An association between Dasatinib, elevated left atrial pressure and pleural effusion.

BACKGROUND: Tyrosine kinase inhibitors (TKI), such as Dasatinib, are effective in the treatment of chronic myeloid leukemia (CML) but associated with development of pleural effusions (PE). The relationship between haemodynamic parameters identified on transthoracic echocardiogram (TTE) such as elevated estimated left atrial pressure (LAP), and PE development is unknown. This study aims to describe associations between Dasatinib, elevated LAP and PE. METHODS: This was a retrospective study of 71 CML patients who underwent TTE during treatment with various TKIs. Descriptive analysis was performed to identify associations between TKI use, PE and elevated LAP on TTE. Multivariate logistic regression was performed to identify predictors of elevated LAP. RESULTS: There were 36 patients treated with Dasatinib, 15 Nilotinib, and 20 Imatinib. Those treated with Dasatinib had higher rates of elevated LAP (44% vs 7% Nilotinib vs 10% Imatinib, p < 0.01) and PE (39% vs 7% vs 0%, p < 0.01). In the 15 patients who developed PE, 14 (93%) patients were treated with Dasatinib. Patients with PE had higher rates of elevated LAP (67% vs 16%, p < 0.01). Nineteen (26.8%) patients in the entire cohort had elevated LAP. After multivariate adjustment, Dasatinib (OR 33.50, 95% CI = 4.99-224.73, p < 0.01) and age (OR 1.12, 95% CI = 1.04-1.20, p < 0.01) were associated with elevated LAP. CONCLUSIONS: Among patients with CML, there was an association between Dasatinib use, PE and elevated LAP on TTE. These findings are hypothesis generating and further studies are required to evaluate the utility of elevated LAP on TTE as a novel marker for prediction and surveillance of PE.

Blood-based multi-cancer detection: A state-of-the-art update.

The early detection of cancer is a key goal of the National Cancer Plan formally released by the National Institutes of Health's (NIH) National Cancer Institute (NCI) in April 2023. To support this effort, many laboratories and vendors are developing multi-cancer detection (MCD) assays that interrogate blood and other bodily fluids for cancer-related biomarkers, most commonly circulating tumor DNA (ctDNA). While this approach holds promise for non-invasively detecting early signals of multiple different cancers and potentially reducing cancer-related mortality, there is a dearth of prospective clinical data to inform the deployment of MCD assays for cancer screening in the general adult population. In this review we highlight differing technologies that underpin various MCD assays in clinical development, the importance of achieving adequate performance specifications for MCD assays, ongoing clinical studies investigating the utility of MCD assays in cancer screening and detection, and efforts by the NCI's Division of Cancer Prevention (DCP) to establish a network infrastructure that has the capacity to comprehensively address the scientific and logistical challenges of evaluating blood-based MCD approaches and other cancer screening tools.

Evaluating the efficacy of combination and single-agent immunotherapies in real-world patterns of disease progression and survival of metastatic melanoma patients.

The objective of this study is to describe survival outcomes in patients with metastatic melanoma in a real-world setting receiving combination and single-agent immunotherapy outside the clinical trial context. We conducted a retrospective single-institution study of patients with metastatic melanoma in a real-world setting. Survival was calculated using log-rank test. Contingency tables were analyzed using Fisher's Exact test. CD8 + T-cell densities were measured using quantitative immunofluorescence and analyzed using Mann-Whitney U test. The median overall survival (OS) for 132 patients was 45.3 months. Brain metastasis did not confer a higher risk of death relative to liver and/or bone disease (39.53 versus 30.00 months, respectively; P  = 0.687). Anti-PD-1 monotherapy was the most common first-line treatment, received by 49.2% of patients. There was no significant difference in OS between patients receiving single-agent anti-PD-1 and combination anti-PD-1 plus CTLA-4 (39.4 months versus undefined; P  = 0.643). Patients treated with combination therapy were more likely to be alive without progression at the last follow-up than those who received monotherapy (70.4% versus 49.2%; P  = 0.0408). Median OS was 21.8 months after initiation of second-line therapy after anti-PD-1 monotherapy. CD8+ T-cell densities were higher in patients who achieved disease control on first-line immunotherapy ( P  = 0.013). In a real-world setting, patients with metastatic melanoma have excellent survival rates, and treatment benefit can be achieved even after progression on first-line therapy. Combination immunotherapy may produce more favorable long-term outcomes in a real-world setting. High pretreatment CD8+ T-cell infiltration correlates with immunotherapy efficacy.

Rethinking Oncologic Treatment Strategies with Interleukin-2.

High-dose recombinant human IL-2 (rhIL-2, aldesleukin) emerged as an important treatment option for selected patients with metastatic melanoma and metastatic renal cell carcinoma, producing durable and long-lasting antitumor responses in a small fraction of patients and heralding the potential of cancer immunotherapy. However, the adoption of high-dose rhIL-2 has been restricted by its severe treatment-related adverse event (TRAE) profile, which necessitates highly experienced clinical providers familiar with rhIL-2 administration and readily accessible critical care medicine support. Given the comparatively wide-ranging successes of immune checkpoint inhibitors and chimeric antigen receptor T cell therapies, there have been concerted efforts to significantly improve the efficacy and toxicities of IL-2-based immunotherapeutic approaches. In this review, we highlight novel drug development strategies, including biochemical modifications and engineered IL-2 variants, to expand the narrow therapeutic window of IL-2 by leveraging downstream activation of the IL-2 receptor to selectively expand anti-tumor CD8-positive T cells and natural killer cells. These modified IL-2 cytokines improve single-agent activity in solid tumor malignancies beyond the established United States Food and Drug Administration (FDA) indications of metastatic melanoma and renal cell carcinoma, and may also be safer in rational combinations with established treatment modalities, including anti-PD-(L)1 and anti-CTLA-4 immunotherapy, chemotherapies, and targeted therapy approaches.

Prediction of cardiovascular events in patients with chronic myeloid leukaemia using baseline risk factors and coronary artery calcium scoring.

A standardised method for cardiovascular risk stratification in chronic myeloid leukaemia patients treated with tyrosine kinase inhibitors is lacking. We report an algorithm for risk stratification applicable to all patients commencing tyrosine kinase inhibitor therapy based on age, prior cardiovascular disease and Framingham Risk Score, incorporating coronary artery calcium scoring in patients at intermediate Framingham Risk Score risk. Of 88 patients retrospectively studied, major adverse cardiovascular event rates in our study-defined low-, intermediate- and high-risk categories were 0%, 10% and 19% respectively. Of nine patients down-classified from intermediate to low risk on the basis of coronary artery calcium scoring, none went on to experience a major adverse cardiovascular event.

An up-to-date review of cardiac pacemakers and implantable cardioverter defibrillators.

Cardiac pacemakers are one of the most frequently encountered cardiac devices seen on chest imaging. They may include single or dual chamber pacemakers, automated implantable cardioverter defibrillators (AICD), biventricular pacemakers used for cardiac resynchronisation therapy (CRT), wireless CRT, leadless pacemakers, and subcutaneous implantable cardioverter defibrillators (SICD). This review aims to provide an up-to-date review on current implantable pacemaker and defibrillator devices.

Seroconversion rates following COVID-19 vaccination among patients with cancer.

As COVID-19 adversely affects patients with cancer, prophylactic strategies are critically needed. Using a validated antibody assay against SARS-CoV-2 spike protein, we determined a high seroconversion rate (94%) in 200 patients with cancer in New York City that had received full dosing with one of the FDA-approved COVID-19 vaccines. On comparison with solid tumors (98%), a significantly lower rate of seroconversion was observed in patients with hematologic malignancies (85%), particularly recipients following highly immunosuppressive therapies such as anti-CD20 therapies (70%) and stem cell transplantation (73%). Patients receiving immune checkpoint inhibitor therapy (97%) or hormonal therapies (100%) demonstrated high seroconversion post vaccination. Patients with prior COVID-19 infection demonstrated higher anti-spike IgG titers post vaccination. Relatively lower IgG titers were observed following vaccination with the adenoviral than with mRNA-based vaccines. These data demonstrate generally high immunogenicity of COVID-19 vaccination in oncology patients and identify immunosuppressed cohorts that need novel vaccination or passive immunization strategies.

Fibroblast Growth Factor 19 modulates intestinal microbiota and inflammation in presence of Farnesoid X Receptor.

BACKGROUND: Disruption of bile acid (BA) homeostasis plays a key role in intestinal inflammation. The gut-liver axis is the main site for the regulation of BA synthesis and BA pool size via the combined action of the nuclear Farnesoid X Receptor (FXR) and the enterokine Fibroblast Growth Factor 19 (FGF19). Increasing evidence have linked derangement of BA metabolism with dysbiosis and mucosal inflammation. Thus, here we aimed to investigate the potential action of an FGF19 analogue on intestinal microbiota and inflammation. METHODS: A novel engineered non-tumorigenic variant of the FGF19 protein, M52-WO 2016/0168219 was generated. WT and FXRnull mice were injected with AAV-FGF19-M52 or the control AAV-GFP and subjected to Sodium Dextran Sulphate-induced colitis. FINDINGS: FGF19-M52 reduced BA synthesis and pool size, modulated its composition and protected mice from intestinal inflammation. These events were coupled with preservation of the intestinal epithelial barrier integrity, inhibition of inflammatory immune response and modulation of microbiota composition. Interestingly, FGF19-M52-driven systemic and local anti-inflammatory activity was completely abolished in Farnesoid X Receptor (FXR)null mice, thus underscoring the need of FXR to guarantee enterocytes' fitness and complement FGF19 anti-inflammatory activity. To provide a translational perspective, we also show that circulating FGF19 levels are reduced in patients with Crohn's disease. INTERPRETATION: Reactivation of the FXR-FGF19 axis in a murine model of intestinal inflammation could bona fide provide positive changes in BA metabolism with consequent reduction of intestinal inflammation and modulation of microbiota. These results point to the therapeutic potential of FGF19 in the treatment of intestinal inflammation with concomitant derangement of BA homeostasis. FUNDING: A. Moschetta is funded by MIUR-PRIN 2017 <- 2017J3E2W2; Italian Association for Cancer Research (AIRC, IG 23239); Interreg V-A Greece-Italy 2014-2020-SILVER WELLBEING, MIS5003627; HDHL-INTIMIC EuJPI-FATMAL; MIUR PON "R&I" 2014-2020-ARS01_01220. No money has been paid by NGM Biopharmaceuticals or any other agency to write this article.

The evolving use of pembrolizumab in combination treatment approaches for non-small cell lung cancer.

Introduction: The immune checkpoint inhibitor, pembrolizumab, has revolutionized the treatment of non-small cell lung cancer (NSCLC). It is currently approved and widely used in patients with advanced NSCLC whose tumors have no EGFR or ALK genomic aberrations that express PD-L1 as single-agent treatment and irrespective of PD-L1 expression in combination with platinum-based doublet chemotherapy in the first-line setting.Areas covered: The authors have reviewed articles discussing pembrolizumab and NSCLC in MEDLINE between July 2013 to August 2019 and focus on recent advances in combining pembrolizumab with chemotherapy, radiotherapy and other novel agents in various stages of NSCLC.Expert opinion: Although pembrolizumab has revolutionized the treatment of advanced NSCLC, only a subset of patients benefit from single-agent therapy. Numerous trials combining pembrolizumab with chemotherapy and radiation have shown benefit and a large spectrum of novel combination strategies are being explored for improved synergies. In addition to PD-L1 tumor proportion score, validation of other biomarkers would be beneficial in stratifying patients and improving the predictive value of combining immune check point inhibitors and chemotherapy.

Differential Efficacy of Anti-VEGF Antibodies Based on Sex and Race in a Diverse Cohort of Advanced Nonsquamous Non-Small Cell Lung Cancer.

OBJECTIVES: Bevacizumab with chemotherapy improved overall survival (OS) in the E4599 trial in metastatic nonsquamous non-small cell lung cancer (NS-NSCLC). A meta-analysis demonstrated an OS benefit with bevacizumab only in a subset of nonwhite patients. We explored the efficacy of antivascular endothelial growth factor antibodies (AVA) in a diverse cohort. MATERIALS AND METHODS: Patients with advanced (stage IIIB/IV, American Joint Committee Cancer 7th edition) recurrent or metastatic NS-NSCLC diagnosed January 2006 to December 2017 at a single medical center were included. Survival analysis was performed with log-rank testing of the Kaplan-Meier estimator. Univariate models were constructed, and significant variables, age, sex, race were incorporated into a multivariate Cox proportional hazard model. Data analysis was performed on SAS. RESULTS: A total of 171 patients, 80 were treated with AVA and 91 were untreated. Median age: 63 years, 55% females, 19% non-Hispanic whites, 44% blacks and 32% Hispanic whites; median 40 pack-years of smoking; 11.7% had sensitizing epidermal growth factor receptor mutations. Patients who received AVA had a survival benefit (26.6 vs. 19 mo, P=0.025). Adjusting for age, sex, race/ethnicity, epidermal growth factor receptor mutations, Eastern Cooperative Oncology Group performance status and number of metastases; AVA therapy was associated with improved OS (adjusted hazard ratio=0.62; P=0.049). In a subgroup analysis, females had survival benefit with AVA (median survival: 29.1 vs. 14.2 mo, log-rank P=0.02) which was significant in the adjusted model (adjusted hazard ratio=0.52; P=0.049). CONCLUSIONS: In a diverse cohort of patients with advanced NS-NSCLC, a survival benefit was confirmed with AVA. The greatest magnitude of benefit was in blacks and non-Hispanic whites. A significant survival benefit was limited to female patients.

Biodegradable nanofiber-based piezoelectric transducer.

Piezoelectric materials, a type of "smart" material that generates electricity while deforming and vice versa, have been used extensively for many important implantable medical devices such as sensors, transducers, and actuators. However, commonly utilized piezoelectric materials are either toxic or nondegradable. Thus, implanted devices employing these materials raise a significant concern in terms of safety issues and often require an invasive removal surgery, which can damage directly interfaced tissues/organs. Here, we present a strategy for materials processing, device assembly, and electronic integration to 1) create biodegradable and biocompatible piezoelectric PLLA [poly(l-lactic acid)] nanofibers with a highly controllable, efficient, and stable piezoelectric performance, and 2) demonstrate device applications of this nanomaterial, including a highly sensitive biodegradable pressure sensor for monitoring vital physiological pressures and a biodegradable ultrasonic transducer for blood-brain barrier opening that can be used to facilitate the delivery of drugs into the brain. These significant applications, which have not been achieved so far by conventional piezoelectric materials and bulk piezoelectric PLLA, demonstrate the PLLA nanofibers as a powerful material platform that offers a profound impact on various medical fields including drug delivery, tissue engineering, and implanted medical devices.

The utility of coronary computed tomography angiography in elderly patients.

BACKGROUND: Coronary computed tomography angiography (CCTA) is often avoided in elderly patients due to a presumption that a high proportion of patients will have heavily calcified plaque limiting an accurate assessment. We sought to assess the image quality, luminal stenosis and utility of CCTA in elderly patients with suspected coronary artery disease (CAD) and stable chest pain. METHODS: Retrospective analysis of elderly patients (> 75 years) who underwent 320-detector row CCTA between 2012-2017 at MonashHeart. The CCTA was analysed for degree maximal coronary stenosis by CAD-RADS classification, image quality by a 5-point Likert score (1-poor, 2-adequate, 3-good, 4-very good, 5-excellent) and presence of artefact limiting interpretability. RESULTS: 1011 elderly patients (62% females, 78.8 ± 3.3 years) were studied. Cardiovascular risk factor prevalence included: hypertension (65%), hyperlipidaemia (48%), diabetes (19%) and smoking (21%). The CCTA was evaluable in 68% of patients which included 52% with non-obstructive CAD (< 50% stenosis), 48% with obstructive CAD (> 50%) stenosis. Mean Likert score was 3.1 ± 0.6 corresponding to good image quality. Of the 323 (32%) of patients with a non-interpretable CCTA, 80% were due to calcified plaque and 20% due to motion artefact. Male gender (P = 0.009), age (P = 0.02), excess motion (P < 0.01) and diabetes mellitus (P = 0.03) were associated with non-interpretable CCTA. CONCLUSION: Although CCTA is a feasible non-invasive tool for assessment of elderly patients with stable chest pain, clinicians should still be cautious about referring elderly patients for CCTA. Patients who are male, diabetic and >78 years of age are significantly less likely to have interpretable scans.

Non-invasive CT-derived fractional flow reserve and static rest and stress CT myocardial perfusion imaging for detection of haemodynamically significant coronary stenosis.

Computed tomography derived fractional flow reserve (FFRCT) and computed tomography stress myocardial perfusion imaging (CTP) are techniques to assess haemodynamic significance of coronary stenosis. To compare the diagnostic performance of FFRCT and static rest/stress CTP in detecting fractional flow reserve (FFR) defined haemodynamically-significant stenosis (FFR ≤ 0.8). Fifty-one patients (96 vessels) with suspected coronary artery disease from a single institution planned for elective invasive-angiography prospectively underwent research indicated 320-detector-CT-coronary-angiography (CTA) and adenosine-stress CTP and invasive FFR. Analyses were performed in separate core-laboratories for FFRCT and CTP blinded to FFR results. Myocardial perfusion was assessed visually and semi-quantitatively by transmural perfusion ratio (TPR). Invasive FFR ≤ 0.8 was present in 33% of vessels and 49% of patients. FFRCT, visual CTP and TPR analysis was feasible in 96%, 92% and 92% of patients respectively. Overall per-vessel sensitivity, specificity and diagnostic accuracy for FFRCT were 81%, 85%, 84%, for visual CTP were 50%, 89%, 75% and for TPR were 69%, 48%, 56% respectively. Receiver-operating-characteristics curve analysis demonstrated larger per vessel area-under-curve (AUC) for FFRCT (0.89) compared with visual CTP (0.70; p < 0.001), TPR (0.58; p < 0.001) and CTA (0.70; p = 0.0007); AUC for CTA + FFRCT (0.91) was higher than CTA + visual CTP (0.77, p = 0.008) and CTA + TPR (0.74, p < 0.001). Per-patient AUC for FFRCT (0.90) was higher than visual CTP (0.69; p = 0.0016), TPR (0.56; p < 0.0001) and CTA (0.68; p = 0.001). Based on this selected cohort of patients FFRCT is superior to visually and semi-quantitatively assessed static rest/stress CTP in detecting haemodynamically-significant coronary stenosis as determined on invasive FFR.

Coexisting chronic obstructive pulmonary disease and cardiovascular disease in clinical practice: a diagnostic and therapeutic challenge.

Chronic obstructive pulmonary disease (COPD) and cardiovascular disease (CVD) frequently coexist but combined disease is often not recognised. Since symptoms overlap significantly, it is common for patients' presentations to be attributed to one disease alone, and for the other to be overlooked. The effect of COPD and CVD goes beyond the shared risk factors of smoking and advancing age. The presence of COPD adversely affects cardiac disease and vice versa. In comparison to individuals with one disease alone, those with both conditions have a higher mortality rate, experience more frequent exacerbations with more hospitalisations and have worse quality of life. More patients with mild and moderate COPD die from CVD than from COPD, and there is a higher rate of arrhythmias, particularly atrial fibrillation. Accurate and timely diagnosis is therefore crucial. Retrospective evidence indicates that individuals with COPD and CVD may have better outcomes with appropriate CVD pharmacotherapy, yet robust prospective evidence is lacking. Inhaled medications for patients with stable COPD improve quality of life and reduce exacerbations, but there is limited evidence that they reduce mortality. A low threshold for investigation and treatment of CVD in COPD and COPD in CVD is essential.

Suppression of Hepatic Bile Acid Synthesis by a non-tumorigenic FGF19 analogue Protects Mice from Fibrosis and Hepatocarcinogenesis.

Critical regulation of bile acid (BA) pool size and composition occurs via an intensive molecular crosstalk between the liver and gut, orchestrated by the combined actions of the nuclear Farnesoid X receptor (FXR) and the enterokine fibroblast growth factor 19 (FGF19) with the final aim of reducing hepatic BA synthesis in a negative feedback fashion. Disruption of BA homeostasis with increased hepatic BA toxic levels leads to higher incidence of hepatocellular carcinoma (HCC). While native FGF19 has anti-cholestatic and anti-fibrotic activity in the liver, it retains peculiar pro-tumorigenic actions. Thus, novel analogues have been generated to avoid tumorigenic capacity and maintain BA metabolic action. Here, using BA related Abcb4-/- and Fxr-/- mouse models of spontaneous hepatic fibrosis and HCC, we explored the role of a novel engineered variant of FGF19 protein, called FGF19-M52, which fully retains BA regulatory activity but is devoid of the pro-tumoral activity. Expression of the BA synthesis rate-limiting enzyme Cyp7a1 is reduced in FGF19-M52-treated mice compared to the GFP-treated control group with consequent reduction of BA pool and hepatic concentration. Treatment with the non-tumorigenic FGF19-M52 strongly protects Abcb4-/- and Fxr-/- mice from spontaneous hepatic fibrosis, cellular proliferation and HCC formation in terms of tumor number and size, with significant reduction of biochemical parameters of liver damage and reduced expression of several genes driving the proliferative and inflammatory hepatic scenario. Our data bona fide suggest the therapeutic potential of targeting the FXR-FGF19 axis to reduce hepatic BA synthesis in the control of BA-associated risk of fibrosis and hepatocarcinoma development.

Lysis-independent potentiation of immune checkpoint blockade by oncolytic virus.

Intratumoral therapy with oncolytic viruses is increasingly being explored as a strategy to potentiate an immune response against cancer, but it remains unknown whether such therapy should be restricted to cancers sensitive to virus-mediated lysis. Using Newcastle Disease Virus (NDV) as a model, we explore immunogenic potential of an oncolytic virus in bladder cancer, where existing immunotherapy with PD-1 and PD-L1-targeting antibodies to date has shown suboptimal response rates. Infection of human and mouse bladder cancer cells with NDV resulted in immunogenic cell death, activation of innate immune pathways, and upregulation of MHC and PD-L1 in all tested cell lines, including the cell lines completely resistant to NDV-mediated lysis. In a bilateral flank NDV-lysis-resistant syngeneic murine bladder cancer model, intratumoral therapy with NDV led to an increase of immune infiltration in both treated and distant tumors and a shift from an inhibitory to effector T cell phenotype. Consequently, combination of intratumoral NDV with systemic PD-1 or CTLA-4 blockade led to improved local and abscopal tumor control and overall survival. These findings encourage future clinical trials combining intratumoral NDV therapy with systemic immunomodulatory agents and underscore the rationale for such treatments irrespective of tumor cell sensitivity to NDV-mediated lysis.

Threading the Eye of the Needle: A Challenging Case of Iatrogenic Spiral Coronary Artery Dissection.

Catheter induced coronary dissection is an uncommon but potentially catastrophic complication of coronary angiography. We report a case of a 48-year-old female with normal coronary arteries on angiography complicated by extensive catheter induced spiral dissection. Wiring into the true lumen was a formidable challenge as a consequence of the large false lumen obliterating the true lumen. We present management strategies and in particular, highlight the important role of intravascular ultrasound (IVUS) imaging.

Chronic myeloid leukaemia and tyrosine kinase inhibitor therapy: assessment and management of cardiovascular risk factors.

Several BCR-ABL1 tyrosine kinase inhibitors (TKIs) are approved for the first-line treatment of chronic phase chronic myeloid leukaemia (CML). Disease control is achieved in the vast majority of patients and disease-specific survival is excellent. Consequently, there is now emphasis on managing comorbidities and minimising treatment-related toxicity. Second-generation TKIs have cardiovascular risks that are greater than with imatinib treatment, but these risks must be balanced against the superior CML responses encountered with more potent TKIs. Cardiovascular risk should be assessed at baseline using a locally validated model based on the Framingham risk equation. Clinicians involved in the care of CML patients should be aware of the vascular complications of TKIs and manage cardiovascular risk factors early to mitigate treatment-related risks. Reversible risk factors, such as dyslipidaemia, smoking, diabetes and hypertension, should be addressed. We summarise the available data on cardiovascular complications in CML patients treated with TKIs. Using the latest evidence and collective expert opinion, we provide practical advice for clinicians to assess, stratify and manage cardiovascular risk in people with CML receiving TKI therapy.

EGFR T790M: revealing the secrets of a gatekeeper.

Non-small-cell lung cancers that harbor activating mutations in the EGFR gene represent an important molecularly defined subset of lung cancer. Despite dramatic initial responses with first- and second-generation EGFR-directed tyrosine-kinase inhibitors (TKIs) against these cancers, the development of a dominant and frequent resistance mechanism through a threonine-methionine amino acid substitution at position 790 (T790M) of EGFR has limited the long-term efficacy of these targeted therapies. This "gatekeeper" EGFR T790M alteration remains the only validated and relevant second-site resistance mutation for EGFR, allowing for focused research to understand and overcome EGFR T790M-mediated resistance. The current review focuses on EGFR T790M by discussing mechanisms of resistance mediated by EGFR T790M, reviewing development of novel third-generation EGFR TKIs targeting EGFR T790M, and highlighting current research on overcoming resistance to third-generation EGFR T790M TKIs.