A real-world study on the clinicopathological profile, treatment outcomes and health-related quality of life, anxiety and depression among patients with desmoid tumor at two tertiary care centers in India.

Background: The medical management of DT comprises tyrosine kinase inhibitors (TKIs), hormonal agents, anti-inflammatory drugs with the recently approved gamma secretase inhibitor nirogacestat being the current standard of care. Real-world data on evolving treatment landscapes of DT remains scarce. Methods: This is a retrospective study of patients with DT registered between 1995 and 2020 at All India Institute of Medical Sciences, New Delhi and Tata Medical Center, Kolkata. Baseline characteristics were analyzed in form of median values and interquartile range. Categorical and continuous variables were compared by chi square and independent samples T- tests respectively. Anxiety, depression and QoL were prospectively measured among 30 patients using Hospital Anxiety and Depression (HADS) and Functional Assessment of Cancer Therapy-General (FACT-G) scales respectively between 2022 to 2023. Results: 200 patients were included with a male-predominant (n=111, 55.5%) population and median age 26.5 (2.5-75) years. Extremity (n=100, 50%) and abdomen (n=65, 32.5%) were commonest primary sites and median of 2 (1-4) lines of treatment were received. First-line included surgery (n=116, 58%), systemic therapy (n=67, 33.5%), radiotherapy (10, n=5%) and active surveillance (n=7, 3.5%). First-line systemic agents included tamoxifen (n=55, 27.5%), imatinib (n=7, 3.5%), sorafenib (n=1, 0.5%) and chemotherapy (n=4, 2%). 2019 onward, 3% and 63% underwent active surveillance and surgery respectively. Best radiological response obtained with tamoxifen was stable disease (SD) (n=76, 59%) and partial response (PR) (n=31, 24.2%). Best radiological response obtained with sorafenib was PR (n=17, 60.7%) and SD (n=9, 32.1%). Thirty patients underwent HADS and FACT-G scale assessment. Mean HADS-Anxiety subscale score was 3.6 (+/-3.9 SD) and HADS-Depression sub-scale score was 2.6 (+/-3.5 SD) with clinically significant anxiety and depression in 2 (6.7%) patients each. The overall mean FACT-G score was 87.5 (+/-12.6 SD) and lower mean physical well-being (p=0.006) and emotional well-being (0.017) scores were significantly associated with higher HADS-anxiety (>/=8) scores. Conclusions: Assessment of anxiety, depression and QoL are paramount to gauge the psychological impact of DT. This study gives an overview of clinical and management profile of patients with DT in India, with limitations of selection bias, heterogeneous population and small sample size for QoL assessment.

The benefit and risk of addition of chemotherapy to EGFR tyrosine kinase inhibitors for EGFR-positive non-small cell lung cancer patients with brain metastases: a meta-analysis based on randomized controlled trials.

Background: Combining epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) with chemotherapy (ETC) offers more advantages for patients with EGFR-positive non-small cell lung cancer (NSCLC) than using EGFR TKIs alone (ET). However, whether this conclusion applies to patients with brain metastases (BM) remains controversial. This meta-analysis was performed to evaluate the benefits and risks of the two groups. Methods: Six databases were systematically searched for relevant literatures comparing ETC versus ET in treating EGFR-positive NSCLC patients with BM. The primary outcome assessed was overall survival (OS), while secondary outcomes included progression-free survival (PFS), and central nervous system (CNS)-PFS, responses, progression status and safety. Results: Seven studies based on five randomized clinical trials with 550 patients were included. The ETC group exhibited better OS (hazard ratio [HR]: 0.64 [0.48, 0.87]), PFS (HR: 0.42 [0.34, 0.52]), and CNS-PFS (HR: 0.42 [0.31, 0.57]). The benefits in survival for OS, PFS, and CNS-PFS were validated in nearly all subgroups. Meanwhile, the overall objective response rate (ORR) (risk ratio [RR]: 1.25 [1.02, 1.52]) and CNS-ORR (RR: 1.19 [0.93, 1.51]) also tended to favor the ETC group. However, the addition of chemotherapy also brought about more grade 3-5/serious adverse events (AEs). The top five grade 3-5 AEs in the ETC group were alanine aminotransferase increase (11.25%), neutropenia (7.5%), nausea (7.5%), anorexia (5%), and diarrhea (5%). Conclusions: ETC appears to be better than ET in treating EGFR-positive NSCLC patients with BM, with better OS, PFS, CNS-PFS, and responses. However, its poorer safety profile also needs to be taken into consideration. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42024551073.

Scedosporium Brain Abscess: A Rare and Fatal Drawback of Bruton Tyrosine Kinase Inhibitor Therapy.

The patient described in this case report was admitted to the San Luigi Hospital in Turin for confusion, drowsiness, and buccal and eye deviation. An acute neurological disease was suspected. He was affected by chronic lymphocytic leukemia (CLL) on active treatment with the novel Bruton tyrosine kinase inhibitor (BTKi) acalabrutinib. Other comorbidities included type II diabetes mellitus, arterial hypertension, and nonalcoholic steatohepatitis. Imaging exams showed multiple brain lesions, which appeared to be of infectious-inflammatory origin. Consequently, therapy with acalabrutinib was withheld. The patient was later transferred to the intensive care unit, because of worsening neurological conditions. The definite diagnosis of fungal abscess was obtained through a stereotactic biopsy of the widest brain lesion. Microbiological tests confirmed Scedosporium spp. as the etiological agent. Once a detailed antibiogram had been obtained, voriconazole therapy was started. However, the patient's clinical conditions decayed rapidly and he later died of neurological complications. BTKis represent a milestone in the treatment of CLL; however, little is known about how these molecules act on the immune system. Fungal brain abscesses are rare conditions more commonly seen in heavily immunocompromised patients, such as those affected by acquired immune deficiency syndrome, after bone marrow transplant or treatment for acute leukemia. Whether or not therapy with BTKis can favor opportunistic fungal infections is still a matter of debate. Various reports of Aspergillosis infections developing after therapy with ibrutinib exist. Evidence does suggest that an iatrogenic impairment in the innate immune system could favor these infections. In addition, the patient's comorbidities, such as diabetes mellitus and advancing hematological disease, might create the ideal breeding ground for these microorganisms.

Efficacy and safety of tyrosine kinase inhibitors with thoracic radiotherapy for patients with oncogene-mutated non-small cell lung cancer: a meta-analysis.

BACKGROUND: Tyrosine Kinase Inhibitors (TKIs) is an important therapy for patients with oncogene-mutated Non-Small Cell Lung Cancer (NSCLC). However, acquired resistance remains a major challenge. The efficacy of TKIs plus thoracic radiotherapy (RT) in oncogene-mutated NSCLC patients is uncertain. Therefore, we performed a meta-analysis to comprehensively evaluate the efficacy and safety of thoracic RT plus TKIs in oncogene-mutated NSCLC patients. METHODS: The following databases were searched for relevant studies: PubMed, EMBASE, and Cochrane Library. Studies comparing the efficacy and safety of TKIs plus RT with TKIs alone in oncogene-mutated NSCLC patients were included in this analysis. Outcomes were median progression-free survival (mPFS), median overall survival (mOS), and incidence of adverse events (AEs). This analysis performed a subgroup analysis of the efficacy of first-line TKIs in combination with RT. RESULTS: This meta-analysis included 12 studies with 2936 patients (n = 823 patients with TKIs plus thoracic RT, n = 2113 patients with TKIs alone). The results showed that patients who received treatment with TKIs plus thoracic RT were associated with superior mPFS and mOS than those who were treated with TKIs alone (hazard ratio [HR]: 0.42, 95% CI 0.30-0.59, p < 0.00001; HR: 0.56, 95% CI 0.41-0.70, p < 0.00001, respectively). Subgroup analyses showed that TKIs plus thoracic RT as first-line treatment was associated with better mPFS and OS (HR: 0.37, 95% CI 0.26-0.52, p < 0.00001; HR: 0.47, 95% CI 0.31-0.70, p = 0.0002, respectively). Although the combination of TKIs with thoracic RT was associated with an increased risk of total AEs (odds ratio [OR]: 1.17, 95% CI 1.06-1.29, P = 0.002), there was no significant difference in serious AEs (grade ≥ 3) (OR: 1.06, 95% CI 0.58-1.92, P = 0.86). The most frequently occurring radiation-related AEs were radiation pneumonitis, radiation esophagitis, and radiation dermatitis, with overall rates of 41.3%, 15.4%, and 11.1%, respectively. The incidence of severe radiation pneumonitis and radiation esophagitis was 4.5% and 6.2%, respectively. CONCLUSIONS: In comparison to TKIs alone, TKIs plus thoracic RT are associated with survival benefits, especially as a first-line treatment option. Although TKIs plus thoracic RT may increase the risk of total AEs, it did not increase the risk of severe AEs. Therefore, TKIs plus thoracic RT may be a promising therapeutic regimen for oncogene-mutated NSCLC patients.

Real-World Evaluation of Treatment Patterns and Clinical Outcomes among Patients With Chronic Myeloid Leukemia in Chronic Phase Treated With Asciminib in Clinical Practice in the United States: Real-world asciminib treatment outcomes in CML-CP.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are the mainstay treatment for chronic myeloid leukemia in chronic phase (CML-CP). Asciminib, an ABL/BCR::ABL1 inhibitor which binds to the myristoyl pocket, was recently approved in the US for patients with CML-CP previously treated with ≥2 TKIs or with the T315I mutation. This study described treatment patterns and real-world clinical outcomes among patients with CML-CP treated with asciminib in US clinical practice. METHODS: Electronic health record data from adult patients with CML-CP who initiated asciminib after ≥2 prior TKIs, without the T315I mutation, were obtained from the Flatiron Health database. Time-to-treatment discontinuation and molecular response (MR; time-to-BCR::ABL ≤0.1% and time-to-BCR::ABL1 ≤1%, separately) were evaluated from asciminib initiation (index date) using Kaplan-Meier analyses. RESULTS: Overall, 97 patients initiated asciminib (median age: 63 years, 50.5% female, 64.9% White) after either 2 (47.4%) or 3 (24.7%), or ≥4 (27.8%) prior TKIs. In total, 85.7% and 78.1% of patients remained on asciminib by 12- and 24-weeks postindex, respectively. Among patients with ≥1 MR assessment postindex, 31.3% (95% confidence interval [CI]: 21.6%, 43.9%) and 49.7% (95% CI: 38.1%, 62.6%) achieved or maintained BCR::ABL1 ≤0.1%, while 51.3% (95% CI: 40.1%, 63.6%) and 64.2% (95% CI: 52.6%, 75.6%) achieved or maintained BCR::ABL1 ≤1%, by 12- and 24-weeks, respectively. CONCLUSIONS: Results of this real-world study describing clinical outcomes among patients with CML-CP treated with asciminib after ≥2 prior TKIs in the US demonstrated that asciminib was well-tolerated and effective. These findings were consistent with results from the ASCEMBL trial.

Prevalence and clinical factors associated with survival in patients with EGFR-mutated lung cancer in Argentina.

Introduction: Lung cancer remains a leading cause of cancer-related mortality worldwide. Detecting mutations in the epidermal growth factor receptor (EGFR) is crucial for treatment selection due to the response to tyrosine kinase inhibitors (TKIs) in these patients. Objective: Describe the prevalence and identify factors associated with survival in stage IV lung cancer patients harboring EGFR mutations in a real-world setting. Materials and methods: A retrospective cohort study was conducted to identify factors associated with progression-free survival (PFS), overall survival (OS) and response rate in stage IV lung cancer patients with EGFR mutations. Results: Data from 771 patients diagnosed with lung cancer between 2017 and 2021 at the Hospital Italiano de Buenos Aires were analysed. The prevalence of EGFR mutations was 18% (139), with a median follow-up of 30 months. Of these, 118 were treated with EGFR TKIs, with a higher objective response rate observed with osimertinib compared to first or second-generation TKIs. Adverse prognostic factors included an ECOG performance status greater than 1, uncommon mutations, high disease burden and the presence of brain or hepatic metastases. Osimertinib was associated with a reduced risk of progression or death, even after adjusting for these prognostic factors. The median PFS was 13 months, with a significant OS difference between patients treated with osimertinib versus first or second-generation inhibitors. Conclusion: This study underscores the importance of EGFR mutation detection in stage IV lung cancer patients and supports the need for personalised therapeutic approaches to improve outcomes in this patient population.

Fatal Case of Immune-Related Myocarditis and Myositis Due to Treatment with Immune Checkpoint and Tyrosine Kinase Inhibitors.

Immune checkpoint inhibitor and tyrosine kinase inhibitor combinations have become the new standard of care in the first-line treatment of metastatic clear cell renal cell carcinoma. However, there is a growing concern regarding severe immune-related adverse events. A 78-year-old man with metastatic clear cell renal cell carcinoma, treated with pembrolizumab and axitinib, was admitted to the emergency department 30 days after initiating treatment due to rapidly progressive myositis. Myocarditis with severe ventricular dysfunction was identified. Muscular biopsy findings were compatible with inflammatory myopathy associated with immune checkpoint inhibitors. Initial treatment with high-dose corticosteroids showed an insufficient response. Therapeutic escalation on the third day with methylprednisolone, immunoglobulin, and abatacept resulted in clinical improvement. On the eleventh day, a sudden malignant arrhythmia occurred, followed by cardiac arrest. This represents one of the first case reports describing myocarditis and myositis during treatment with pembrolizumab-axitinib. While immune checkpoint inhibitor may play a major role, it is also possible that the tyrosine kinase inhibitor, while attempting to promote immune modulation, also increases severe toxicities.

Real-World Data Presenting the Descriptive Analysis of the Use of Tyrosine Kinase Inhibitors (TKIs) Among Metastatic Non-Small-Cell Lung Cancer (mNSCLC) Patients in Qatar: A Nationwide Retrospective Cohort Study.

Background: There has been significant improvement in treating metastatic non-small-cell lung cancer (mNSCLC) over the past 2 decades. The aim of this study is to describe the use of tyrosine kinase inhibitors (TKIs) in Qatar. This study focuses on the objective response rate (ORR) and reported adverse drug events (ADEs) of TKIs used for the management of patients with mNSCLC. Methods: This is a descriptive retrospective cohort study. All non-small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations who received TKIs between 2015 and 2019 in Qatar were included. The TKIs used during this period include EGFR inhibitors such as afatinib, erlotinib, gefitinib, and osimertinib and ALK inhibitors such as alectinib and crizotinib. The response on each TKI was identified by reporting the ORR (as the sum of the complete response [CR] and the partial response [PR]), in addition stable disease (SD) and disease progression (DP) were reported. While ADEs were reported using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE). Results: A total of 63 patients were included, of which 36 cases (57.1%) expressed EGFR mutation, and 27 patients (42.9%) expressed ALK rearrangement. The ORR in EGFR inhibitors was as follows: osimertinib 40%, gefitinib 33%, afatinib 22%, and erlotinib 18%. However, the response to the ALK-targeted therapy was 43% with alectinib and 40% with crizotinib. A total of 112 ADEs were reported. They were distributed as 63.4% (71 of 112) with the anti-EGFR and 36.6% (41 of 112) ADEs with the ALK inhibitors. In the anti-EGFR group, the most common types of ADEs were dermatological toxicity 30%, whereas, in the anti-ALK group, gastrointestinal toxicity was the most common (29%). Conclusions: The EGFR-targeted and ALK-targeted therapies appear to have acceptable clinical response rate and safety profile in our population. Close and frequent monitoring of adverse events is advised to ensure a good quality of life and prevent serious complications.

Erlotinib and curcumin-loaded nanoparticles embedded in thermosensitive chitosan hydrogels for enhanced treatment of head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) remain a major oncological challenge with significant morbidity and mortality rates. Erlotinib (Er) and Curcumin (Cm) are potential therapeutic agents for HNSCC, yet they are hindered by poor solubility and bioavailability. This study explored the optimization of poly(lactic-co-glycolic acid) nanoparticles co-loaded with Er and Cm (Er/Cm-NP), prepared via a D-optimal response surface design-guided nanoprecipitation process. The optimized formulation, optEr/Cm-NP, was then incorporated into chitosan/ß-glycerophosphate hydrogels (optEr/Cm-NP-HG) to create an injectable intratumoral (IT) nanocomposite hydrogel (HG) delivery system. Physicochemical properties of the formulations, including gelation time, injectability, mechanical strength and drug release profiles were assessed alongside hemolytic activity. Compared to optEr/Cm-NP alone, the NP-loaded HG formulation exhibited a more pronounced modulation effect, enabling sustained and controlled drug release. The cytotoxicity of the developed formulations was evaluated using the FaDu HNSCC cancer cell line. Both optEr/Cm-NP and optEr/Cm-NP-HG21 displayed enhanced cytotoxicity compared to free drugs. Confocal laser microscopy and flow cytometry confirmed superior cellular uptake of Er and Cm when delivered via NPs or NP-loaded HG. Furthermore, a significant increase in apoptotic cell death upon treatment with optEr/Cm-NP was observed, highlighting its potential for HNSCC therapy. In vivo studies conducted on a xenograft HNSCC mouse model revealed the significant capacity of the intratumorally-injected optEr/Cm-NP-HG21 formulation to retard the tumor growth. Conclusively, the results presented herein report the successful development of a nanocomposite HG system incorporating NPs co-loaded with Er and Cm that could be efficiently utilized in the treatment of HNSCC.

Repotrectinib: Redefining the therapeutic landscape for patients with ROS1 fusion-driven non-small cell lung cancer.

The ROS1 proto-oncogene encodes a receptor tyrosine kinase with structural homology to other oncogenic drivers, including ALK and TRKA-B-C. The FDA-approved tyrosine kinase inhibitors (TKIs) crizotinib and entrectinib have demonstrated efficacy in treating ROS1 fusion-positive NSCLC. However, limitations such as poor blood-brain barrier penetration and acquired resistance, particularly the ROS1 G2032R solvent-front mutation, hinder treatment durability. Repotrectinib, a next-generation macrocyclic TKI, was rationally designed to overcome on-target resistance mutations and improve brain distribution through its low molecular weight. In the TRIDENT-1 clinical trial, repotrectinib demonstrated significant efficacy in both TKI-naïve and TKI-pretreated patients with ROS1-rearranged NSCLC, including those with CNS metastases and G2032R resistance mutations. In the TKI-naïve cohort (n = 71), 79% of patients achieved an objective response, with a median progression-free survival (PFS) of 35.7 months, surpassing all previously approved ROS1 TKIs. In patients who had received one prior ROS1 TKI but were chemotherapy-naïve (n = 56), objective responses were observed in 38%, and median PFS was 9.0 months. The safety profile of repotrectinib was consistent with earlier-generation ROS1 TKIs and common adverse events included anemia, neurotoxicity, increased creatine kinase levels, and weight gain. These findings underscore the potential of repotrectinib to address unmet needs in ROS1-rearranged NSCLC, offering durable responses and improved intracranial activity. Future research should prioritize developing next-generation, selective ROS1 inhibitors to reduce Trk-mediated toxicities and improve treatment tolerance.

Structure-Activity Relationship of Substituted Pyrazoline Derivatives as Small Molecule Tyrosine Kinase Inhibitors.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) target certain cell signalling pathways, and have become a promising class of medications for the treatment of cancer in recent years. Because of their distinct structure and adaptable chemistry, pyrazolines have drawn a lot of interest from organic and medicinal chemists. Their exceptional TKI activity has prompted them to investigate chemotherapy for cancer. OBJECTIVE: We aim to develop agents that inhibit tyrosine kinases highly effective with the least amount of harm possible, perhaps improving the course of cancer treatment. METHODS: This review compiled current information from recent literature sources, includ-ing in vitro, in vivo, approved medications, active clinical trials, and the structure-activity relationships (SAR) linked to various pyrazoline analogues used as small-molecule Tyro-sine Kinase Inhibitors in cancer treatment. RESULTS: This study focuses on SAR inside the pyrazoline ring and its derivatives as TKIs, and it emphasizes current developments, including patents, authorized medications, and compounds in clinical trials. CONCLUSION: By enhancing our understanding of these compounds, our goal is to aid in making the roles of pharmacologists, scientists, and researchers who are designing and developing next-generation anticancer drugs with pyrazoline scaffolds easier. The future holds immense potential for the continued evolution of pyrazoline-based therapies, offer-ing renewed hope in the ongoing battle against cancer.

Asciminib in Advanced-Line Treatment of Chronic Myeloid Leukemia.

OBJECTIVES: Asciminib, a novel allosteric BCR::ABL1 inhibitor, targets the ABL1 myristoyl pocket to potentially reduce toxicity and enhance efficacy. It is approved for Philadelphia chromosome-positive chronic-phase chronic myeloid leukemia (CML-CP) in patients with resistance or intolerance to two or more tyrosine kinase inhibitors (TKIs) or those with the T315I mutation. METHODS: This retrospective analysis evaluated patients with CML treated with asciminib under a managed-access program across eight Israeli centers from July 2019 to August 2022. We assessed treatment responses, toxicities, event-free survival (EFS), and overall survival (OS) using Kaplan-Meier methods. RESULTS: The study included 30 patients who had received a median of three prior TKIs, with 73% starting asciminib due to intolerance. After a median follow-up of 7.1 months, 85% of those without prior complete cytogenetic response (CCyR) achieved CCyR, and 60% previously not in major molecular response (MMR) attained MMR. Resistance was rare (10%), with no cardiovascular events reported despite high baseline comorbidity (73%). Median EFS was 47 months; median OS was not reached. CONCLUSION: Asciminib demonstrates significant efficacy and tolerability in heavily pretreated patients with CML-CP, with no new cardiovascular events observed. Further long-term studies are necessary to explore its full cardiovascular impact.

Outcomes of First-line Microwave Ablation of Treatment-Naive Epidermal Growth Factor Receptor-Mutated Advanced Lung Adenocarcinoma Treated with Tyrosine Kinase Inhibitors.

PURPOSE: To investigate the outcomes of first-line image-guided microwave ablation (MWA) plus tyrosine kinase inhibitors (TKIs) in untreated epidermal growth factor receptor (EGFR)-mutant advanced lung adenocarcinoma (LUAD), and to compare with TKIs alone. MATERIALS AND METHODS: This retrospective cohort study included patients between December 2015 and December 2021, and was divided into two groups (group A: first-line MWA+TKIs; group B: TKIs alone). Progression-free survival (PFS) was the primary endpoint, whereas overall survival (OS) was the secondary endpoint, and were compared via the Kaplan-Meier methods. Univariate and multivariate analyses were used to investigate the predictors of PFS and OS. Propensity score matching (PSM; 1:1 ratio) was applied between group B and the subgroup of complete ablation in group A. RESULTS: A total of 117 patients were included (group A: n=43; group B: n=74). In a mean follow-up of 47.0±19.4 months, group A had significantly longer median PFS (19.0 vs. 10.0 months, P<0.001) and OS (41.0 vs. 25.0 months, P=0.044) than group B. Predictors of PFS included first-line MWA (P<0.001) and tumor stage (P=0.020), while that of OS included first-line MWA (P=0.039), tumor stage (P=0.014) and usage of third-generation TKIs (P=0.001). There were 23 pairs of patients obtained after PSM (group A1: complete ablation+TKIs; group B1: TKIs alone). Group A1 had significantly longer median PFS (24.0 vs. 10.0 months, P<0.001) and OS (48.0 vs. 24.0 months, P=0.012) than group B1. CONCLUSIONS: First-line MWA significantly improved the outcomes of patients with untreated EGFR-mutant advanced LUAD treated with TKIs. Complete ablation predicts a better prognosis.

A Comprehensive Review of Epidermal Growth Factor Receptor Mutation Abundance in Non-Small Cell Lung Cancer Treated with Tyrosine Kinase Inhibitors.

BACKGROUND: Lung cancer is a major contributor to cancer-related death worldwide. Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancers. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are currently viewed as the established first-line therapy for patients with advanced NSCLC with EGFR mutations. SUMMARY: The potential predictive value of the quantitative abundance of epidermal growth factor receptor (EGFR) mutations in the treatment of NSCLC is widely recognized and regarded as a significant indicator. The definition of mutation abundance in the EGFR gene in most current studies is mainly calculated based on the ratio of mutation to wild-type gene copy number or based on the ratio of allele number; for example, variant allele frequency is the ratio of the number of mutant alleles to the total number of alleles at a particular locus. Results of the included primary studies are as follows. (1) Significant association between EGFR mutation abundance and progression-free survival (PFS): median PFS was significantly longer in the high abundance group (11.0 months, 95% CI: 9.7-12.3 months) than in the low abundance group (5.3 months, 95% CI: 3.6-7.0 months) in the study by Liu et al. High mutation abundance (HR: 0.77, 95% CI: 0.66-0.82, p = 0.037) was an independent prognostic determinant of PFS in the study by Wang et al. Among patients receiving EGFR-TKI as first-line therapy, the median PFS was significantly longer in the high mutation abundance group than in the low mutation abundance group (12.7 months vs. 8.7 months, p = 0.002). EGFR mutation abundance ≥30% was an independent risk factor for PFS (HR: 1.64, 95% CI: 1.17-2.31). (2) Significant association between EGFR mutation abundance and overall survival (OS): the median OS in the high abundance group in the study by Liu et al. was 20.9 months (95% CI: 18.3-23.5 months), while that in the low abundance group was 13.0 months (95% CI: 10.0 months) (95% CI: 10.3-15.7 months); longer OS was independently associated with high mutation abundance (HR: 0.62, 95% CI: 0.50-0.79, p = 0.027). KEY MESSAGES: The objective of this article was to conduct a comprehensive examination and analysis of the association between the abundance of EGFR mutations in NSCLC and the effectiveness of treatment with TKIs while also considering the development of drug resistance.

Automated kapok fiber-based pipette-tip solid-phase extraction coupled with liquid chromatography-tandem mass spectrometry for rapid and sensitive analysis of tyrosine kinase inhibitors in plasma.

This study delineates the development of a novel automated pipette-tip solid-phase extraction (SPE) methodology, employing kapok fiber as a naturally efficient and cost-effective adsorbent for the selective extraction of eleven tyrosine kinase inhibitors (TKIs) from plasma. The uniqueness of this method lies in its assembly, where kapok fibers are ingeniously wrapped around a stainless-steel spring within the pipette tip, ensuring an obstruction-free central space for effortless solution aspiration and dispensation. This design significantly minimizes backpressure, enhancing operational efficiency and ensuring compatibility with pipettors, including the implementation of an electric pipettor to streamline the sample preparation process and facilitate automation. The method's analytical performance, rigorously validated through liquid chromatography-tandem mass spectrometry, exhibits outstanding linearity in ranges of 0.1/0.5-200 ng mL-1 (R² > 0.993), commendable accuracy (86.3%-114.8%), and consistent precision (3.4-11.3%), alongside remarkably low detection limits that span from 0.024 to 0.130 ng mL-1. The assembly of kapok fiber within the pipette tip, in this unique configuration, results in a practical, cost-effective, eco-friendly, and automated pipette-tip SPE method. This innovation signifies a significant advancement in bioanalytical methodologies, offering an efficient and sustainable approach for extracting analytes from complex biological samples. This process notably enhances both the sensitivity and selectivity of subsequent instrumental analyses.

In silico and in vitro study of FLT3 inhibitors and their application in acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common hematological cancer in the adult population worldwide. Approximately 35% of patients with AML present internal tandem duplication (ITD) mutations in the FMS­like tyrosine kinase 3 (FLT3) receptor associated with poor prognosis, and thus, this receptor is a relevant target for potential therapeutics. Tyrosine kinase inhibitors (TKIs) are used to treat AML; however, their molecular interactions and effects on leukemic cells are poorly understood. The present study aimed to gain insights into the molecular interactions and affinity forces of four TKI drugs (sorafenib, midostaurin, gilteritinib and quizartinib) with the wild­type (WT)­FLT3 and ITD­mutated (ITD­FLT3) structural models of FLT3, in its inactive aspartic acid­phenylalanine­glycine motif (DFG­out) and active aspartic acid­phenylalanine­glycine motif (DFG­in) conformations. Furthermore, the present study evaluated the effects of the second­generation TKIs gilteritinib and quizartinib on cancer cell viability, apoptosis and proliferation in the MV4­11 (ITD­FLT3) and HL60 (WT­FLT3) AML cell lines. Peripheral blood mononuclear cells (PBMCs) from a healthy volunteer were included as an FLT3­negative group. Molecular docking analysis indicated higher affinities of second­generation TKIs for WT­FLT3/DFG­out and WT­FLT3/DFG­in compared with those of the first­generation TKIs. However, the ITD mutation changed the affinity of all TKIs. The in vitro data supported the in silico predictions: MV4­11 cells presented high selective sensibility to gilteritinib and quizartinib compared with the HL60 cells, whereas the drugs had no effect on PBMCs. Thus, the current study presented novel information about molecular interactions between the FLT3 receptors (WT or ITD­mutated) and some of their inhibitors. It also paves the way for the search for novel inhibitory molecules with potential use against AML.

Efficacy and safety of HAIC-FOLFOX plus tyrosine kinase inhibitors and immune checkpoint inhibitors as first-line treatment for unresectable advanced hepatocellular carcinoma: A systematic review and meta-analysis.

BACKGROUND: Advanced hepatocellular carcinoma (HCC) has been treated with targeted therapy, immunotherapy, or a combination of both, however, the overall clinical efficacy is still unsatisfactory. Hepatic arterial infusion chemotherapy (HAIC), as a localized treatment modality, has demonstrated favorable therapeutic efficacy in patients with advanced HCC accompanied by portal vein tumor thrombus and extensive intrahepatic metastasis. In recent years, the combination of HAIC with immune and targeted therapy has gradually gained acceptance in East Asian countries. However, further investigation is necessary to assess the efficacy and safety of this triple therapy. METHOD: PubMed, Embase, the Cochrane Library, and Web of Science databases were systematically searched for studies conducted within the past 5 years on HAIC combined with immunotherapy and targeted therapy as first-line treatment for advanced HCC. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted this meta-analysis. Additionally, the quality of included studies was assessed using the Joanna Briggs Institute (JBI) scale. Outcomes such as overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs)were extracted and pooled from eligible studies. RESULT: Twelve studies involving 1072 patients were enrolled in this meta-analysis. In terms of tumor response, the pooled ORR and DCR were 65.7% (95% CI, 58.7%-72.7%) (I2 = 83%, P = 0.000) and 89.2% (95% CI, 83.9%-93.6%) (I2 = 83%, P = 0.000), respectively. When analyzing PFS, the upper limit of 95% confidence interval of PFS in one study was not reached, which could potentially impact the statistical analysis. Therefore, we analyzed the remaining 11 studies a total of 1019 patients to pool mPFS, ultimately the pooled mPFS was 9.77months (95% CI, 7.73-11.80) (I2 = 93.9%, P = 0.000). Follow-up time in some studies was insufficient, only eight studies reported OS, we systematically analyzed these eight studies and extracted the pooled mOS was 16.65 months (95% CI, 14.17-19.14) (I2 = 76.9%, P = 0.000). In terms of safety, the incidence rates of any grade AEs, ranked from high to low, were as follows: aminotransferase increased (61.3%), nausea and vomiting (40.5%), hypertension (37.8%), thrombocytopenia (37.4%), hyperbilirubinemia (36.7%), abdominal pain (35.6%), leukopenia (34.6%), hypothyroidism (19.0%), rash (14.4%). Grade 3-4 AEs ranked from high to low were as follows: aminotransferase increased (10.8%), thrombocytopenia (7.9%), hypertension (7.4%), leukopenia (5.0%). No treatment-related deaths occurred, patients receiving this triple therapy demonstrated favorable tolerability. CONCLUSION: The combination of hepatic arterial infusion chemotherapy with tyrosine kinase inhibitors and immune checkpoint inhibitors as a first-line therapy for unresectable advanced HCC demonstrates promising therapeutic efficacy and favorable safety.

Insights into existing and futuristic treatment approach for chronic myeloid leukaemia.

Oncogenes play a crucial part in human cancer development, and when particular drugs obstruct the proteins produced by these oncogenes, the tumoural process can be ceased. For instance, in chronic myeloid leukaemia (CML), all pathological traits are associated with a single oncogene, BCR-ABL1. CML is a triphasic cancerous disorder of haematopoietic stem cells, marked by a balanced translocation between chromosomes 9 and 22, leading to the genesis of a Philadelphia chromosome encompassing the BCR-ABL1 fusion gene. This fusion oncogene further produces a constitutive active tyrosine kinase protein, enhancing the downstream signalling pathways and constitutes cancer. The treatment for CML has been entirely altered from chemotherapy and immunotherapy to targeted therapy with the emergence of tyrosine kinase inhibitors (TKIs) which inhibit BCR-ABL1 kinase activity. However, the inhibitory mechanism of TKIs is constrained by BCR-ABL1 dependent and independent resistance mechanisms, prompting the exploration of novel therapeutics through extensive clinical trials to develop next-generation drugs with enhanced potency. The persistent challenges posed by CML have motivated researchers to seek innovative strategies for its eradication, such as the application of the genome editing tool CRISPR/Cas9. This review provides insights into existing CML diagnoses, treatment modalities, resistance mechanisms, drugs under trial phases and new potential therapeutic drugs. Furthermore, the review looks ahead to a visionary perspective wherein the CRISPR/Cas9 approach holds the potential to evolve into a prospective curative measure for CML.