Administration Of Imatinib Research Articles

Development and validation of a nomogram to predict poor efficacy of imatinib in the treatment of newly diagnosed chronic phase chronic myeloid leukemia patients.

Imatinib is the most widely used tyrosine kinase inhibitor (TKI) in patients with newly diagnosed chronic-phase chronic myeloid leukemia(CML-CP). However, failure to achieve optimal response after imatinib administration, and subsequent switch to second-generation TKI therapy results in poor efficacy and induces drug resistance. In the present study, we developed and validated a nomogram to predict the efficacy of imatinib in the treatment of patients newly diagnosed with CML-CP in order to help clinicians truly select patients who need 2nd generation TKI during initial therapy and to supplement the risk score system. We retrospectively analyzed 156 patients newly diagnosed with CML-CP who met the inclusion criteria and were treated with imatinib at the Second Affiliated Hospital of Xi'an Jiao Tong University from January 2012 to June 2022. The patients were divided into a poor-response cohort (N = 60)and an optimal-response cohort (N = 43) based on whether they achieved major molecular remission (MMR) after 12 months of imatinib treatment. Using univariate and multivariate logistic regression analyses, we developed a chronic myeloid leukemia imatinib-poor treatment (CML-IMP) prognostic model using a nomogram considering characteristics like age, sex, HBG, splenic size, and ALP. The CML-IMP model was internally validated and compared with Sokal, Euro, EUTOS, and ELTS scores. The area under the curve of the receiver operator characteristic curve (AUC)of 0.851 (95% CI 0.778-0.925) indicated satisfactory discriminatory ability of the nomogram. The calibration plot shows good consistency between the predicted and actual observations. The net reclassification index (NRI), continuous NRI value, and the integrated discrimination improvement (IDI) showed that the nomogram exhibited superior predictive performance compared to the Sokal, EUTOS, Euro, and ELTS scores (P < 0.05). In addition, the clinical decision curve analysis (DCA) showed that the nomogram was useful for clinical decision-making. In predicting treatment response, only Sokal and CML-IMP risk stratification can effectively predict the cumulative acquisition rates of CCyR, MMR, and DMR (P<0.05). We constructed a nomogram that can be effectively used to predict the efficacy of imatinib in patients with newly diagnosed CML-CP based on a single center, 10-year retrospective cohort study.

Formulation and Development of Tara Gum-mediated Tablets for Delivery of Anticancer Drugs

Abstract Background: Natural polysaccharide tara gum (TG) has been investigated for several biological uses. The current study involved the administration of imatinib, an anticancer model medication, via TG. Methods: Imatinib-modified release tablets were developed using a direct compression method with different concentrations of TG and other excipients. Compressed tablets were evaluated for physicochemical properties. Result: All formulations had an in vitro disintegration time ranging from 10–23 min. Among the formulations, F6 exhibited excellent extended-release behaviour with 72% release over 12 h. TG tablets were rich in phytoconstituents, including saponins, tannins, phenolics, flavonoids, carbohydrates, proteins, and amino acids. Conclusion: TG has potential in the drug delivery application of anticancer medications as a rate-retarding polymer.

Effect of tyrosine protein kinase blockade on the state of retinal microglia in diabetic retinopathy

Background. Impaired homeostasis of the retinal tissue in diabetes primarily involves microglia, which triggers a cascade of inflammatory reactions, one of the main mechanisms of diabetic retinopathy (DR). The purpose of the study was to determine the state of microglia in experimental DR and the effect of the tyrosine protein kinase blocker imatinib. Materials and methods. In 45 three-month-old male Wistar rats, diabetes was simulated by a single injection of streptozotocin (50 mg/kg; Sigma-Aldrich). The rats were divided into 3 groups: controls; short-acting insulin; insulin and imatinib (Grindex, Latvia). Immunohistochemically, CD68-positive cells were detected in the retina, and the levels of ionized calcium-binding adapter molecule 1 (Iba-1) and matrix metalloproteinase 9 (MMP-9) was evaluated by immunoblotting. Results. The retinal content of Iba-1 progressively increased and exceeded the initial level by 2.0 times after 7 days, and by 3.55 times after 28 days (p &lt; 0.05). The insulin introduction inhibited the Iba-1 increase, which, although exceeding the initial level by 1.8 times, was significantly lower than the protein level in the control group after 28 days. The administration of imatinib together with insulin prevented the accumulation of Iba-1 in the retinal tissue: the protein content did not differ from the initial level (p &gt; 0.05). CD68-positive cells in the retina were noted in the vessels of the choroid plexus throughout the observation, from the 14th day — in the dilated venules of the outer plexiform layer (monocytic pool), and from day 28 — diffusely in the parenchyma of the inner layers (microglial pool). The latter had either a rounded or a ramified shape, which corresponded to the morphology of amoeboid (phagocytic) or activated microglia. Tyrosine protein kinase blockade prevented the microglial activation in the retina. Signs of inflammation in the form of retinal MMP-9 increase and fibrotic retinal proliferations were absent on the 28th day when using insulin and imatinib. Conclusions. The blockade of retinal inflammation and microglial activation by imatinib indicated the prospects of tyrosine protein kinases inhibition in DR and substantiated the prospect of further research with the clarification of such an effect on other mechanisms of DR development.

#3939 EFFECTIVENESS OF IMATINIB FOR MCTO NEPHROPATHY

Abstract Background and Aims MAFB is a podocyte-specific transcription factor. Point mutations in the MAFB transactivation domain in humans result in multicentric carpometacarpal-tarsal osteolysis (MCTO). MCTO patients show focal segmental glomerulosclerosis (FSGS) due to podocyte damage, known as MCTO nephropathy. Effective treatment for MCTO has not been found. Imatinib is a tyrosine kinase inhibitor (TKI), which inhibits PI3K-Akt pathway, and is in long-term use for the treatment of chronic myeloid leukemia. Method In order to develop a new treatment for MCTO, we generated disease model mice using the CRISPR-Cas9 system. These animals have the same genetic mutation as human MCTO patients. Albuminuria was evaluated at 4 weeks of age, and renal histological analysis was performed at 26 weeks of age. In addition, RNA-seq for isolated glomeruli of 10-week-old MCTO mice and wild-type animal was performed for genetic and pathway analysis. Results MCTO mice exhibited growth retardation, and presented albuminuria from 4 weeks of age. Foot process effacement and FSGS-like renal histological changes were shown. Nephropathy symptoms were similar to that of human MCTO patients. Interestingly, the upregulated genes in RNA-seq analysis were a group of receptor genes associated with PI3K-Akt signaling, including lpar1 and csfr1.Transesophageal administration of imatinib, a PI3K-Akt pathway inhibitor, treatment for 5 consecutive weeks decreased albuminuria and ameliorated histological renal damage. RNA-seq of isolated glomeruli of MCTO mice after imatinib treatment showed decreased expression of genes associated with TGFβ-related signaling pathways compared to the non-treated group. Recently, enhanced PI3K-Akt signaling in podocytes has been linked to several renal diseases associated with podocyte injury. In addition, lpar1 inhibition in glomeruli is known to suppress TGFβ. Imatinib suppressed PI3K-Akt signaling, which is enhanced in podocytes of MCTO mice. This may have shown a podocyte-protective effect by suppressing fibrosis-related genes such as TGFβ. Imatinib is classified as a TKI, but frequency of podocyte toxicity is lower than other TKIs. Conclusion The podocyte injury mechanism of MCTO nephropathy is associated with enhanced PI3K-Akt signaling in podocytes. Imatinib inhibits this pathway and suppresses TGFβ. Imatinib may become a therapeutic agent for MCTO nephropathy.

Oral targeted delivery of Imatinib by pH responsive copolymer modulates liver fibrosis in the mice model

Liver fibrosis is a significant cause of morbidity and mortality without approved treatment. The therapeutic effects of Imatinib as a tyrosine kinase inhibitor on reversing liver fibrosis have already been shown. However, considering the conventional route of Imatinib administration, the amount of drug to be used is very high, and its side effects are raised. Therefore, we designed an efficient pH-sensitive polymer for the targeted delivery of Imatinib in treating a carbon tetrachloride (CCl4)-induced liver fibrosis. This nanotherapeutic system-based Vitamin A (VA)-modified Imatinib-loaded poly (lactic-co-glycolic acid)/Eudragit S100 (PLGA-ES100) has been successfully fabricated by adapting the solvent evaporation technique. The applying ES100 on the surface of our desired nanoparticles (NPs) protects drug release at the acidic pH of the gastric and guarantees the effective release of Imatinib at a higher pH of the intestine.Besides, VA-functionalized NPs could be an ideal efficient drug delivery system due to the high capacity of hepatic cell lines to absorb VA. For induction of liver fibrosis, CCL4 was intraperitoneally (IP) injected twice a week for six weeks in BALB/c mice. Oral administration of VA-targeted PLGA-ES100 NPs loaded with Rhodamine Red™ by live animal imaging showed a preferential accumulation of the selected NPs in the liver of mice. Besides, administrating targeted Imatinib-loaded NPs significantly decreased serum levels of ALT, and AST, and also reduced the expression of extracellular matrix components, including collagen I, collagen III, and α-SMA, considerably. Interestingly, histopathological evaluation of liver tissues through H&E and Masson's trichrome staining showed that oral administration of targeted Imatinib-loaded NPs reduced hepatic damage by enhancing hepatic structure condition. Also, the Sirius-red staining indicated a reduction in collagen expression during treatment with targeted NP containing Imatinib. The immunohistochemistry result on liver tissue shows a significant decrease in the expression of α-SMA in groups treated with targeted NP. In the meantime, administration of a very scarce dose of Imatinib via targeted NP caused a substantial decline in the expression of fibrosis marker genes (Collagen I, Collagen III, α-SMA).Our results confirmed that novel pH-sensitive VA-targeted PLGA-ES100 NPs could efficiently deliver Imatinib to the liver cells. Loading Imatinib in the PLGA-ES100/VA might overcome many challenges facing conventional Imatinib therapy, including gastrointestinal pH, the low concentration at the target region, and toxicity.

Imatinib-Functionalized Galactose Hydrogels Loaded with Nanohydroxyapatite as a Drug Delivery System for Osteosarcoma: In Vitro Studies.

This study reports an impact of structure (XRPD, FT-IR) and surface morphology (SEM-EDS) of imatinib-functionalized galactose hydrogels, loaded and unloaded with nHAp, on osteosarcoma cell (Saos-2 and U-2OS) viability, levels of free oxygen radicals, and nitric oxide, levels of BCL-2, p53, and caspase 3 and 9, as well as glycoprotein-P activity. It was investigated how the rough surface of the crystalline hydroxyapatite-modified hydrogel affected amorphous imatinib (IM) release. The imatinib drug effect on cell cultures has been demonstrated in different forms of administration-directly to the culture or the hydrogels. Administration of IM and hydrogel composites could be expected to reduce the risk of multidrug resistance development by inhibiting Pgp.

C-Kit signaling modulated group 3 innate lymphoid cell functions in mouse neutrophilic asthma model

Abstract Group 3 innate lymphoid cells (ILC3s) are involved in air pollution- and bacterial infection-associated neutrophilic asthma. Studies showed that asthmatic patients have higher stem cell factor (SCF) expression in airway and sera. Of note, ILC3s express SCF receptor, c-Kit, suggesting a potential role of SCF/c-Kit signaling in ILC3 functions and neutrophilic asthma. In this study, we aimed to determine whether SCF/c-Kit signaling could modulate ILC3 functions and neutrophilic asthma. Wild-type (WT) and c-Kit deficient mice (Kit w-sh) were intranasally treated with IL-1β/IL-23 or particulate matter (PM) 2.5 to induce neutrophilic asthma. While IL-1β/IL-23 or PM2.5 caused increases in neutrophil infiltration to bronchoalveolar lavage fluid (BALF) and airway hyperreactivity (AHR) in WT mice, Kit w-shmice had decreased infiltration of neutrophils and ameliorated AHR. Concomitantly, flow cytometry results showed a decreased number of IL-17+ ILC3 in the lung of Kit w-shmice compared to WT mice, which may be due to the reduced proliferation of c-Kit-deficient ILC3. In addition, we showed SCF enhanced IL-17 secretion from ILC3s in vitro. Based on re-analysis of published mouse whole lung cells scRNAseq data, we hypothesized fibroblasts are the source of SCF. Indeed, mice with SCF knockout in fibroblast exhibited decreased neutrophil infiltration and reduced IL-17+ ILC3 number in response to IL-1β/IL-23. Finally, administration of imatinib, a FDA-approved drug targeting c-Kit signaling, ameliorated AHR and ILC3 activation in the mouse neutrophilic asthma model. Taken together, our data suggested that inhibition of ILC3 activation by targeting c-Kit signaling may provide a potential therapeutic management for neutrophilic asthma.

Effect of Imatinib treatment on renal anaemia in chronic myeloid leukemia patients.

In this study, we investigate renal function and anaemia during imatinib treatment in patients with chronic myeloid leukaemia. The patients with chronic myeloid leukaemia with chronic phase who had been treated with only imatinib for 12 months at Rajiv Gandhi Cancer Institute and Research Centre (New Delhi, India) were enrolled and prospectively analysed. The chronic renal impairment parameters, including estimated glomerular filtration rate and haemoglobin levels for anaemia from June 2020 to June 2022, were monitored in newly diagnosed in patients with chronic myeloid leukaemia-chronic phase. The data were analysed by SPSS software version 22. In total 55 patients with chronic myeloid leukaemia chronic phase who had been on imatinib for 12 months were monitored. The mean estimated glomerular filtration rate was significantly decreased (74 ± 14 to 59 ± 12 mL/min/1.73m2, p < 0.001) with a decrease in mean haemoglobin levels after 12 months (10.9 ± 2.01 to 9.0 ± 1.02, p < 0.004). The decreased estimated glomerular filtration rate was negatively correlated with haemoglobin levels after 1 year of imatinib administration (correlation coefficient = 0.892, R2 = 0.7976, p < 0.05). We recommended close monitoring of renal function and haemoglobin levels in patients with chronic myeloid leukaemia patients.

Pharmacokinetics and pharmacodynamics of imatinib for optimal drug repurposing from cancer to COVID-19

IntroductionIn the randomized double-blind placebo-controlled CounterCOVID study, oral imatinib treatment conferred a positive clinical outcome and a signal for reduced mortality in COVID-19 patients. High concentrations of alpha-1 acid glycoprotein (AAG) were observed in these patients and were associated with increased total imatinib concentrations. AimsThis post-hoc study aimed to compare the difference in exposure following oral imatinib administration in COVID-19 patients to cancer patients and assess assocations between pharmacokinetic (PK) parameters and pharmacodynamic (PD) outcomes of imatinib in COVID-19 patients. We hypothesize that a relatively higher drug exposure of imatinib in severe COVID-19 patients leads to improved pharmacodynamic outcome parameters. Methods648 total concentration plasma samples obtained from 168 COVID-19 patients were compared to 475 samples of 105 cancer patients, using an AAG-binding model. Total trough concentration at steady state (Cttrough) and total average area under the concentration-time curve (AUCtave) were associated with ratio between partial oxygen pressure and fraction of inspired oxygen (P/F), WHO ordinal scale (WHO-score) and liberation of oxygen supplementation (O2lib). Linear regression, linear mixed effects models and time-to-event analysis were adjusted for possible confounders. ResultsAUCtave and Cttrough were respectively 2.21-fold (95%CI 2.07–2.37) and 1.53-fold (95%CI 1.44–1.63) lower for cancer compared to COVID-19 patients. Cttrough, not AUCtave, associated significantly with P/F (β=-19,64; p-value=0.014) and O2lib (HR 0.78; p-value= 0.032), after adjusting for sex, age, neutrophil-lymphocyte ratio, dexamethasone concomitant treatment, AAG and baseline P/F-and WHO-score. Cttrough, but not AUCtave associated significantly with WHO-score. These results suggest an inverse relationship between PK-parameters, Cttrough and AUCtave, and PD outcomes. ConclusionCOVID-19 patients exhibit higher total imatinib exposure compared to cancer patients, attributed to differences in plasma protein concentrations. Higher imatinib exposure in COVID-19 patients did not associate with improved clinical outcomes. Cttrough and AUCtave inversely associated with some PD-outcomes, which may be biased by disease course, variability in metabolic rate and protein binding. Therefore, additional PKPD analyses into unbound imatinib and its main metabolite may better explain exposure-response.

Changes in imatinib plasma trough level during long-term treatment in patients with intermediate- or high-risk gastrointestinal stromal tumors: Relationship between covariates and imatinib plasma trough level.

Imatinib is the first-line adjuvant treatment for gastrointestinal stromal tumors (GISTs). Considering that some studies have suggested that imatinib (IM) plasma trough levels (Cmin) change with time, the aim of this study is to assess the changes in IM Cmin in patients with GIST in a long-term study and to elucidate the relationships between clinicopathological features and IM Cmin. In 204 patients with intermediate- or high-risk GIST who were taking IM, IM Cmin was analyzed. Patient data were grouped according to the duration of medication (A: 1-3 months, B: 4-6 months, C: 7-9 months, D: 10-12 months, E: ≤12 months, F: 12<-≤36 months, G: >36 months). The correlation between IM Cmin at different time stages and clinicopathological characteristics was assessed. Statistically significant differences were observed between Groups A, C, and D (P = 0.049 and 0.01, respectively). In Group E, IM Cmin correlated with sex (P = 0.049) and age (P = 0.029) and negatively correlated with body weight, height, and body surface area (P = 0.007, 0.002, and 0.001, respectively). In Groups F and G, IM Cmin was significantly higher in non-gastric operation patients than in patients with gastrectomy (P = 0.002, 0.036) and was significantly higher in patients with the primary sites of others than in the stomach (P < 0.001, = 0.012). In addition, IM Cmin was much higher in patients with mutation sites other than KIT exon 11 in Group F (P = 0.011). This is the first study of IM Cmin during the long-term treatment of patients with intermediate- or high-risk GIST. IM Cmin was the highest for the first 3 months and then declined, and long-term administration of IM showed a relatively stable plasma trough level. The IM Cmin correlated with different clinical characteristics at different durations of medication. This meant that future "trough level-clinicopathological characteristics" analyses should be time-point-specific. We also need to formulate time-specific medication monitoring plans in clinical practice to study disease progression caused by the occurrence of drug resistance.

The Interrelationship Between FYN and miR-128/193a-5p/494 in Imatinib Resistance in Prostate Cancer.

C-KIT is a receptor tyrosine kinase with oncogenic properties overexpressed in PCa cases. Through the use of an alternative promoter, a truncated c-KIT protein (tr-KIT) of 30-50 kDa is generated, lacking the extracellular and transmembrane domain. Tr-KIT promotes the formation of a multi-molecular complex composed of Fyn, Plcγ1, and Sam68. Imatinib blocks the activity of full-length c-KIT but has no effect on tr-KIT. LNCaP is the human PCa cell line that shows tr-KIT overexpression and PC3 does not show tr-KIT overexpression. miR-128/193a- 5p/494 are miRNAs targeting FYN, PLCγ1, and SAM68 combinatorially. The study's question is: can miR-128/193a- 5p/494 be related to imatinib resistance in PCa? LNCaP and PC3 cells were treated with imatinib in IC50 doses. Before and after imatinib administration, RNA was isolated and cDNA conversion was performed. By qPCR analysis, expression changes of tr-KIT specific pathway elements and miR-128/193a-5p/494 were analyzed before and after imatinib administration. After imatinib administration, miR-128/193a-5p/494 were significantly overexpressed in LNCaP cells while downregulated significantly in PC3 cells (p<0.05). Also, FYN was upregulated in LNCaP cells (p<0.05) but there was no change in PC3 after imatinib administration. Especially upregulation of FYN may sponge miR128/193a-5p/494 and downregulate their transcriptional activity in LNCaP cells having tr-KIT activity. So, miR-128/193a-5p/494 may have a critical role in imatinib resistance via a tr-KIT pathway.

Imatinib suppresses activation of hepatic stellate cells by targeting STAT3/IL-6 pathway through miR-124.

The activation of hepatic stellate cells is the primary function of facilitating liver fibrosis. Interfering with the coordinators of different signaling pathways in activated hepatic stellate cells (aHSCs) could be a potential approach in ameliorating liver fibrosis. Regarding the illustrated anti-fibrotic effect of imatinib in liver fibrosis, we investigated the imatinib's potential role in inhibiting HSC activation through miR-124 and its interference with the STAT3/hepatic leukemia factor (HLF)/IL-6 circuit. The anti-fibrotic effect of imatinib was investigated in the LX-2 cell line and carbon tetrachloride (CCl4 )-induced Sprague-Dawley rat. The expression of IL-6, STAT3, HLF, miR-124, and α-smooth muscle actin (α-SMA) were quantified by quantitative real-time PCR (qRT-PCR) and the protein level of α-SMA and STAT3 was measured by western blot analysis both in vitro and in vivo. The LX-2 cells were subjected to immunocytochemistry (ICC) for α-SMA expression. After administering imatinib in the liver fibrosis model, histopathological examinations were done, and hepatic function serum markers were checked. Imatinib administration alleviated mentioned liver fibrosis markers. The expression of miR-124 was downregulated, while IL-6/HLF/STAT3 circuit agents were upregulated in vitro and in vivo. Notably, imatinib intervention decreased the expression of IL-6, STAT3, and HLF. Elevated expression of miR-124 suppressed the expression of STAT3 and further inhibited HSCs activation. Our results demonstrated that imatinib not only ameliorated hepatic fibrosis through tyrosine kinase inhibitor (TKI) activity but also interfered with the miR-124 and STAT3/HLF/IL-6 pathway. Considering the important role of miR-124 in regulating liver fibrosis and HSCs activation, imatinib may exert its anti-fibrotic activity through miR-124.

Multi-targeted anti-inflammatory drugs for the treatment of neurological disorders.

Multi-targeted anti-inflammatory drugs for the treatment of neurological disorders.

Severe persistent marrow aplasia in chronic myeloid leukemia (CML): An unusual complication of imatinib.

Imatinib has changed the treatment of chronic myeloid leukemia (CML) drastically since 15 years. It is usually well tolerated, but severe persistent marrow aplasia is an unusual complication of imatinib while using it in CML. The aim of this study is to describe our experience confronting this rare side effect and review the available data worldwide. It was a retrospective analysis conducted at a center from February 2002 to February 2015. This study was endorsed by our Institutional Review Board (IRB) and written consent was taken from all patients. Patients diagnosed as Philadelphia (Ph) chromosome-positive CML either in chronic phase (CP), accelerated phase (AP), or blastic crisis (BC) were included. There were a total of 1,576 patients with CML treated with imatinib during this period. Karyotyping and quantitative reverse transcriptase polymerase chain reaction (RT-qPCR) were done at the time of pancytopenia for all patients. In total, 11 (males = 5, females = 6) patients met our inclusion criteria from 1,576 patients of CML. The median age was 58 years (range 32-76). Out of 11 patients 8, 2, and 1 patients were in CP, AP, and BC phases, respectively. The median time of administration of imatinib was 3.3 months (range 1.5-6). The average time of marrow recovery was 10.4 months (range 5-15). Two patients expired (one from septicemia and the other from intracranial hemorrhage). BCR-ABL transcripts level by RT-PCR revealed the existence of the disease in all patients. Imatinib is a very well-tolerated tyrosine kinase inhibitor (TKI), but is associated with persistent myelosuppression when used in older age, advanced phase of the disease, and treated previously. After confirming persistent marrow aplasia, the treatment is mainly supportive. It is striking that the disease is still persistent, which is confirmed by RT-PCR. There is no consensus regarding recalling imatinib at lower doses or the use of second-generation TKI (nilotinib, dasatinib) in these patients.

The c-Abl/p73 pathway induces neurodegeneration in a Parkinson's disease model.

Parkinson's disease is the second most common neurodegenerative disorder. Although it is clear that dopaminergic neurons degenerate, the underlying molecular mechanisms are still unknown, and thus, successful treatment is still elusive. One pro-apoptotic pathway associated with several neurodegenerative diseases is the tyrosine kinase c-Abl and its target p73. Here, we evaluated the contribution of c-Abl and p73 in the degeneration of dopaminergic neurons induced by the neurotoxin 6-hydroxydopamine as a model for Parkinson's disease. First, we found that in SH-SY5Y cells treated with 6-hydroxydopamine, c-Abl and p73 phosphorylation levels were up-regulated. Also, we found that the pro-apoptotic p73 isoform TAp73 was up-regulated. Then, to evaluate whether c-Abl tyrosine kinase activity is necessary for 6-hydroxydopamine-induced apoptosis, we co-treated SH-SY5Y cells with 6-hydroxydopamine and Imatinib, a c-Abl specific inhibitor, observing that Imatinib prevented p73 phosphorylation, TAp73 up-regulation, and protected SH-SY5Y cells treated with 6-hydroxydopamine from apoptosis. Interestingly, this observation was confirmed in the c-Abl conditional null mice, where 6-hydroxydopamine stereotaxic injections induced a lesser reduction of dopaminergic neurons than in the wild-type mice significantly. Finally, we found that the intraperitoneal administration of Imatinib prevented the death of dopaminergic neurons induced by injecting 6-hydroxydopamine stereotaxically in the mice striatum. Thus, our findings support the idea that the c-Abl/p73 pathway is involved in 6-hydroxydopamine degeneration and suggest that inhibition of its kinase activity might be used as a therapeutical drug in Parkinson's disease.

Adjuvant therapy with imatinib for an incompletely resected multilobular tumour of bone in a dog

A 5-year-old neutered male Shiba Inu dog presented with a history of oral bleeding, dysphagia, and depression for 3 weeks. The physical examination revealed a firm mass in the right caudal palatal region along the level of PM4–M2. On the computed tomography, the mass was round-to-oval in shape and 22 mm × 30 mm × 15 mm in size. The mass contained multiple bone attenuated materials with a palatal bone lysis of 4 mm × 6 mm. A complete resection of the mass was proposed; however, the owner declined due to the risk of complications associated with the radical surgery. Therefore, a palliative resection and biopsy of the mass were performed. On the histological examination, the mass was diagnosed as grade 2 multilobular tumour of bone (MTB). Since the mass was incompletely resected, adjuvant therapy was pursued along with targeted therapy using a tyrosine kinase inhibitor. The tumour cells showed overexpression of the receptor of tyrosine kinase for c-KIT, PDGFR-α, PDGFR-β, and FGFR1 compared to normal tissue cells. Additionally, the cytotoxic effect of imatinib on the MTB cells was confirmed in vitro. Four weeks postoperatively, the administration of imatinib and carprofen was initiated and continued for 259 days. The patient maintained a good functional outcome for 306 days after the initial presentation.

INHALED IMATINIB FOR PULMONARY ARTERIAL HYPERTENSION CLINICAL TRIAL: DESIGN OF THE IMPACT PHASE 2B/3 STUDY DESIGN

INHALED IMATINIB FOR PULMONARY ARTERIAL HYPERTENSION CLINICAL TRIAL: DESIGN OF THE IMPACT PHASE 2B/3 STUDY DESIGN

389. BENEFITS OF BILATERAL THORACOSCOPIC SURGERY IN THE PRONE POSITION FOR A LARGE ESOPHAGEAL TUMOR

Abstract Esophageal gastrointestinal stromal tumors (GISTs) are relatively less symptomatic and may have a significantly large tumor diameter at diagnosis. Large esophageal tumors are difficult to resect because it is tough to maintain the surgical field in the narrow mediastinal region. In addition, because GIST has a risk of dissemination if the tumor collapses during surgery, it must be resected with as little force as possible. We herein report a middle and lower thoracic esophageal GIST with a maximum lateral diameter of 12 cm that could be safely resected by a bilateral thoracoscopic approach in the prone position. The case was that of a 70-year-old man. Since his tumor diameter was large and the surrounding organs were severely compressed, it was deemed to be borderline resectable, and preoperative chemotherapy with imatinib was decided. However, administration of imatinib did not result in tumor shrinkage, and interstitial pneumonia occurred. Thus, the final decision was to resect it. It was difficult to remove the left side of the tumor by normal thoracoscopic operation from the right side as the tumor was large. There was also the risk of the tumor collapsing due to unreasonable traction. Therefore, we selected a surgical procedure in which the left and right sides of the tumor were detached by bilateral thoracoscopic operation in the prone position and then the tumor was removed from the abdominal cavity by a transesophageal hiatal operation under laparotomy. Followed by gastric tube reconstruction by the posterior sternal route. The postoperative course was uneventful. In this case, taking advantage of the thoracoscopic approach from both sides, the tumor could be safely resected without unreasonable traction. Furthermore, the prone position has the advantage that bilateral thoracoscopic operation is possible without changing the position. This technique could also be applied for the excision of esophageal cancer involving the left side.

Exploring the Pain Attenuating Potential of Imatinib in Chronic Constriction Injury Model of Neuropathic Pain

Background: Preclinical studies have identified three members of tyrosine kinase receptor family (Trk), TrkA, TrkB, and TrkC in dorsal root of ganglia (DRG), which carry sensory neural signals to the central nervous system from the peripheral nervous system in neuropathic pain. Imatinib is a selective tyrosine kinase inhibitor and widely employed as anti-cancer drug in myeloid leukemia and gastrointestinal stromal tumor. The present study was designed to investigate the potential of imatinib in neuropathic pain. Method: Neuropathic pain was induced by chronic constriction injury in rats by putting four loose ligatures around sciatic nerve. The extent of neuropathic pain was assessed by noting paw withdrawal threshold (mechanical hyperalgesia) in pin prick test, paw withdrawal latency in hot plate test (heat hyperalgesia) and paw withdrawal duration in acetone drop test (cold allodynia) before surgery and on 14th day post surgery. Result: There was a significant development of cold allodynia, mechanical and heat hyperalgesia on 14th day in CCI-subjected rats. Administration of imatinib (25 mg/kg and 50 mg/kg) significantly abolished the behavioural deficits (hyperalgesia and allodynia) induced by CCI in a dose-dependent manner. Conclusion: The observed beneficial effects of imatinib in reduction of behavioral deficits in CCI-subjected rats may be possibly attributed to tyrosine kinase inhibition in dorsal root ganglia neurons associated with the neuropathic pain.

EP-262 Neoadjuvant imatinib for Resectable Gastrointestinal Stromal Tumors. A State-of-the-art

Abstract Aims Surgical removal remains the cornerstone of primary GIST treatment and complete surgical resection offers prognostic value toward risk of relapse. However, primary tumors, particularly of the stomach, are of advanced size when detected, and multivisceral resection seems to be the treatment of choice. Existing results of recent clinical trials have established the feasibility of neoadjuvant imatinib therapy mainly in unresectable GISTs. Yet, proof of the survival effectiveness of neoadjuvant imatinib therapy in borderline resectable tumors has not been sufficiently demonstrated. Methods A review of the literature was performed to identify the current evidence for preoperative treatment of large GISTs with Imatinib regarding R0 resection and oncological outcome. Results Data supporting benefit of neoadjuvant imatinib are available from several case reports and small retrospective series, most of which include a mix of patients with borderline resectable and unresectable primary disease. In addition, a single-phase II United States Intergroup trial and an Asian phase II trial of neoadjuvant therapy in large stomach tumors, concluded that Neoadjuvant imatinib therapy is preferred for marginally resectable tumors. Progressive disease after neoadjuvant treatment was a rare event, and partial response was achieved in 40–80% of all patients. Conclusion Neoadjuvant therapy with imatinib is safe and recommended for patients with resectable, locally advanced GIST. It may also enable less invasive and organ-sparing surgery, increase the complete resection rate, and avoid the surgical rupture by decreasing the tumor size. Clinical questions still remain about the most appropriate period of pre- and post-operative imatinib administration in the neoadjuvant protocol.