Phenotypically plastic drug-resistant chronic myeloid leukaemia cell line displays enhanced cellular dynamics in a zebrafish xenograft model.

Understanding the mechanisms by which cancer cells switch between different adaptive states and evade therapeutic interventions is essential for clinical management. In this study, the in vivo cellular dynamics of a new chronic myeloid leukaemia cell line displaying altered phenotype and resistance to tyrosine kinase inhibitors were investigated in correlation with their parental cells for invasiveness/metastasis, angiogenic potential and population kinetics. We showed that the cells exhibiting drug resistance and plastic phenotype possess an increased capacity for invasion compared to their parental cells, that exposure to imatinib mesylate has the potential to enhance cellular motility and that in a leukaemic cell population, even a minority of plastic cells exhibit improved migratory ability. Furthermore, we show that these plastic cells have angiogenic and extravasation potential. The present study provides significant insights into the cellular dynamics displayed by a TKI-resistant, phenotypically plastic CML cell line, using a zebrafish (Danio rerio) xenograft model.

Impact of systemic steroids on the efficacy of first line imatinib treatment of patients with advanced gastrointestinal stromal tumors (GISTs).

BACKGROUND: Effective management of adverse events is required to maintain sufficient imatinib dosing when treating patients with gastrointestinal stromal tumors (GISTs). Skin rash is a common adverse event of imatinib, which can be effectively controlled by systemic steroid treatment without imatinib dose modification or interruption. However, the impact of the use of systemic steroids on the efficacy of imatinib treatment remains unclear. METHODS: Between October 2014 and February 2022, 277 consecutive patients from a prospective registry of GIST patients were included as the study population. Patients who started systemic steroids due to grade ≥ 3 skin rash or grade 2 skin rash with grade 2 pruritis were classified as the steroid group, whereas patients who did not develop a skin rash or those who did not require steroids for a mild skin rash were classified as the control group. Efficacy outcomes were compared between the two groups. RESULTS: Among the 277 patients, 30 (10.8%) were treated with systemic steroids for skin rash. There was no significant difference in progression free survival (PFS) or overall survival (OS) between the steroid and control groups (3-year PFS, 67.7% vs. 65.1%, p = 0.53; 3-year OS, 91% vs. 89.9%, p = 0.67, respectively). The use of systemic steroids was not an independent factor associated with PFS (hazard ratio 0.73, 95% confidence interval 0.36-1.49, p = 0.39) and OS (hazard ratio 0.37, 95% confidence interval 0.12-1.18, p = 0.09). In the steroid group, patients who successfully maintained the imatinib dosage showed a trend toward more favorable survival outcomes than those who did not (3-year PFS, 73.3% vs. 44.4%, p = 0.34; 3-year OS, 95.8% vs. 75.0%, p = 0.15, respectively). CONCLUSIONS: The use of systemic steroids for the control of imatinib induced severe skin rash did not adversely affect the efficacy outcomes of imatinib in patients with advanced GIST.

Response to Imatinib in a Patient With Gastric Adenocarcinoma With KIT Q556_K558 In-Frame Deletion: A Case Report.

Imatinib may be a useful targeted agent for patients with advanced gastric adenocarcinoma who have KIT mutations.

Clinical efficacy and safety of first-line nilotinib or imatinib therapy in patients with chronic myeloid leukemia-Nationwide real life data.

BACKGROUND: To evaluate the outcomes of first-line imatinib versus nilotinib treatment for chronic myeloid leukemia in the chronic phase (CML-CP) in real-world clinical practice. METHODS: A propensity score analysis was performed to eliminate imbalances between the treatment groups. In the analysis, 163 patients in the nilotinib group and 163 patients in the matched imatinib group were retrospectively evaluated. RESULTS: Nilotinib-treated patients achieved complete cytogenetic response (CCyR) and major molecular response more rapidly than imatinib-treated patients. However, there was no significant difference in 5-year overall survival (OS) or progression-free survival (PFS) between the two groups (OS: 94.3% vs. 90.5%, p = 0.602; PFS: 92.9% vs. 88.0%, p = 0.614). Nilotinib-treated patients had a higher failure-free survival (FFS) and event-free survival (EFS) than imatinib-treated patients (FFS: 71.7% vs. 54.3%, p = 0.040; EFS: 71.7% vs. 53.5%, p = 0.025). CONCLUSIONS: This retrospective analysis from clinical practice did not confirm any benefit of frontline nilotinib treatment for OS and PFS; however, it did demonstrate higher FFS and EFS in the nilotinib cohort.

Safety, effectiveness and the optimal duration of preoperative imatinib in locally advanced gastric gastrointestinal stromal tumors: A retrospective cohort study.

BACKGROUND: The optimal duration of preoperative imatinib (IM) remains controversial. This study aimed to evaluate the safety, therapeutic effectiveness, and optimal duration of preoperative IM in patients with locally advanced gastric gastrointestinal stromal tumors (GIST). METHODS: The clinicopathologic data of 41 patients with locally advanced gastric GIST who received preoperative IM and underwent surgical resection from January 2014 and December 2021 were retrospectively analyzed. RESULTS: After a median of 7.0 (IQR: 4.5-10) months of preoperative IM treatment, 30 patients experienced adverse events (AEs), 80% of which were grade 1/2 AEs. The mean tumor size decreased from 12.71 ± 5.34 cm to 8.26 ± 4.00 cm, with a reduction rate of 35%. Setting 8 months as the cut-off value according to the results of ROC analysis. The proportion of laparoscopic surgery was higher in patients with short-term (≤8 months) versus long-term (>8 months) preoperative IM. Compared with the subtotal/total gastrectomy group, patients in the local gastrectomy group exhibited less intraoperative blood loss, shorter length of postoperative hospital stay, and fewer postoperative complications. The 3-year recurrence-free survival (RFS) and overall survival (OS) rates were 82.9% and 97.6%, and the expected 5-year RFS and OS rates were 75.6% and 90.2% respectively. RFS was better in the short-term than in the long-term preoperative IM treatment group, and it was also better in pre- plus postoperative IM treatment group than that in the preoperative IM alone group. Both univariate and multivariate COX analysis showed that a higher mitotic index and long-term preoperative IM treatment were associated with worse RFS, while postoperative IM treatment could significantly improve RFS. CONCLUSIONS: The study suggests that in patients with locally advanced gastric GIST, preoperative short-term (≤8 months) use of IM is associated with higher RFS than long-term use.

A Rare Case of X-Linked Four-Way Philadelphia Chromosome Translocation with Therapeutic Challenges and Clonal Evolution.

BACKGROUND: Chronic myeloid leukemia (CML), a myeloproliferative neoplasm defined by the BCR::ABL1 fusion gene arising from the Philadelphia chromosome (Ph) translocation t(9:22)(q34;q11), exhibits diverse clinical courses often influenced by additional chromosomal aberrations (ACAs). This report presents a case of CML har-boring a novel four-way Ph translocation involving the X chromosome, offering insights into the interplay between complex karyotypes and treatment response and emphasizing the need for further research into the role of ACAs in CML management. METHODS: A 42-year-old man diagnosed with CML in the accelerated phase presented a novel four-way Ph translocation involving chromosomes X, 5, 9, and 22: 46,Y,t(X;5;9;22)(q26;q15;q34;q11.2). Despite achieving a major molecular response initially with imatinib and nilotinib, BCR::ABL1 levels (international scale) increased up to 24.0%, which prompted the use of second-line nilotinib. RESULTS: Follow-up bone marrow (BM) studies revealed clonal evolution with trisomy 8 and an unclassified ABL1 mutation (E292V), potentially contributing to resistance. Though a transient major molecular response (MMR) occurred after a switch to third-line dasatinib, this change failed to achieve a deep molecular response, and BCR-ABL1 levels were elevated above the MMR. CONCLUSIONS: This case highlights the challenge of ACAs impacting CML treatment response and prognosis. Limited knowledge exists on complex Ph translocations involving the X chromosome, but this report contributes data for further research. Understanding ACA effects on therapeutic response and prognosis requires a detailed study of such complex chromosomal aberrations.

Imatinib­ and ponatinib­mediated cardiotoxicity in zebrafish embryos and H9c2 cardiomyoblasts.

Tyrosine kinase inhibitors (TKIs) offer targeted therapy for cancers but can cause severe cardiotoxicities. Determining their dose­dependent impact on cardiac function is required to optimize therapy and minimize adverse effects. The dose­dependent cardiotoxic effects of two TKIs, imatinib and ponatinib, were assessed in vitro using H9c2 cardiomyoblasts and in vivo using zebrafish embryos. In vitro, H9c2 cardiomyocyte viability, apoptosis, size, and surface area were evaluated to assess the impact on cellular health. In vivo, zebrafish embryos were analyzed for heart rate, blood flow velocity, and morphological malformations to determine functional and structural changes. Additionally, reverse transcription­quantitative PCR (RT­qPCR) was employed to measure the gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), established markers of cardiac injury. This comprehensive approach, utilizing both in vitro and in vivo models alongside functional and molecular analyses, provides a robust assessment of the potential cardiotoxic effects. TKI exposure decreased viability and surface area in H9c2 cells in a dose­dependent manner. Similarly, zebrafish embryos exposed to TKIs exhibited dose­dependent heart malformation. Both TKIs upregulated ANP and BNP expression, indicating heart injury. The present study demonstrated dose­dependent cardiotoxic effects of imatinib and ponatinib in H9c2 cells and zebrafish models. These findings emphasize the importance of tailoring TKI dosage to minimize cardiac risks while maintaining therapeutic efficacy. Future research should explore the underlying mechanisms and potential mitigation strategies of TKI­induced cardiotoxicities.

Late presentation of chronic myeloid leukaemia patients in a low-income country: the prognostic implications and impact on treatment outcome.

BACKGROUND: In Nigeria, since 2002, Imatinib mesylate (glivec®) has been available freely to chronic myeloid leukaemia (CML) patients but only at a tertiary health care centre in the southwestern part of the country. Despite this, it is not readily accessible to many patients due to the distance and other challenges including low socioeconomic status and political problems, preventing timely access to specialist care. This study evaluated the effect of the baseline characteristics on the prognostic implication and treatment outcome of CML patients in Nigeria. METHOD: This study retrospectively evaluated the baseline characteristics, clinical presentations and treatment outcomes of 889 CML patients over 18 years (2002-2020). Of these, 576 (65%) patients had complete information with up-to-date BCR::ABL1 records. These 576 patients were categorized based on their responses to Imatinib therapy into three groups viz.; Optimal response (OR) defined as BCR::ABL1 ratio of < 0.1% or major molecular remission (≥ 3-log reduction of BCR::ABL1 mRNA or BCR::ABL1 ratio of < 0.1% on the International Scale), Suboptimal response (SR) with BCR::ABL ratio of 0.1-1%, and Treatment failure (TF) when MMR has not been achieved at 12 months. The variables were analyzed using descriptive and inferential statistics and a p-value < 0.05 was considered statistically significant. RESULTS: The result revealed a median age of 37 years at diagnosis with a male-to-female ratio of 1.5:1. The majority (96.8%) of the patients presented with one or more symptoms at diagnosis with a mean symptom duration of 12 ± 10.6 months. The mean Sokal and EUTOS scores were 1.3 ± 0.8 and 73.90 ± 49.09 respectively. About half of the patients presented with high-risk Sokal (49%) and EUTOS (47%) scores. Interestingly, both the Sokal (r = 0.733, p = 0.011) and EUTOS (r = 0.102, p = 0.003) scores correlated positively and significantly with the duration of symptoms at presentation. Based on response categorization, 40.3% had OR while 27.1% and 32.6% had SR and TF respectively. CONCLUSION: This study observed a low optimal response rate of 40.3% and treatment failure rate of 32.6% in our CML cohort while on first-line Imatinib therapy. This treatment response is strongly attributable to the long duration of symptoms of 12 months or more and high Sokal and EUTOS scores at presentation. We advocate prompt and improved access to specialist care with optimization of tyrosine kinase inhibitor therapy in Nigeria.

Imatinib mesylate reduces c-MYC expression in double-hit lymphoma cells by suppressing inducible cytidine deaminase.

BACKGROUND: Double-hit lymphoma (DHL) with c-MYC gene translocation is highly aggressive and has a poor prognosis. In DHL cells, activation-induced cytidine deaminase (AID) promotes antibody class switch recombination (CSR), ultimately leading to c-MYC gene translocation caused by Myc/IgH DNA double-strand breaks. However, currently there is still no method to suppress the expression of AID. METHODS: In this study, we compared the clinical significance of AID expression in DHL, Additionally, two human double-hit lymphoma cell lines were used to analyze the effect of imatinib mesylate on c-MYC in vitro, and the therapeutic effect was also evaluated in xenograft mouse models. RESULTS: Imatinib mesylate downregulated the AID and c-MYC proteins in patients with chronic myelogenous leukemia associated with DHL. In addition, imatinib mesylate reduced AID and c-MYC expression in SU-DHL-4 and OCI-Ly18 DHL cells. Imatinib mesylate exerted significant inhibitory effects on the proliferation and metastasis of SU-DHL-4 and OCI-Ly18 cells. Finally, imatinib mesylate reduced not only tumor burden in DHL mouse models, but also AID and c-MYC expression in vivo. CONCLUSION: These findings reveal that imatinib mesylate effectively reduces the carcinogenic function of c-MYC in DHL, providing novel strategies for developing therapies targeting c-MYC-driven DHL.

Nanoreactors with Cascade Catalytic Activity Reprogram the Tumor Microenvironment for Enhanced Immunotherapy by Synchronously Regulating Treg and Macrophage Cells.

Immunotherapy has been extensively utilized and studied as a prominent therapeutic strategy for tumors. However, the presence of a hypoxic immunosuppressive tumor microenvironment significantly reduces the efficacy of the treatment, thus impeding its application. In addition, the hypoxic microenvironment can also lead to the enrichment of immunosuppressive cells and reduce the effectiveness of tumor immunotherapy; nanoparticles with biocatalytic activity have the ability to relieve hypoxia in tumor tissues and deliver drugs to target cells and have been widely concerned and applied in the field of tumor therapy. The present study involved the development of a dual nanodelivery system that effectively targets the immune system to modify the tumor microenvironment (TME). The nanodelivery system was developed by incorporating R848 and Imatinib (IMT) into Pt nanozyme loaded hollow polydopamine (P@HP) nanocarriers. Subsequently, their surface was modified with specifically targeted peptides that bind to M2-like macrophages and regulatory T (Treg) cells, thereby facilitating the precise targeting of these cells. When introduced into the tumor model, the nanocarriers were able to selectively target immune cells in tumor tissue, causing M2-type macrophages to change into the M1 phenotype and reducing Treg activation within the tumor microenvironment. In addition, the carriers demonstrated exceptional biocatalytic activity, effectively converting H2O2 into oxygen and water at the tumor site while the drug was active, thereby alleviating the hypoxic inhibitory conditions present in the tumor microenvironment. Additionally, this further enhanced the infiltration of M1-type macrophages and cytotoxic T lymphocytes. Moreover, when used in conjunction with immune checkpoint therapy, the proposed approach demonstrated enhanced antitumor immunotherapeutic effects. The bimodal targeted immunotherapeutic strategy developed in the present study overcomes the drawbacks of traditional immunotherapy approaches while offering novel avenues for the treatment of cancer.

Small RNA activation of CDH13 expression overcome BCR-ABL1-independent imatinib-resistance and their signaling pathway studies in chronic myeloid leukemia.

BCR-ABL1-independent resistance to imatinib has no effective treatment due to its complexity and diversity. We previously reported that the CDH13 oncogene was expressed at low levels in BCR-ABL1-independent resistant CML cell lines. However, its effects on CML resistant cells and mechanisms remain unknown. This study investigated the effects of saRNA-based CDH13 activation on BCR-ABL1-independent imatinib resistance in CML and its underlying mechanism, and proposes a unique treatment method to overcome imatinib resistance. Specifically, this study demonstrated that using the DSIR (Designer of Small Interfering RNA) website tool, saRNAs targeting the CDH13 promoter region were generated and validated using qPCR and western blotting. Among the predicted sequences, C2 and C3 efficiently elevated CDH13 mRNA and protein expression, as well as inhibited the relative vitality of cells and the ability to form clones. After promoting CDH13 expression in K562-IMR cells, it inhabited the NF-κB signaling pathway and induced apoptosis in imatinib-resistant CML cells. LNP-saRNA (C3) was also observed to limit the growth of K562-IMR cells in vivo. From the above, the activation of CDH13 expression by saRNA promotes cell apoptosis by inhibiting the NF-κB signaling pathway to overcome to BCR-ABL1-independent resistance to imatinib in patients with CML.

Protective Effects of Imatinib on a DSS-induced Colitis Model Through Regulation of Apoptosis and Inflammation.

BACKGROUND/AIM: Inflammatory bowel disease (IBD) is characterized by dysregulated immune responses and a multifactorial etiology. While imatinib has demonstrated efficacy in the treatment of immune-related diseases, its potential effects in IBD treatment remain underexplored. MATERIALS AND METHODS: This study aimed to investigate the therapeutic effects of imatinib in colitis treatment. A dextran sulfate sodium (DSS)-induced colitis model was used to mimic IBD in mice. Imatinib was administered orally to mice simultaneously with DSS treatment. The effects of imatinib on DSS-induced colitis were evaluated by analyzing colitis-related pathology, including the disease activity index (DAI), histological lesions, inflammatory markers, and tight junction integrity. Additionally, western blot analysis and quantitative real-time polymerase chain reaction were used to assess inflammatory markers, tight-junction proteins, and cell death. RESULTS: In the DSS-induced colitis model, imatinib treatment exerted protective effects by attenuating weight loss, restoring colon length, reducing spleen weight, and improving the DAI score and histological lesions. Additionally, imatinib reduced the level of proinflammatory cytokines, including TNF-α, IL-6, and IL-1ß. Furthermore, imatinib treatment restored tight-junction integrity and decreased the expression of apoptosis marker proteins. CONCLUSION: Overall, imatinib treatment significantly alleviated the symptoms of DSS-induced colitis by influencing the expression of proinflammatory cytokines, tight junction proteins, and apoptotic markers in mice. These findings highlight imatinib as a potential therapeutic candidate for IBD.

[Effect of Csn-B Combined with Imatinib on Apoptosis of Chronic Myeloid Leukemia Cells through Nur77/Pim-1/Drp1 Pathway].

OBJECTIVE: To investigate the anti- chronic myelogenous leukemia (CML) activity of Nur77-specific agonist Csn-B combined with imatinib by promoting Nur77 expression, and explore the potential role of its signaling pathway. METHODS: Firstly, CCK-8 and Transwell assay were used to detect the inhibitory effects of Csn-B, imatinib, and their combination on the proliferation and migration of K562 cells. Furthermore, the apoptosis rate of K562 cells treated with Csn-B, imatinib, and their combination was detected by flow cytometry. The expression levels of Nur77, Pim-1, Drp1, p-Drp1 S616, Bcl-2 and Bax in K562 cells were detected by Western blot. Finally, the expression levels of reactive oxygen species (ROS) in K562 cells treated with Csn-B, imatinib and their combination were detected by immunofluorescence assay. RESULTS: The level of Nur77 in CML patients decreased significantly compared with normal population in dataset of GSE43754 (P < 0.001). Csn-B combined with imatinib could significantly inhibit the proliferation and migration of K562 cells (both P < 0.001), and induce apoptosis (P < 0.001). Csn-B promoted Nur77 expression in K562 cells, and synergistically enhanced imatinib sensitivity when combined with imatinib. Csn-B combined with imatinib could significantly enhanced ROS levels in K562 cells and mitochondria compared with single-drug treatment (both P < 0.001). CONCLUSION: Csn-B combined with imatinib can enhance ROS expression and induce apoptosis of K562 cells through Nur77/Pim-1/Drp1 pathway.

Imatinib therapy of chronic myeloid leukemia significantly reduces carnitine cell intake, resulting in adverse events.

OBJECTIVE: A prominent, safe and efficient therapy for patients with chronic myeloid leukemia (CML) is inhibiting oncogenic protein BCR::ABL1 in a targeted manner with imatinib, a tyrosine kinase inhibitor. A substantial part of patients treated with imatinib report skeletomuscular adverse events affecting their quality of life. OCTN2 membrane transporter is involved in imatinib transportation into the cells. At the same time, the crucial physiological role of OCTN2 is cellular uptake of carnitine which is an essential co-factor for the mitochondrial ß-oxidation pathway. This work investigates the impact of imatinib treatment on carnitine intake and energy metabolism of muscle cells. METHODS: HTB-153 (human rhabdomyosarcoma) cell line and KCL-22 (CML cell line) were used to study the impact of imatinib treatment on intracellular levels of carnitine and vice versa. The energy metabolism changes in cells treated by imatinib were quantified and compared to changes in cells exposed to highly specific OCTN2 inhibitor vinorelbine. Mouse models were used to test whether in vitro observations are also achieved in vivo in thigh muscle tissue. The analytes of interest were quantified using a Prominence HPLC system coupled with a tandem mass spectrometer. RESULTS: This work showed that through the carnitine-specific transporter OCTN2, imatinib and carnitine intake competed unequally and intracellular carnitine concentrations were significantly reduced. In contrast, carnitine preincubation did not influence imatinib cell intake or interfere with leukemia cell targeting. Blocking the intracellular supply of carnitine with imatinib significantly reduced the production of most Krebs cycle metabolites and ATP. However, subsequent carnitine supplementation rescued mitochondrial energy production. Due to specific inhibition of OCTN2 activity, the influx of carnitine was blocked and mitochondrial energy metabolism was impaired in muscle cells in vitro and in thigh muscle tissue in a mouse model. CONCLUSIONS: This preclinical experimental study revealed detrimental effect of imatinib on carnitine-mediated energy metabolism of muscle cells providing a possible molecular background of the frequently occurred side effects during imatinib therapy such as fatigue, muscle pain and cramps.

Intratumoral microbiome promotes liver metastasis and dampens adjuvant imatinib treatment in gastrointestinal stromal tumor.

Understanding the determinants of long-term liver metastasis (LM) outcomes in gastrointestinal stromal tumor (GIST) patients is crucial. We established the feature selection model of intratumoral microbiome at the surgery, achieving robust predictive accuracies of 0.953 and 0.897 AUCs in discovery (n = 74) and validation (n = 34) cohorts, respectively. Notably, despite the significant reduction in LM occurrence with adjuvant imatinib (AI) treatment, intratumoral microbiome exerted independently stronger effects on post-operative LM. Employing both 16S and full-length rRNA sequencing, we pinpoint intracellular Shewanella algae as a foremost LM risk factor in both AI- and non-AI-treated patients. Experimental validation confirmed S. algae's intratumoral presence in GIST, along with migration/invasion-promoting effects on GIST cells. Furthermore, S. algae promoted LM and impeded AI treatment in metastatic mouse models. Our findings advocate for incorporating intratumoral microbiome evaluation at surgery, and propose S. algae as a therapeutic target for LM suppression in GIST.

Natural compounds combined with imatinib as promising antileukemic therapy: An updated review.

Natural products (NP) have been an alternative therapy for several diseases for centuries, and they also serve as an essential source of bioactive molecules, enhancing our drug discovery capacity. Among these NP, some phytochemicals have shown multiple biological effects, including anticancer activity, with higher effectiveness and less toxicity than actual treatments, suggesting their possible use on resilient human malignancies such as leukemia. Imatinib mesylate (Im) is a selective tyrosine kinase inhibitor widely used as an anticancer drug, the gold standard to attend chronic myeloid leukemia (CML). Nevertheless, resistance to this drug in patients with CML renders it insufficient to eliminate cells with Philadelphia chromosome (BCR/ABL+). Moreover, recent studies show that imatinib can induce genotoxic and chromosomic damage in some in vitro and in vivo models. These facts urge finding new therapeutic alternatives to increase the effectiveness of antileukemic treatment. Recent research has shown that the combined effects of phytochemicals with imatinib can improve the cytotoxicity or resensitized the resistant cells to this drug in diverse leukemia cell lines. Independent mechanisms of action among phytochemicals and imatinib include BCR/ABL regulation, downregulation of transcription factors, inhibition of anti-apoptotic and activation of pro-apoptotic proteins, apoptosis induction dependent- and independent of ROS-overproduction, membrane functions disruption, induction of cell cycle arrest, and cell death. This review summarizes and discusses the synergic effect of some phytochemicals combined with imatinib on leukemia cells and the mechanism of action proposed for these combinations, looking to contribute to developing new effective alternatives for leukemia treatment.

Evaluation of in vivo pharmacokinetic study of the anti-cancer drug imatinib using silkworms as an animal model.

Imatinib is an oral molecular targeted therapy that acts as a tyrosine kinase inhibitor. Silkworms present a promising experimental model for elucidating the pharmacokinetic and toxicity profiles of various compounds. This study aimed to establish an experimental paradigm for investigating the pharmacokinetics of imatinib in silkworms. A comparative analysis of imatinib pharmacokinetic parameters across silkworms, humans, mice, and rats revealed similarities in time to maximum concentration (Tmax) and apparent clearance values between silkworms and humans. However, differences in elimination half-life (t1/2) and apparent volume of distribution between silkworms and humans remained within 5- and 4-fold ranges, respectively. Importantly, mice demonstrated pharmacokinetic parameters closer to those of humans than rats during imatinib studies. Additionally, silkworms and mice exhibit similar Tmax and t1/2 values. This study highlights the potential of silkworms as valuable tools for investigating imatinib metabolism in pharmacokinetic studies. Furthermore, it underscores the applicability of silkworms in elucidating the pharmacokinetic parameters of various molecular-targeted drugs, thus facilitating advancements in drug development and evaluation.

Gastrointestinal stromal tumours: incidence, recurrence and mortality. A decade of patients from a New Zealand tertiary surgical centre.

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract. The New Zealand (NZ) population incidence has not previously been documented nor has the potential effect of ethnicity been reviewed. We furthermore wanted to assess the difference between those undergoing a wedge resection versus a more extensive operation which we hypothesised would correlate with recurrence and mortality. METHODS: All patients (n = 103) with a GIST diagnosed and treated at Te Whatu Ora Waitemata (Auckland, New Zealand) between 2012 and 2021 are presented. Patient demographics, method of GIST detection, management approach, index surgery, histological features, use of adjuvant and neoadjuvant imatinib, follow-up, recurrence and mortality rates were analysed. RESULTS: This paper reports the largest NZ GIST cohort to date and estimates an incidence of 17 cases per million per year. Eighty-four patients underwent surgical resection, 58 received a wedge resection and 17 received a more extensive operation. Five-year disease-free survival rates were 100% in the low/very low risk, 90% in the intermediate and 59% in the high risk groups as determined by the modified NIH criteria. Our overall 5-year GIST-specific survival rate was 83%; it was 91% in those who underwent a wedge resection and 60% in the extensive operation group. There is evidence that Maori have higher rates of GIST recurrence compared to non-Maori and are more likely to require an extensive surgical resection.