Survival analysis and prognostic factors in advanced NSCLC harboring EGFR PACC mutations: A multicenter retrospective study.

Asciminib represents a significant advancement in the treatment of chronic myeloid leukemia, establishing a novel therapeutic paradigm by specifically targeting the ABL1 myristoyl pocket, a mechanism distinct from that of conventional adenosine triphosphate-competitive inhibitors. Such a selective inhibitor offers an alternative treatment strategy for patients with chronic myeloid leukemia who have developed resistance to previous tyrosine kinase inhibitor therapies. Although asciminib demonstrates a superior safety profile, primarily characterized by a reduction in cardiovascular adverse events associated with prior tyrosine kinase inhibitors, its clinical significance extends further. The effectiveness of asciminib, combined with its capacity to overcome resistance through combination strategies with adenosine triphosphate-binding site tyrosine kinase inhibitors, establishes it as a focal point in emerging chronic myeloid leukemia treatment approaches. It remains essential to continue research and clinical trials to enhance the therapeutic efficacy of asciminib and manage its associated side effects.

Patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) have a poor prognosis. In Ph+ALL04, allogeneic hematopoietic stem cell transplantation (HSCT) in first complete remission (CR) was indicated for all patients, and was performed in those who remained in CR at the scheduled time of transplantation, with 4-year event-free survival (EFS) and overall survival (OS) rates of 54% (95% confidence interval [CI]: 38%-68%) and 78% (95% CI: 62%-88%), respectively. The Japan Children's Cancer Group conducted ALL-Ph13, a multicenter single-arm Phase 2 clinical trial, to improve outcomes and reduce HSCTs by using chemotherapy with tyrosine kinase inhibitors (TKIs) guided by minimal residual disease (MRD). The primary endpoint was the 3-year EFS rate. Between 2013 and 2017, 41 of 43 enrolled patients with Ph+ ALL aged 1-19years were eligible. Imatinib was started on Day 15 of induction and switched to dasatinib if MRD-positive after consolidation IB. TKIs were administered until the end of maintenance treatment (Week 104), with temporary discontinuation due to the severity of nonhematological adverse events and resumption at 80% of the original dose. When MRD was positive after the three HR blocks, HSCT was performed. Following four sepsis-related deaths, the protocol was amended in 2016, after which no such deaths occurred. Six patients (15%) underwent HSCT in the first CR, one per protocol indication and five without. The 3-year EFS and OS rates were 65% (95% CI: 48%-78%) and 85% (95% CI: 70%-93%), respectively. As several relapses occurred beyond 3years, the 5-year EFS and OS rates were also calculated: 48% (95% CI: 30%-64%) and 85% (95% CI: 70%-93%), respectively. Compared with Ph+ALL04, HSCT was substantially reduced in ALL-Ph13 while maintaining comparable outcomes. Further optimization of treatment, particularly the duration of TKI administration, is needed to maintain long-term EFS.

Tumor stiffness as an imaging biomarker of tyrosine kinase inhibitor response: A preclinical study.

Determinants of morbidity and local control after cryoablation of sporadic extra-abdominal desmoid tumors.

Mitochondrial dynamics play a crucial role in thyroid cancer progression by regulating apoptosis, metabolism, and oxidative stress. Ceritinib, a tyrosine kinase inhibitor, shows potential anticancer effects; however, its impact on mitochondrial function in thyroid cancer remains obscure. Herein, we aim to investigate the impact of ceritinib on the mitochondrial functionality in TPC-1 thyroid carcinoma cells and the underlying mechanism. Cell viability was assessed with the CCK-8 assay, and the cytotoxicity was determined by evaluation of the lactate dehydrogenase (LDH) release assay. Mitochondrial reactive oxygen species (ROS) were detected by MitoSOX Green staining. Enzyme-linked immunosorbent assay (ELISA) was applied for 8-hydroxydeoxyguanosine (8-OHdG) determination. Real-time PCR was employed for mRNA levels assessment, and western blotting was applied for protein levels. The morphology of mitochondria was evaluated by means of Mitotracker Red CMXRos staining. Ceritinib triggered mitochondrial oxidative stress, evidenced by elevated ROS and 8-OHdG levels, while suppressing manganese superoxide dismutase (Mn-SOD) activity. It also impaired mitochondrial respiration, ATP production, and Complex III activity, leading to dysfunction. Notably, ceritinib promoted mitochondrial fragmentation by enhancing dynamin-related protein 1 (Drp1) translocation to mitochondria, reducing l-OPA1 and increasing S-OPA1 levels, without altering mitofusins 1 and 2 (Mfn-1 and -2) expression. Mechanistically, ceritinib activated the Mitochondrial Calcium Uniporter (MCU)/calpain pathway, increasing MCU, calpain1/2, and calpain activity. Inhibition of MCU by RU360 reversed ceritinib-induced Drp1 mitochondrial translocation, fragmentation, and ATP depletion. Our findings reveal that ceritinib disrupts mitochondrial dynamics via the MCU/calpain/Drp1 axis. This study identifies a previously unreported mechanism for ceritinib in thyroid carcinoma, suggesting a novel therapeutic strategy.

Cancer arises and is resistant to therapy via intricate molecular networks that are poorly characterised. While individually, Cullin-3 (CUL3) and circular RNAs (circRNAs) have been reported to modulate cancer, their synergistic effect in the modulation of tyrosine kinase inhibitor (TKI) resistance is yet to be studied. An emerging circRNA-CUL3-TKI regulatory framework is highlighted as a potential contributor to oncogenesis and drug sensitivity in this review. We discuss how circRNA-associated networks may influence CUL3-dependent pathways implicated in tumour resistance to therapy by modulating autophagy, ferroptosis, stress-responses, and redox signalling. Exosomal circRNAs and circRNAs of the CUL3 gene itself are highlighted as dynamic mediators of resistance as well as biomarkers. How they interact with Kelch-like ECH-associated protein 1- Nuclear factor erythroid 2-related factor 2 (KEAP1-NRF2) signalling reveals that they enhance tumour survival under therapy pressure. By highlighting key processes of carcinogenesis and resistance, the circRNA-CUL3-TKI axis represents a testable therapeutic framework. Modeling circRNA networks, predicting TKI response, finding biomarkers, and developing personalised treatment plans are all made possible by applications of artificial intelligence and machine learning (AI/ML), as explored in this review. Antisense oligonucleotides, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based molecules, neddylation inhibitors or PROteolysis TArgeting Chimera (PROTACs) are examples of potential interventions that, when combined with AI/ML techniques, improve therapeutic efficacy and may inform future desensitisation strategies. These collectively emphasize the emerging applications for AI/ML in understanding the circRNA-CUL3-TKI crosstalk and developing methods to resensitize cancers that are resistant to therapy.

Demystifying targeting potential of surface-functionalized liposome for BTK inhibitor delivery in breast cancer therapy: Multiphase validation from in-silico to in-vivo.

Quercetin alleviates imatinib-induced premature ovarian insufficiency by regulating mitophagy via the ROS/JNK/c-JUN pathway.

HDAC1-modified lamin A/C drives nuclear deformation in RB1-deficient lung adenocarcinoma.

Identification of therapeutic targets and potential phytochemicals for UTI treatment from Myristica fragrans through CADD.

ABL2 rearrangements represent a subtype of acute lymphoblastic leukaemia (ALL) associated with poor prognosis and survival. This study reports a high-risk T-cell ALL (T-ALL) case with a novel TPR::ABL2 gene fusion resulting from a chromosomal deletion. Overexpression of TPR::ABL2 in Ba/F3 cells promoted cytokine-independent growth, demonstrating its oncogenic nature. Both primary patient and Ba/F3 cells carrying TPR::ABL2 exhibited kinase activation and sensitivity to tyrosine kinase inhibitors (TKIs). This study expands the repertoire of ABL2 fusions identified in ALL and supports the incorporation of TKIs into T-ALL treatment regimens to improve outcomes for this subtype.

Objective: To compare and analyze the efficacy and safety of immune checkpoint inhibitors (ICIs) combined with tyrosine kinase inhibitors (TKIs) as adjuvant therapy after surgery for hepatocellular carcinoma (HCC) with microvascular invasion (MVI). Methods: Patients with HCC accompanied with MVI who underwent R0 liver resection at the First Medical Center of the PLA General Hospital between January 2016 and December 2024 were retrospectively enrolled. The clinicopathological data, surgical details, and follow-up data were recorded. Adverse events after medication were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Recurrence-free survival (RFS) and overall survival (OS) curves were plotted using the Kaplan-Meier method and compared with the Log-rank test. The Cox proportional hazards regression model was used to analyze factors influencing recurrence. Results: The study included 39 patients in the adjuvant therapy group and 41 patients in the follow-up observation group. There were no significant differences in baseline characteristics between the two groups (all P>0.05). The follow-up time [M(Q1, Q3)] was 21.8 (10.9, 50.7) months. The RFS rates at 6, 12, 24, and 36 months in the adjuvant therapy group were 92.3%, 76.0%, 71.2%, and 51.8%, respectively, all higher than those in the follow-up observation group (75.1%, 56.3%, 44.3%, and 16.9%). The median RFS in the adjuvant therapy group was 46.7 months (95%CI:15.19-78.22), significantly better than the 19.33 months (95%CI: 3.22-35.44) in the follow-up observation group (P=0.004). The median OS was not reached in either group(P=0.480). Multivariate Cox analysis showed that postoperative adjuvant therapy (HR=0.46, 95%CI: 0.24-0.89, P=0.020) and liver cirrhosis (HR=2.22, 95%CI: 1.00-4.92, P=0.050) were influencing factors for RFS. In terms of safety, 43.59% (17/39) of patients in the adjuvant therapy group experienced grade 1-4 adverse events, and 15.38% (6/39) experienced grade 3 or higher adverse events, primarily manifested as abnormal liver and kidney function, rash, etc. No treatment-related deaths occurred, and the safety profile was manageable. Conclusion: For patients with HCC accompanied by MVI, postoperative adjuvant therapy with immunotherapy combined with targeted therapy significantly prolongs recurrence-free survival, reduces the risk of recurrence, and demonstrates a manageable safety profile.

Chronic myeloid leukemia (CML) was the first leukemia to be described in medical literature and remains one of the most well-studied hematologic malignancies. This review traces the historical evolution of CML research, from its first clinical recognition in the mid-19th century to modern molecular diagnostics and targeted therapy. Key milestones include the discovery of the Philadelphia chromosome in 1960, identification of the BCR::ABL1 fusion gene in the 1980s, and the subsequent development of tyrosine kinase inhibitors (TKIs). The introduction of imatinib in the early 2000s revolutionized CML treatment, transforming a fatal disease into a chronic condition with near-normal life expectancy for most patients. Second- and third-generation TKIs have since been introduced to overcome drug resistance and target specific BCR::ABL1 mutations, such as T315I. Recently, research has focused on mechanisms of TKI resistance, novel signaling pathways, and strategies to achieve treatment-free remission (TFR). Emerging therapies such as vamotinib, KF1601, and combination regimens are being explored. Furthermore, new insights into non-kinase functions of BCR::ABL1 and the role of microRNAs in resistance open additional therapeutic avenues. This review provides a concise overview of CML from a historical and molecular perspective, highlighting diagnostic advances, evolving response criteria, and future directions in treatment.

When EGFR meets MET: Dual blockade as the next post-TKI standard?

Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) typically have a poor prognosis. In preclinical studies, lenalidomide and a Bruton tyrosine kinase (BTK) inhibitor demonstrated synergistic antitumor effects. Zanubrutinib, a next-generation BTK inhibitor, has greater selectivity to minimize off-target binding. BGB-3111-110 was a phase 1 multicenter dose escalation/expansion study. Patients with R/R DLBCL received zanubrutinib 160 mg twice daily + lenalidomide (15, 20, or 25 mg once daily) until progression or unacceptable toxicity. Primary endpoints were safety, recommended phase 2 dose (RP2D), and overall response rate (ORR; Lugano 2014 criteria). Sixty-six patients were enrolled and treated. Patients had a median of 2 prior therapies, 83% had stage III/IV disease, and approximately 67% had non-geminal center B-cell-like or activated B-cell-like DLBCL. No dose-limiting toxicities occurred; the lenalidomide RP2D was 25 mg once daily when combined with zanubrutinib 160 mg twice daily. Grade ≥3 treatment-emergent AEs (TEAEs) occurred in 74%; the most common (>20%) grade ≥3 TEAEs were neutrophil count decreased (58%) and white blood cell count decreased (29%). TEAEs led to 7 treatment discontinuations (11%) and 2 deaths (3%). At the RP2D, ORR and complete response rate were 58% and 42%, respectively; median time to response was 2.8 months. Median duration of response was 14.9 months. Median progression-free survival was 5.5 months (95% CI, 2.9-11.1 months); the 12-month event-free rate was 34% (95% CI, 21%-48%). Zanubrutinib + lenalidomide demonstrated acceptable tolerability and antitumor activity in patients with R/R DLBCL. This trial was registered at ClinicalTrials.gov as #NCT04436107.

Nintedanib, a multitargeted tyrosine kinase inhibitor, is approved for idiopathic pulmonary fibrosis (IPF) for its ability to slow lung function decline. This study systematically evaluated the effects of nintedanib across three independent treatment intervention studies in the single-dose bleomycin (BLEO) mouse model of IPF. In each study, male C57BL/6J mice received a single intratracheal instillation of BLEO (n = 15-18) or saline (n = 10). Animals were randomised and stratified by body weight, and treatment assignment was assessed using noninvasive whole-body plethysmography 6 days after BLEO administration. BLEO-IPF mice were administered (PO, BID) vehicle, nintedanib (50 or 60 mg/kg), or an activin receptor-like kinase 5 inhibitor (ALK5i, SB525334, 60 mg/kg) for up to 21 days. In all studies, nintedanib consistently failed to improve lung health, as evaluated by lung function tests, biochemistry, histology and RNA sequencing. Plasma concentrations of nintedanib showed no correlation to any efficacy endpoint applied. Lung transcriptome signatures in nintedanib-treated BLEO-IPF mice indicated upregulated mRNA expression of p-glycoprotein, a known nintedanib efflux transporter, suggesting limited lung exposure of nintedanib in the model. In comparison, ALK5i significantly improved lung function and exhibited robust antifibrotic efficacy. Collectively, these findings challenge the use of nintedanib as a benchmarking drug in the single-dose BLEO-IPF mouse model.

Thyroid hormone (TH) homeostasis depends on the coordination of several key events to maintain proper local TH signaling, including iodide uptake, hormone synthesis, metabolism, and elimination. Three selenoprotein isoenzymes, deiodinases 1-3 (DIO1-3), are essential components of TH metabolism, and their activities have been identified as relevant endpoints regarding the screening of compounds influencing the TH system. Given the importance of DIO2 as the key enzyme for local activation of the prohormone T4 to the active T3 in various tissues, and limited data on selective biochemical DIO2 inhibition, there is a clear need to identify potent and selective DIO2-inhibiting compounds. Human-recombinant DIO2 enzyme pools were prepared from HEK293 cells overexpressing DIO2 and used as a robust enzyme source for the development, optimization, and semiautomated miniaturization of a nonradioactive DIO2 high-throughput screening (HTS) enzyme assay for the identification of DIO2-selective small molecule inhibitors. LT4 was used as substrate, and enzymatic release of iodide was colorimetrically quantified by the iodide-catalyzed Sandell-Kolthoff reaction. Eight comprehensive small molecule libraries were screened, covering ∼1/5 of the synthetic chemicals currently registered, natural products, as well as FDA-approved drugs. A total of 59,928 compounds were first screened at a single 10 µM concentration, followed by a validation screen to confirm the primary hits. Subsequently, DIO isoenzyme selectivity and cytotoxicity were evaluated. Utilizing this highly reproducible and robust HTS test system with a determined median Z'-factor of 0.70 identified 356 primary inhibitory hits. Concentration-response experiments verified 17 potent inhibitors, further characterized regarding their DIO isoenzyme selectivity and cytotoxicity. Six potent DIO2-selective inhibitors, including two FDA-approved drugs and various novel pan-DIO inhibitors, for example, the fungicide fluazinam, were identified. Specific DIO2 inhibitors, such as the FDA-approved drugs racecadotril and ibrutinib and the tyrosine kinase inhibitor rociletinib, might serve as a future toolbox for reversible pharmacological interference with the local provision of DIO2-generated T3 from T4 during development, tissue regeneration, and various DIO2-dependent metabolic processes. Furthermore, they can serve as reference compounds for the development and validation of regulatory in vitro tests. Identified FDA-approved drugs warrant a closer look at potential disturbances of local TH availability.

Molecular findings have led to adeeper understanding of the pathophysiology of numerous diseases and now form the basis for targeted treatment. An example of this is chronic myeloid leukemia (CML). The identification of the BCR::ABL1 translocation enabled the development of specific tyrosine kinase inhibitors. While the median survival time used to be 4 years, CML is now often achronic disease with anear-normal life expectancy thanks to targeted treatment; however, most tumor diseases are more complex at the molecular level. Advances in genome analysis enable increasingly more refined molecular characterization. Common tumor diseases are thus divided into increasingly smaller molecularly distinct segments, which become rarer as individual entities but can also be treated in amore targeted and individualized manner. The concept of personalized medicine is manifested in molecular tumor boards. Asimilar approach can start from rare genetic syndromes. In this case, understanding the underlying pathophysiology does not necessarily lead to acausal treatment of the syndrome itself but it does enable new treatment options for frequent diseases. An example is thyroid hormone resistance (RTH)β. Findings on the effect of thyroid hormone receptorβ in the liver have contributed to the development of analogues that can now be used specifically to treat metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis and can possibly also have the potential to reduce the progression of liver cirrhosis. Overall, close cooperation between human genetics and internal medicine can substantially contribute to an improvement in treatment success. Abetter understanding of molecular disease mechanisms enables an increasingly more precise, individualized and effective treatment.

Until the early 2020s, standard mantle cell lymphoma (MCL) treatment in Germany primarily included chemoimmunotherapy, autologous stem cell transplantation (autoSCT) for eligible patients in first line, and covalent Bruton tyrosine kinase inhibitors (cBTKis; ibrutinib at the time) for relapsed/refractory disease. However, real-world data on MCL treatment patterns and outcomes in Germany remain scarce. This retrospective observational study analyzed administrative claims data between 2015 and 2020. Annual incidence and prevalence, treatment patterns, healthcare visits, and overall survival (OS) were evaluated. Extrapolated to the German statutory health insurance population, annual MCL prevalence and incidence rates (per 100,000 individuals) ranged from 6.64 to 10.02 and from 1.28 to 2.06, respectively, showing an upward trend. Among 369 patients with MCL in the database (2015-2020) receiving at least one anti-cancer treatment, median age at diagnosis was 71 years and average Charlson Comorbidity Index was 2.9. In first-line, patients mainly received chemoimmunotherapy (77.2%; n = 285); 13.8% (n = 51) underwent autoSCT, and 30.9% (n = 114) received rituximab maintenance; in second-line (n = 193), 45.6% received chemoimmunotherapy and 22.3% a cBTKi. Median OS from diagnosis was 6.3 years. In cBTKi-treated patients (n = 82), median OS from first cBTKi therapy initiation (> 75% of the patients received cBTKi in second or third line) was 11.2 months, decreasing to 3.0 months from cBTKi discontinuation (n = 45). This study presents the first comprehensive analysis of MCL epidemiology, treatment patterns, and survival outcomes in Germany using claims data. Findings indicate rising MCL incidence and prevalence, a high treatment burden and poor survival outcomes, underscoring the need for treatment advancements.