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Imatinib (Glivec)

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Latest Research Publications

Web Resources: Imatinib (Glivec) (6 links)

Latest Research Publications

Lu Y, Li Y, Chai X, et al.
Long noncoding RNA HULC promotes cell proliferation by regulating PI3K/AKT signaling pathway in chronic myeloid leukemia.
Gene. 2017; 607:41-46 [PubMed] Related Publications
Aberrant expression of long noncoding RNA (lncRNA) HULC is associated with various human cancers. However, the role of HULC in chronic myeloid leukemia (CML) is unknown. In this study, we found that HULC was remarkably overexpressed in both leukemia cell lines and primary hematopoietic cells derived from CML patients. The increase in HULC expression was positively correlated with clinical stages in CML. Moreover, the knockdown of HULC significantly inhibited CML cell proliferation and induced apoptosis by repressing c-Myc and Bcl-2. Furthermore, inhibition of HULC enhanced imatinib-induced apoptosis of CML cells. Further experiments demonstrated that HULC silencing markedly suppressed the phosphorylation of PI3K and AKT, indicating that enhancement of imatinib-induced apoptosis by HULC inhibition is related with the reduction of c-Myc expression and inhibition of PI3K/Akt pathway activity. Furthermore, HULC could modulate c-Myc and Bcl-2 by miR-200a as an endogenous sponge. Taken together, these results reveal that HULC promotes oncogenesis in CML and suggest a potential strategy for the CML treatment.

Hamzaoui L, Medhioub M, Bouassida M, et al.
Gastrointestinal stromal tumours (GISTs): A descriptive study on 29 cases.
Arab J Gastroenterol. 2016; 17(4):185-187 [PubMed] Related Publications
BACKGROUND AND STUDY AIM: Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract, originating from Cajal cells in different sites of the digestive tract. The aim of the study is to report on epidemiological, clinical, histological, and therapeutic characteristics of GISTs.
PATIENTS AND METHODS: A retrospective descriptive study of 29 cases of GIST in gastroenterology and general surgery departments of Mohamed Tahar Maamouri Hospital (Nabeul, Tunisia) was conducted from January 2005 to March 2012.
RESULTS: Among the 29 patients, there were 18 males (62%) and 11 females (38%) with a median age of 63 years (range, 30-96years). The main symptoms were abdominal pain (40%) and weight loss (28%). The tumour was revealed by a complication in 5 cases (17%). Six patients (20.7%) had metastatic lesions. The most common sites were the stomach (41.4%) and the small intestine (17.3%). The median tumour size was 9.5cm (range, 1-30cm). Spindle cell tumours were the main histological type (62%). KIT was positive in the majority of cases (75%). Twenty-one patients with primary disease (72%) underwent a surgical resection. Imatinib was prescribed in 7 patients (24%). Sunitinib malate was indicated in 3 patients who had tumour progression under imatinib. Median survival was 17 months (range, 1-69months). Ten patients died.
CONCLUSION: The management of GISTs has considerably evolved during the last years. Surgical resection, which remains the mainstay of treatment, was indicated in the majority of patients. Imatinib treatment has not improved overall survival in metastatic and/or inoperable cases.

Yin Y, Xiang J, Tang S, et al.
A lower dosage of imatinib in patients with gastrointestinal stromal tumors with toxicity of the treatment.
Medicine (Baltimore). 2016; 95(49):e5488 [PubMed] Free Access to Full Article Related Publications
This study investigated the efficiency and safety of imatinib in the lower dose (300 mg/d) in patients with gastrointestinal stromal tumor (GIST) who cannot tolerate imatinib in the standard dose (400 mg/d).Steady-state imatinib trough concentration (Cmin) values in 18 patients with GIST who were taking 300 mg/d or 400 mg/d imatinib were measured. The clinical features, toxicity data, and follow-up data were collected.Around 18 patients with GIST were investigated in which 9 patients received 300 mg/d imatinib. The mean imatinib Cmin value of the 18 patients was 1841 ng/mL (1018-3897 ng/mL). The difference between the patients treated with 400 mg/d (n=9) and those treated with 300 mg/d (n = 9), which have imatinib Cmin values of 2122±1003 ng/mL and 1559±478 ng/mL, respectively, was not significant (P = 0.148). In total, 12 of the 18 patients had complete resection of the primary tumor, 8 of whom received postoperative imatinib 300 mg/d. After the average follow-up of 15.4 months, no recurrence was documented. Of the 6 patients with unresected GIST, 1 received imatinib 300 mg/d for 13 months. The tumor size of this patient continued to decrease. In contrast to patients treated with imatinib 400 mg/d, patients treated with imatinib 300 mg/d notably exhibited lesser drug-related side effects.Patients with GIST who exhibited intolerance to the standard dose of imatinib (400 mg/d), a lower dose of 300 mg/d could provide not only sufficient plasma Cmin and good disease control but also the alleviation of the side effects.

Poveda A, Martinez V, Serrano C, et al.
SEOM Clinical Guideline for gastrointestinal sarcomas (GIST) (2016).
Clin Transl Oncol. 2016; 18(12):1221-1228 [PubMed] Free Access to Full Article Related Publications
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, and this disease has served as a paradigmatic model for successful rational development of targeted therapies. The introduction of tyrosine kinase inhibitors with activity against KIT/PDGFRA in both localized and advanced stages has remarkably improved the survival in a disease formerly deemed resistant to all systemic therapies. The Spanish Society of Medical Oncology (SEOM) guidelines provide a multidisciplinary and updated consensus for the diagnosis and treatment of GIST patients. We strongly encourage that the managing of these patients should be performed within multidisciplinary teams in reference centers.

Xu H, Liu C, Chen Y, et al.
Diagnosis and treatment of gastrointestinal stromal tumor extending to prostate: A case report and literature review.
Medicine (Baltimore). 2016; 95(46):e5439 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Gastrointestinal stromal tumor (GIST) is the neoplasm of gastrointestinal tract.
PATIENT CONCERNS: The patient complained about the retention of urinary.
INTERVENTIONS: radical prostatectomy and the imatinib therapy.
OUTCOMES: No recurrence and metastasis have been found during a 14-month follow-up.
LESSONS: comprehensive treatment is necessary for the GIST treatment. Furthermore, we summarize a review of the literature of GIST occurring in the prostate gland treated by different methods and 4 kinds of rare diseases in prostate.

Xiao Y, Jiao C, Lin Y, et al.
lncRNA UCA1 Contributes to Imatinib Resistance by Acting as a ceRNA Against miR-16 in Chronic Myeloid Leukemia Cells.
DNA Cell Biol. 2017; 36(1):18-25 [PubMed] Related Publications
Imatinib (IM) has been applied to the chronic phase of chronic myeloid leukemia (CML) and has great benefit on the prognosis of patients with CML. The function of drug efflux mediated by multidrug resistance protein-1 (MDR1) is considered as a main reason for IM drug resistance in CML cells. However, the exact mechanisms of MDR1 modulation in IM resistance of CML cells remain unclear. In the present study, long noncoding RNA (lncRNA) UCA1 was identified as an important modulator of MDR1 by a model system of leukemia cell lines with a gradual increase of MDR1 expression and IM resistance. Overexpression of UCA1 increased MDR1 expression to promote IM resistance of CML cells. Furthermore, for the first time, we demonstrated that UCA1 functions as a competitive endogenous (ceRNA) of MDR1 through completely binding the common miR-16. UCA1-MDR1 might be a novel target for enhancing the therapeutic efficacy of CML patients with IM resistance.

Dybko J, Jaźwiec B, Haus O, et al.
The Hasford Score May Predict Molecular Response in Chronic Myeloid Leukemia Patients: A Single Institution Experience.
Dis Markers. 2016; 2016:7531472 [PubMed] Free Access to Full Article Related Publications
The Sokal, Hasford, and EUTOS scores were established in different treatment eras of chronic myeloid leukemia (CML). None of them was reported to predict molecular response. In this single center study we tried to reevaluate the usefulness of three main scores in TKI era. The study group included 88 CML patients in first chronic phase treated initially with standard imatinib dose. All of them achieved major molecular response (MMR) in time points defined by European LeukemiaNet (ELN). 42 patients lost MMR in a median time of 47 months and we found a significant difference in MMR maintenance between intermediate-risk (IR) and low-risk (LR) patients assessed by Hasford score. All 42 patients were switched to second-generation TKI (2G-TKI) treatment. At 18 months of 2G-TKI therapy we have still found a significant difference in BCR-ABL transcript levels and MMR rate between IR and LR groups. We did not find any of the described differences discriminating patients by Sokal or EUTOS score. In this retrospective single center analysis we found Hasford score to be useful in predicting molecular response in first chronic phase of CML patients.

Wu J, Xiao L, Zhou H, et al.
ZFX modulates the growth of human leukemic cells via B4GALT1.
Acta Biochim Biophys Sin (Shanghai). 2016; 48(12):1120-1127 [PubMed] Related Publications
Zinc finger protein X-linked (ZFX) is a key regulator of both embryonic stem cells (ESCs) and hematopoietic stem cells (HSCs), which is required for both Notch intracellular domain (NotchIC)-induced acute T-cell leukemia and MLL-AF9-induced myeloid leukemia in mouse models. However, the role of ZFX and its underlying mechanism in human leukemic cells remain unclear yet, though accumulating data have demonstrated that ZFX is aberrantly expressed in various human tumors and plays an important role. Herein, we found that ZFX was aberrantly expressed in various human leukemic cell lines and primary cells from leukemia patients compared with control cells. The silence of ZFX led to the growth suppression through either the deregulated cell cycle or the induction of apoptosis in various cells including K562, Jurkat, Namalwa, and THP-1 cells. The gene expression analysis revealed that UDP-Gal:βGlcNAc β 1,4-galactosyltransferase, polypeptide 1 (B4GALT1) was significantly down-regulated upon ZFX silencing, which is implicated in the response of K562 cells to the treatment of imatinib mesylate (IM). In addition, lectin blot assay showed that the galactosylation of glycoproteins in K562 cells was suppressed upon ZFX silencing. Interestingly, overexpression of B4GALT1 restored the growth and conferred drug resistance to ZFX-silenced cells. Taken together, we have demonstrated that ZFX is aberrantly expressed in multiple human leukemic cells and it modulates the growth and drug response of leukemic cells partially via B4GALT1, which suggests that ZFX is a new regulator of leukemic cells and warrants intensive investigations on this 'stemness' regulator in these deadly diseases.

Zhang GF, Zhou M, Bao XB, et al.
Imatinib Mesylate Versus Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Chronic Myelogenous Leukemia.
Asian Pac J Cancer Prev. 2016; 17(9):4477-4481 [PubMed] Related Publications
PURPOSE: To compare the relative merits of imatinib and allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelogenous leukemia (CML).
MATERIALS AND METHODS: This cohort study was designed to compare the outcomes of imatinib (n=292) versus allo-HSCT (n=141) for CML, the clinical data of these patients being retrospectively analyzed so as to compare the event free survival (EFS) and overall survival (OS) between these two groups with patients in the chronic phase (CP) and advanced phases, including accelerate (AP) and blast phases (BP).
RESULTS: (1) Patients treated with imatinib (278 in the CP) demonstrated superior EFS, OS, 5-year EFS and 5-year OS rates of 88.5% versus 70.0% (P<0.05), 93.2% versus 80.0% (P<0.05), 84% versus 75.0% (P<0.05) and 92% versus 79.0% (P<0.05), respectively, to those treated with allo-HSCT (120 patients in the CP). (2) Both treatments resulted in similar survival, with EFS and OS rates of 42.9% versus 47.6% (P>0.05), 42.9% versus 57.1% (P>0.05), respectively, for imatinib (14 patients in the AP and BP) and allo-HSCT (21 patients in the AP and BP).
CONCLUSIONS: Imatinib confers signi cant survival advantage (EFS and OS) for CML patients with CP compared with allo-HSCT treatment. However, the outcomes are equally good with both treatments in AP and BP patients.

Inayat F, Saif MW
New Drug and Possible New Toxicity - Squamous Cell Carcinoma Following Imatinib in Patients with Gastrointestinal Stromal Tumors.
Anticancer Res. 2016; 36(11):6201-6204 [PubMed] Related Publications
BACKGROUND: Molecularly targeted therapy has revolutionized the treatment of advanced gastrointestinal stromal tumors (GISTs). Specifically, the consistent dependence of GISTs on proto-oncogene c-KIT signaling led to the development and successful implementation of imatinib, a small-molecule c-KIT inhibitor. Imatinib induces, rapid and sustained clinical benefit by blocking the signaling via c-KIT. The most frequently reported adverse reactions (>30%) include edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain.
CASE SERIES: Herein, we report a case series of cutaneous squamous cell carcinoma (SCC) occurring secondary to imatinib in two patients treated for GISTs. Both patients were successfully managed with surgical resection of SCC and the discontinuation of the drug. Furthermore, we undertook a comprehensive literature review on this association. Few cases of cutaneous SCC secondary to imatinib therapy were reported in patients with chronic myeloid leukemia. However, there was no clinical evidence on causation of imatinib-associated SCC in patients with GIST.
CONCLUSION: To our knowledge, the present report is the first to describe imatinib-related SCC in patients undergoing treatment for GISTs. This implicates that safety and long-term tolerability of imatinib in patients with GISTs warrant rigorous testing and close monitoring.

Abu-Amna M, Awadie H, Bar-Sela G
Imatinib-induced Gastrointestinal Vascular Ectasia in a Patient with Advanced GIST: Case Report and Literature Review.
Anticancer Res. 2016; 36(11):6151-6154 [PubMed] Related Publications
BACKGROUND: Imatinib is generally well tolerated in the treatment of advanced gastrointestinal stromal tumors (GIST). Gastrointestinal vascular ectasia (GIVE) and gastric antral vascular ectasia (GAVE), while rare, are significant under-reported complications of imatinib therapy.
CASE REPORT: We present one patient with GIVE complicating imatinib therapy with a literature review of this rare side-effect.
RESULTS: A 68-year-old woman was diagnosed with advanced GIST, wild-type CKIT. After 3 months of treatment with imatinib, she had partial response. However, she was diagnosed with GAVE and, later, also with GIVE. During her 3-year imatinib treatment, she suffered from severe anemia and required blood transfusions. Conservative treatments were not helpful and the ectatic lesions resolved only with cessation of imatinib.
CONCLUSION: This confirms a causal relationship between GIVE and imatinib. GIVE and GAVE should be considered possible causes of anemia and upper gastrointestinal bleeding in patients receiving imatinib therapy.

Pala L, Bergamini C, Imbimbo M, et al.
Safety of combination treatment with imatinib mesylate, carboplatin, and cetuximab in a patient with multiple cancers: a case report.
Tumori. 2016; 102(Suppl. 2) [PubMed] Related Publications
PURPOSE: Therapies directed against multiple signaling pathways have been validated in the clinical setting as effective anticancer treatments. The combination of different agents is particularly helpful in patients with multiple cancer diagnoses, while data on cross-toxicity are frequently missing, as for imatinib and cetuximab plus platinum drugs.
METHODS: We present the case of a 76-year-old man with advanced laryngeal squamous cell carcinoma and chronic myeloid leukemia (CML). Combined treatment with imatinib mesylate and cetuximab plus carboplatin was well-tolerated by the patient, who did not develop neutropenia. By an interdisciplinary approach with hematology specialists, the anticipated neutropenia was managed by the temporary interruption of imatinib treatment when the white blood cell (WBC) count nadir was expected to occur.
RESULTS: Although treatment with imatinib, carboplatin, and cetuximab can be associated with hematologic toxicities, a combination regimen based on the concomitant administration of these 3 drugs and on the discontinuation of imatinib at the predicted nadir of WBC count was feasible and well-tolerated in a patient with concomitant CML and locally advanced laryngeal squamous cell carcinoma.
CONCLUSIONS: Our report indicates the feasibility of combination imatinib and cetuximab plus carboplatin in a case of multiple cancer diagnoses, provided that the treatment with imatinib is modulated according to the expected bone marrow depression.

Zheng X, Zhang Y, Zhang L, et al.
Synergistic inhibition of sunitinib and ethaselen against human colorectal cancer cells proliferation.
Biomed Pharmacother. 2016; 83:212-220 [PubMed] Related Publications
Sunitinib, a multi-targeted tyrosine kinase inhibitor, has been widely used in the therapy of advanced renal cell cancer and imatinib-resistant gastrointestinal stromal tumors. However, little benefits could be obtained from sunitinib for patients with other types of solid tumors including colorectal cancer (CRC). Ethaselen (BBSKE), a specific thioredoxin reductase 1 inhibitor, has shown convincing anticancer effects both in vivo and in vitro. In this study, we explored the combinatory effect of sunitinib and BBSKE in human CRC cell lines LoVo, HT-29 and RKO. Cotreatment of BBSKE and sunitinib with the ratio of 2:1 for 24h displayed synergistic effect against CRC cells proliferation. Apoptosis analysis also revealed that combination treatment of BBSKE and sunitinib (2:1) for 24h induced higher apoptosis rate than either single treatment. The synergistic effect against LoVo cells proliferation may be explained by sharp reduction of Bcl-2/Bax protein expression ratio, decrease of pro-Caspase-3 protein expression along with significantly augmented Caspase-3 enzymatic activity, and release of cytochrome C from mitochondria to cytoplasm in the combination treatment group. The significant inhibition of vascular endothelial growth factor receptor 2 (VEGFR2) phosphorylation might also account for the synergism in cotreatment group. In short, sunitinib plus BBSKE is perhaps a promising strategy for colorectal cancer therapy.

Paulmichl A, Summer D, Manzl C, et al.
Targeting Gastrointestinal Stromal Tumor with (68)Ga-Labeled Peptides: An In Vitro Study on Gastrointestinal Stromal Tumor-Cell Lines.
Cancer Biother Radiopharm. 2016; 31(8):302-310 [PubMed] Related Publications
The gastrointestinal stromal tumor (GIST) is a rare disease with limited therapeutic options when resistance to tyrosine kinase inhibitor (TKI) treatment occurs. The authors investigated binding of various (68)Ga-labeled peptides, targeting receptors reported to be overexpressed in GIST, in different cell lines. For this purpose, three GIST cell lines were tested: GIST-T1, GIST882 (Imatinib sensitive), and GIST430 (Imatinib resistant). DOTA-NT 8-13 (targeting NTR1), DOTA-TATE (targeting SSTR2), CP04 (a minigastrin derivative targeting CCK2-R), VIP-DOTA (targeting VPAC2-R), and 2 DOTA-bombesin derivatives [targeting gastrin releasing peptide receptors (GRPR)] were radiolabeled with (68)Ga and incubated with the respective tumor cell and control cell lines. Membrane-bound and internalized activity was measured. Very low or no specific binding to GIST cells was found for all (68)Ga-labeled DOTA peptides except for bombesin derivatives indicating no or very low expression of respective receptors. Related to GRPR a pronounced specific binding to all GIST cell lines with no preference related to TKI resistance status was found, both for an agonist (AMBA) with high internalization and for an antagonist (NeoBOMB1) with mainly membrane-bound activity (with up to >80% bound/mg protein). GRPR expression was confirmed by immunohistochemistry. The results show that radiolabeled bombesin analogues, especially antagonists are very promising candidates for targeting GIST.

Huang L, Wang SA, Konoplev S, et al.
Well-differentiated systemic mastocytosis showed excellent clinical response to imatinib in the absence of known molecular genetic abnormalities: A case report.
Medicine (Baltimore). 2016; 95(41):e4934 [PubMed] Free Access to Full Article Related Publications
INTRODUCTION: Well-differentiated systemic mastocytosis (WDSM) is a rare, recently recognized provisional subvariant of systemic mastocytosis (SM). We report a case of WDSM that showed excellent clinical and cutaneous response to imatinib in the absence of known molecular genetic abnormalities.
CLINICAL FINDINGS/DIAGNOSES: We present a 24-year-old woman with childhood onset of skin manifestations that progressed to mediator-related systemic events, and a gastrointestinal tract mastocytoma. A subsequent bone marrow examination showed WDSM. Treatment with imatinib resulted in complete resolution of cutaneous lesions and systemic symptoms, which relapsed with the discontinuation of the drug. Targeted next-generation sequencing-based mutation analysis did not demonstrate any mutations in the coding regions of KIT or other genes commonly associated with myeloid neoplasms.
CONCLUSIONS: The diagnosis of WDSM is challenging in the absence of spindle-shaped mast cells, CD2 or CD25 expression, and KIT D816 mutation. This case illustrated the need for recognizing this unique variant of SM for diagnostic and therapeutic implications.

Cervantes F, Correa JG, Pérez I, et al.
Imatinib dose reduction in patients with chronic myeloid leukemia in sustained deep molecular response.
Ann Hematol. 2017; 96(1):81-85 [PubMed] Related Publications
To determine whether a lower imatinib dose could minimize toxicity while maintaining the molecular response (MR), imatinib dose was reduced to 300 mg daily in 43 patients with chronic myeloid leukemia (CML) in sustained deep molecular response to first-line imatinib 400 mg daily. At the time of dose reduction, median duration of the deep response was 4.1 (interquartile range (IQR) 2.2-5.9) years; molecular response was MR(4), MR(4.5), and MR(5) of the international scale in 6, 28, and 9 patients, respectively. Toxicity grade was 1, 2, and 3 in 28, 8, and 1 patients, respectively; 6 patients underwent dose reduction without having side effects. With a median of 1.6 (IQR 0.7-3.2) years on imatinib 300 mg daily, only one patient lost the deep molecular response to MR(3). At the last follow-up, response was MR(3), MR(4), MR(4.5), and MR(5) in 1, 3, 9, and 30 patients, respectively. Toxicity improvement was observed in 23 (62.2 %) of the 37 patients with side effects, decreasing to grade 0 in 20 of them. All but one anemic patients improved (p = 0.01), the median Hb increase in this subgroup of patients being 1 g/dL. In CML patients with sustained deep response to the standard imatinib dose, reducing to 300 mg daily significantly improves tolerability and preserves efficacy.

Liu MY, Wang WZ, Liao FF, et al.
Selective and effective targeting of chronic myeloid leukemia stem cells by topoisomerase II inhibitor etoposide in combination with imatinib mesylate in vitro.
Cell Biol Int. 2017; 41(1):16-23 [PubMed] Related Publications
Imatinib mesylate (IM) and other BCR-ABL tyrosine kinase inhibitors (TKIs) have improved chronic myeloid leukemia (CML) patient survival markedly but fail to eradicate quiescent CML leukemia stem cells (LSCs). Thus, strategies targeting LSCs are required to induce long-term remission and achieve cure. Here, we investigated the ability of topoisomerase II (Top II) inhibitor etoposide (Eto) to target CML LSCs. Treatment with Eto combined with IM markedly induced apoptosis in primitive CML CD34(+) CD38(-) stem cells resistant to eradication by IM alone, but not in normal hematopoietic stem cells, CML and normal mature CD34(-) cells, and other leukemia and lymphoma cell lines. The interaction of IM and Eto significantly inhibited phosphorylation of PDK1, AKT, GSK3, S6, and ERK proteins; increased the expression of pro-apoptotic gene Bax; and decreased the expression of anti-apoptotic gene c-Myc in CML CD34(+) cells. Top II inhibitors treatment represents an attractive approach for targeting LSCs in CML patients undergoing TKIs monotherapy.

Nerich V, Fleck C, Chaigneau L, et al.
Cost-Effectiveness Analysis of Tyrosine Kinase Inhibitors for Patients with Advanced Gastrointestinal Stromal Tumors.
Clin Drug Investig. 2017; 37(1):85-94 [PubMed] Related Publications
INTRODUCTION: The management of advanced gastrointestinal stromal tumors (GISTs) has been modified considerably by the availability of costly tyrosine kinase inhibitors (TKIs); however, the best therapeutic sequence in terms of cost and effectiveness remains unknown.
OBJECTIVE: The aim of this study was to compare four potential strategies (reflecting the potential daily practice), each including imatinib 400 mg/day, as first-line treatment: S1 (imatinib400/best supportive care [BSC]); S2 (imatinib400/imatinib800/BSC); S3 (imatinib400/sunitinib/BSC); and S4 (imatinib400/imatinib800/sunitinib/BSC).
METHODS: A Markov model was developed with a hypothetical cohort of patients and a lifetime horizon. Transition probabilities were estimated from the results of clinical trials. The analysis was performed from the French payer perspective, and only direct medical costs were included. Clinical and economic parameters were discounted, and the robustness of results was assessed.
RESULTS: The least costly and effective strategy was S1, at a cost of €65,744 for 32.9 life months (reference). S3 was the most cost-effective strategy, with an incremental cost-effectiveness ratio (ICER) of €48,277/life-year saved (LYS). S2 was dominated, and S4 yielded an ICER of €363,320/LYS compared with S3. Sensitivity analyses confirmed the robustness of these results; however, when taking into account a price reduction of 80 % for imatinib, S2 and S4 become the most cost-effective strategies.
CONCLUSION: Our approach is innovative to the extent that our analysis takes into account the sequential application of TKIs. The results suggest that the S1 strategy is the best cost-effective strategy, but a price reduction of imatinib impacts on the results. This approach must continue, including new drugs and their impact on the quality of life of patients with advanced GISTs.

Zhang P, Deng R, Liu K, et al.
Clinicopathologic features and prognosis of primary gastrointestinal stromal tumor patients under 35 years of age: A 10-year retrospective study.
J Surg Oncol. 2016; 114(8):977-981 [PubMed] Related Publications
OBJECTIVES: To investigate gastrointestinal stromal tumor (GIST) clinicopathologic characteristics in young adults.
METHODS: Clinicopathologic data from GIST patients under 35 years diagnosed at our hospital from January 2005 to December 2014 were retrospectively collected.
RESULTS: Thirty-one (5.3%, 31/585) patients were included; 17 (54.8%) were female. The most common presentation and primary tumor site were gastrointestinal bleeding (n = 18, 58.1%) and the small intestine (n = 13, 41.9%), respectively. Fifteen (48.4%) GISTs were classified as having a high relapse risk; two (6.4%), intermediate; nine (29.0%), low; and five (16.1%), very low. All patients underwent tumor resection. With a median follow-up of 51 months for 20 (64.5%) patients, 12 (60%) were given imatinib methylate as adjuvant therapy. One (5%) patient died of peritoneal GIST dissemination, four (20%) developed abdominal recurrences, two (10%) had hepatic metastasis, and thirteen (65%) were disease free. The 5-year disease-free survival rate was 51.2%.
CONCLUSIONS: GISTs rarely occur in young adults. The most common location is the small intestine. A slight female predominance was observed in the current study. Adjuvant therapy longer than the recommended duration may be beneficial for GISTs with a high relapse risk. Combined targeted therapy and surgery is appropriate for recurrent and metastatic GISTs in select patients. J. Surg. Oncol. 2016;114:977-981. © 2016 Wiley Periodicals, Inc.

Patrikidou A, Le Cesne A
Key messages from the BFR14 trial of the French Sarcoma Group.
Future Oncol. 2017; 13(3):273-284 [PubMed] Related Publications
The BRF14 trial is a prominent study that investigated the effect of prolonged imatinib treatment in advanced gastrointestinal stromal tumor patients. The key messages deduced from this study are as follows: imatinib drastically improved progression-free and overall survival in advanced gastrointestinal stromal tumor patients. Treatment ought to be maintained indefinitely in nonprogressing patients, as interruption entails a high risk of progression, even in patients in complete response. Imatinib rechallenge is effective, achieving new disease control in patients progressing after imatinib interruption. Rechallenge response profiles reflect the initial responses, albeit of poorer quality. Imatinib interruption does not affect the incidence of secondary resistance; however, the imatinib-free interval influences the time to secondary resistance. Specific clinical, biological and molecular characteristics seem to identify the patients who are long responders to imatinib. Surgery of residual disease after maximal imatinib response improves progression-free and overall survival.

Szucs Z, Thway K, Fisher C, et al.
Molecular subtypes of gastrointestinal stromal tumors and their prognostic and therapeutic implications.
Future Oncol. 2017; 13(1):93-107 [PubMed] Related Publications
Gastrointestinal stromal tumors (GISTs) are composed of various molecular subtypes, with differing prognostic and predictive relevance. Previously, tumors lacking mutations in the KIT and PDGFRA genes have been designated as 'wild-type' GISTs; however, they represent a heterogeneous group currently undergoing further subclassification. Primary and secondary resistance to imatinib poses a significant clinical challenge, therefore ongoing research is trying to evaluate mechanisms to overcome resistance. Thorough understanding of the prognostic and predictive relevance of different genetic subtypes of GIST can guide clinical decision-making both in the adjuvant and the metastatic setting. Further work is required to identify tailored therapies for specific subgroups of GISTs wild-type for KIT and PDGFRA mutations and to identify predictive factors of resistance to currently approved systemic therapies.

Li HF, Meng WT, Jia YQ, et al.
Development-associated immunophenotypes reveal the heterogeneous and individualized early responses of adult B-acute lymphoblastic leukemia.
Medicine (Baltimore). 2016; 95(34):e4128 [PubMed] Related Publications
B cell acute lymphoblastic leukemia (B-ALL) exhibits phenotypes reminiscent of normal stages of B-cell development. As demonstrated by flow cytometry, the immunophenotypes are able to determine the stages of B cell development. Multicolor flow cytometry (MFC) is more accurate at identifying cell populations. In this study, 9-color panels, including CD10, CD19, CD20, CD22, CD34, CD79a, CD179a, and IgM, which are sequentially expressed during B cell development, were designed to detect the leukemia cell subpopulations in adult B-ALL patients. In 23 patients at diagnosis, 192 heterogeneous subpopulations of leukemia cells were detected. Compared with their counterparts at diagnosis and after the 1st course of induction therapy, the responses of the subpopulations were also heterogeneous. In the CD10 population, the residual B cell subpopulations in the BCR/ABL patients were obviously reduced compared to those in the BCR/ABL patients. New subpopulations were detected in 22 of 23 patients and were primarily located in the CD34CD10 populations. Subpopulations of clonal evolution were heterogeneous after induction therapy. Our results suggest that the subpopulations in B-ALL patients should be dynamically monitored by development-associated immunophenotyping before, during, and after induction therapy and to predict the prognosis of the disease.

Yousefi B, Shafiei-Irannejad V, Azimi A, et al.
PPAR-gamma in overcoming kinase resistance in chronic myeloid leukemia.
Cell Mol Biol (Noisy-le-grand). 2016; 62(8):52-5 [PubMed] Related Publications
Peroxisome proliferator-activated receptor gamma (PPARγ) plays key roles in regulating cellular differentiation, proliferation and apoptosis pathways. As such, they are considered promising targets for anticancer drug development, especially for breast cancer, multiple myeloma and hematologic malignancies. Chronic myeloid leukemia (CML) is a myeloproliferative disorder arising from an oncogenic Bcr-Abl tyrosine kinase. Inhibitors of this oncogene by small molecules such as imatinib are effective only in 75% of the patient's population. One of the potential strategies to overcome this resistance is to devise combination therapy protocols with other therapeutic agents including PPAR ligands. Since PPAR ligands are potentially interesting in different hematologic malignancies, this article will review the potential of PPAR ligands for use in CML treatment.

Iqbal N, Sharma A, Shukla N, et al.
Advanced gastrointestinal stromal tumors: 10-years experience from a tertiary care centre.
Trop Gastroenterol. 2015 Jul-Sep; 36(3):168-73 [PubMed] Related Publications
BACKGROUND: Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. We aimed to study the pattern of presentation and treatment outcome of advanced GIST patients seen by us in a 10- year period.
METHODS: Medical records of GIST patients seen between years 2002-2012 were retrieved from institute as well as database maintained by authors. Patient included in this analysis had metastatic disease and unresectable and/or residual disease after surgery.
RESULTS: During the study period 62 patients fulfilled the inclusion criteria but 6 were lost to follow up before treatment and hence 56 patients were analysed. Median age was 45.5 years (range 17-70 years) with a male female ratio of 2:1. Thirty eight (67%) patients had metastatic disease whereas 32% patients had unresectable or incompletely resected disease. The most common primary site was small intestine in 24 (42.8%) which was followed by stomach in 11 (19.6%) patients. The most common site of metastases was liver in 27 (48%) patients. Median tumor size was 12 cm (range 4-50 cm). Thirty two (57%) patients had mitotic counts of > 5/50 HPF. All patients received imatinib. The most common response seen with imatinib was stable disease achieved in 29 (52%) patients. Imatinib was well tolerated by all patients without any drug discontinuation. The 5-year EFS and OS were 35% and 49%, respectively at a median follow up of 55 months. None of the patient or tumor factors were found to have prognostic significance in univariate survival analysis.
CONCLUSIONS: This is a single center experience of advanced GIST patients where small intestine was found to be the commonest disease site with imatinib producing disease stabilization in more than half of patients. Even though the survival was comparable to published reports, the major limitation was lack of mutation analysis.

Farhadi E, Zaker F, Safa M, Rezvani MR
miR-101 sensitizes K562 cell line to imatinib through Jak2 downregulation and inhibition of NF-κB target genes.
Tumour Biol. 2016; 37(10):14117-14128 [PubMed] Related Publications
Imatinib mesylate (IM) is a frontline treatment in the early chronic phase of chronic myeloid leukemia (CML). However, intrinsic and acquired resistance against this drug has been defined and this issue has become a problem and a challenge in CML treatment. According to new findings, the inhibition of Janus kinase 2 (Jak2) in Bcr-Abl+ cells can promote apoptosis in IM-resistant cells. microRNAs (miRNAs) regulate the gene expression by targeting the messenger RNA (mRNA) for degradation. Recently, a growing body of evidence has implicated that dysregulation of miRNAs is associated with cancer initiation and development. In this report, we proposed that miRNA-101 targets Jak2 mRNA and regulates its expression and induces K562 leukemia cell apoptosis. Here, we transduced the K562 cell line with a miR-101-overexpressing vector and evaluated the Jak2 mRNA level. Our results showed that miR-101 overexpression in Bcr-Abl+ cells reduced the Jak2 mRNA level. Moreover, imatinib treatment and miR-101 upregulation led to miR-23a overexpression, which has putative binding site(s) on 3'-untranslated regions (3'-UTRs) of STAT5, CCND1, and Bcl-2 genes. Our results also indicated that miR-101 overexpression inhibited cell proliferation indicated by the MTT assay and promoted apoptosis detected via flow cytometry. Importantly, mRNA expression of NF-kappa B-regulated anti-apoptotic (Bcl-2, Bcl-xl, MCL-1, XIAP, and survivin) and proliferative (c-Myc and CCND1) genes was decreased. These findings suggest that miR-101 acts as a tumor suppressor by downregulating Jak2 expression and sensitizing K562 cells to imatinib. Therefore, restoration of miR-101 may be a therapeutic approach for CML treatment.

Elias F, Khuri FR, Adib SM, et al.
Financial Burden of Cancer Drug Treatment in Lebanon.
Asian Pac J Cancer Prev. 2016; 17(7):3173-7 [PubMed] Related Publications
BACKGROUND: The Ministry of Public Health (MOPH) in Lebanon provides cancer drugs free of charge for uninsured patients who account for more than half the total caseload. Other categories of cancer care are subsidized under more stringent eligibility criteria. MOPH's large database offers an excellent opportunity to analyze the cost of cancer treatment in Lebanon.
MATERIALS AND METHODS: Using utilization and spending data accumulated at MOPH during 20082013, the cost to the public budget of cancer drugs was assessed per case and per drug type.
RESULTS: The average annual cost of cancer drugs was 6,475$ per patient. Total cancer drug costs were highest for breast cancer, followed by chronic myeloid leukemia (CML), colorectal cancer, lung cancer, and NonHodgkin's lymphoma (NHL), which together represented 74% of total MOPH cancer drug expenditure. The annual average cancer drug cost per case was highest for CML ($31,037), followed by NHL ($11,566). Trastuzumab represented 26% and Imatinib 15% of total MOPH cancer drug expenditure over six years.
CONCLUSIONS: Sustained increase in cancer drug cost threatens the sustainability of MOPH coverage, so crucial for socially vulnerable citizens. To enhance the bargaining position with pharmaceutical firms for drug cost containment in a small market like Lebanon, drug price comparisons with neighboring countries which have already obtained lower prices may succeed in lowering drug costs.

Katagiri S, Tauchi T, Saito Y, et al.
Musculoskeletal pain after stopping tyrosine kinase inhibitor in patients with chronic myeloid leukemia: a questionnaire survey.
Rinsho Ketsueki. 2016; 57(7):873-6 [PubMed] Related Publications
We conducted a questionnaire survey to assess the state of patients with CML after discontinuation of TKI therapy. Nine of 27 patients developed musculoskeletal pain after TKI discontinuation. One had discontinued nilotinib and eight had discontinued imatinib therapy. Median time to symptom development after discontinuation was 2 weeks. Four experienced grade 3 symptoms as per the CTCAE ver. 4.0. One had pain persisting over a period of 21 months. There was a significant difference between patients with and without symptoms as regards female gender and the probability of persistent MMR. Awareness of this withdrawal syndrome after TKI discontinuation is imperative.

Cheung CY, Lo SH, Chan CK, et al.
Gastrointestinal stromal tumors in kidney transplant recipients: Report of two cases and literature review.
Asia Pac J Clin Oncol. 2017; 13(1):104-106 [PubMed] Related Publications
Gastrointestinal stromal tumors (GISTs) are the most common primary mesenchymal gastrointestinal neoplasms. However, GISTs occurring in kidney transplant recipients, including their treatment and outcome, are rarely described in literature. We hereby report two kidney transplant recipients with GISTs. Our first patient was diagnosed with high-risk epithelioid gastric GIST 2 years after kidney transplant. He received everolimus after resection and remained disease-free for 2 years before liver metastasis was confirmed. Imatinib therapy was planned but he died of fulminant pneumonia shortly. Our second patient was diagnosed with spindle cell GISTs in the mesentery 1 year after kidney transplant. Only partial response was obtained with imatinib as new lesions continued to develop. Withdrawal of cyclosporine and introduction of sirolimus resulted in complete shrinkage of existing tumors and no new lesions. He remained disease-free for more than 10 years. Combination therapy consisting of imatinib and inhibitors of mammalian target of rapamycin (mTORi) seems to be safe and effective in kidney transplant recipients. However, therapeutic drug monitoring of mTORi is essential to avoid nephrotoxicity. Further trials addressing the optimal dosage of imatinib and mTORi in kidney transplant recipients are recommended.

Ravegnini G, Nannini M, Simeon V, et al.
Polymorphisms in DNA repair genes in gastrointestinal stromal tumours: susceptibility and correlation with tumour characteristics and clinical outcome.
Tumour Biol. 2016; 37(10):13413-13423 [PubMed] Related Publications
DNA repair pathways play an essential role in cancer susceptibility by maintaining genomic integrity. This led us to investigate the influence of polymorphisms in the genes coding repair pathway enzymes on gastrointestinal stromal tumours (GIST) susceptibility, tumour characteristics and clinical outcome. We investigated a panel of 20 polymorphisms in 11 genes in 81 cases and 147 controls. The XPD rs13181 wild-type allele and hOGG1 rs1052133 and XPF rs1800067 minor alleles were significantly associated with disease susceptibility. XPA rs1800975 and rs2808668 were associated with tumour size (P = 0.018), metastatic status at onset (P = 0.035) and mitotic index (P = 0.002). With regards to outcome treatment, the XPD rs50872 minor allele had a significant favourable impact on time to progression (TTP). Similarly, the XPC rs2228000 minor allele was correlated with a longer TTP (P = 0.03). On the contrary, the XPC rs2228001 and hOGG1 rs1052133 minor alleles were associated with a diminished TTP (P = 0.005 and P = 0.01, respectively). Regarding OS, we found the presence of at least one hOGG1 (rs1052133) minor allele that had a 60 % lower risk to die compared to the wild-type carriers (P = 0.04). Furthermore, the XRCC3 rs861539 variant allele is associated with a hazard of early death compared with the wild-type genotype (P = 0.04). To the best of our knowledge, this is the first study on polymorphisms in DNA repair genes, belonging to the different pathways, extensively evaluated in GIST patients. Through this multiple candidate gene approach, we report for the first time the significant associations between polymorphisms in DNA repair genes, susceptibility, clinical pathological features and clinical outcome in GIST.

Pavkovic M, Angelkovic R, Popova-Simjanovska M, et al.
Molecular Response in Patients with Chronic Myeloid Leukemia Treated with Imatinib - Single Centre Experience.
Pril (Makedon Akad Nauk Umet Odd Med Nauki). 2015; 36(2):179-86 [PubMed] Related Publications
Introduction of tyrosine kinase inhibitors (TKI) dramatically improves the treatment and survival of the patients with chronic myeloid leukemia (CML) in the last decade. Imatinib (IM) and other TKI induce larger percentage of complete cytogenetic response (CCyR) and major molecular response (MMR). Treatment resistance to TKIs still remains an important problem in the treatment of CML. The aim of our study was to analyze the molecular response (MR) in CML patients treated with Imatinib in our institution. We have analyzed 53 CML patients (pts), 28 females and 25 males, treated with IM as a front or second line treatment. Only 15 pts were treated with IM as a front-line therapy, while 38 pts were pretreated with hydroxyurea or/and interferon. Median duration of CML was 6 years (range: 1 year- 17 years). Median duration of IM treatment was 3 years (range: 1 year-10 years). MR was analyzed in one up to 8 time points with Real Time Quantitative RT-PCR method. Forty six pts (87%) had complete hematological response and 55% of pts had MMR, 13/53(24.5%) pts had MMR at 4.0-4.5 log and 16/53(30.2%) pts had MMR at 3.0-4.0 log. MMR was not achieved in 24/53(45.3%). Our results have shown smaller percentage of patients (55%) with MMR, mostly due to the fact that larger proportion of patients (38/53) were heavily pretreated with HU or/and Interferon for a prolonged period of time, before the IM treatment. This is a major risk factor for acquisition of additional molecular and cytogenetic abnormalities responsible for IM resistance and poor treatment response.

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