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Chronic Myeloid Leukemia (CML) requires consistent medication adherence to Imatinib (IM) for optimal outcomes, however, adherence to oral chemotherapy is challenging. This observational study explores the relationship between patient knowledge, motivation, and adherence to IM therapy, and their collective impact on clinical outcomes. A prospective, observational study was conducted with 101 CML patients. The 6-Item Morisky Medication Adherence Scale (MMAS-6) was used to assess adherence, motivation, and knowledge levels. The study found that high motivation was significantly associated with lower BCR-ABL expression (p = 0.025). Patients with high knowledge and motivation had a 71% favorable response rate, compared to 0% in those with low knowledge and motivation (p = 0.01). As conclusion both patient motivation and knowledge are crucial for favorable treatment outcomes in CML. High levels of both significantly correlate with better clinical responses. Tailored interventions to enhance patient knowledge and motivation are essential. [ABSTRACT FROM AUTHOR]

Background: Chronic Myeloid Leukemia (CML) is the most prevalent blood malignancy in India. Anemia, splenomegaly, weight loss, fatigue are the most common symptoms and Imatinib, a first generation Tyrosine kinase inhibitor (TKI) is the choice of treatment. Aim: The objective of the study was to assess the etiology of anemia in CML and the pattern of pharmacotherapy, medication adherence, and adverse drug reaction (ADR) in these patients in a tertiary care government hospital. Methods: This cross-sectional observational study was conducted between January 2023 and May 2024 on 40 patients of all age groups and of both sexes, presented with CML and anemia to the outpatient department of hematology. General, hematological and cytogenetic investigations were done to assess the outcome of treatment. Drug adherence and ADRs were also assessed. Results: Of the participants 25% were male and Imatinib mesylate, was the mainstay of treatment (92%) which is supplied free of cost. A high rate of medication adherence was noted (85%). A total of 70 ADRs were noted among the patients participating in the study commonest being anemia (55%). Conclusion: Anemia remains a major problem in the management of CML patients and needs continuous assessment and management. [ABSTRACT FROM AUTHOR]

Copyright of Journal of China Medical University is the property of Journal of China Medical University Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Aim: Paclitaxel and imatinib mesylate are drugs used in the treatment of breast cancer. Conventional drug-delivery systems have limitations in the effective treatment of breast cancer using the drugs. Materials & methods: Combination index studies were used to identify the optimum ratio of both drugs showing maximum synergistic effect. Using a systematic quality-by-design approach, protamine-coated PLGA nanoparticles co-loaded with paclitaxel and imatinib mesylate were formulated. Further characterization and cell line evaluations were performed. Results: Encapsulation efficiency obtained was 92.54% for paclitaxel and 75.12% for imatinib mesylate. A sustained (24 h) and controlled zero-order drug release was obtained. Conclusion: Formulated nanoparticles had a low IC50 value and enhanced cellular uptake. Graphical Abstract Article highlights Paclitaxel and imatinib (PXL and IMA) show synergistic efficacy against the MCF-7 cell line of breast cancer. PXL and IMA in the ratio of 4:1 show maximum effect and lowest combination index (CI). Quality-by-design methodology led to optimization and systematic formulation of coloaded protamine-coated PLGA nanoparticles. Protamine decreased the initial burst release of the formulations. A sustained zero-order drug release was obtained for both the formulations. Protamine coating was clearly visible on images using transmission electron microscopy analysis. Significant reduction in IC50 values showing increased cytotoxicity was observed. Roughly 30-fold increase in cellular uptake was obtained as compared with free drugs. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Steroid-refractory cGVHD (SR-cGVHD) presents new great challenges for treatment. We have reported that imatinib monotherapy was effective to SR-cGVHD, but the CR rate was not satisfactory and the benefit was not showed specific to some target organs, previously. Imatinib and statin drugs have been recognized to regulate T-cell function, statins also have been demonstrated endothelia protection, but whether this combination therapy was able to improve the efficacy remains unknown. Therefore, we designed this prospective, single-arm, open-label trial to investigate the efficacy of imatinib-based combination therapy in the treatment of SR-cGVHD for the first time. Methods: Sixty SR-cGVHD patients were entered into this trial to investigate the combination of imatinib mesylate and atorvastatin calcium for the treatment of SR-cGVHD. The primary endpoint included the overall response rate (ORR) after 6 months of combined treatment. The secondary endpoints included an evaluation of survival, changes in T-cell subsets, and adverse events. Results: At baseline, 45% (27/60) of patients had moderate cGVHD, and 55.0% (33/60) of patients had severe cGVHD. At the 6-month follow-up, a clinical response was achieved in 70.0% of patients, and a complete response (CR) was achieved in 26.7%. A total of 11.7% (7/60) of patients stopped immunosuppressive therapy at this point. After 6 months of treatment, the ORR rates of the liver, skin, eyes, and oral cavity were 80.6%, 78.1%, 61.5%, and 60.9%, respectively, with the liver also having the highest CR of 58.1%. The patients with moderate cGVHD had a better CR rate than those with severe cGVHD (55.6% vs. 3.0%, p < 0.0001). The overall survival in patients with ORR was improved (p = 0.0106). Lung involvement is an independent risk factor to affected ORR achievement (p = 0.021, HR = 0.335, 95% CI: 0.133–0.847), and the dosage of steroids was reduced in ORR patients. In clinical response patients, the ratio of CD8+ T cells (p = 0.0117) and Th17 cells (p = 0.0171) decreased, while the number of Treg cells (p = 0.0147) increased after 3 months. The most common adverse events were edema, nausea, and neutropenia, which were 13.3%, 11.7%, and 11.7%, respectively. Conclusion: Combination treatment with imatinib mesylate and atorvastatin calcium was effective in treating SR-cGVHD and significantly decreased target organ injury, especially liver damage, indicating that T-cell regulatory function may play an important role in this process. [ABSTRACT FROM AUTHOR]

Objective: Rare coexistence of disease or pathology. Background: Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by the presence of the Philadelphia (Ph) chromosome, which results from the fusion of the translocation of the ABL1 gene from chromosome 9 to the BCR gene located in chromosome 22, forming the BCR-ABL gene on chromosome number 22, which accounts for approximately 95% of CML cases. Complex translocation involving other chromosomes can occur. Case Report: We present a rare case of CML with a variant Ph chromosome, in which chromosome 16 was involved with the usual translocation. A 34-year-old woman presented with a history of left upper quadrant pain and excessive sweating, with no hepatosplenomegaly on examination. She was found to have leukocytosis, with elevated neutrophils (34 000/mm3), basophils (1460/mm3), and eosinophils (2650/mm3). Karyotyping showed a translocation (16;22) (q24,q11.2), and FISH analysis showed BCR-ABL fusion as a result of (9,22) translocation, with a third chromosome (chromosome 16) involved and fused with chromosome 22, with a different breakpoint, which has never been reported in the literature, affecting the long arm of chromosome 16. The patient was treated with a first-generation tyrosine kinase inhibitor (imatinib) and achieved a deep molecular remission. The repeated FISH analysis confirmed the disappearance of both translocations (9,22) and (16,22). Conclusions: The impact of the additional chromosomal aberration in CML is widely heterogeneous, and the outcome is dependent on multiple factors. Larger studies are needed to clarify the outcome in CML with variant Ph chromosomes, as most of the available data come from reported cases. [ABSTRACT FROM AUTHOR]

Copyright of Iraqi Journal of Science is the property of Republic of Iraq Ministry of Higher Education & Scientific Research (MOHESR) and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

BACKGROUND: Thyroid toxicity has been reported with tyrosine kinase inhibitors (TKIs) such as sunitinib and sorafenib, targeting angiogenic tyrosine kinase receptors. However, the effect of imatinib, a first-line TKI for chronic myeloid leukemia (CML) patients on the thyroid, has been inconclusive. Of note, imatinib remains the mainstay of treatment for BCR::ABL1-positive Nigerian CML patients. AIM: We evaluated the effect of imatinib mesylate on the thyroid and its function in BCR::ABL1 positive CML patients and assessed the effect of the continuous imatinib use on thyroid features. PATIENTS AND METHODS: This prospective cohort study included 50 imatinib-naive patients with BCR::ABL1-positive CML and 50 age- and sex-matched apparently normal controls without any underlying thyroid disorder or on any thyroid medication. Serum free triiodothyronine (fT3), free thyroxine (fT4), and thyroid-stimulating hormone (TSH) were measured at baseline for both the CML patients and the controls and were repeated at 1, 3, and 6 months for the CML patients while on imatinib therapy. RESULTS: Subclinical hypothyroidism was observed in 7 of 50 (14%) of the patients with CML at 6 months on imatinib. Six of these patients were female, while 1 was male. The mean values for the serum fT3 (pmol/L), serum fT4 (pmol/L), and TSH (μIU/mL) for the CML subjects versus controls were 4.22 ± 0.79 versus 4.31 ± 0.31 (t = −0.27 P = 0.532), 17.13 ± 2.49 vs. 16.39 ± 2.16 (t = 1.605 P = 0.112), and 1.58 ± 0.74 versus 1.63 ± 0.64 (t = −0.399 P = 0.691), respectively. CONCLUSION: This study confirmed subclinical hypothyroidism as an adverse effect of continuous imatinib use with a prevalence of 14% in Nigerian CML patients. [ABSTRACT FROM AUTHOR]

Objective: Congenital defects/diseases Background: H syndrome is an autosomal recessive disorder of histiocytic proliferation with clinical spectrum of unique cutaneous and systemic manifestations. There is no consistent treatment for the disease, and all available options are based on case reports. Here, we present the chronological progression of a case of H syndrome with typical cutaneous manifestations that was misdiagnosed early as meningitis-induced sensorineural hearing loss and later as a non-defined autoimmune connective tissue disease. A new tried, although failed, treatment option is described as well. Case Report: A 31-year-old Saudi woman born of a consanguineous marriage presented to our dermatology clinic with symmetrical indurated hyperpigmented to violaceous plaques over the medial thighs, upper legs, lower back, volar wrists, and upper arms, associated with hypertrichosis. Hallux valgus of the big toes was clinically detected as well. She had a history of sensorineural deafness, diabetes mellitus, chronic anemia, and hypothyroidism. Genetic analysis of the patient showed a homozygous frameshift pathogenic variant of the SLC29A3 gene, c.243del p.(Lys81Asnfs*20). Systemic treatments in the form of methotrexate and imatinib had been tried; however, both failed to control her sclerotic cutaneous changes. Conclusions: Knowing the early life presentation and the variable clinical symptoms of H syndrome is crucial in early intervention and further prevention of the non-reversible changes. Moreover, avoiding unnecessary immunosuppressive medication use is warranted in certain circumstances. [ABSTRACT FROM AUTHOR]

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the digestive tract and arise from the interstitial cells of Cajal in the mesenteric plexus. These tumors can originate in any part of the GI tract; however, a higher burden has been observed in the stomach and small intestines. Mesenteric GISTs are exceedingly rare, with unique clinicopathological features and a poorer prognosis. Herein, we describe a unique case of a 66-year-old female with a remote history of appendectomy who presented to the emergency room complaining of severe abdominal pain and vomiting. On imaging, the patient was found to have a large inflammatory mass associated with small bowel loops, and the pathology confirmed a mesenteric GIST. The tumor was resected, and the genomic test results confirmed the KIT (exon 11) mutation. Although the tumor had a low mitotic rate, the tumor was large enough to warrant the initiation of adjuvant imatinib mesylate for 36 months with regular bloodwork and imaging. [ABSTRACT FROM AUTHOR]

Idiopathic Inflammatory Myopathies are rare conditions with several heterogeneous disease subtypes. They can range from limited muscle or skin involvement to severe, systemic, life-threatening disease. Although the etiology is unknown, some evidence suggests a role for external agents, particularly drugs. Herein, we present a case of a 71-year-old woman with chronic myeloid leukemia who developed imatinib-induced dermatomyositis sine dermatitis. The presentation was predominantly muscular, characterized by proximal muscle weakness and myalgia of the lower limbs, with positive anti-Mi2a antibodies. Spontaneous recovery was observed after drug discontinuation, without the need for immunosuppressive therapy. This is the first confirmed description of an imatinib-induced dermatomyositis sine dermatitis. It reflects the importance of a high awareness from rheumatologists and hematologists to accurately anticipate and identify similar situations. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Anorectal gastrointestinal stromal tumors are extremely rare, constituting less than 0.1% of rectal tumors. Surgical resection using a transanal wide excision followed by adjuvant therapy with tyrosine kinase inhibitors can be a successful treatment combination to remove the mass and prevent recurrence while preserving the integrity of the anal sphincter. Gastrointestinal stromal tumors (GISTs) are a rare subset of neoplasms, accounting for about 1%–2% of primary gastrointestinal malignancies. The stomach is the most common site for GISTs, with anorectal GISTs being exceptionally rare, representing only 0.1% of all rectal tumors. The standard approach for managing localized GIST involves complete surgical excision to achieve negative microscopic margins (R0) while preserving the tumor capsule and maintaining anal sphincter function. Surgical resection with transanal wide excision followed by adjuvant therapy using tyrosine kinase inhibitors can successfully remove the mass, prevent recurrence, and preserve the anal sphincter's integrity. Adjuvant therapy with imatinib is the recommended treatment for all localized GISTs assessed to have an intermediate or high risk of relapse. Here, we report a case of a 63‐year‐old male with a rectal GIST who underwent transanal wide excision followed by adjuvant therapy with tyrosine kinase inhibitors. [ABSTRACT FROM AUTHOR]

A novel, sensible, rapid, reliable and economical analytical hyphenated LC-MS/MS method has been developed as a key for the safety surveillance in chronic leukemia patients, and as a part of therapeutic drug monitoring of imatinib mesylate in human saliva. Imatinib mesylate or imatinib methane sulfonate is a tyrosine kinase inhibitor, apoptosis inducer and also known to be an anticoronaviral agent. Imatinib mesylate is a monomesylate salt of imatinib used for the treatment of gastrointestinal tumors and chronic myelogenous leukemia, and also in other complex malignancies. The lmax of imatinib mesylate was observed at 258 nm by UV spectrometry, establishing a very good linearity along with sensitivity. The detection limit (LOD) =0.2925 µg mL-1 and quantitation limit (LOQ)= 0.8977 µg mL-1 were obtained from the linear concentrations taken in the range of 2-12 µg mL-1. The correlation coefficient (r2) found was 0.999. The method validation parameters according to ICH Q2 (R1) were performed. The developed method described here, UPLC-MS/MS, was found to be novel, sensitive and rapid with improved results when successfully tested for human saliva samples without significant differences in the steady state imatinib mesylate concentrations. Current method could overcome the safety issues during therapeutic drug monitoring and pharmacokinetic behavior of the drug when tested clinically. [ABSTRACT FROM AUTHOR]

To develop a PEGylated and CD44-targeted liposomes, enabled by surface coating with hyaluronic acid (HA) via amide bond to improve the efficacy of imatinib mesylate (IM), for tumor-targeted cytoplasmic drug delivery. HA was covalently grafted on DSPE-PEG2000-NH2 polymer. HA-modified or unmodified PEGylated liposomes were prepared with ethanol injection method, and the stability, drug release, and cytotoxicity of these liposomes were studied. Meanwhile, intracellular drug delivery efficiency, antitumor efficacy, and pharmacokinetics were also investigated. Ex vivo fluorescence biodistribution was also detected by small animal imaging. In addition, endocytosis mechanism was also explored HA-coated PEGylated liposomes (137.5 nm ± 10.24) had a negative zeta potential (−29.3 mV ± 5.44) and high drug loading (27.8%, w/w). The liposomes were stable with cumulative drug leakage (<60%) under physiological conditions. Blank liposomes were nontoxic to Gist882 cells, and IM-loaded liposomes had higher cytotoxicity to Gist882 cells. HA-modified PEGylated liposomes were internalized more effectively than non-HA coating via CD44-mediated endocytosis. Besides, the cellular uptake of HA-modified liposomes also partly depends on caveolin-medicated endocytosis and micropinocytosis. In rats, both liposomes produced a prolonged half-life of IM (HA/Lp/IM: 14.97h; Lp/IM: 11.15h) by 3- to 4.5-folds compared with the IM solution (3.61h). HA-decorated PEGylated liposomes encapsulated IM exhibited strong inhibitory effect on tumor growth in Gist882 cell-bearing nude mice and formation of 2D/3D tumor spheroids. The Ki67 immunohistochemistry result was consistent with the above results. IM-loaded PEGylated liposomes modified with HA exerted the excellent anti-tumor effect on tumor-bearing mice and more drugs accumulated into the tumor site. [ABSTRACT FROM AUTHOR]

Background: Barely two per million Belgian children/adolescents are diagnosed with chronic myeloid leukemia (CML) annually. In this retrospective study, we aimed to investigate the diagnostic features, clinical and laboratory characteristics, and treatment outcome of this rare entity. Methods: Medical records of all pediatric CML patients (age ≤ 17 years) diagnosed at the University Hospitals Leuven between 1986 and 2021 were reviewed. Results: Fourteen patients (median age at diagnosis 12.5 years) were included, all presenting in chronic phase. Five patients were diagnosed before 2003; main therapy included hydroxyurea (n = 5/5), interferon‐alfa (n = 3/5) and allogeneic hematopoietic stem cell transplantation (allo‐Tx) (n = 3/5). Complete hematologic response (CHR), complete cytogenetic response (CCyR) and major molecular response (MMR) was reached in resp. 4/5, 4/5 and in 2/3 of evaluable patients. Three patients progressed to accelerated/blast phase (median time 19 months) and 1/5 is alive and disease‐free at last follow‐up. Nine patients were diagnosed after 2003 and were treated with first generation (1°G) tyrosine kinase inhibitors (TKI): 3/9 subsequently underwent an allo‐Tx, 4/9 were switched to 2°G TKI, one patient was additionally switched to 3°G TKI. CHR, CCyR and MMR was reached in 9/9, 9/9 and 8/9 of these patients. No progression to accelerated/blast phase was observed and none of these patients deceased. At last follow‐up, 7/9 patients were in MMR or disease free, the two remaining patients did not reach or lost MMR, both related to compliance issues. Conclusion: Our study confirmed that TKI significantly improved the prognosis of pediatric CML. However, drug compliance poses a considerable challenge. [ABSTRACT FROM AUTHOR]

Cancer is still a global health problem. Among cancer types, breast cancer is the most frequently diagnosed one, and it causes a high mortality rate if not diagnosed in the early stages. In our study, imatinib encapsulated, nanosized, neutral/cationic liposome formulations were prepared as theranostic agents for breast cancer. After the characterization studies in which all liposomes exhibited proper profile owing to their particle size between 133 and 250 nm, polydispersity index values lower than 0.4, neutral and cationic zeta potential values, and high drug encapsulation efficiency, controlled drug release behaviors with zero‐order kinetic were obtained. The higher than 90% radiolabeling efficiency values were obtained thanks to the determination of optimum radiolabeling condition (80°C temperature, 5 mCi radioactivity, and 10 min incubation period). According to the resazurin assay evaluating the cytotoxic profile of liposomes on MCF7 cells, neutral empty liposome was found as biocompatible, while both cationic liposomes (empty and drug‐loaded ones) exhibited high nonspecific cytotoxicity at even low drug concentration due to the existence of stearyl amine in the formulations. However, dose‐dependent cytotoxic effect and the highest cellular binding capacity were obtained by imatinib loaded neutral liposomes. In conclusion, 68Ga‐radiolabeled, imatinib‐loaded, neutral, nanosized liposome formulation is the most promising one as a theranostic agent among all formulations. [ABSTRACT FROM AUTHOR]

The formation of the BCR-ABL fusion gene drives human chronic myeloid leukemia (CML). The last 2 decades have witnessed that specific tyrosine kinase inhibitors (TKIs, e.g., imatinib mesylate, IM) against ABL1 improve disease treatment, although some patients still suffer from relapse and TKI resistance. Therefore, a better understanding of the molecular pathology of CML is still urgently needed. miR-181a-5p (miR-181a) acts as a tumor suppressor in CML; however, the molecular mechanism of miR-181a in CML stem/progenitor cells remains elusive. Herein, we showed that miR-181a inhibited the growth of CML CD34+ cells, including the quiescent subset, and sensitized them to IM treatment, while miR-181a inhibition by a sponge sequence collaborated with BCR-ABL to enhance the growth of normal CD34+ cells. Transcriptome data and biochemical analysis revealed that SERPINE1 was a bona fide and critical target of miR-181a, which deepened the understanding of the regulatory mechanism of SERPINE1. Genetic and pharmacological inhibition of SERPINE1 led to apoptosis mainly mediated by caspase-9 activation. The dual inhibition of SERPINE1 and BCR-ABL exhibited a significantly stronger inhibitory effect than a single agent. Taken together, this study demonstrates that a novel miR-181a/SERPINE1 axis modulates CML stem/progenitor cells, which likely provides an important approach to override TKI resistance. [ABSTRACT FROM AUTHOR]

Imatinib mesylate (IM), a tyrosine kinase inhibitor, has become a standard of care for the management of chronic myeloid leukemia. The safety profile of IM is favorable; however, few adverse effects such as gastrointestinal disturbances, fluid retention, skin rashes, and myelosuppression have been reported. Hypopigmentation of the skin is a rare adverse effect of IM. In this report, we describe two cases of chronic myeloid leukemia who developed skin hypopigmentation while on IM. [ABSTRACT FROM AUTHOR]

The aim of the project is to develop a fast, simple, precise, and cost-efficient RP-HPLC method for measuring the amounts of Imatinib mesylateand Anastrazole simultaneously in both pharmaceutical products and bulk samples. This technique has effectively achieved the separation of Imatinib mesylateand Anastrazole in large quantities. The separation was performed using a Phenomenex C18 150 x 4.6 mm, 5m analytical column at a wavelength of 280 nm. The mobile phase consisted of a mixture of methanol, water and acetonitrile in a ratio of 30:60:10. The pH of the buffer was adjusted to 5.5. The separation was carried out in isocratic elution mode with a flow rate of 1.0 ml/min. Imatinib mesylate had a retention time of 1.885 minutes, whereas Anastrazole showed a retention duration of 3.139 minutes. Quantitative analysis of Imatinib mesylate and Anastrazole was achieved using PDA detection at 285 nm using a linear calibration curve. The concentration ranges of 10-50 μg/ml (with a correlation coefficient of 0.9995) and 1-5 μg/ml (with a correlation coefficient of 0.9995) were used for reliable quantification. The limit of detection (LOD) for Imatinib mesylate was 3.1245 μg/ml, whereas the LOD for Anastrazole was 0.3356 μg/ml. The proposed method is highly suitable for use in quality-control laboratories for the bulk and pharmaceutical quantitative analysis of pharmaceuticals, whether used individually or in combination. This technique is characterised by its simplicity and efficiency, while yet ensuring a high level of accuracy and precision. [ABSTRACT FROM AUTHOR]

ETV6::ABL1 rearranged neoplasms are rare hematological diseases. To date, about 80 cases have been reported, including myeloid and lymphoid leukemias. The ETV6 gene codes for an ETS family transcription factor and several fusion partners have been described. When translocated, ETV6 causes the constitutive activation of the partner genes. Here, we report the case of a 54-year-old woman with a cryptic insertion of the 3′ region of ABL1 in the ETV6 gene. The patient was first diagnosed with idiopathic hypereosinophilic syndrome, according to the clinical history, conventional cytogenetics, standard molecular analyses and pathologist description. Next generation sequencing of diagnosis samples unexpectedly detected both ETV6::ABL1 type A and B fusion transcripts, which were then confirmed by FISH. The diagnosis was Myeloid/Lymphoid neoplasm with ETV6::ABL1 fusion, and the patient received imatinib mesylate treatment. In a follow-up after more than one year, the patient still maintained the molecular and complete hematological responses. This case highlights the importance of timely and proper diagnostics and prompt tyrosine kinase inhibitor treatment. [ABSTRACT FROM AUTHOR]

Introduction: Imatinib is a first-line selective tyrosine kinase inhibitor used for the treatment of chronic myeloid leukemia. Although imatinib-induced hepatotoxicity may aggravate the patient's clinical condition and alter the treatment plan, the mechanism of imatinib-induced hepatotoxicity has rarely been investigated. Case report: We report a 51-year-old man, suffering from acute toxic hepatitis after 5 months of imatinib treatment for chronic myeloid leukemia. Management and outcome: The outcome was favorable after discontinuation of treatment with normalization of biological liver function after 12 weeks. The treatment was switched to nilotinib without any incidents. Discussion: Regular liver function test monitoring is recommended during imatinib treatment. In fact of acute hepatic toxicity, treatment with imatinib should be stopped in the case of cytolysis more than five times the upper limit of normal. [ABSTRACT FROM AUTHOR]

In this work, copper oxide nanoparticles (CuO NPs) were successfully synthesized by a simple chemical process. After conjugation of 3-glycidoxypropyltrimethoxysilane (GPTMS), the surfaces of CuO NPs@ GPTMS were functionalized with hyaluronic acid (HA) and folic acid (FA) for the formation of CuO NPs@ GPTMS@HA-FA. The samples were characterized by field emission scanning electron microscopy (FE-SEM) and X-ray diffraction (XRD). Surface modification of CuO NPs with Fourier-transform infrared (FT-IR), thermo-gravimetric analysis (TGA), and CHN analysis was proven. Imatinib mesylate (IM) adsorption was studied under various conditions. The maximum sorption capacity was achieved at pH = 6, a contact time of 30 min, an adsorbent dosage of 0.01 g, and a temperature of 298 K. The evaluation of kinetic and isotherm models showed that the pseudo-second-order and Langmuir models were selected as the best fitting model to describe the adsorption method. In vitro release investigations of IM from the CuO NPs@ GPTMS@HA-FA were performed in stimulated human blood fluid (pH = 7.4) and cancer fluid (pH = 5.6) at 37 °C. Release of − 47.10% of IM from CuO NPs@ GPTMS@HA-FA was observed within a period of 6 h at pH = 5.6. The investigation shows that IM, an anticancer drug can be successfully entrapped in the CuO NPs@ GPTMS@HA-FA for the targeted delivery of cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Zinc finger protein X-linked (ZFX) has been shown to promote the growth of tumor cells, including leukemic cells. However, the role of ZFX in the growth and drug response of chronic myeloid leukemia (CML) stem/progenitor cells remains unclear. Methods: Real-time quantitative PCR (RT–qPCR) and immunofluorescence were used to analyze the expression of ZFX and WNT3 in CML CD34+ cells compared with normal control cells. Short hairpin RNAs (shRNAs) and clustered regularly interspaced short palindromic repeats/dead CRISPR-associated protein 9 (CRISPR/dCas9) technologies were used to study the role of ZFX in growth and drug response of CML cells. Microarray data were generated to compare ZFX-silenced CML CD34+ cells with their controls. Chromatin immunoprecipitation (ChIP) and luciferase reporter assays were performed to study the molecular mechanisms of ZFX to regulate WNT3 expression. RT–qPCR and western blotting were used to study the effect of ZFX on β-catenin signaling. Results: We showed that ZFX expression was significantly higher in CML CD34+ cells than in control cells. Overexpression and gene silencing experiments indicated that ZFX promoted the in vitro growth of CML cells, conferred imatinib mesylate (IM) resistance to these cells, and enhanced BCR/ABL-induced malignant transformation. Microarray data and subsequent validation revealed that WNT3 transcription was conservatively regulated by ZFX. WNT3 was highly expressed in CML CD34+ cells, and WNT3 regulated the growth and IM response of these cells similarly to ZFX. Moreover, WNT3 overexpression partially rescued ZFX silencing-induced growth inhibition and IM hypersensitivity. ZFX silencing decreased WNT3/β-catenin signaling, including c-MYC and CCND1 expression. Conclusion: The present study identified a novel ZFX/WNT3 axis that modulates the growth and IM response of CML stem/progenitor cells. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant treatment is recommended for large GISTs due to their friability and risk of extensive operations; however, studies on the indications and long-term results of this approach are lacking. Methods: Patients with large (≥ 10 cm) gastric GISTs were enrolled from multiple centers in Korea and Japan after a pathologic confirmation of c-KIT (+) GISTs. Imatinib (400 mg/d) was given for 6–9 months preoperatively, and R0 resection was intended. Postoperative imatinib was given for at least 12 months and recommended for 3 years. Results: A total of 56 patients were enrolled in this study, with 53 patients receiving imatinib treatment at least once and 48 patients undergoing R0 resection. The 5-year overall survival and progression-free survival rates were 94.3% and 61.6%, respectively. Even patients with stable disease by RECIST criteria responded well to preoperative imatinib treatment and could undergo R0 resection, with most being evaluated as partial response by CHOI criteria. The optimal reduction in tumor size was achieved with preoperative imatinib treatment for 24 weeks or more. No resumption of imatinib treatment was identified as an independent prognostic factor for recurrence after R0 resection. No additional size criteria for a higher risk of recurrence were identified in this cohort with a size of 10 cm or more. Conclusions: Neoadjuvant imatinib treatment is an effective treatment option for gastric GISTs 10 cm or larger. Postoperative imatinib treatment is recommended even after R0 resection to minimize recurrence. [ABSTRACT FROM AUTHOR]

The aim of this study was to prepare and characterize the imatinib mesylate (IM)-loaded gamboge-based ISG system for local administration of an anticancer agent against colorectal carcinoma. The ISG formulations were prepared in dimethyl sulfoxide (DMSO) and N-methyl-2-pyrrolidone (NMP). The physicochemical properties, drug release profile, and cytotoxicity of the developed formulations were assessed. The developed ISG demonstrated Newtonian flow behavior with acceptable rheological and mechanical properties. The viscosity of the developed ISG, measured at less than 80 cP, and the applied forces of less than 50 N·mm, indicated easy administration using clinical injection techniques. Upon contact with an aqueous phase, the ISG immediately formed a porous cross-sectional structure, enabling sustained release of IM over 14 days. The release profile of IM was fitted to the quasi-Fickian diffusion mechanism, and the release rate could be controlled by the types of solvent and the amount of IM content. The developed IM-loaded gamboge ISG effectively inhibited colorectal cancer cells, including HCT116 and HT29 cell lines, with less than 20% cell viability observed at a concentration of 1% w/w IM after 2 days of incubation. This suggests that the developed ISG may potentially serve as an injectable system for localized anticancer delivery against colorectal cells, potentially reducing the side effects of systemic chemotherapy and improving patient adherence. [ABSTRACT FROM AUTHOR]

In this case series we present the cases of two patients at a metastatic stage of stomach gastrointestinal stromal tumor, who received treatment with imatinib. After a period of disease stability patients showed signs of resistance to the first-line therapy and despite the promising switch to sunitinib, developed life-threatening complications. Salvage surgeries were performed, aimed at preserving patients life and simultaneously reducing the tumor mass. Operation greatly improved patients condition and allowed for successful continuation of tyrosine kinase inhibitor treatment, showing that surgery should be considered a viable complement to the chemotherapeutical treatment. [ABSTRACT FROM AUTHOR]

Introduction: Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the Philadelphia (Ph) chromosome. After the introduction of imatinib mesylate (IM) in 2000, the natural history of the disease changed. Data on the treatment of CML with IM are from randomized clinical trials. Establishing whether these results can be reproduced or if caution is needed when extrapolating data to the general population with CML is essential. Objectives: To evaluate the molecular response (MR) in patients with chronic-phase CML (CML-CP) not included in clinical studies and correlate them with the responses obtained in clinical trials. Methods: Between January 2007 and January 2017, 227 patients newly diagnosed with CML-CP treated with IM as first-line treatment were included. This study is an observational, retrospective, and single-center study. Results: At a median follow-up time of 7.3 years, 60.3% of the 227 patients who started IM were still on IM. Early molecular response (EMR) at 3 and 6 months was achieved by 74.2% and 65%, respectively. The median time to a MMR was nine months. The MR4.0 and MR4.5 were 67.2% and 51.1%, respectively. The overall survival (OS), progression-free survival (PFS), and event-free survival (EFS) of the patients who exclusively used IM were 91%, 91%, and 85.1%, respectively. Conclusion: The results presented are similar to those described in prospective and randomized trials, demonstrating that the outcomes are reproducible in the real world. EMR at 3 and 6 months reflects better long-term responses, including higher rates of deeper molecular responses. Considering treatment costs, the absence of literature evidence of an impact on overall survival demonstrated by first-line second-generation tyrosine kinase inhibitors (TKIs), and the global OS of 85.8%, imatinib mesylate (IM) is still an excellent therapeutic option. [ABSTRACT FROM AUTHOR]

Psoriasis is a chronic skin disorder characterized by a skin rash with scaly patches. Microvascular abnormalities are a characteristic feature of psoriasis and play a crucial role in the pathogenesis of psoriatic lesions. Angiogenic factors are upregulated in psoriatic skin lesions and are thought to induce angiogenesis. Platelet‐derived growth factor (PDGF) induces vascular endothelial growth factor (VEGF), and PDGF is upregulated in keratinocytes in psoriatic skin lesions. The present study aimed to investigate the effect of topical imatinib mesylate (IMT) in inhibiting the activation of PDGF signalling in the pathogenesis of psoriasis. When topically applied to the skin of mice with imiquimod (IMQ)‐induced psoriasis, IMT ameliorated skin symptoms similar to those of human psoriasis. Hyperproliferation of keratinocytes, hyperkeratosis, inflammatory cell infiltration and hypervascularity were histologically suppressed by topical IMT. The expression of angiogenic factors including fibroblast growth factor (FGF) and VEGF was decreased. The expression of FGF and VEGF in a PDGF‐stimulated fibroblast cell line was inhibited by IMT. PDGF is required for the signalling pathway producing angiogenic factors in fibroblast. Thus, topically applied IMT inhibits PDGFR activation in fibroblast and suppresses the production of angiogenic factors, thereby mitigating the symptoms of psoriasis. The inhibitory effect of IMT on angiogenesis suggests that topical application IMT may be a viable treatment option for psoriasis. [ABSTRACT FROM AUTHOR]

Imatinib mesylate, an anticancer drug, is prescribed to treat gastrointestinal stromal tumors and chronic myelogenous leukemia. A hybrid nanocomposite of N,S-doped carbon dots/carbon nanotube-poly(amidoamine) dendrimer (N,S-CDs/CNTD) was successfully synthesized and used as a significant modifier to design a new and highly selective electrochemical sensor for the determination of imatinib mesylate. A rigorous study with electrochemical techniques, such as cyclic voltammetry and differential pulse voltammetry, was performed to elucidate the electrocatalytic properties of the as-prepared nanocomposite and the preparation procedure of the modified glassy carbon electrode (GCE). A higher oxidation peak current was generated for the imatinib mesylate on a N,S-CDs/CNTD/GCE surface compared to the GCE and CNTD/GCE. The N,S-CDs/CNTD/GCE showed a linear relationship between the concentration and oxidation peak current of the imatinib mesylate in 0.01–100 μM, with a detection limit of 3 nM. Finally, the imatinib mesylate's quantification in blood-serum samples was successfully performed. The N,S-CDs/CNTD/GCE's reproducibility and stability were indeed excellent. [ABSTRACT FROM AUTHOR]

Background: Imatinib mesylate (IM) treatment adherence is a challenge, especially in an economic-social population neglected from developing countries. Objective: To create a new complementary audiovisual educational intervention model to improve IM treatment adherence of CML patients. Methods: Two adherence verification methods were applied before and after intervention: modified Morisky-Green test and molecular responses (BCR-ABL transcripts quantification). Adherence estimates were calculated using univariate and multivariate component analysis (MCA) for the socio-demographic and clinical characteristics of patients. Results: Modified Morisky-Green test results demonstrated a substantial increase of CML patient adherence from 23% (pre-film) to 65% (post-film). Greater improvement was obtained for patients presenting major molecular response (MMR) from 38% (pre-film) to 60% (post-film). Although slight gain for complete molecular response (CMR) from 23% (pre-film) to 26% (post-film) was achieved, it represents a total tumour regression. MCA identified that females <50 years-old, using less than two medications (no disease associated) and CMR condition were the most benefited with intervention. Conclusion: Audiovisual educational intervention was an effective complementary pro-adherence model, activating patient memory and improving IM treatment adherence. Although this intervention shows effective, not all patients responded as expected, being necessary a combination of educational and clinical interventions to improve IM adherence. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is an allergic disease mediated by Th2 cells. In AD, externally stimulated keratinocytes release inflammatory cytokines, such as IL‐33 and TSLP. Inflammatory cells infiltrate skin tissue and increase vascular permeability. Therefore, we hypothesized that imatinib mesylate (IMT), which suppresses vascular permeability, may be a candidate therapeutic agent for AD. A vitamin D3 analog (MC903) was administered daily to both ears of Balb/c mice to create a murine AD model to which IMT was applied. The skin lesions were evaluated histopathologically and by immunostaining. Cytokine expression in the skin was assessed by using real‐time polymerase chain reaction (PCR) and immunostaining and was investigated using Evans Blue to determine whether IMT suppressed vascular permeability due to histamine. The suppressive effect of TNF‐α/IL‐4‐induced TSLP expression in primary mouse keratinocytes (MKCs) treated with IMT was then investigated. Tslp gene and protein expression in the lesion was measured using real‐time PCR and ELISA. The activation of signal transduction was analysed by western blotting. Topical application of IMT significantly reduced ear thickness, Evans blue leakage, and scratch onset. IMT suppressed the number of infiltrating cells (CD4+ T cells, eosinophils, and basophils), and the expression of IL‐13, IL‐33, and TSLP in a MC903‐induced, murine AD model and inhibited TNF‐α/IL‐4‐induced TSLP expression via downregulation of ERK phosphorylation in MKCs. IMT reduced the skin symptoms in a MC903‐induced, murine AD model, suggesting that it may have potential as a new treatment for AD. [ABSTRACT FROM AUTHOR]

Background: Gastrointestinal stromal tumors (GISTs) are the prevailing sarcomas of the gastrointestinal tract. Tyrosine kinase inhibitors (TKIs) therapy, exemplified by Imatinib mesylate (IM), constitutes the established adjuvant therapy for GISTs. Nevertheless, post-treatment resistance poses a challenge that all patients must confront. The presence of tumor heterogeneity and secondary mutation mechanisms fail to account for some instances of acquired drug resistance. Certain investigations suggest a strong association between tumor drug resistance and mesenchymal stromal cells (MSC) in the tumor microenvironment, but the underlying mechanism remains obscure. Scarce research has explored the connection between GIST drug resistance and the tumor microenvironment, as well as the corresponding mechanism. Methods: Immunofluorescence and fluorescence-activated cell sorting (FACS) methodologies were employed to detect the presence of MSC in GIST samples. The investigation encompassed the examination of MSC migration towards tumor tissue and the impact of MSC on the survival of GIST cells under IM treatment. Through ELISA, western blotting, and flow cytometry analyses, it was confirmed that Transforming Growth Factor Beta 2 (TGF-β2) triggers the activation of the PI3K-AKT pathway by MSC, thereby facilitating drug resistance in GIST. Results: Our findings revealed a positive correlation between a high proportion of MSC and both GIST resistance and a poor prognosis. In vitro studies demonstrated the ability of MSC to migrate towards GIST. Additionally, MSC were observed to secrete TGF-β2, consequently activating the PI3K-AKT pathway and augmenting GIST resistance. Conclusions: Our investigation has revealed that MSC within GISTs possess the capacity to augment drug resistance, thereby highlighting their novel mechanism and offering a promising target for intervention in GIST therapy. [ABSTRACT FROM AUTHOR]

Targeted chemotherapies offer a great potential advantage due to their ability to enhance specificity to deliver high doses directly to the target site. Solid lipid nanoparticles (SLNs) of imatinib mesylate (IM) were formulated by high shear homogenization and probe sonication using glyceryl palmitostearate (GP) as lipid carrier and quillaja saponin (QS) as surfactant. Additionally, the SLNs were coated with hyaluronic acid (HA) to enhance specificity towards cancerous cells. The prepared SLNs were characterized for particle size, zeta potential, surface morphology, entrapment efficiency, in vitro release, and cytotoxicity. The least particle size of 92.1 ± 2.41 nm was observed for HA surface-modified SLNs of IM. As IM is a hydrophilic drug, the entrapment efficiencies of the formulations were low, with a maximum of 65.9 ± 0.6%, and in vitro release studies performed using phosphate buffer saline indicated that 100% of the drug was released in 10 h. The cytotoxicity and apoptosis studies of the free IM and its encapsulated form in SLNs, and HA-coated SLNs evaluated in MCF-7 breast cancer cell line suggested a synergistic effect. [ABSTRACT FROM AUTHOR]

Purpose: 9.4 T magnetic resonance imaging (MRI) has been initially tested on healthy human volunteers, but its future application will benefit more from experiments with animal disease models. In the meantime, high static magnetic fields (SMFs) have been shown to improve mice mental health and have anti-tumor potentials. Methods: We compared the anti-tumor effects of 9.4 T SMF with or without a commonly used chemotherapy drug imatinib mesylate on BALB/c (Nu/Nu) mice bearing gastrointestinal stromal tumor GIST-T1 cells. The body weight, food/water consumption, complete blood count, blood biochemistry, tumor weight, HE and Ki67 stains were examined. Locomotor activity and cognitive functions were also measured by four behavior tests, including open field, elevated plus maze, three-chamber and tail suspension tests. Results: We found that the tumor growth was inhibited up to 62.88% when treated with 9.4 T SMF alone for 200 h. More importantly, 9.4 T SMF combined with 20 mg/kg imatinib mesylate can result in 92.75% tumor suppression, which is close to the anti-tumor effect of high dose (80 mg/kg) imatinib. However, 80 mg/kg imatinib caused severe side effects, including significantly reduced gain of body weight, abnormal liver function and depressive behaviors in mice. In contrast, 9.4 T SMF treatment significantly reduced these side effects, especially for the depressive behaviors. Conclusion: Our results demonstrate that 9.4 T SMF not only has anti-tumor effects on its own, but also could improve the anti-tumor effect of imatinib mesylate, reduce its toxicity and improve the mice mental health, which unraveled the great clinical potentials of high SMF in future applications. [ABSTRACT FROM AUTHOR]

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Introduction: Imatinib Mesylate (IM), a tyrosine kinase inhibitor, has been reported to cause several adverse reactions, most of them with cutaneous involvement. Non- Lichenoid IM associated skin reactions have been sufficiently- recorded. To our knowledge, Lichenoid Drug Eruption (LDE) is recorded in a minority of registries. Case report: To describe an LDE induced case by IM treatment. Treatment and outcome: Histological Confirmation and promptly dermatological consultation relieved successfully the cutaneous adverse event. Discussion: Ongoing expansion of IM usage in a wide spectrum of new indications is more likely to make physicians experience such LDE cutaneous side effects more often. Hence, they should be highly suspicious to early detect these distinct histologic entities, handle these undesired complications and guarantee satisfactory immediate outcomes, avoiding frivolous IM dosage modifications. [ABSTRACT FROM AUTHOR]

Background: Imatinib mesylate (IM) is the treatment of choice in patients with chronic myeloid leukemia (CML). Among its nonhematological adverse events, water retention is the most common, together with weight gain. However, no thorough description of the body composition in these patients has been informed. Therefore, our purpose was to evaluate the nutritional status, body composition and handgrip-strength in patients with CML treated with IM. Methods: We conducted a cross-sectional study in 78 patients (n = 48 men, 30 women) with chronic myeloid leukemia in the chronic (82%) or accelerated (18%) phases. We assessed body mass index (BMI), body composition by bioelectrical impedance, performed vector analysis through Bioelectrical Impedance Vector Analysis, and handgrip-strength measurement in patients with at least 3 months of IM treatment. Hematocrit and hemoglobin values were collected from the medical charts. Results: BMI was within the normal range in 28.2%, indicated overweight in 39.7% and obesity in 30.8%. According to BIVA, 25.6% of the patients were muscle-depleted and were older (p = 0.006) and received lower doses of IM (p < 0.001). Conclusions: In patients with CML with ≥3 months of IM treatment muscular depletion is frequent and is related to lower doses of IM. [ABSTRACT FROM AUTHOR]

Introduction: In this research, a fit-for-purpose LC-MS/MS method for quantification of Imatinib Mesylate in rat plasma was developed and utilized for the pharmacokinetic study. Imatinib extraction was done and isolated from plasma samples using protein precipitation method. Imatinib quantification was done using Liquid Chromatography (LC) tandem Mass Spectrometry (MS) with Electro Spray Ionization (ESI) and Multiple Reaction Monitoring (MRM) in positive ionization mode. Objective: A simple and fast fit for purpose LC-MS/ MS method was developed and utilized for the quantification of Imatinib mesylate and was applied to a pharmacokinetic study. Methods: All the sample preparation was acquired and accepted through protein precipitation. High performance chromatographic partition was achieved on a PURITAS PNCN, (100 x 4.6 mm, 5 µm) CHROMACHEMIE analytical column by using an isocratic elution. Pump A (40%): 0.1% Formic acid in 5 mM Ammonium Formate Solution Pump B (60%): 0.1% Formic acid in acetonitrile at a flow rate of 0.8 mL/ min. for 5 mintues. Results: The retention time of Imatinib mesylate and its internal standard, Verapamil was 3.21 ± 0.8 min and 3.64 ± 0.5 min, respectively. The total run time was 5.0 minutes. The elution detection was obtained obtained with +ve electrospray ionization multiple reaction monitoring of the ion transitions at m/z 494.40 → 394.20 for Imatinib and second mass transitions were monitored: Imatinib at m/z 494.40 → 217.20 while internal standard Verapamil was selected for m/z 455.30 → 165.10. The method was developed and validated over the concentration range of 50- 5000 ng/mL for Imatinib mesylate, with correlation coefficient greater than 0.9991. The extraction recovery was more than 105.37% and the matrix effect was not significant. The intra and inter-day precisions were below 4.65% and accuracies ranged from 91.7 to 102.0%. The quantification limit for Imatinib was 5.05 ng/mL. Imatinib mesylate was demonstrated to be stable in rat plasma under the tested conditions. Conclusion: The developed LC-MS/MS fit-for purpose procedure for the quantification of Imatinib Mesylate in rat plasma can be used for pharmacokinetic studies in preclinical applications. [ABSTRACT FROM AUTHOR]

An intraarticular, liposphere-based, formulation of Imatinib mesylate for weekly administration was developed. Lipospheres were prepared using double emulsion technique using dierucoyl phosphatidylcholine, 1,2-dipalmitoyl-sn-glycero-3-phospho-rac-(1-glycerol) sodium salt), cholesterol, and tricaprylin as lipid phase in dichloromethane in a four-step process. Primary emulsion, formed using a high-pressure homogenizer, was diluted using a secondary aqueous phase in an Inline mixer to form the liposomal dispersion. Nitrogen flushing was done to remove dichloromethane, and the dispersion was finally centrifuged and adjusted for potency. The amount of cholesterol and triglyceride was taken as formulation variables, and speed of homogenization was used as a process variable in the Box-Behnken design while particle size, % drug entrapment, and drug release at the end of 4 h and 5 days were taken as response variables. Multivariate data analysis grouped the variables in two latent variable sets, one based on the speed and the other on the composition of lipospheres. Multiple linear regression analysis was used to generate mathematical model for each response. Constraints were put on the values of responses, as per the requirements of the final product, and the “freedom to operate” design space was located using an overlay plot. The center point batch sufficed all the set criteria, and Monte Carlo simulations on the factor variables indicated a defect rate of 5%. The center point batch was characterized for viscosity, osmolality, pH, drug release, and lipocrit value. The dispersion was charged in a prefilled syringe and studied for stability. The product was found to be stable at 2–8°C over a period of 6 months. [ABSTRACT FROM AUTHOR]

Purpose Desmoid tumor, also known as aggressive fibromatosis, is well-characterized by abnormal Wnt/β-catenin signaling. Various therapeutic options, including imatinib, are available to treat desmoid tumor. However, the molecular mechanism of why imatinib works remains unclear. Here, we describe potential roles of NOTCH2 and HES1 in clinical response to imatinib at genome and transcriptome levels. Materials and Methods We identified somatic mutations in coding and noncoding regions via whole-genome sequencing. To validate the genetic interaction with expression level in desmoid-tumor condition, we utilized large-scale whole-genome sequencing and transcriptome datasets from the Pan-Cancer Analysis of Whole Genomes project. RNA-sequencing was performed using prospective and retrospective cohort samples to evaluate the expressional relevance with clinical response. Results Among 20 patients, four (20%) had a partial response and 14 (66.7%) had stable disease, 11 of which continued for ≥ 1 year. With gene-wise functional analyses, we detected a significant correlation between recurrent NOTCH2 noncoding mutations and clinical response to imatinib. Based on Pan-Cancer Analysis of Whole Genomes data analyses, NOTCH2 mutations affect expression levels particularly in the presence of CTNNB1 missense mutations. By analyzing RNA-sequencing with additional desmoid tumor samples, we found that NOTCH2 expression was significantly correlated with HES1 expression. Interestingly, NOTCH2 had no statistical power to discriminate between responders and non-responders. Instead, HES1 was differentially expressed with statistical significance between responders and non-responders. Conclusion Imatinib was effective and well tolerated for advanced desmoid tumor treatment. Our results show that HES1, regulated by NOTCH2, as an indicator of sensitivity to imatinib, and an important therapeutic consideration for desmoid tumor. [ABSTRACT FROM AUTHOR]

(1) Background: The management of gastrointestinal stromal tumors (GIST) has significantly evolved over the last two decades, with the introduction of tyrosine kinase inhibitors (TKI). We aim to report 10 years of experience of GIST management at a regional cancer center in Canada. (2) Methods: We retrospectively analyzed the records of 248 consecutive patients diagnosed with GIST between 2011 and 2021. We describe the clinical and pathological data, management, and outcome, including survival. (3) Results: The most common GIST sites were the stomach 63% (156), followed by the small bowel 29% (73). At diagnosis, 83% (206) of patients had localized disease (stage I–III). According to the modified National Institutes of Health consensus criteria (NIH) for GIST, around 45% (90) had intermediate or high-risk disease. Most patients, 86% (213), underwent curative surgical resection. Forty-nine patients received adjuvant imatinib, while forty-three patients had advanced disease and received at least one line of TKI. With a median follow-up of 47 months, the 5-year recurrence-free survival (RFS) rates for very low and low risk were 100% and 94%, respectively, while those for intermediate and high risk were 84% and 51%, respectively. The 5-year overall survival (OS) rates for very low and low risk were 100% and 94%, while intermediate, high risk, and advanced were 91%, 88%, and 65%, respectively. Using the Kaplan–Meier method, there were statistically significant differences in RFS and OS between NIH risk groups, p < 0.0005. In univariate analysis, ECOG, site, mitosis, secondary malignancy, and size were predictors for OS. High mitosis and large size (>5 cm) were associated with worse RFS. (4) Conclusions: Curative surgical resection remains the gold standard management of GIST. Our results are comparable to the reported literature. Further research is needed to explore histology's role in risk stratification and initiating adjuvant TKI. [ABSTRACT FROM AUTHOR]

Dermatofibrosarcoma protuberans (DFSP) is a fibrohistiocytic tumor characterized by a high risk of local recurrence but a low risk of metastasis. A small subpopulation of DFSP undergoes fibrosarcomatous (FS) change, and approximately 15%–57% of cases of DFSP with FS change metastasizes, leading to a poor prognosis. In this report, a case of metastatic FS‐DFSP that was successfully treated with imatinib mesylate in which the IHC staining pattern of recurrent DFSP was quantitatively analyzed in primary and metastatic DFSP areas, is described. Importantly, the recurrent area was composed of two IHC staining patterns (CD34low PD‐L1high Ki67high, and CD34high PD‐L1low Ki67low pattern), while the metastatic area showed a clonal pattern (CD34high PD‐L1low Ki67intermediate) in the present case. In this report, we described a case of metastatic fibrosarcomatous DFSP successfully treated with imatinib mesylate. This case suggests a subpopulation of DFSP with a favorable metastatic pattern. [ABSTRACT FROM AUTHOR]

BACKGROUND: Imatinib mesylate is the cornerstone therapy in the management of chronic myeloid leukemia (CML). Monitoring of adverse drug reactions (ADRs) of imatinib in our patients is very important to ensure their safety. Aims and Objectives: The current study aims to monitor ADRs encountered in CML patients in the chronic phase with imatinib (400 mg/day). MATERIALS AND METHODS: This prospective, observational study was conducted from November 2011 to May 2015 on 310 patients presented to the Departments of Clinical Hematology and Pharmacology of SCB MCH, Cuttack, diagnosed with CML at chronic phase. Collected ADRs were entered in the ADR reporting form (PvPI) and were analyzed for causality and severity. RESULTS: Anemia was the most common hematological ADR, whereas hyperpigmentation and nausea were the most common nonhematological ADRs reported. Maximum ADRs were mild to moderate and required no change in the treatment course. CONCLUSION: The study revealed that imatinib mesylate, a well tolerated drug, has very few cases of severe ADRs in Indian patients at the chronic stable phase of CML. [ABSTRACT FROM AUTHOR]

Imatinib mesylate is used to treat various cancerous diseases. Lately, investigations have focused on the enhancement of chemotherapeutic agents. Thus, rifampicin is a promising candidate due to its chemosensitizing potential beyond its anti-infectious effects. In this study, a reliable separation method for imatinib mesylate and rifampicin have been developed. The HPLC analysis were performed on a C18 column (150 x 4.6 mm, 3 µm particle size) at 25 °C. The best UV decetection was observed at 254 nm. The mobile phase was set as acetonitrile and TEA/phosphate buffer (pH: 7.04; 0.1 M) (50:50, v/v) with isocratic elution. The flow rate was set as 0.8 mL/min. The method validation was performed according to the international guidelines with respect to selectivity, linearity, precision and accuracy, recovery and sensitivity. The detection and quantification limit of the method were 0.63 µg/mL and 1.90 µg/mL, respectively for imatinib mesylate, and 3.04 µg/mL and 9.22 µg/mL for rifampicin. The method was linear in the range of 10--90 µg/mL with determination coefficients (r2≥0.99) for both drugs. Precision, accuracy and recovery values (RSD<3%) of the method was convincing. Considering the various usage of imatinib mesylate and rifampicin, the developed method is applicable to different dosage forms. [ABSTRACT FROM AUTHOR]

Localized delivery systems have been typically designed to enhance drug concentration at a target site and minimize systemic drug toxicity. A rosin/cinnamon oil (CO) in situ forming gel (ISG) was developed for the sustainable delivery of imatinib mesylate (IM) against colorectal cancer cells. CO has been claimed to express a potent anticancer effect against various cancer cells, as well as a synergistic effect with IM on colorectal cancer cells; however, poor aqueous solubility limits its application. The effect of rosin with the adding CO was assessed on physicochemical properties and in vitro drug release from developed IM-loaded rosin/CO-based ISG. Moreover, in vitro cytotoxicity tests were conducted against two colorectal cancer cells. All formulations exhibited Newtonian flow behavior with viscosity less than 266.9 cP with easier injectability. The adding of CO decreased the hardness and increased the adhesive force of the obtained rosin gel. The gel formation increased over time under microscopic observation. CO-added ISG had a particle-like gel appearance, and it promoted a higher release of IM over a period of 28 days. All tested ISG formulations revealed cytotoxicity against HCT-116 and HT-29 cell lines at different incubation times. Thus, CO-loaded rosin-based ISG can act as a potentially sustainable IM delivery system for chemotherapy against colorectal cancer cells. [ABSTRACT FROM AUTHOR]

The emergence of additional chromosome abnormalities (ACAs) in chronic myeloid leukemia (CML) patients during treatment with a tyrosine kinase inhibitor (TKI) regime is generally associated with resistance to treatment and a sign of disease progression to accelerated phase or blast phase. We report the type, frequency, and differential prognostic impact of stratified ACAs with treatment response in 251 Malaysian CML patients undergoing TKI therapy. ACAs were observed in 40 patients (15.9%) of which 7 patients (17.5%) showed ACAs at time of initial diagnosis whereas 33 patients (82.5%) showed ACAs during the course of IM treatment. In order to assess the prognostic significance, we stratified the CML patients with ACAs into four groups, group 1 (+8/+Ph), group 2 (hypodiploidy), group 3 (structural/complex abnormalities); group 4 (high-risk complex abnormalities), and followed up the disease outcome of patients. Group 1 and group 2 relatively showed good prognosis while patients in group 3 and group 4 had progressed or transformed to AP or blast phase with a median survival rate of 12 months after progression. Novel ACAs consisting of rearrangements involving chromosome 11 and chromosome 12 were found to lead to myeloid BP while ACAs involving the deletion of 7q or monosomy 7 led toward a lymphoid blast phase. There was no evidence of group 2 abnormalities (hypodiploidy) contributing to disease progression. Compared to group 1 abnormalities, CML patients with group 3 and group 4 abnormalities showed a higher risk for disease progression. We conclude that the stratification based on individual ACAs has a differential prognostic impact and might be a potential novel risk predictive system to prognosticate and guide the treatment of CML patients at diagnosis and during treatment. [ABSTRACT FROM AUTHOR]

Hypereosinophilia can be primary, including idiopathic hypereosinophilic syndrome (HES) and chronic eosinophilic leukemia, or secondary/reactive to various infective and non‑infective stimuli. Chronic oro‑genital ulcerations can occur due to various dermatological and non‑dermatological disorders, and many times it serves as a useful indicator of an underlying systemic disorder. Hence, a case presenting with chronic oro‑genital ulcerations needs a thorough evaluation. We are reporting an interesting case of a middle‑aged male who had chronic oro‑genital ulcerations as a presenting feature of chronic eosinophilic leukemia with FIP1L1‑PDGFRA fusion (FIP1‑like 1/platelet‑derived growth factor receptor alpha). The patient’s oro‑genital ulcerations responded excellently to imatinib. [ABSTRACT FROM AUTHOR]

Imatinib mesylate is an oral tyrosine kinase inhibitor used chiefly to treat chronic myeloid leukemia. In the literature, hypopigmentation is a commonly reported side effect of imatinib therapy; however, the cases of melasma-like hyperpigmentation due to imatinib have also been sparingly reported. We report a 35-year-old male patient who had asymptomatic hyperpigmentation over the cheeks and nose for 3 months after being started with oral imatinib. Examination showed pigmentation confined to the cheeks and nose. The diagnosis was made clinically along with dermoscopy, and the patient was treated with conventional skin-lightening regimen and sunscreen. [ABSTRACT FROM AUTHOR]