Search Results (50)

Objectives: A high-performance liquid chromatography (HPLC) with mass spectrometry (MS) detection method was developed to quantify several tyrosine kinase inhibitors (TKIs) and their relevant metabolites. This method is suitable for therapeutic drug monitoring (TDM) of alectinib, brigatinib, dabrafenib, lenvatinib, lorlatinib, osimertinib and trametinib in patients with solid tumors using volumetric absorptive microsampling (VAMS^®). Methods: The HPLC-MS system contained four pumps, a Turboflow HTLC CycloneTM 1.0 × 50 mm solid phase extraction column for analyte enrichment, and a Kinetex 2.6 µm C18 100Å, 100 × 3.0 mm column for analyte separation. An acetonitrile–water gradient was used for the separation, and the ions generated by ESI (+)-ionization were detected in single-ion mode. This method was validated according to recent European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines. Results: The accuracy and precision shown during method validation were within the acceptable limits for all analytes in plasma and whole blood. All analytes showed acceptable stability in both matrices for at least 28 days when stored at −21 °C. So far, 100 venous plasma and 94 capillary blood samples have been collected and analyzed. Conclusions: We developed a reliable method to quantify several TKIs from plasma and capillary blood, which is intended for TDM purposes in clinical practice. Full article

Background: Neuroblastoma is a common extracranial solid malignant tumor of early childhood; however, mandibular involvement is rare and may mimic odontogenic or inflammatory disease. Case Presentation: We report an 8-month-old girl with left paramandibular swelling initially suspected to represent parotitis or odontogenic inflammation. Imaging revealed a destructive mandibular lesion with sunburst periosteal reaction, and histology confirmed undifferentiated neuroblastoma. Staging identified a left primary adrenal tumor with extensive bone marrow infiltration and MYCN proto-oncogene amplification. The patient received multimodal high-risk neuroblastoma therapy, including chemotherapy, surgery, autologous stem cell transplantation, proton therapy, antibody therapy, and Lorlatinib. Despite radiological remission, she developed severe pulmonary complications and died shortly before the age of five years. Methods: A focused literature review was conducted to identify published pediatric cases of metastatic neuroblastoma involving the mandible. Results: Through our review, we identified 31 published pediatric cases of mandibular metastatic neuroblastoma. Reported cases most commonly described mandibular swelling, pain, tooth mobility, and facial asymmetry. Most mandibular lesions represented metastatic disease from an adrenal or abdominal primary tumor. Conclusions: Mandibular involvement of neuroblastoma is rare but clinically important. In infants and young children, persistent or atypical (para-/peri)mandibular swelling should not be assumed to be odontogenic or inflammatory. Early imaging, biopsy, and interdisciplinary referral are essential for timely diagnosis and treatment. Full article

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have dramatically transformed the clinical management of ALK-rearranged non-small cell lung cancer (NSCLC). Successive generations of ALK inhibitors have been developed to overcome resistance mediated by kinase domain mutations, culminating in the third-generation inhibitor lorlatinib. Despite these advances, resistance remains inevitable, and durable disease control is rarely achieved. While resistance driven by single ALK mutations has been extensively characterized and structurally classified, the emergence of compound ALK mutations under sequential TKI therapy represents a qualitatively distinct and insufficiently conceptualized resistance state. This issue is becoming more complex as lorlatinib is increasingly used in the first-line setting, where resistance may arise from an ALK TKI-naïve background rather than from tumors already shaped by sequential ALK inhibition. In this review, we propose a unified framework that integrates structural single ALK resistance mutations (Types 1–3) with compound ALK mutations (Type 4) as a distinct evolutionary entity. We argue that compound mutations mark a critical inflection point at which ALK dependency reaches its functional limit, explaining the failure of even highly potent inhibitors such as lorlatinib. Importantly, we discuss how certain compound mutations paradoxically restore sensitivity to earlier-generation TKIs, highlighting the value of structural interpretation over linear drug sequencing. Finally, we discuss the transition toward ALK-independent resistance and future strategies incorporating dynamic molecular monitoring and structure-agnostic therapies. This framework may help clinicians interpret resistance mechanisms and guide rational treatment selection in daily practice. Full article

Background: Lung adenocarcinoma (LUAD) is the most common type of lung cancer and a major cause of cancer death. Zinc finger proteins (ZNFs) have been implicated in LUAD progression, functioning either as oncogenes or tumor suppressors. Therefore, an in-depth investigation of ZNFs may contribute to the development of novel diagnostic and therapeutic strategies for LUAD. Methods: Transcriptomic and clinical data were obtained from the TCGA and GEO databases. Prognosis-related ZNF genes were identified using univariate Cox, LASSO, and multivariate Cox regression analyses. An eight-gene ZNF-based prognostic signature was constructed and validated in two independent external cohorts (GSE50081 and GSE26939). A nomogram integrating independent prognostic factors was developed. Immune infiltration, somatic mutation profiles, and drug sensitivity were systematically analyzed. We further focused on FGD3, a key gene from the signature, examining its expression in LUAD cells and tissues, including lorlatinib-resistant models. Results: The prognostic signature comprising TRIM6, TRIM29, CTCFL, FGD3, GATA4, CASZ1, TRAF2, and ZNF322 effectively stratified patients into distinct risk groups with significantly different overall survival (p < 0.05). The risk score, together with T and N stage, served as independent prognostic predictors (n = 500, p < 0.05). High-risk patients exhibited an immune-desert phenotype, increased tumor mutational burden, and distinct drug sensitivity patterns. Notably, FGD3 expression was downregulated in LUAD tissues (n = 14, p < 0.0001) and lorlatinib-resistant cells, and its restoration suppressed resistant cell proliferation and partially reversed drug resistance. Conclusions: This study establishes a promising ZNF-based prognostic model for LUAD, providing a potential tool for risk stratification and individualized therapeutic decision-making. The identification of FGD3 as a potential mediator of drug resistance highlights its promise as a candidate biomarker and therapeutic target in LUAD. Full article

Anaplastic lymphoma kinase (ALK) rearrangement is a well-established oncogenic driver alteration in non-small cell lung cancer (NSCLC), and ALK tyrosine kinase inhibitors (TKIs), particularly lorlatinib, have significantly improved the prognosis of ALK-positive NSCLC patients. Although high programmed death-ligand 1 (PD-L1) expression (≥50%) is generally associated with favorable responses to immune checkpoint inhibitors (ICIs), PD-L1 has not been shown to reliably predict ICI benefit in ALK-rearranged disease, and optimal management after ALK TKI resistance remains challenging. Herein, we report a case of an elderly patient with ALK-rearrangement and exceptionally high PD-L1 expression (TPS ≥ 95%) NSCLC who experienced disease progression following first-line lorlatinib with genetically confirmed MET amplification. The patient subsequently received an exploratory combination of continued lorlatinib plus envafolimab and achieved partial response (PR) with manageable tolerability after 4 months, highlighting a potential sequential strategy that may warrant further investigation in select ALK-positive NSCLC patients exhibiting both bypass pathway activation and exceptionally high PD-L1 expression. Full article

Anaplastic lymphoma kinase (ALK), a member of the receptor tyrosine kinase family, plays a central oncogenic role in the initiation and progression of diverse malignancies. Aberrant ALK activation generally results from structural alterations or dysregulated expression, leading to persistent activation of downstream signaling pathways that drive tumor cell proliferation, survival, and metastasis. ALK gene abnormalities predominantly encompass fusions, point mutations, and amplifications, with EML4-ALK-positive non–small cell lung cancer representing a canonical example. The advent of ALK-targeted inhibitors has constituted a major therapeutic milestone for ALK-positive tumors. From first-generation Crizotinib to third-generation Lorlatinib, successive agents have been refined for target selectivity, central nervous system penetration, and coverage of resistance-associated mutations, substantially improving patient survival and intracranial disease control. Nonetheless, the emergence of acquired resistance remains an overarching challenge, mediated by secondary kinase domain mutations, activation of bypass signaling pathways, and tumor phenotypic transformation. This review presents an integrative synthesis of ALK-targeted therapeutic developments, elucidates underlying resistance mechanisms, and surveys emerging strategies, providing a comprehensive perspective on current advances and future directions in precision management of ALK-driven malignancies. Full article

ROS1 gene rearrangements define a distinct molecular subtype of non-small cell lung cancer (NSCLC), occurring in approximately 2% of cases and frequently associated with younger age, non-smoker status, and a high incidence of brain metastases. The discovery of ROS1 as an oncogenic driver has led to the development of targeted tyrosine kinase inhibitors (TKIs). Crizotinib first demonstrated substantial clinical benefit, but its limitations, including poor central nervous system (CNS) penetration and acquired resistance, highlighted the need for next-generation inhibitors. Several agents have since been developed, including entrectinib, lorlatinib, repotrectinib, taletrectinib, and zidesamtinib, each offering improved intracranial (IC) activity and efficacy against resistance mutations, notably ROS1^G2032R. Despite these advances, optimal sequencing strategies remain undefined, and resistance ultimately emerges in most patients. This review provides an updated overview of ROS1 biology, diagnostic approaches, clinical outcomes with currently available TKIs, mechanisms of resistance, and ongoing challenges, emphasizing the rapidly evolving therapeutic landscape. Full article

Pediatric-type diffuse high-grade gliomas (pHGGs) tend to have a dismal prognosis. Some of these gliomas feature alterations in genes such as ROS1, ALK, MET, and NTRK1–3. Despite development of targeted agents, the therapeutic application of these agents in pHGGs is still unclear. The aim of this retrospective case series is to report the outcome of two patients with pHGGs who were treated at Arkansas Children’s Hospital with targeted agents (Cabozantinib for a MET fusion in patient 1 and Lorlatinib for an ALK fusion in patient 2) with an initial, objective response followed by treatment resistance. Each diagnosis was determined based on histology, targeted tumor sequencing, and methylation profiling. In both cases, relapse occurred while on targeted inhibition. Recurrent tumor sequencing for patient 2 revealed a MET copy gain suggesting a mechanism of resistance in this patient. Pediatric high-grade gliomas with targetable alterations can show objective responses to pathway inhibition. Relapse after initial response may warrant additional surgical samples to identify new alterations which can lead to changes in therapy. Larger prospective cohorts are needed to study targeted agents in this population, and earlier integration of these agents may be beneficial. Full article

Non-small cell lung carcinoma (NSCLC) is a prominent type, with an 85–90% incidence in all lung cancer cases. The evidence for a particular therapy strategy for people with NSCLC is still inadequate. This review evaluates NSCLC therapies that have passed phase IV trials, emphasizing their efficiency and adverse effects. Crucial therapeutic approaches, including dacomitinib, lorlatinib, durvalumab, osimertinib, and rivaroxban, are discussed, highlighting their mechanisms of action, uses, and adverse effects. Immune checkpoint medications are recommended because of their specific activity and minimal adverse reactions. The review also investigates cooperation therapies, such as targeting immune checkpoint inhibitors and hemostasis, alongside chemotherapy, as they offer potential for future therapies. However, further research is needed to improve the safety and efficacy of current treatments, and to explore novel ways to achieve better long-term outcomes. Full article

Background and Clinical Significance: Inflammatory myofibroblastic tumors (IMTs) are rare neoplasms with low metastatic potential but a high recurrence rate. Approximately 60–80% of IMTs harbor anaplastic lymphoma kinase (ALK) gene rearrangements, making ALK inhibitors (ALKis) a key therapeutic option. However, resistance to ALKis remains a significant clinical challenge, necessitating alternative treatment strategies. Case Presentation: We report the case of a 23-year-old woman diagnosed with a metastatic TPM3::ALK fusion-positive IMT, initially managed with crizotinib and ceritinib. Disease progression prompted a switch to alectinib, followed by lorlatinib in combination with immune checkpoint inhibitors (nivolumab + ipilimumab). The patient tolerated this regimen well, with manageable side effects, and has remained progression-free for over three years, demonstrating the potential efficacy of ALK-ICI combination therapy. Conclusions: This case highlights the rapid development of resistance to first- and second-generation ALKis and the emerging role of immune checkpoint inhibitors (ICIs) in IMT treatment. PD-L1 expression in ALK-positive IMTs suggests an immune escape mechanism, supporting combination ALK-ICI therapy as a viable approach. The successful long-term disease control achieved in this case underscores the importance of molecular profiling in guiding personalized treatment strategies for IMT. This report contributes to the growing body of evidence supporting precision medicine and immunotherapy in rare sarcomas. Full article

Cancer remains a major global health burden driven by complex biological mechanisms, and while targeted therapies like tyrosine kinase inhibitors (TKIs) have revolutionized treatment, their efficacy and safety are significantly influenced by drug–drug interactions (DDIs). Tyrosine-kinase receptors (RTKs) regulate critical cellular processes, and their dysregulation through mutations or overexpression drives oncogenesis, with TKIs designed to inhibit these aberrant signaling pathways by targeting RTK phosphorylation. Pharmacokinetic DDIs can critically impact the efficacy and safety of TKIs such as erlotinib, gefitinib, and pazopanib by affecting their absorption, distribution, and metabolism. The modification of pH can influence drug absorption; furthermore, the inhibition or induction of metabolizing enzymes may affect biotransformation, while distribution can be altered through the modulation of transmembrane transporters. Additionally, ensuring quality of life during TKI treatment requires vigilant monitoring and management of adverse events, which range from mild (e.g., rash, diarrhea, fatigue) to severe (e.g., hepatotoxicity, cardiotoxicity). Drug-specific toxicities, such as hyperlipidemia with lorlatinib or visual disturbances with crizotinib, must be assessed using specific criteria, with dose adjustments and supportive care tailored to individual patient responses. Thus, optimal TKI therapy relies on managing drug interactions through multidisciplinary care, monitoring, and patient education to ensure safety and treatment efficacy. Full article

Choosing the optimal first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK) rearrangements can be challenging in daily practice. Although clinical trials with next-generation ALK-tyrosine kinase inhibitors (TKIs) have played a key role in evaluating their efficacy and safety, which patients benefit from a specific ALK-TKI may still be questioned. The methodological inconsistencies in these trials, which led to the inclusion of different patient populations, appear to have been inadequately addressed. ALK-rearranged NSCLC is a heterogeneous disease, and co-existing molecular alterations may affect the outcome. The questions explored in these trials appear insufficient to support a personalized approach to the first-line treatment, while defining long-term responders and early progressors would be clinically useful. This narrative review presents several considerations from oncologists’ and pathologists’ perspectives. We propose defining favorable and unfavorable features, such as histology, type of ALK fusion, co-existing molecular alterations, plasma circulating tumor DNA (ctDNA, performance status, and brain metastases, to help identify patients with lower and higher risk of progression. Consequently, the most potent ALK-TKI to date, Lorlatinib, may be considered as the first-line treatment for high-risk patients with unfavorable features, while sequencing of ALK-TKIs may be appropriate for low-risk patients with favorable features. Although ALK signal inhibition is critical in this disease, it may not be sufficient for clinical control due to de novo co-alterations. A more personalized approach to first-line therapy requires consideration of risk factors for each patient. Full article

Background/Objectives: Neuroblastoma (NB) is a childhood cancer with heterogeneous characteristics, posing challenges to effective treatment. NBs express somatostatin receptors that facilitate the use of somatostatin analogs (SSTAs) as tumor-seeking agents for diagnosis and therapy. High-risk (HR) NBs often have gain-of-function mutations in the receptor tyrosine kinase anaplastic lymphoma kinase (ALK). Despite intensive multimodal treatment, survival rates remain below 40% for children with HR-NB. The aim of this work was to investigate the combined effect of the SSTA ¹⁷⁷Lu-octreotide with the ALK inhibitor lorlatinib. Methods: Mice bearing human HR-NB CLB-BAR tumors were treated with lorlatinib, ¹⁷⁷Lu-octreotide, and a combination of these pharmaceuticals or saline (control). Tumor volume was monitored and tumor samples were evaluated for cleaved caspase-3 and expression of 84 human genes involved in apoptosis. Results: Combination treatment with ¹⁷⁷Lu-octreotide and lorlatinib demonstrated synergistic antitumor effects. An increased number of cleaved caspase 3-positive cells was observed in tumors from mice treated with ¹⁷⁷Lu-octreotide alone and in combination with lorlatinib. Modulation of Bcl-2 family gene expression was observed only in the presence of both ¹⁷⁷Lu-octreotide and lorlatinib, with BID down-regulated and HRK up-regulated on days 2 and 7, respectively. Conclusions: The data suggest that ALK signaling pathway inhibition may contribute to radiosensitization in radionuclide therapy with ¹⁷⁷Lu-octreotide and could improve treatment outcomes in patients with HR-NB. Full article

Lorlatinib has been FDA-approved as a systemic therapy for ALK/ROS1-positive non-small cell lung cancer (NSCLC) patients. However, it has been associated with an increased frequency of neurocognitive adverse events (NAEs). Therefore, we conducted a systematic review and meta-analysis to assess the NAEs related to lorlatinib therapy in NSCLC patients. PubMed, Scopus, the Cochrane Library, and prominent conference proceedings were searched for eligible studies of lorlatinib in NSCLC patients. NAEs included cognitive, mood, speech, and psychotic effects. A total of 1147 patients from 12 studies were included; 62% had brain metastases. A pooled analysis of NAEs showed frequencies of cognitive effects of 14.57% (95% CI, 8.37 to 24.14, I2 = 84%), mood effects of 11.17% (95% CI, 5.93 to 20.07, I2 = 84%), speech effects of 7.24% (95% CI, 3.39 to 15.20, I2 = 72%), and psychotic effects of 4.97% (95% CI, 3.27 to 7.49, I2 = 21%). Clinical trials reported a significantly higher frequency of mood effects than was indicated by real-world data. These results highlight the importance of educating patients and healthcare professionals about lorlatinib-related NAEs for early detection and management to improve NSCLC patients’ quality of life. Full article

Lorlatinib is a pharmaceutical ALK kinase inhibitor used to treat ALK driven non-small cell lung cancers. This paper analyses the intersection of past published data on the physiological consequences of two unrelated drugs from general medical practice—itraconazole and cilostazol—with the pathophysiology of ALK positive non-small cell lung cancer. A conclusion from that data analysis is that adding itraconazole and cilostazol may make lorlatinib more effective. Itraconazole, although marketed worldwide as a generic antifungal drug, also inhibits Hedgehog signaling, Wnt signaling, hepatic CYP3A4, and the p-gp efflux pump. Cilostazol, marketed worldwide as a generic thrombosis preventative drug, acts by inhibiting phosphodiesterase 3, and, by so doing, lowers platelets’ adhesion, thereby partially depriving malignant cells of the many tumor trophic growth factors supplied by platelets. Itraconazole may enhance lorlatinib effectiveness by (i) reducing or stopping a Hedgehog-ALK amplifying feedback loop, by (ii) increasing lorlatinib’s brain levels by p-gp inhibition, and by (iii) inhibiting growth drive from Wnt signaling. Cilostazol, surprisingly, carries minimal bleeding risk, lower than that of aspirin. Risk/benefit assessment of the combination of metastatic ALK positive lung cancer being a low-survival disease with the predicted safety of itraconazole-cilostazol augmentation of lorlatinib favors a trial of this drug trio in ALK positive lung cancer. Full article