and canceration areas were significantly higher than those in surrounding normal skin area (Z=-6.819, -6.393; -6.819, -6.393; -6.819, -6.393, P<0.01), the protein expression levels of HIF-1α and EGFR in ulcer area were significantly lower than those in epitheliomatous hyperplasia and canceration areas (Z=-6.118, -5.638; -6.640, -6.393, P<0.01), and the protein expression levels of HIF-1α and EGFR in canceration area were significantly higher than those in epitheliomatous hyperplasia area (Z=-6.558, -6.819, P<0.01). In ulcer tissue of patients in group MU, the total protein expression levels of VEGF, HIF-1α, and EGFR were significantly positively correlated with the total protein expression level of CD34 (r=0.772, 0.415, 0.502, P<0.01) respectively; the total protein expression level of EGFR was significantly positively correlated with that of HIF-1α (r=0.839, P<0.01), both of which were significantly positively correlated with the total protein expression level of VEGF (r=0.531, 0.440, P<0.01) respectively. Conclusions: The expressions of VEGF, HIF-1α, and EGFR are the highest in Marjolin ulcer canceration area, and EGFR may promote angiogenesis through HIF-1α or directly increasing the expression of VEGF.

Genetic and Environmental Influences on the Correlations between Traits of Metabolic Syndrome and CKD.

BACKGROUND AND OBJECTIVES: Metabolic syndrome is a cluster of risk factors associated with CKD. By studying the genetic and environmental influences on how traits of metabolic syndrome correlate with CKD, the understanding of the etiological relationships can be improved. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From the population-based TwinGene project within the Swedish Twin Registry, 4721 complete twin pairs (9442 European ancestry participants) were included in this cross-sectional twin study. Metabolic syndrome-related continuous traits were measured, and the binary components as well as the status of metabolic syndrome were defined according to the National Cholesterol Education Program-Adult Treatment Panel III. The eGFR was calculated by cystatin C-based equations from the CKD epidemiology collaboration group, and CKD was defined by eGFR<60 ml/min per 1.73 m2. Genetic and environmental contributions to the correlations between traits of metabolic syndrome and CKD were estimated by using twin-based bivariate structural equation models. RESULTS: The correlation between metabolic syndrome and eGFR-defined CKD was 0.16 (95% confidence interval [95% CI], 0.12 to 0.20), out of which 51% (95% CI, 12% to 90%) was explained by genes, whereas 15% (95% CI, 0% to 42%) and 34% (95% CI, 16% to 52%) was explained by the shared and nonshared environment, respectively. The genetic and environmental correlations between metabolic syndrome and CKD were 0.29 (95% CI, 0.07 to 0.51) and 0.27 (95% CI, 0.13 to 0.41), respectively. For the correlation between abdominal obesity and eGFR, 69% (95% CI, 10% to 100%) was explained by genes and 23% (95% CI, 5% to 41%) was explained by environment. The genetic correlation between abdominal obesity and eGFR was -0.30 (95% CI, -0.54 to -0.06), whereas the environmental correlation was -0.14 (95% CI, -0.22 to -0.06). CONCLUSIONS: Both genes and environment contribute to the correlation between metabolic syndrome and eGFR-defined CKD. The genetic contribution is particularly important to the correlation between abdominal obesity and eGFR.

[The effective mutation of epidermal growth factor receptor in synchronous multiple primary lung cancers: study of clinical, radiographic and pathological factors].

Objective: To investigate the clinical, pathological and CT features associated with the effective mutation of epidermal growth factor receptor (EGFR) in multiple primary lung cancers (MPLCs) , and to determine the target population of EGFR mutations tests. Methods: A total of 558 nodules from 232 patients with MPLCs who underwent surgery in the Cancer Hospital of Chinese Academy of Medical Sciences from August 2017 to December 2017 were selected. Two hundreds and sixteen nodules were detected by DNA direct sequencing. Chi-square test and Mann-Whitney U test were used to compare the clinical, pathological and CT features of 216 nodules in the EGFR effective mutation group and the non-effective mutation group. Logistic regression analysis was used to explore the independent risk factors of EGFR mutation. The cut off value was determined using the receiver operating characteristic(ROC) curve. Of 232 cases 558 nodules of surgically resected MPLCs, EGFR mutation of 216 nodules was determined by direct DNA sequencing. Results: There were 58 males and 174 females with MPLCs(male︰female=1︰3). There were 117 cases of age ≥59 years old and 115 cases of age <59 years old. There were 192 non-smokers, accounting for 82.8% of all patients. There were 2-7 nodules in the patient's lungs, of which 170 patients had two nodules in the lungs, 44 patients had 3 nodules, and another patient had 7 nodules. Among them, 216 nodules were detected by EGFR gene, 136 were effective mutations, and 80 were non-effective mutations (including wild type and null mutation). EGFR effective mutation group and non-effective mutation group were statistically significant in lung adenocarcinoma patients with different gender, age, smoking history, histological type, and differentiation degree (P=0.006, 0.002, 0.002, 0.015, 0.025).Among them, the effective mutation group were 107 females, 85 cases≥ 59 years old, 117 cases with no smoking history, 68 acinar-based, 89 moderate differentiation. In the count data, 127 nodule edges were lobed, and only 9 nodule edges were smooth. Among the measurement data, the GGO CT value was approximately (-459±147) HU in the EGFR mutation group, with statistical difference (P=0.037). The GGO diameter was approximately (11±9)mm,P=0.279.Multivariate Logistic regression analysis showed that GGO diameter (OR=0.873, 95%CI: 0.780-0.997; P=0.018) and smooth margins (OR=0.183,95%CI: 0.041-0.824; P=0.027) were independent protective factors of effective mutations of EGFR. Conclusions: In MPLCs, effective EGFR mutation is more common, and associated with elder female, age≥59 years, non-smoking, GGO attenuation <-548 HU, moderately differentiated, predominant invasive papillary adenocarcinoma. Patients with MPLCs and these risk factors may be encouraged to have postoperative EGFR molecular test.

Development and Validation of a Pragmatic Electronic Phenotype for CKD.

BACKGROUND AND OBJECTIVES: Poor identification of individuals with CKD is a major barrier to research and appropriate clinical management of the disease. We aimed to develop and validate a pragmatic electronic (e-) phenotype to identify patients likely to have CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The e-phenotype was developed by an expert working group and implemented among adults receiving in- or outpatient care at five healthcare organizations. To determine urine albumin (UA) dipstick cutoffs for CKD to enable use in the e-phenotype when lacking urine albumin-to-creatinine ratio (UACR), we compared same day UACR and UA results at four sites. A sample of patients, spanning no CKD to ESKD, was randomly selected at four sites for validation via blinded chart review. RESULTS: The CKD e-phenotype was defined as most recent eGFR <60 ml/min per 1.73 m2 with at least one value <60 ml/min per 1.73 m2 >90 days prior and/or a UACR of ≥30 mg/g in the most recent test with at least one positive value >90 days prior. Dialysis and transplant were identified using diagnosis codes. In absence of UACR, a sensitive CKD definition would consider negative UA results as normal to mildly increased (KDIGO A1), trace to 1+ as moderately increased (KDIGO A2), and ≥2+ as severely increased (KDIGO A3). Sensitivity, specificity, and diagnostic accuracy of the CKD e-phenotype were 99%, 99%, and 98%, respectively. For dialysis sensitivity was 94% and specificity was 89%. For transplant, sensitivity was 97% and specificity was 91%. CONCLUSIONS: The CKD e-phenotype provides a pragmatic and accurate method for EHR-based identification of patients likely to have CKD.

Gait Abnormalities and the Risk of Falls in CKD.

BACKGROUND AND OBJECTIVES: Older adults with CKD are at high risk of falls and disability. It is not known whether gait abnormalities contribute to this risk. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Quantitative and clinical gait assessments were performed in 330 nondisabled community-dwelling adults aged ≥65 years. CKD was defined as an eGFR <60 ml/min per 1.73 m2. Cox proportional hazards models were created to examine fall risk. RESULTS: A total of 41% (n=134) of participants had CKD. In addition to slower gait speed, participants with CKD had gait cycle abnormalities including shorter stride length and greater time in the stance and double-support phases. Among people with CKD, lower eGFR was independently associated with the severity of gait cycle abnormalities (per 10 ml/min per 1.73 m2 lower eGFR: 3.6 cm [95% confidence interval (95% CI), 1.4 to 5.8] shorter stride length; 0.7% [95% CI, 0.3 to 1.0] less time in swing phase; 1.1% [95% CI, 0.5 to 1.7] greater time in double-support phase); these abnormalities mediated the association of lower eGFR with slower gait speed. On clinical gait exam, consistent with the quantitative abnormalities, short steps and marked swaying or loss of balance were more common among participants with CKD, yet most had no identifiable gait phenotype. A gait phenotype defined by any of these abnormal signs was associated with higher risk of falls among participants with CKD: compared with people without CKD and without the gait phenotype, the adjusted hazard ratio was 1.72 (95% CI, 1.06 to 2.81) for those with CKD and the phenotype; in comparison, the adjusted hazard ratio was 0.71 (95% CI, 0.40 to 1.25) for people with CKD but without the phenotype (P value for interaction of CKD status and gait phenotype =0.01). CONCLUSIONS: CKD in older adults is associated with quantitative gait abnormalities, which clinically manifest in a gait phenotype that is associated with fall risk.

Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia: A 12-Month Phase 3 Study.

BACKGROUND AND OBJECTIVES: Oral sodium zirconium cyclosilicate (formerly ZS-9) binds and removes potassium via the gastrointestinal tract. Sodium zirconium cyclosilicate-associated restoration and maintenance of normokalemia and adverse events were evaluated in a two-part, open label, phase 3 trial. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In the correction phase, adult outpatients with plasma potassium ≥5.1 mmol/L (i-STAT Point-of-Care) received sodium zirconium cyclosilicate 10 g three times daily for 24-72 hours until normokalemic (potassium =3.5-5.0 mmol/L). Qualifying participants entered the ≤12-month maintenance phase and received sodium zirconium cyclosilicate 5 g once daily titrated to maintain normokalemia without dietary or medication restrictions. Prespecified primary end points were restoration of normal serum potassium values (3.5-5.0 mmol/L) during the correction phase and maintenance of serum potassium ≤5.1 mmol/L during the maintenance phase. Adverse events were assessed throughout. RESULTS: Of 751 participants, 746 (99%) achieved normokalemia during the correction phase (mean serum potassium =4.8 mmol/L; 95% confidence interval, 4.7 to 4.8) and entered the maintenance phase; 466 (63%) participants completed the 12-month trial. Participants were predominantly white, men, and age ≥65 years old; 74% had an eGFR<60 ml/min per 1.73 m2, and 65% used renin-angiotensin-aldosterone system inhibitors. Mean time on sodium zirconium cyclosilicate was 286 days. Mean daily sodium zirconium cyclosilicate dose was 7.2 g (SD=2.6). Over months 3-12, mean serum potassium was 4.7 mmol/L (95% confidence interval, 4.6 to 4.7); mean serum potassium values ≤5.1 and ≤5.5 mmol/L were achieved by 88% and 99% of participants, respectively. Of 483 renin-angiotensin-aldosterone system inhibitor users at baseline, 87% continued or had their dose increased; 11% discontinued. Among 263 renin-angiotensin-aldosterone system inhibitor-naïve participants, 14% initiated renin-angiotensin-aldosterone system inhibitor therapy. Overall, 489 (66%) participants experienced adverse events during the maintenance phase, and 22% experienced a serious adverse event. Of eight (1%) deaths, none were considered related to sodium zirconium cyclosilicate. Nine (1%) and 34 (5%) participants experienced serum potassium <3.0 and 3.0-3.4 mmol/L, respectively. CONCLUSIONS: After achieving normokalemia, individualized once daily sodium zirconium cyclosilicate was associated with maintenance of normokalemia without substantial renin-angiotensin-aldosterone system inhibitor changes for ≤12 months.

[Diagnosis of lung biopsy employing the 2015 WHO criteria and detection of related oncogenic driver mutations].

Objective: The diagnostic criteria of lung biopsy specimens by 2015 WHO lung tumor classification were used to evaluate lung biopsy specimens along with detection of genetic alterations of major tumor driving genes including epidermal growth factor receptor (EGFR). Methods: The clinical data, histological slides, immunohistochemical stains and special stains of 806 lung biopsy specimens at Beijing Hospital from July 2015 to July 2018 were retrospectively analyzed. Diagnosis of lung cancer was reclassified according to the 2015 WHO lung tumor classification and related gene mutation data were analyzed. Results: During a three-year period, the total number of lung cancer diagnosis was 483 cases, including 221 female and 262 male patients with age ranging from 37 to 85 years (median age of 65 years). There were 40 cases(8.28%) of small cell carcinoma,11 cases (2.28%) of large cell neuroendocrine carcinoma, 3 cases (0.62%) of combined neuroendocrine carcinoma, 2 cases(0.41%) of atypical carcinoid, 208 cases (43.06%) of adenocarcinoma, 92 cases(19.05%) of non-small cell carcinoma, favor adenocarcinoma, 66 cases (13.66%) of squamous cell carcinoma, 42 cases(8.70%) of non-small cell carcinoma, favor squamous cell carcinoma, 16 cases(3.31%) of non-small cell carcinoma, not otherwise specified, and 3 cases (0.62%) of non-small cell carcinoma, possible adenosquamous carcinoma. Among 202 cases tested, 107 cases (52.97%) showed EGFR mutations, including 86 of 133 cases (64.66%) of adenocarcinoma and 18 of 52 cases (34.62%) of non-small cell carcinoma, favor adenocarcinoma. Twenty two cases were found to have T790M mutation among 27 patients after EGFR TKI targeted drug therapy. Immunohistochemical staining of ALK (D5F3) was positive in 3 of 354 cases of non-small cell lung cancer, confirmed by EML4-ALK fusion gene fluorescence PCR. ROS1 gene fusion was found in 1 of 38 cases. Splicing mutations in exon 14 of MET gene were seen in one case of non-small cell carcinoma with spindle cell differentiation. Conclusion: The new diagnostic criteria by the 2015 WHO lung tumor classification is better suited for diagnosing lung biopsy specimens and providing accurate treatment guidance and improving the patient outcome.

Pneumatosis intestinalis induced by osimertinib in a patient with lung adenocarcinoma harbouring epidermal growth factor receptor gene mutation with simultaneously detected exon 19 deletion and T790 M point mutation: a case report.

BACKGROUND: Pneumatosis intestinalis is a rare adverse event that occurs in patients with lung cancer, especially those undergoing treatment with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI). Osimertinib is the most recently approved EGFR-TKI, and its usage is increasing in clinical practice for lung cancer patients who have mutations in the EGFR gene. CASE PRESENTATION: A 74-year-old woman with clinical stage IV (T2aN2M1b) lung adenocarcinoma was determined to have EGFR gene mutations, namely a deletion in exon 19 and a point mutation (T790 M) in exon 20. Osimertinib was started as seventh-line therapy. Follow-up computed tomography on the 97th day after osimertinib administration incidentally demonstrated intra-mural air in the transverse colon, as well as intrahepatic portal vein gas. Pneumatosis intestinalis and portal vein gas improved by fasting and temporary interruption of osimertinib. Osimertinib was then restarted and continued without recurrence of pneumatosis intestinalis. Overall, following progression-free survival of 12.2 months, with an overall duration of administration of 19.4 months (581 days), osimertinib was continued during beyond-progressive disease status, until a few days before the patient died of lung cancer. CONCLUSIONS: Pneumatosis intestinalis should be noted as an important adverse event that can occur with administration of osimertinib; thus far, such an event has never been reported. This was a valuable case in which osimertinib was successfully restarted after complete recovery from pneumatosis intestinalis, such that further extended administration of osimertinib was achieved.

[Prognostic implication of alterations in epidermal growth factor receptor and MGMT in glioblastoma].

Objective: To investigate the prognostic impact of alterations of epidermal growth factor receptor(EGFR) and MGMT in glioblastoma. Methods: The retrospective study included 161 supratentorial glioblastomas diagnosed in the Department of Pathology, Xuanwu Hospital, Capital Medical University from 2009 to 2015. EGFR and EGFRvⅢ protein expression was detected by immunohistochemistry; EGFR amplification was detected by fluorescence in situ hybridization; MGMT promoter methylation was detected by pyrosequencing. The change of molecular genetics EGFR and MGMT and outcome were assessed statistically. Results: There were 161 patients, including 85 (52.8%) males and 76 (47.2%) females. The mean age was 53 years, and the median overall survival was 13 months. The integrated classification of glioblastoma included 16 IDH-mutant, 134 wild type, and 11 NOS. The rate of overexpression of EGFR protein was 32.9%(53/161), and that of EGFR amplification was 37.5%(18/48). There was high concordance between immunohistochemistry and FISH(85.4%, Kappa=0.475, P<0.01) and between the level of EGFR protein and EGFR amplification (P<0.01). Twelve cases showed EGFRvⅢ expression, and all also showed EGFR protein overexpression; 149 cases were EGFRv Ⅲ wild type, and EGFR protein overexpression was seen in 27.5%(41/149) of cases. There was no correlation between EGFR and EGFRv Ⅲ expression. Of all cases, 70.2%(106/151) showed MGMT promoter methylation by pyrosequencing. The changes of molecular genetics of EGFR and MGMT were not related. EGFR amplification and protein overexpression had no significant relationship with prognosis. Patients with EGFRv Ⅲ-mutant had shorter survival time than the EGFRv Ⅲ-wild type(P=0.014); patients with MGMT promoter methylation had better prognosis than without (PFS:P=0.002,OS:P=0.006),and MGMT promoter methylation was an independent predictor for overall survival (HR=0.269, 95%CI 0.124-0.583, P=0.001). Conclusions: EGFR protein expression by immunohistochemistry correlates with the status of EGFR amplification. Patients with EGFRv Ⅲ-mutant tumors have poorer prognosis than that with EGFRv Ⅲ-wild type tumors. MGMT promoter methylation is closely associated with prognosis and an independent predictor for overall survival.

Safety of trastuzumab emtansine (T-DM1) in patients with HER2-positive advanced breast cancer: Primary results from the KAMILLA study cohort 1.

BACKGROUND: Many patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC) are candidates for trastuzumab emtansine (T-DM1) treatment sometime in their disease history. KAMILLA evaluated safety of T-DM1 in patients with previously treated HER2-positive locally advanced or metastatic BC (advanced BC). METHODS: KAMILLA (NCT01702571) is a single-arm, open-label, international, phase IIIb safety study of patients with HER2-positive advanced BC with progression after prior treatment with chemotherapy and a HER2-directed agent for MBC or within 6 months of completing adjuvant therapy. Patients received T-DM1 (3.6 mg/kg every 3 weeks) until unacceptable toxicity, withdrawal or disease progression. RESULTS: Among 2002 treated patients, median age was 55 years (range, 26-88; 373 [18.6%] aged ≥65 years), 1321 (66.0%) received ≥2 prior metastatic treatment lines and 398 (19.9%) had baseline central nervous system metastases. Adverse events (AEs) and serious AEs occurred in 1862 (93.0%) and 427 (21.3%) patients, respectively. Grade ≥3 AEs occurred in 751 (37.5%) patients; the three most common (individual Medical Dictionary for Regulatory Activity terms) were anaemia (3.0%), thrombocytopaenia (2.7%) and fatigue (2.5%). Median progression-free survival (PFS) was 6.9 months (95% confidence interval [CI], 6.0-7.6). Median overall survival (OS) was 27.2 months (95% CI, 25.5-28.7). With increasing lines of prior advanced therapy (0-1 versus 4+), median PFS and OS decreased numerically from 8.3 to 5.6 months and from 31.3 to 22.5 months, respectively. CONCLUSIONS: KAMILLA is the largest cohort of T-DM1-treated patients studied to date. Results are consistent with prior randomised studies, thereby supporting T-DM1 as safe, tolerable and efficacious treatment for patients with previously treated HER2-positive advanced BC.

Factors that Predict Clinical Benefit of EGFR TKI Therapy in Patients with EGFR Wild-Type Lung Adenocarcinoma.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancers have emerged as key predictive biomarkers in EGFR tyrosine kinase inhibitor (TKI) treatment. However, a few patients with wild-type EGFR also respond to EGFR TKIs. This study investigated the factors predicting successful EGFR TKI treatment in lung adenocarcinoma patients with wild-type EGFR. METHODS: We examined 66 patients diagnosed with lung adenocarcinoma carrying wide-type EGFR who were treated with EGFR TKIs. The EGFR gene copy number was assessed by silver in situ hybridization (SISH). We evaluated the clinical factors and EGFR gene copy numbers that are associated with a favorable clinical response to EGFR TKIs. RESULTS: The objective response rate was 12.1%, while the disease control rate was 40.9%. EGFR SISH analysis was feasible in 23 cases. Twelve patients tested EGFR SISH-positive, and 11 were EGFR SISH-negative, with no significant difference in tumor response and survival between EGFR SISH-positive and -negative patients. The overall median progression-free survival (PFS) and overall survival (OS) of 66 patients were 2.1 months and 9.7 months, respectively. Female sex and Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0-1 were independent predictors of PFS. ECOG PS 0-1 and a low tumor burden of extrathoracic metastasis were independent predictors of good OS. CONCLUSION: Factors such as good PS, female sex, and low tumor burden may predict favorable outcomes following EGFR TKI therapy in patients with EGFR wild-type lung adenocarcinoma. However, EGFR gene copy number was not predictive of survival.

[Comparison of epidermal growth factor receptor (EGFR) gene T790M mutation by droplet digital PCR and Super-ARMS PCR in plasma ctDNA samples of non-small cell lung cancer patients with the resistance to EGFR-tyrosine kinase inhibitor].

Objective: To compare droplet digital PCR (ddPCR) and Super-amplification refractory mutation system (ARMS) in the detection of T790M mutation of epidermal growth factor receptor (EGFR) in the plasma of non-small cell lung cancer patients who had developed resistance to EGFR tyrosine kinase inhibitor (TKI) , and to investigate the clinical application of ddPCR. Methods: Plasma samples were collected from non-small cell lung cancer patients who had acquired EGFR-TKI resistance at Shanghai Pulmonary Hospital, Tongji University, from May 2017 to November 2017. Extracted ctDNA was analyzed by ddPCR and Super-ARMS to evaluate the T790M mutation status of EGFR gene. Results: A total of 37 patients with activating EGFR mutation that acquired resistance to EGFR-TKI were selected in the study, including 17 male and 20 female with a median age of 64 years (range 40-83 years). Before TKI treatment, all the patients harbored EGFR inhibitor sensitive mutations but without T790M mutation. After acquiring resistance to EGFR-TKI treatment, the T790M mutation rate detectable by ddPCR was 45.9% (17/37). In contrast, the mutation rate of T790M detectable by Super-ARMS was 35.1% (13/37, P<0.05). For the 13 positive cases detected by Super-ARMS (ΔCt<8), they were all positive by ddPCR assay; Among the 10 negative cases detected by Super-ARMS (ΔCt≥8), there were 3 cases positive by ddPCR assay. For patients without ΔCt by Super-ARMS assay, there was one weak positive case detectable by ddPCR assay. Among 17 EGFR T790M positive patients, 9 received EGFR inhibitor Osimertinib treatment, and 7 of them had good therapeutic response after the treatment. Conclusions: While a significant correlation between the two methods is shown. ddPCR is more sensitive than Super-ARMS in the detection of EGFR T790M mutation, indicating that it is a better method in guiding target drug therapy of non-small cell lung cancer patients after acquiring the resistance to EGFR-TKI.

[Detection of epidermal growth factor receptor mutations using bronchial washing fluid in lung cancer patients with negative results by rapid on-site evaluation].

Objective: To evaluate the clinical application of bronchial washing fluid (BWF) in the detection of epidermal growth factor receptor (EGFR) gene mutation in lung cancer patients during diagnostic bronchoscopic procedure. Methods: Patients with suspected lung cancer lesions but failed to be identified as malignancy by rapid on-site cytologic evaluation (ROSE) were enrolled. Performed blocker PCR for EGFR mutation detection using the supernatant and cell pellet of BWF samples and compared the detective results to the EGFR mutation status detected using histologic tumor samples. Results: A total of 85 BWF and paired histological samples were collected at Fudan University Affiliated Zhongshan Hospital from October 2016 to June 2017. There were 46 male and 39 female, with a mean age of 61 years (range 30-87 years). Thirty-one patients had benign diseases and 54 patients had primary lung cancer. Among these 54 lung cancer patients, the diagnoses were made basing on bronchoscopic biopsy samples in 31 patients. The detection rate of EGFR gene mutation in BWF samples was 100.0% concordant with that using histological samples.Another 23 cases whose bronchoscopic biopsy failed to establish malignant diagnoses were further identified by other sampling methods including surgical resection, lung biopsy, etc. A total of 15 patients were identified as EGFR mutated type by pathologic detection or clinically effect assessment, and BWF could detect 11 of them, accounting for 11/15 of all cases. Overall, BWF had achieved an overall accuracy of 95.3% (81/85) comparing to paired tumor histologic samples. Conclusions: BWF is an effective complementary specimen to bronchoscopic biopsy samples in EGFR gene mutation detection in patients with suspected lung cancer lesion and negative biopsy results evaluated by ROSE during bronchoscopy.

[The concomitant gene alterations impact the therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors in advanced non-small cell lung cancer patients with epidermal growth factor receptor sensitive mutation].

Objective: To investigate if concomitant gene alterations impact the therapeutic efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) sensitive mutation. Methods: From November 2016 to December 2017, 51 patients (19 males and 32 females, age 37-85 years) with histology or cytology diagnosed,locally advanced or metastatic NSCLC from Zhongshan Hospital Fudan University were prospectively recruited in the study. All patients harboring EGFR sensitive mutation detected by a 123 lung cancer specific gene panel of next-generation sequencing(NGS) analysis were under treatment of EGFR-TKIs. Multi-factors analysis of the correlation between EGFR-TKIs efficacy and concomitant gene alterations were analyzed by multivariate Cox regression model. Results: 82% of the NSCLC patients with EGFR mutation presented concomitant gene alterations with an average number of 2.1. Patients not harboring concomitant gene alterations had a longer median progression free survival (mPFS: not reached vs 8.8 m, P=0.008). Those who had less than 2 concomitant genes had a higher objective response rate[ORR: 52% (17/33) vs 33% (6/18) , P=0.251]and better mPFS (13.8 vs 8.0 m, P=0.003). The top 3 concomitant gene alterations were TP53 gene mutation(55%, 28/51), EGFR gene amplification (26%, 13/51) and RB1 gene mutation (18%,9/51) respectively. The mPFS of EGFR-TKI treatment in patients with either one of these 3 concomitant genes was 8.0, 8.0, and 6.0 months respectively, significantly shorter than those without one of the 3 gene alterations (13.8, 13.1, and 10.8 months respectively). Multivariate Cox regression revealed that concomitant gene abnormalities (P=0.036) and accompanied by RB1 gene mutation (P=0.025) were independent risk factors for the survival benefit of EGFR-TKI in the treatment of advanced NSCLC with EGFR-sensitive mutation. Conclusions: The efficacy of EGFR-TKI decreased significantly in advanced NSCLC with EGFR-sensitive mutation who had concomitant gene abnormalities, especially accompanied by more than 2 of the 3 gene alterations (TP53 gene mutation, EGFR gene amplification or RB1 gene mutation). This study suggested that the concomitant gene alterations should be an important issue for consideration when applying a personalized combination therapy for advanced NSCLC harboring EGFR sensitive mutation.