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Drug resistance severely limits the clinical therapeutic value of molecularly targeted drugs. Growth factors gain a tremendous amount of focus due to the ability to promote drug resistance in non-small-cell lung cancer (NSCLC). However, whether tumor cells themselves can mediate drug resistance by secreting growth factors needs further clarification. Here, we first screened growth factors to identify autocrine epidermal growth factor (EGF) and transforming growth factor alpha (TGF-α) that caused primary resistance to the ALK inhibitor TAE684 in H3122 cells and the c-MET-specific inhibitor SGX-523 in EBC-1 cells. Next, we discovered increased autocrine production of EGF and TGF-α in established acquired resistant H3122/TR and EBC-1/SR cells. Importantly, overexpression of EGF and TGF-α in two NSCLC cell lines produced resistance to TAE684 and SGX-523. Clinically, NSCLC patients with high expression of EGF and TGF-α developed primary resistance to crizotinib. Mechanistically, autocrine EGF and TGF-α activated EGFR signaling pathways to survive targeted c-Met and ALK inhibition. Furthermore, combined treatment with gefitinib circumvented EGF- and TGF-α-mediated primary and acquired resistance to TAE684/SGX-523. Taken together, these results suggested increased autocrine EGF and TGF-α conferred primary and acquired resistance to ALK/c-Met kinase inhibitors in NSCLC. [ABSTRACT FROM AUTHOR]

Simple Summary: Resistance to antiangiogenic therapy represents a challenge in the therapeutic approach for hepatocellular carcinoma (HCC). The advent of immune checkpoint inhibitors (ICIs) seems to be a solution to this issue; however, other gaps have emerged since they have only been shown to provide benefit in approximately 20% of patients. Combination strategies have introduced in clinical development to overcome this issue. This review deals with the resistance to antiangiogenic drugs by focusing on two protagonists, the tumor microenvironment and vascular normalization, to offer possible overcoming strategies. Antiangiogenic drugs were the only mainstay of advanced hepatocellular carcinoma (HCC) treatment from 2007 to 2017. However, primary or secondary resistance hampered their efficacy. Primary resistance could be due to different molecular and/or genetic characteristics of HCC and their knowledge would clarify the optimal treatment approach in each patient. Several molecular mechanisms responsible for secondary resistance have been discovered over the last few years; they represent potential targets for new specific drugs. In this light, the advent of checkpoint inhibitors (ICIs) has been a new opportunity; however, their use has highlighted other issues: the vascular normalization compared to a vessel pruning to promote the delivery of an active cancer immunotherapy and the development of resistance to immunotherapy which leads to a better selection of patients as candidates for ICIs. Nevertheless, the combination of antiangiogenic therapy plus ICIs represents an intriguing approach with high potential to improve the survival of these patients. Waiting for results from ongoing clinical trials, this review depicts the current knowledge about the resistance to antiangiogenic drugs in HCC. It could also provide updated information to clinicians focusing on the most effective combinations or sequential approaches in this regard, based on molecular mechanisms. [ABSTRACT FROM AUTHOR]

Background: Alpha-fetoprotein (AFP) is the only biomarker with proven prognostic value in advanced hepatocellular carcinoma. Preliminary data indicate crosstalk between AFP and VEGF signaling. Methods: The authors looked at 69 patients with advanced hepatocellular carcinoma who were previously tested for VEGFR2 expression, had available baseline AFP serum concentrations and were treated with sorafenib within clinical trials. Results: Shorter progression-free survival and overall survival were associated with increased AFP level and elevated VEGFR2 staining. At multivariate analysis of AFP level was the only independent prognostic factor for progression-free survival and overall survival. Conclusion: The authors' study confirms the adverse prognostic role of elevated baseline AFP and also suggests a possible role of AFP in primary resistance to sorafenib therapy. [ABSTRACT FROM AUTHOR]

No data concerning antiretroviral drug's (ARV) primary resistance mutation rates in Chad are available. We retrospectively analysed frozen-stored dried blood spot samples that were collected from 48 Chadian human immunodeficiency virus (HIV)-1 seropositive patients naïve of ARV. HIV-1 protease and reverse transcriptase genes were successfully sequenced for 24 (60.0%) of the 40 patients displaying a viral load > 1000 copies/ml. Seven (29.2%) displayed mutations conferring resistance against one or more classes of ARV. We evidenced high levels of primary ARV resistance mutations in Chad, but lower than those observed in patients with failure to first-line ARV. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) mutation‐positive non‐small cell lung cancer (NSCLC) patients benefit from EGFR tyrosine kinase inhibitors (TKIs), while some patients demonstrate a resistance to EGFR‐TKIs. In the case reported here, the NSCLC patient harboring an EGFR‐sensitive mutation and YES1 amplification was treated with afatinib as first‐line therapy, but was found to have progressive disease four weeks later. During subsequent chemotherapy, this patient's disease progressed rapidly. Mechanisms of primary resistance to EGFR‐TKIs remain unclear. This case suggested that YES1 amplification might be associated with primary resistance to EGFR‐TKIs and YES1 amplification might be a negative predictor of EGFR‐TKI treatment in NSCLC patients harboring EGFR sensitive mutations. [ABSTRACT FROM AUTHOR]

In Fortaleza, the capital of Ceara State, Brazil, the detection rate of tuberculosis (TB) in 2018 was 65.5/100,000 inhabitants with a cure rate of 59.1%, which is higher than the country average. This study investigated the risk factors associated with drug-resistant tuberculosis (DR-TB) and identified the drug-resistance phenotype and resistance-conferring mutations. The geographic distribution of DR-TB in Fortaleza, Brazil, was also determined. From March 2017 to February 2018, 41 DR-TB isolates and 69 drug-susceptible pulmonary TB isolates were obtained from patients seen at a referral hospital in Fortaleza, Brazil. Samples were subjected to phenotypic and genetic analysis of resistance; the spatial distribution of the participants was also analyzed. Primary resistance was high (50.9%) among participants. The following risk factors for DR were identified: being female (p = 0.03), having diabetes (p < 0.01), history of previous TB disease (p < 0.01), and the number of intra-domiciliary contacts (p < 0.01). Analysis by multiplex allele-specific polymerase chain reaction detected mutations in the genes katG (65.8%), rpoB (43.9%), inhA promoter (14.6%), and gyrA (9.8%). Sequencing identified mutations in the the genes katG (75.6%), inhA promoter (19.5%), rpoB (85.4%), and gyrA (100%). There was no mutation in the rrs gene. Spatial analysis showed DR-TB isolates distributed in areas of low socioeconomic status in the city of Fortaleza. Our results emphasized the importance of detecting resistance to TB drugs. The resistance found in the gene gyrA is of concern due to the high number of pre-extensive DR-TB cases in Fortaleza. [ABSTRACT FROM AUTHOR]

EGFR‐activating mutations have been recognized as the most important predictor of response to EGFR‐tyrosine kinase inhibitors (TKIs); however, 20–30% of patients harboring EGFR‐activating mutations show poor responses. The mechanisms of such EGFR‐TKI primary resistance are still poorly understood. In our case, a non‐small cell lung cancer patient developed intrinsic EGFR‐TKI resistance and was then confirmed to simultaneously harbor an L858R mutation and ROS1 rearrangement. Salvage chemotherapy plus Endostar showed enduring therapeutic effects, achieving a disease‐free survival period of 24 months and overall survival of 30 months. This suggests that co‐activation of different oncogenic signal pathways might be a potential mechanism of EGFR‐TKI primary resistance. Chemotherapy combined with anti‐angiogenesis should be considered an important salvage strategy. Further studies are warranted to verify these findings and explore the underlying mechanisms involved. [ABSTRACT FROM AUTHOR]

Objective: In this study, we aimed to evaluate the data of 1753 patients diagnosed with tuberculosis (TB) in Süreyyapaşa Chest Diseases and Chest Surgery Training and Research Hospital for one year. Method: The study was planned as a single center retrospective. Patients diagnosed with TB were included in the study. Patient data were obtained from TB surveillance forms, bacteriology laboratory drug resistance database and octomed patient follow-up program. Results: N=1146 (65.4%) of the cases were male and n=607 (34.6%) were female. The male/female ratio was 1.8 and the highest cases were observed in the 15-24 age group in both sexes. N=1422 (81%) of all cases were pulmonary TB (PTB) (76.5% new case PTB), n=331 (18.9%) were extra pulmonary tuberculosis (EPTB) (pleural TB 86.1%, TB lymphadenitis 10.6%). Smear positivity rate was 78.7% only in patients with PTB. It was found that culture contributed 8.7% to the diagnosis. In our study, primary and secondary drug resistance was most frequently detected against H; respectively (20.2%, 34.7%). Total R primary and secondary resistance were (7.6%, 22.4%) respectively. Primary and secondary resistance for HR were (3.2%, 7%) respectively. Primary resistance to single drug was 15.4%, primary resistance to double drug was 6.0%, primary resistance to three drugs was 1.3%, and primary resistance to four drugs was 2.7%. Secondary resistance to single drug was 15.9%, secondary resistance to double drug was 10.9%, secondary resistance to three drugs was 4.3%, and secondary resistance to four was 9.9%. Primary and secondary resistance to multi-drug were found respectively (7.2%, 21.2%). 70.5% of the patients who underwent resistance test were sensitive to all drugs. Conclusions: This study is one of the largest series in a single center in our country. Smear positivity rates in patients with PTB were found to be higher than the data of our country. Drug resistance rates were found to be high due to referral of multidrug-resistant cases to our center. [ABSTRACT FROM AUTHOR]

Highlights • We conducted tumor mutation profiling of 69 EGFRm+ lung adenocarcinomas. • High concordance of activating mutation status between tumor tissue and cfDNA. • We identified mechanisms that potentially confer primary resistance to EGFR-TKIs. • We reported signaling pathways enriched in patients with primary resistance. Abstract Introduction Increasing evidence leads to a ratiocination that genetic heterogeneity of the lung adenocarcinoma with EGFR mutations may impact clinical responses and outcomes to EGFR tyrosine kinase inhibitor (TKI) treatments. Methods We performed genetic profiling of pre-treatment samples of 69 lung adenocarcinoma patients, including tumor FFPE and cell-free DNA (cfDNA), targeting 416 cancer-related genes using next generation sequencing. We analyzed mutation concordance across sample types and investigated potential mechanisms that confer primary resistance to EGFR-TKIs in patients with short progression-free survival (PFS) versus those with long PFS. Results We detected a total of 200 actionable genetic alterations (mean: 2.9 variants/patient, range: 1–7 variants) in tumor FFPE and 140 actionable genetic alterations (mean: 2.0 variants/patient, range: 0–5 variants) in matched cfDNA, respectively. All patients had EGFR TKI-sensitizing mutations, including EGFR Ex19del, L858R, G719S/C, and L861Q. Concurrent TP53 mutations were most commonly observed in 72.5% of patients, followed by EGFR amplification (20.3%), RB1 (10.1%), PIK3CA (7.2%), and MYC (5.8%). For EGFR activating mutations, the concordance rate was 88.2% between cfDNA and FFPE samples. Furthermore, we identified genes that potentially confer primary resistance to EGFR-TKIs including CDC73, SMAD4, RB1 and PIK3CA. We also report signaling pathways enriched in patients with TKI primary resistance. Conclusions We note the genetic complexity and heterogeneity of EGFR -mutated lung adenocarcinoma and underscore that mutation status is highly concordant between tumor FFPE and cfDNA samples. This study also highlights the alterations that potentially confer primary resistance to EGFR TKI treatments in patients who demonstrated short PFS. [ABSTRACT FROM AUTHOR]

Abstract: Background: Portugal presents both a high prevalence of Helicobacter pylori (Hp) infection and a high prevalence of antibiotic resistance. However, conclusive data on its magnitude are lacking. We aimed at summarizing the existing data. Materials and Methods: A systematic review was conducted after searching in two databases (PubMed and SciELO). Meta‐analysis was performed, and comparison of resistance rates between children and adults and by type of resistance (primary and secondary) was made. Results: Eight cross‐sectional studies assessing Hp resistance to antibiotics were included. Overall resistance rates were as follows: clarithromycin (CLA) 42% (95% CI: 30‐54), metronidazole (MTZ) 25% (95% CI: 15‐38), ciprofloxacin (CIP) 9% (95% CI: 3‐18), levofloxacin (LVX) 18% (95% CI: 2‐42), tetracycline (TTC) 0.2% (95% CI: 0‐1), and amoxicillin (AMX) 0.1% (95% CI: 0‐0.2). Multidrug resistance was also an important problem, with the following global resistance rates: CLA plus MTZ of 10% (adults 20% (95% CI: 15‐26) vs children 6% (95% CI: 4‐9)) and CLA plus CIP of 2% (primary resistance in children's group). High secondary resistance rates were found for all antibiotics. Resistance was higher among adults for all antibiotics, except CLA that had high resistance levels both among adults and children (42% 95% CI: 14‐71 and 40% 95% CI: 33‐47). Conclusions: Hp resistance to the most widely used antibiotics is high in Portugal. Accordingly, our results suggest that the best therapeutic strategy for Hp in Portugal may be quadruple therapy with bismuth for adults and triple therapy including AMX plus MTZ or bismuth‐based therapy for children. [ABSTRACT FROM AUTHOR]

HIV primary resistance, drug resistance in treatment-naïve patients, is an emerging public health issue. The prevalence of HIV primary resistance mutations down to the level of 1% minor variants was investigated using ultradeep pyrosequencing (UDPS) in HIV-positive Korean blood donors and in treatment naïve chronic patients for the comparison. The entire pol region was sequenced from 25 HIV-positive blood donors, and 18 treatment-naïve chronic HIV patients. UDPS was successful in 19 blood donors and 18 chronic patients. In total, 1,011,338 sequence reads were aligned, and 28,093 sequence reads were aligned on average per sample. The prevalence of HIV primary resistance mutations in the HIV-positive blood donors and chronic HIV patients were 63.2% and 44.4% according to UDPS, respectively. Protease inhibitor (PI) drugs demonstrated different patterns in HIV-positive blood donors and chronic HIV patients, whereas non-nucleoside reverse transcriptase inhibitors (NNRTI), nucleoside reverse transcriptase inhibitors (NRTI), and integrase inhibitor (INI) drugs showed similar patterns between the two groups. Higher level of primary resistance prevalence was observed mainly because UDPS method could detect mutations in minor variants with 1–10% frequency. The higher resistance prevalence was observed in HIV-positive blood donors than in chronic patients. Considering that treatments for HIV-infected patients were recently amended to start at an earlier stage, information about degree of drug resistance to each drug between the two groups would help to establish future policies, design additional clinical trials, assess HIV patient care in Korea. [ABSTRACT FROM AUTHOR]

Our ability to detect and directly target the oncogenic alterations responsible for tumor proliferation has contributed significantly to the management of lung cancer in the last decade. The therapeutic efficacy of molecularly targeted therapy is, however, mainly limited to patients harboring certain genetic mutations and is generally short-lived. Herein, we review primary and secondary drug resistance using the most well-studied of the molecularly targeted agents, the tyrosine kinase inhibitors targeting the epidermal growth factor (EGF) receptor, and the anaplastic lymphoma kinase (ALK) rearrangement, the current limitations of targeted therapies and their consequences on the management of patients with lung cancer. [ABSTRACT FROM AUTHOR]

Purpose: Subclones bearing the epidermal growth factor receptor (EGFR) T790M mutation concomitant with deletional mutation in exon 19 (Del19) or a point mutation in exon 21 (L858R) have been reported in non-small cell lung cancer patients before any EGFR tyrosine-kinase inhibitor (TKI) treatment. The effect of pretreatment T790M mutation on the survival of patients with both mutations treated with EGFR TKI is still being debated. Methods: A meta-analysis was undertaken to pool eligible trials to better elucidate whether pretreatment T790M mutation predicts a poorer outcome of EGFR TKI treatment. Hazard ratios and their 95% confidence intervals for progression-free survival (PFS) were extracted and used under the random-effects model. Results: A total of 246 patients with activating EGFR mutation such as Del19 or L858R participated in four selected trials from 350 articles. The overall incidence of patients with pretreatment T790M mutation was 43.10% (106/246), ranging from 34.88% to 80.00% in the individual trials. The combined hazard ratio for PFS in all four eligible studies was 2.602 (95% confidence interval 1.011-6.695; P=0.047), indicating a shorter PFS in patients who had the T790M mutation before receiving EGFR TKI treatment. Heterogeneity testing indicated significant heterogeneity but the absence of publication bias. Conclusion: The meta-analysis reported here found that pretreatment T790M mutation had a negative impact on the PFS of non-small cell lung cancer patients with a Del19 or L858R EGFR mutation who received EGFR TKI treatment [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer (nsclc) constitutes about 85% of all lung cancers. Approximately 50% of patients diagnosed with nsclc present with advanced disease (stage iii or iv) that is not amenable to curative treatment. The number of patients with stage iiib or iv disease who are alive at 1 year after diagnosis has increased from 10% in the untreated population in the early 1980s to 50% in patients with a good performance status receiving treatment today. However, those statistics remain dismal, and the two dominant reasons are the large number of patients diagnosed with advanced-stage disease and the observed primary or secondary resistance to current therapies. The present article addresses the question of drug resistance in lung cancer, focusing on subjects that are currently topical and under intense scrutiny. [ABSTRACT FROM AUTHOR]

Summary: Background: Monitoring of primary drug resistance is of interest for long-term evaluation of the efficacy of a national tuberculosis program. The objective was to describe changes over time in primary drug resistance among new tuberculosis patients. Methods: Stratified analysis by birth cohorts, region of birth, HIV-coinfection of data from 14,610 culture-positive new tuberculosis patients diagnosed by a network of university hospitals between 1995 and 2008. Results: Half of the patients were foreign-born, and 9% HIV-coinfected. For foreign-born and French-born patients, there was an upward trend in resistance rates to streptomycin, isoniazid, and rifampicin from the oldest to the youngest cohorts. For a same age at tuberculosis diagnosis, the risk of isoniazid resistance was higher in younger cohorts, revealing a cohort effect. Among French-born patients, the only factor independently associated with primary resistance to streptomycin, or isoniazid was birth after 1950, and particularly after 1980. Risk of streptomycin resistance increased in youngest cohorts among European-born patients. HIV-coinfection was associated to rifampicin resistance among foreign-born and French-born patients, Conclusions: Theses results indicate that among French-born patients, isoniazid-resistant strains are currently circulating in younger patients that are more likely to be infected recently, and that among foreign-born patients, HIV-coinfection is a strong risk factor for primary resistance. [ABSTRACT FROM AUTHOR]

Background As access to antiretroviral drugs increases in developing countries, it will become increasingly important to monitor the emergence of resistance and to define the molecular pathways involved to identify optimal therapeutic regimens. Methods We performed genotypic resistance testing on plasma obtained from 101 HIV-infected treatment-naïve individuals from Mali. Genotyping was carried out using the Virco protocols and HXB2 was used as the reference strain. Results CRF02_AG was the most common subtype, present in 71.3% of our patient population. Other subtypes included B, C, G, CRF06_CPX, CRF09_CPX, CRF01_AE, A2/CRF16_A2D, A1 and CRF13_CPX. A total of 9.9% [95% confidence interval (CI) 6.9–12.9%] of patients had at least one resistance mutation. The prevalences of mutations conferring resistance to nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs) were 5% (95% CI 0.7–9.2%), 6% (95% CI 1.3–10.6%) and 0%, respectively. The most frequent mutations were T215A/Y for NRTIs and K103N/T for NNRTIs. One patient harboured three NRTI resistance mutations and one NNRTI mutation. This is the first reported case of multi-drug-resistant viral transmission in Mali. Polymorphisms at protease codons 10I/V and 33F potentially associated with resistance were observed in 18.8% and 1% of patients, respectively. Several polymorphisms in the C-terminal domain of reverse transcriptase were observed: A371V (in 63.4% of patients), G335D (76.2%), E399D (10.9%) and G333E (1%). Conclusion Primary resistance was seen in 9.9% of subjects, which is higher than previously reported in Mali. Taking into consideration other polymorphisms in protease such as L10I/V and 33F, primary resistance could reach 28.7% (95% CI 19.9–37.5%). Our study reflects the need to monitor the evolution of resistance on a regular basis and trends of transmitted resistance. [ABSTRACT FROM AUTHOR]

Objectives The aim of the study was to elucidate primary drug resistance and transmission of HIV-1 in acute and recent drug-naïve seroconverters in Singapore. Methods Acute and recent HIV-1 seroconverters were enrolled in the study. The HIV-1 polymerase ( pol) gene was sequenced and used for genotypic drug resistance analysis and phylogenetic analysis. HIV-1 transmission clusters were inferred from phylogenetic clustering analysis. Results Of the 60 subjects analysed, 95% were men, and 73.3% were men who have sex with men (MSM). Six HIV-1 subtypes were identified, including CRF01_AE (46.7%), subtypes B (30%), B′ (15%) and G (1.7%), CRF33_01B (1.7%) and CRF34_01B (5%). Primary genotypic resistance was detected in only one (1.7%) subtype B variant. Thirty-one patients (51.7%) were phylogenetically clustered, of whom 90% reported having local risk exposure, compared with 59% of the patients who were not phylogenetically clustered [odds ratio (OR) 6.35, 95% confidence interval (CI) 1.65–23.95]. MSM (OR 5.63, 95% CI 1.17–27.15), high viral load (OR 4.28, 95% CI 1.37–13.36) and young age (OR 0.92, 95% CI 0.85–0.99) were independently associated with clustered individuals. Conclusions In Singapore, HIV-1 primary resistance is insignificant; individuals with seroconversion account for about half of onward transmission among recently infected seroconverters. MSM, high viral load and young age are factors that facilitate transmission. Early detection of these individuals is of paramount importance for the prevention of HIV-1 transmission. [ABSTRACT FROM AUTHOR]

Tuberculosis is a global human health threat, especially in developing countries. The present study aimed to describe the genetic diversity of Mycobacterium tuberculosis and to measure the transmission rates of primary and acquired resistance. A total of 755 M. tuberculosis isolates from a cohort study of patients with culture-confirmed pulmonary tuberculosis in Orizaba, Veracruz, performed between 1995 and 2010 were genotyped by the 24-locus mycobacterial interspersed repetitive unit–variable number of tandem repeats (MIRU-VNTR) method. Drug susceptibility was determined. Logistic regression models were constructed to identify the variables associated with resistance and clusters. The recent transmission index (RTI), the Hunter-Gaston discrimination index (HGDI) for the MIRU-VNTR test and allelic diversity (h) were calculated. The Haarlem and LAM lineages were the most common in the population. A total of 519 isolates were grouped into 128 clusters. The overall drug resistance rate was 19%, isoniazid monoresistance (10%) was the most common, and 3.4% of the isolates were multidrug resistant. Among the 116 isolates resistant to at least one drug, the primary and acquired resistance rates were 81.9% and 18.1%, respectively. Primary resistance was associated with belonging to a cluster (aOR 4.05, 95% CI 1.5–11.2, p = 0.007). Previous treatment history (aOR 9.05, 95% CI 3.6–22.5, p < 0.001) and LAM lineage (aOR 4.25, 95% CI 1.4–12.7, p = 0.010) were associated with multidrug-resistant tuberculosis (MDR-TB). The RTI was 51.7%, and the 24-locus MIRU-VNTR HGDI was 0.98. The alleles with the greatest diversity were 4056-QUB26 (h = 0.84), 2163b-QUB11b (h = 0.79), and 424-Mtub04 (h = 0.72). Primary resistance transmission, high LAM lineage prevalence and its association with MDR-TB represent public health problems. The implementation of molecular tools is needed to improve the existing control surveillance tuberculosis program. • Haarlem and LAM were the most prevalent M. tuberculosis lineages in Southern Mexico. • Recent Transmission Index (RTI) was high (51.7%). • Population was affected by high transmission rates of primary resistance. • LAM lineage isolates and patients previously treated were associated with MDR-TB. [ABSTRACT FROM AUTHOR]

Approximately 20–30% of patients with metastatic renal cell carcinoma (mRCC) in first-line treatment with tyrosine kinase inhibitors (TKIs) do not respond due to primary resistance to this drug. At present, suitable robust biomarkers for prediction of a response are not available. Therefore, the aim of this study was to evaluate a panel of microRNAs (miRNAs) in nephrectomy specimens for use as predictive biomarkers for TKI resistance. Archived formalin-fixed, paraffin embedded nephrectomy samples from 60 mRCC patients treated with first-line TKIs (sunitinib, n = 51; pazopanib, n = 6; sorafenib, n = 3) were categorized into responders and non-responders. Using the standard Response Evaluation Criteria in Solid Tumors, patients with progressive disease within 3 months after the start of treatment with TKI were considered as non-responders and those patients with stable disease and complete or partial response under the TKI treatment for at least 6 months as responders. Based on a miRNA microarray expression profile in the two stratified groups of patients, seven differentially expressed miRNAs were validated using droplet digital reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) assays in the two groups. Receiver operating characteristic curve analysis and binary logistic regression of response prediction were performed. MiR-9-5p and miR-489-3p were able to discriminate between the two groups. MiR-9-5p, as the most significant miRNA, improved the correct prediction of primary resistance against TKIs in comparison to that of conventional clinicopathological variables. The results of the decision curve analyses, Kaplan-Meier analyses and Cox regression analyses confirmed the potential of miR-9-5p in the prediction of response to TKIs and the prediction of progression-free survival after the initiation of TKI treatment. [ABSTRACT FROM AUTHOR]