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Introduction: Metastatic castration-resistant prostate cancer (mCRPC) remains incurable and develops from biochemically recurrent PC treated with androgen deprivation therapy (ADT) following definitive therapy for localized PC, or from metastatic castration-sensitive PC (mCSPC). In the mCSPC setting, treatment intensification of ADT plus androgen receptor (AR)-signaling inhibitors (ARSIs), with or without chemotherapy, improves outcomes vs ADT alone. Despite multiple phase 3 trials demonstrating a survival benefit of treatment intensification in PC, there remains high use of ADT monotherapy in real-world clinical practice. Prior studies indicate that co-inhibition of AR and poly(ADP-ribose) polymerase (PARP) may result in enhanced benefit in treating tumors regardless of alterations in DNA damage response genes involved either directly or indirectly in homologous recombination repair (HRR). Three recent phase 3 studies evaluated the combination of a PARP inhibitor (PARPi) with an ARSI as first-line treatment for mCRPC: TALAPRO-2, talazoparib plus enzalutamide; PROpel, olaparib plus abiraterone acetate and prednisone (AAP); and MAGNITUDE, niraparib plus AAP. Results from these studies have led to the recent approval in the United States of talazoparib plus enzalutamide for the treatment of mCRPC with any HRR alteration, and of both olaparib and niraparib indicated in combination with AAP for the treatment of mCRPC with BRCA alterations., Summary: Here, we review the newly approved PARPi plus ARSI treatments within the context of the mCRPC treatment landscape, provide an overview of practical considerations for the combinations in clinical practice, highlight the importance of HRR testing, and discuss the benefits of treatment intensification for patients with mCRPC., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: R.R.M. reports a consulting or advisory board role for AstraZeneca, AVEO Pharmaceuticals, Bayer, Blue Earth Diagnostics, Bristol Myers Squibb, Calithera, Caris, Dendreon, Eisai, Eli Lilly, Exelixis, Janssen, Merck, MOMA, Myovant, Novartis, Pfizer, Sanofi, Seagen, Sorrento Therapeutics, Telix, and Tempus; and research funding (to her institution) from AstraZeneca, Artera, Bayer, Bristol Myers Squibb, Exelixis, Oncternal, and Tempus. A.K.M. reports a consulting role for Antev, Astellas, AstraZeneca, Bayer, Exelixis, Janssen, Lantheus, Merck, Myovant, Novartis, Pfizer, Sanofi, and Telix; and research funding from Bayer, Lantheus, Myovant, Pfizer, and Sanofi. N.D.S. reports a consulting or advisory role for AbbVie, Alessa Therapeutics, AIkido, Amgen, Arquer, Asieris, Astellas Pharma, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb, CG Oncology, Clarity Pharmaceuticals, Clovis Oncology, Dendreon, Exact Imaging, Exact Sciences, FerGene, Ferring, FIZE Medical, Foundation Medicine, GenesisCare, Genentech, Guardant Health, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, Mdxhealth, Merck, Minomic, Myovant Sciences, Myriad Genetics, Nymox, Pacific Edge Biotechnology, Pfizer, Photocure, PlatformQ, Profound, Promaxo, Propella Therapeutics, Protara, Sanofi, Sesen Bio, Speciality Networks, Telix Pharmaceuticals, Tolmar, UroGen Pharma, Vaxiion, and Vessi; providing expert testimony for Ferring; and leadership or other fiduciary role in other board, society, committee, or advocacy group with Photocure. C.D. reports participation on advisory boards for Astellas Pharma, Bayer, Janssen, and Pfizer; and research funding from AstraZeneca, Bayer, Dendreon, Hengrui Pharmaceuticals, Janssen, Laekna Therapeutics, Myovant Sciences, and Pfizer. G.D. is an employee of Pfizer and may hold Pfizer stock/stock options. N.A. has received an honorarium for consultancy before May 2021 from Astellas Pharma, AstraZeneca, AVEO, Bayer, Bristol Myers Squibb, Calithera Biosciences, Eisai, EMD Serono, Exelixis, Foundation Medicine, Genentech, Gilead Sciences, Immunomedics, Janssen, Lilly, and MEI Pharma; and research funding (to his institution) from Arvinas, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Calithera Biosciences, Celldex, Clovis Oncology, CRISPR Therapeutics, Eisai, EMD Serono, Exelixis, Genentech, Gilead Sciences, GlaxoSmithKline, Immunomedics, Janssen, Lava, Lilly, Merck, Nektar, Neoleukin, Novartis, ORIC Pharmaceuticals, Pfizer, Rexahn, Roche, Sanofi, Seagen, Takeda, and TRACON., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Aim: We aimed to establish and validate a simple and sensitive UPLC-MS/MS method for the determination of UNC1999, a dual inhibitor against EZH1 and EZH2 in plasma samples. Materials & methods: UNC1999 in rat plasma was processed with protein precipitation method and then separated on a C 18 column and detected under positive ionization mode. The method presented good linearity over the range of 1.0-2000 ng/ml with good accuracy and precision. UNC1999 was absorbed slowly and achieved a maximum concentration of 118.8 ± 12.0 ng/ml 1.5 h after oral administration. Conclusion: The method provides a favorable character in selectivity, linearity, accuracy, precision, recovery, matrix effects and stabilities and was suitable for describing the pharmacokinetic profile of UNC1999.

Both EZH2 and its homolog EZH1 function as histone H3 Lysine 27 (H3K27) methyltransferases and repress the transcription of target genes. Dysregulation of H3K27 trimethylation (H3K27me3) plays an important role in the development and progression of cancers such as hepatocellular carcinoma (HCC). This study investigated the relationship between the expression of EZH1/2 and the level of H3K27me3 in HCC. Additionally, the role of EZH1/2 in cell growth, tumorigenicity, and resistance to sorafenib were also analyzed. Both the lentiviral knockdown and the pharmacological inhibition of EZH1/2 (UNC1999) diminished the level of H3K27me3 and suppressed cell growth in liver cancer cells, compared with EZH1 or EZH2 single knockdown. Although a significant association was observed between EZH2 expression and H3K27me3 levels in HCC samples, overexpression of EZH1 appeared to contribute to enhanced H3K27me3 levels in some EZH2 low H3K27me3 high cases. Akt suppression following sorafenib treatment resulted in an increase of the H3K27me3 levels through a decrease in EZH2 phosphorylation at serine 21. The combined use of sorafenib and UNC1999 exhibited synergistic antitumor effects in vitro and in vivo. Combination treatment canceled the sorafenib-induced enhancement in H3K27me3 levels, indicating that activation of EZH2 function is one of the mechanisms of sorafenib-resistance in HCC. In conclusion, sorafenib plus EZH1/2 inhibitors may comprise a novel therapeutic approach in HCC., (© 2021. The Author(s).)

Ferroptosis is a type of programmed cell death induced by the accumulation of lipid peroxidation and lipid reactive oxygen species in cells. It has been recently demonstrated that cancer cells are vulnerable to ferroptosis inducers (FIN). However, the therapeutic potential of FINs in prostate cancer in preclinical settings has not been explored. In this study, we demonstrate that mediators of ferroptosis, solute carrier family 7 member 11, SLC3A2, and glutathione peroxidase, are expressed in treatment-resistant prostate cancer. We further demonstrate that treatment-resistant prostate cancer cells are sensitive to two FINs, erastin and RSL3. Treatment with erastin and RSL3 led to a significant decrease in prostate cancer cell growth and migration in vitro and significantly delayed the tumor growth of treatment-resistant prostate cancer in vivo , with no measurable side effects. Combination of erastin or RSL3 with standard-of-care second-generation antiandrogens for advanced prostate cancer halted prostate cancer cell growth and migration in vitro and tumor growth in vivo . These results demonstrate the potential of erastin or RSL3 independently and in combination with standard-of-care second-generation antiandrogens as novel therapeutic strategies for advanced prostate cancer. SIGNIFICANCE: These findings reveal that induction of ferroptosis is a new therapeutic strategy for advanced prostate cancer as a monotherapy and in combination with second-generation antiandrogens., (©2021 American Association for Cancer Research.)

Delta opioid receptor (DOR) agonists have been identified as a promising novel therapy for headache disorders. DORs are broadly expressed in several peripheral and central regions important for pain processing and mood regulation; and it is unclear which receptors regulate headache associated symptoms. In a model of chronic migraine-associated pain using the human migraine trigger, nitroglycerin, we observed increased expression of DOR in cortex, hippocampus, and striatum; suggesting a role for these forebrain regions in the regulation of migraine. To test this hypothesis, we used conditional knockout mice with DORs deleted from forebrain GABAergic neurons (Dlx-DOR), and investigated the outcome of this knockout on the effectiveness of the DOR agonist SNC80 in multiple headache models. In DOR loxP controls SNC80 blocked the development of acute and chronic cephalic allodynia in the chronic nitroglycerin model, an effect that was lost in Dlx-DOR mice. In addition, the anti-allodynic effects of SNC80 were lost in a model of opioid induced hyperalgesia/medication overuse headache in Dlx-DOR conditional knockouts. In a model reflecting negative affect associated with migraine, SNC80 was only effective in loxP controls and not Dlx-DOR mice. Similarly, SNC80 was ineffective in the cortical spreading depression model of migraine aura in conditional knockout mice. Taken together, these data indicate that forebrain DORs are necessary for the action of DOR agonists in relieving headache-related symptoms and suggest that forebrain regions may play an important role in migraine modulation.

Purpose: NCI-MATCH is a nationwide, histology-agnostic, signal-finding, molecular profile-driven trial for patients with refractory cancers, lymphomas, or myelomas. Patients with tumors harboring actionable aberration(s) in fibroblast growth factor receptor ( FGFR ) 1-3 were treated with AZD4547, an oral FGFR1-3 inhibitor., Methods: Patients' tumors were screened by next-generation sequencing for predefined FGFR amplification, activating mutations, or fusions. Patients were treated with AZD4547, 80 mg orally twice daily until progression of disease or drug intolerance. A response rate of 16% was considered promising., Results: Between July 2016 and June 2017, 70 patients were assigned and 48 received protocol therapy and are eligible for analysis. Patients' tumors harbored FGFR1 or FGFR2 amplification (n = 20), FGFR2 or FGFR3 single-nucleotide variants (n = 19), or FGFR1 or FGFR3 fusions (n = 9). The most common primary tumors were breast (33.3%), urothelial (12.5%), and cervical cancer (10.4%).Grade 3 adverse events were consistent with those described in previous clinical trials. Confirmed partial responses were seen in 8% (90% CI, 3% to 18%) and were observed only in patients whose tumors harbored FGFR1-3 point mutations or fusions. Stable disease was observed in 37.5% (90% CI, 25.8% to 50.4%). The median progression-free survival (PFS) was 3.4 months, and the 6-month PFS rate was 15% (90% CI, 8% to 31%). For patients with tumors harboring FGFR fusions, the response rate was 22% (90% CI, 4.1% to 55%), and 6-month PFS rate was 56% (90% CI, 31% to 100%)., Conclusion: Preliminary signals of activity appeared to be limited to cancers harboring FGFR activating mutations and fusions, although AZD4547 did not meet the primary end point. Different FGFR somatic alterations may confer different levels of signaling potency and/or oncogene dependence., Competing Interests: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government.

Objectives: Currently, there is no optimal salvage therapy for patients with malignant pleural mesothelioma (MPM) who relapse after treatment with first-line chemotherapy. In line with the strong preclinical rationale for targeting fibroblast growth factor receptor (FGFR) signalling in malignant mesothelioma, we conducted a phase II study assessing the efficacy of AZD4547, an oral tyrosine multi-kinase FGFR 1-3 inhibitor, as a second or third-line treatment., Materials and Methods: We conducted a single-center, open-label, single-arm phase II study of AZD4547 in eligible patients with confirmed, measurable MPM and radiological progression after first or second-line systemic chemotherapy. Patients received continuous, twice-daily oral AZD4547 on a 3-weekly cycle. The primary end point was 6-month progression free survival (PFS6). Response was assessed with CT scan every 6 weeks according to the modified RECIST criteria for mesothelioma (mRECIST) and toxicities were also assessed. The study used a Simon's two-stage design: 26 patients would be recruited to the first stage and more than 7 (27 %) of 26 patients were required to achieve PFS6 to continue to stage two, for a potential total cohort of 55 patients., Results: 3 of 24 patients (12 %) were progression-free at 6 months. Hence, the study fulfilled stopping criteria regardless of further recruitment and warranted discontinuation. The most common toxicities (across all grades) were hyperphosphatemia, xerostomia, mucositis, retinopathy, dysgeusia, and fatigue. Maximum toxicities were grade 2 or below for all patients across all cycles. There was no association between tumour BAP1 protein loss and clinical outcomes., Conclusions: The FGFR 1-3 inhibitor AZD4547 did not demonstrate efficacy in patients with MPM who had progressed after first line treatment with platinum-based chemotherapy., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: S1400D is a biomarker-driven therapeutic substudy of Lung-MAP evaluating the fibroblast growth factor (FGF) receptor (FGFR) inhibitor AZD4547 in patients with FGF pathway-activated squamous cell. This is the first phase II trial to evaluate AZD4547 as a targeted approach in patients with previously treated FGFR-altered squamous cell NSCLC and is the first demonstration of successful implementation and conduct of a national umbrella protocol in this disease setting., Methods: Eligible patients had tumoral FGFR alteration or mutation and had progressive disease after at least one line of platinum-based systemic therapy. Patients received AZD4547 80 mg twice daily orally. Primary endpoint was response by Response Evaluation Criteria in Solid Tumors version 1.1; secondary endpoints included progression-free survival, overall survival, and duration of response (DoR)., Results: Ninety-two patients were assigned to S1400D, 43 were enrolled, and 27 AZD4547-treated patients were evaluable. Evaluable patients were predominantly white (n = 24, 89%), median age 66 years (range, 49-88 years old), and female (n = 7, 26%). FGFR alterations included FGFR1 amplification (n = 23; 85%), FGFR3 amplification (n = 2; 7%), FGFR3 S249C (n = 2; 7%), and FGFR3 fusion (n = 1; 4%). Treatment with ADZ4547 was well tolerated; grade 3 adverse events occurred in six patients, and one patient had grade 4 sepsis. Of 27 response-evaluable patients, 1 patient with FGFR3 S249C had unconfirmed partial response with a DoR of 1.5 months and 1 patient with FGFR1 amplification had a confirmed partial response with a DoR of 2.9 months (7%, 95% confidence interval [CI]: 0%-17%). Median progression-free survival and overall survival for the AZD4547-treated cohort were 2.7 months (95% CI: 1.4- 4.5 months) and 7.5 months (95% CI: 3.7-9.3 months)., Conclusions: AZD4547 had an acceptable safety profile but minimal activity in this predominantly FGFR1/FGFR3-amplified cohort. Evaluation of other targeted agents in Lung-MAP is ongoing., (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: Lung adenocarcinoma accounts for approximately half of lung cancer cases. Twenty to 50% of tumors of this type harbor mutations affecting epidermal growth factor receptor (EGFR) expression or activity, which can be therapeutically targeted. EGFR inhibitors in this context exhibit high efficacy and are currently used in the clinical setting. However, not all adenocarcinomas harboring EGFR mutations respond to therapy, so predictive biomarkers of therapeutic outcomes, as well as novel therapies sensitizing these tumors to EGFR inhibition, are needed., Materials and Methods: We performed in vitro gene overexpression/silencing and tumorigenic surrogate assays, as well as in vitro and in vivo combination treatments with Fibroblast Growth Factor Receptor (FGFR)/EGFR inhibitors. At the clinical level, we determined FGFR4 expression levels in tumors from patients treated with EGFR inhibitors and correlated these with treatment response., Results: We describe a cooperative interaction between EGFR and FGFR4, which results in their reciprocal activation with pro-oncogenic consequences in vitro and in vivo. This cooperation is independent of EGFR activating mutations and increases resistance to different EGFR inhibitors. At the therapeutic level, we provide evidence of the synergistic effects of the combination of EGFR and FGFR inhibitors in high FGFR4-expressing, EGFR-activated tumors in vitro and in vivo. Correlated with these results, we found that patients treated with EGFR inhibitors relapse earlier when their tumors exhibit high FGFR4 expression., Conclusions: We propose a novel predictive biomarker for EGFR-targeted therapy, and a highly efficacious combinatory therapeutic strategy to treat EGFR-dependent; this may may extend the use of appropriate inhibitors beyond EGFR-mutated adenocarcinoma patients., (Copyright © 2019. Published by Elsevier B.V.)

Headaches are highly disabling and are among the most common neurological disorders worldwide. Despite the high prevalence of headache, therapeutic options are limited. We recently identified the delta opioid receptor (DOR) as an emerging therapeutic target for migraine. In this study, we examined the effectiveness of a hallmark DOR agonist, SNC80, in disease models reflecting diverse headache disorders including: chronic migraine, post-traumatic headache (PTH), medication overuse headache by triptans (MOH), and opioid-induced hyperalgesia (OIH). To model chronic migraine C57BL/6J mice received chronic intermittent treatment with the known human migraine trigger, nitroglycerin. PTH was modeled by combining the closed head weight drop model with the nitroglycerin model of chronic migraine. For MOH and OIH, mice were chronically treated with sumatriptan or morphine, respectively. The development of periorbital and peripheral allodynia was observed in all four models; and SNC80 significantly inhibited allodynia in all cases. In addition, we also determined if chronic daily treatment with SNC80 would induce MOH/OIH, and we observed limited hyperalgesia relative to sumatriptan or morphine. Together, our results indicate that DOR agonists could be effective in multiple headache disorders, despite their distinct etiology, thus presenting a novel therapeutic target for headache., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

KRAS mutations are one of the most prevalent genetic alterations in colorectal cancer (CRC). Although directly targeting KRAS still is a challenge in anti-cancer therapies, alternatively inhibiting KRAS related signaling pathways has been approached effectively. Here we firstly reported that MAP kinase, transforming growth factor-β-activated kinase 1 (TAK1), commonly expressed in CRC cell lines and significantly associated with KRAS mutation status. Inhibition of TAK1 by the small molecular inhibitor NG25 could inhibit CRC cells proliferation in vitro and in vivo, especially in KRAS-mutant cells. NG25 induced caspase-dependent apoptosis in KRAS-mutant cells and in orthotopic CRC mouse models by regulating the B-cell lymphoma-2 (Bcl-2) family and the inhibitor of apoptosis protein (IAP) family. Besides inhibiting molecules downstream of MAPK, including ERK, JNK and p38 phosphorylation, NG25 could block NF-κB activation in KRAS-mutant cells. As a target gene of NF-κB, down-regulated XIAP expression may be not only involved in apoptosis induced by NG25, but also reducing the formation of TAK1-XIAP complex that can activate TAK1 downstream signaling pathways, which forms a positive feedback loop to further induce apoptosis in KRAS-mutant CRC cells. Together, these findings indicated that TAK1 is an important kinase for survival of CRCs harboring KRAS mutations, and that NG25 may be a potential therapeutic strategy for KRAS-mutant CRC.

Background and Purpose: Opioid δ receptor agonists are potent antihyperalgesics in chronic pain models, but tolerance develops after prolonged use. Previous evidence indicates that distinct forms of tolerance occur depending on the internalization properties of δ receptor agonists. As arrestins are important in receptor internalization, we investigated the role of arrestin 2 (β-arrestin 1) in mediating the development of tolerance induced by high- and low-internalizing δ receptor agonists., Experimental Approach: We evaluated the effect of two δ receptor agonists with similar analgesic potencies, but either high-(SNC80) or low-(ARM390) internalization properties in wild-type (WT) and arrestin 2 knockout (KO) mice. We compared tolerance to the antihyperalgesic effects of these compounds in a model of inflammatory pain. We also examined tolerance to the convulsant effect of SNC80. Furthermore, effect of chronic treatment with SNC80 on δ agonist-stimulated [ 35 S]-GTPγS binding was determined in WT and KO mice., Key Results: Arrestin 2 KO resulted in increased drug potency, duration of action and decreased acute tolerance to the antihyperalgesic effects of SNC80. In contrast, ARM390 produced similar effects in both WT and KO animals. Following chronic treatment, we found a marked decrease in the extent of tolerance to SNC80-induced antihyperalgesia and convulsions in arrestin 2 KO mice. Accordingly, δ receptors remained functionally coupled to G proteins in arrestin 2 KO mice chronically treated with SNC80., Conclusions and Implications: Overall, these results suggest that δ receptor agonists interact with arrestins in a ligand-specific manner, and tolerance to high- but not low-internalizing agonists are preferentially regulated by arrestin 2., (© 2018 The British Pharmacological Society.)

L-DOPA-induced dyskinesia (LID) remains a significant problem in the management of Parkinson's disease (PD). In rodent and macaque models of PD, delta opioid receptor agonists have anti-parkinsonian actions while mu opioid antagonists can reduce the expression of LID. DPI-289 is a novel molecule with a unique combination of opioid receptor DAMA actions: delta agonist (K i : 0.73 nM); mu antagonist (K i : 12 nM). We demonstrated that DPI-289 has oral bioavailability and established its pharmacokinetic profile in both rat and primate. We hypothesised that these combined DAMA actions would provide an enhancement of L-DOPA effect without an associated increase in dyskinesia. In parkinsonian 6-OHDA lesioned rats and MPTP-lesioned macaques, DPI-289 provided anti-parkinsonian actions as monotherapy and an enhancement of L-DOPA benefit. Thus, acute administration of DPI-289 (3 mg/kg, p.o.) to 6-OHDA-lesioned rats produced a significant reduction in forelimb asymmetry (by 48%) that was maintained throughout the fifteen-day repeat-treatment period. Importantly, and in contrast to L-DOPA administration (6 mg/kg, i.p.), these benefits were not compromised by the development of abnormal involuntary movements. In the macaque, as monotherapy, DPI-289 (10 and 20 mg/kg) had significant, though incomplete, anti-parkinsonian actions lasting approximately 4 h. These benefits were not associated with dyskinesia. In fact, over the 6 h period of observation, DPI-289 (20 mg/kg) decreased parkinsonism by 19% and increased activity by 67% compared to vehicle treatment. By contrast, while high-dose L-DOPA (LDh) alone alleviated parkinsonism (for 3 h) this benefit was accompanied by significant dyskinesia that was disabling in nature. LDh provided a 50% reduction in parkinsonism over 6 h and 151% increase in activity. The combination of DPI-289 (20 mg/kg) and a low-dose of L-DOPA (LDl) provided anti-parkinsonian benefits greater than LDl alone without eliciting any significant dyskinesia. Treatment with LDl alone provided only transient statistically significant anti-parkinsonian benefit. However, the combination of LDl and DPI-289 reduced parkinsonism for 6 h (duration of monitoring), with parkinsonism being reduced by 35% and activity increased by 90% but with no increase in dyskinesia over that observed with LDl alone. Thus, DPI-289 has potential to improve the benefits of dopaminergic therapy in Parkinson's disease., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Squamous cell lung cancers (SQCLC) account for 25% of all NSCLCs, yet the prognosis of these patients is poor and treatment options are limited. Amplified FGFR1 is one of the most common oncogenic events in SQCLCs, occurring in approximately 20% of cases. AZD4547 is a potent and selective FGFR1-3 inhibitor with antitumor activity in FGFR1 -amplified SQCLC cell lines and patient-derived xenografts. Experimental Design: On the basis of these data, we performed a phase I study of AZD4547 in patients with previously treated stage IV FGFR1 -amplified SQCLCs (NCT00979134). FGFR1 amplification (FGFR1:CEP8 ≥ 2) was determined by FISH. The primary endpoint was safety/tolerability. Secondary endpoints included antitumor activity, pharmacokinetics, pharmacodynamics, and molecular analyses. Results: Fifteen FGFR1 -amplified patients were treated. The most common related adverse events (AE) were gastrointestinal and dermatologic. Grade ≥3-related AEs occurred in 3 patients (23%). Thirteen patients were evaluable for radiographic response assessment. The overall response rate was 8% (1 PR). Two of 15 patients (13.3%) were progression-free at 12 weeks, and the median overall survival was 4.9 months. Molecular tests, including next-generation sequencing, gene expression analysis, and FGFR1 immunohistochemistry, showed poor correlation between gene amplification and expression, potential genomic modifiers of efficacy, and heterogeneity in 8p11 amplicon. Conclusions: AZD4547 was tolerable at a dosage of 80 mg oral twice a day, with modest antitumor activity. Detailed molecular studies show that these tumors are heterogeneous, with a range of mutational covariates and stark differences in gene expression of the 8p11 amplicon that likely explain the modest efficacy of FGFR inhibition in this disease. Clin Cancer Res; 23(18); 5366-73. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background AZD4547 is a potent, oral, highly selective fibroblast growth factor receptor (FGFR) inhibitor in clinical development for treating tumours with a range of FGFR aberrations, including FGFR mutations, amplifications and fusions. Methods This open-label, Phase I, multicentre study (NCT01213160) evaluated the safety, pharmacokinetics, and preliminary antitumour efficacy (RECIST v1.1) of AZD4547 monotherapy in Japanese patients with advanced solid tumours. Part A was a dose-escalation part; Part B was a dose-expansion part in patients with FGFR-amplified tumours, confirmed by fluorescence in situ hybridization. Results Thirty patients enrolled in Part A (dose range: 40 mg twice daily [bid] to 120 mg bid; 160 mg once daily [qd]), four in Part B (80 mg bid). No dose-limiting toxicities were observed and maximum tolerated dose was not determined. Most common adverse events (AEs; any grade) were: dysgeusia (50% of patients); stomatitis (41%); diarrhoea (38%); hyperphosphataemia (38%); dry mouth (35%). Common grade ≥3 AEs were nausea (12% of patients) and neutropenia (9%). No complete or partial responses were observed: 21/30 patients had stable disease ≥4 weeks in Part A, and 1/4 patients had stable disease ≥10 weeks in Part B. Following single and multiple dosing, absorption rate appeared moderate; peak plasma concentrations generally occurred 3-4 h post-dose, then declined biphasically with terminal half-life ~30 h. Steady state was reached by day 8. Compared with single dosing, plasma concentrations were, on average, 2.4- and 3.3- to 5.4-fold higher after qd and bid dosing, respectively. Conclusions AZD4547 was well tolerated in Japanese patients, with best response of stable disease ≥4 weeks.

Rationale: Regulator of G protein signaling (RGS) proteins act as negative modulators of G protein signaling. RGS4 has been shown to negatively modulate G protein signaling mediated by the delta opioid receptor (DOPr) in vitro. However, the role of RGS4 in modulating DOPr-mediated behaviors in vivo has not been elucidated., Objective: The aim of this study was to compare the ability of the DOPr agonist SNC80 to induce DOPr-mediated antinociception, antihyperalgesia, antidepressant-like effects, and convulsions in wild-type and RGS4 knockout mice., Methods: Antinociception was assessed in the acetic acid stretch assay. Antihyperalgesia was measured in a nitroglycerin-induced thermal hyperalgesia assay. Antidepressant-like effects were evaluated in the forced swim and tail suspension tests. Mice were also observed for convulsive activity post-SNC80 treatment. SNC80-induced phosphorylation of MAP kinase in striatal tissue from RGS4 wild-type and knockout mice was quantified by Western blot. DOPr number from forebrain tissue was measured using [ 3 H]DPDPE saturation binding., Results: Elimination of RGS4 potentiated SNC80-induced antinociception and antihyperalgesia. SNC80-induced antidepressant-like effects were potentiated in RGS4 knockout mice in the forced swim test but not in the tail suspension test. Additionally, RGS4 knockout did not alter SNC80-induced convulsions. SNC80-induced phosphorylation of MAP kinase was potentiated in striatum from RGS4 knockout mice. Loss of RGS4 did not affect total DOPr number., Conclusions: Overall, these findings demonstrate that reduction of RGS4 functionally may increase the therapeutic index of SNC80. These results provide the first evidence of differential regulation of DOPr-mediated behaviors by RGS proteins and G protein signaling pathways.

As the first tyrosine kinase inhibitor (TKI), imatinib (Gleevec or Glivec, Novartis Pharmaceuticals) was introduced, the treatment of chronic myeloid leukemia (CML) has changed radically, and the TKIs are now the mainstay of CML treatment. The substantially high treatment cost has unfortunately been a major issue, which puts a strain on health-care budgets even in developed countries. So reimbursement policies encourage generic drug (i.e. generic imatinib) use to lower the expenses, and it is true that generics would lead to considerable cost savings, but they also give rise to questions associated with their efficacy, safety and quality. In this commentary, we discuss the current evidence on generic imatinib based mainly on our "Cerrahpaşa" experience along with other data available in the literature together with the data discussed by de Lemos and colleagues., (© The Author(s) 2015.)

Rationale: Patients with anxious major depressive disorder (AMDD) have more severe symptoms and poorer treatment response than patients with non-AMDD. Increasing evidence implicates the endogenous opioid system in the pathophysiology of depression. AZD2327 is a selective delta opioid receptor (DOR) agonist with anxiolytic and antidepressant activity in animal models., Objective: This double-blind, parallel group design, placebo-controlled pilot study evaluated the safety and efficacy of AZD2327 in a preclinical model and in patients with AMDD., Methods: We initially tested the effects of AZD2327 in an animal model of AMDD. Subsequently, 22 subjects with AMDD were randomized to receive AZD2327 (3 mg BID) or placebo for 4 weeks. Primary outcome measures included the Hamilton Depression Rating Scale (HAM-D) and the Hamilton Anxiety Rating Scale (HAM-A). We also evaluated neurobiological markers implicated in mood and anxiety disorders, including vascular endothelial growth factor (VEGF) and electroencephalogram (EEG)., Results: Seven (54 %) patients responded to active drug and three (33 %) responded to placebo. No significant main drug effect was found on either the HAM-D (p = 0.39) or the HAM-A (p = 0.15), but the HAM-A had a larger effect size. Levels of AZ12311418, a major metabolite of AZD2327, were higher in patients with an anti-anxiety response to treatment compared to nonresponders (p = 0.03). AZD2327 treatment decreased VEGF levels (p = 0.02). There was a trend (p < 0.06) for those with an anti-anxiety response to have higher EEG gamma power than nonresponders., Conclusion: These results suggest that AZD2327 has larger potential anxiolytic than antidepressant efficacy. Additional research with DOR agonists should be considered., Competing Interests: The authors declare that they have no competing interests.

Background and Purpose: While cannabinoids have been proposed as a potential treatment for neuropathic pain, they have limitations. Cannabinoid receptor agonists have good efficacy in animal models of neuropathic pain; they have a poor therapeutic window. Conversely, selective fatty acid amide hydrolase (FAAH) inhibitors that enhance the endocannabinoid system have a better therapeutic window, but lesser efficacy. We examined whether JZL195, a dual inhibitor of FAAH and monacylglycerol lipase (MAGL), could overcome these limitations., Experimental Approach: C57BL/6 mice underwent the chronic constriction injury (CCI) model of neuropathic pain. Mechanical and cold allodynia, plus cannabinoid side effects, were assessed in response to systemic drug application., Key Results: JZL195 and the cannabinoid receptor agonist WIN55212 produced dose-dependent reductions in CCI-induced mechanical and cold allodynia, plus side effects including motor incoordination, catalepsy and sedation. JZL195 reduced allodynia with an ED50 at least four times less than that at which it produced side effects. By contrast, WIN55212 reduced allodynia and produce side effects with similar ED50s. The maximal anti-allodynic effect of JZL195 was greater than that produced by selective FAAH, or MAGL inhibitors. The JZL195-induced anti-allodynia was maintained during repeated treatment., Conclusions and Implications: These findings suggest that JZL195 has greater anti-allodynic efficacy than selective FAAH, or MAGL inhibitors, plus a greater therapeutic window than a cannabinoid receptor agonist. Thus, dual FAAH/MAGL inhibition may have greater potential in alleviating neuropathic pain, compared with selective FAAH and MAGL inhibitors, or cannabinoid receptor agonists., (© 2015 The British Pharmacological Society.)

Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology. In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. Chronic myeloid leukaemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL. During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph(+): t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukaemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival markedly. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined as the point when BCR-ABL transcripts become undetectable in blood cells. Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukaemia stem cells (LSCs). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor-γ (PPARγ). We found that activation of PPARγ by the glitazones decreases expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of the quiescence and stemness of CML LSCs. When pioglitazone was given temporarily to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool.

Background: Patients with gastrointestinal stromal tumour (GIST) are often followed up after surgery with longitudinally repeated imaging examinations to detect recurrence early. Studies on follow-up of GIST patients are few, the optimal follow-up methods are unknown and the recommendations for follow-up vary in guidelines., Methods: We reviewed the current evidence for follow-up of patients treated with surgery alone and of patients who were treated with adjuvant or neoadjuvant imatinib., Results: Imaging of the abdomen and the pelvis with computerised tomography (CT) or magnetic resonance imaging (MRI) usually suffices, since metastases are uncommon at other sites. The frequency of imaging may be adjusted with the risk of recurrence with time. Very low risk GISTs are very frequently cured with surgery and usually require no regular follow-up after complete surgery, and annual CT of the abdomen and the pelvis for 5 years suffices for most patients with a low to intermediate risk for recurrence. Most high-risk patients are treated with imatinib for at least 3 years after surgery. CT or MRI may be carried out 6-monthly during adjuvant imatinib, 3 to 4-monthly during the 2 years that follow discontinuation of imatinib when the risk of recurrence is high, and then at 6-12 month intervals to complete 10 years of follow-up. Recurrence after the first 10 years of follow-up is infrequent., Conclusions: The follow-up schedules are best tailored with the risk of recurrence. The risk of recurrence should be estimated with the prognostic tools that consider the most relevant prognostic factors., (Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Tyrosine kinase inhibitors (TKI) have improved the management of patients with chronic myeloid leukemia (CML). However, a significant proportion of patients does not achieve the optimal response or are resistant to TKI. ABL1 kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance. Although deletion or insertion of nucleotides in BCR-ABL1 has rarely been described, we identified a CML patient with an already described 35 nucleotides insertion (BCR-ABL1(35INS)) of controversial significance, that confers resistance to imatinib but sensitivity to dasatinib., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: Adiponectin, a functional ligand of adiponectin receptor-1 (AdipoR1) and adiponectin receptor-2 (AdipoR2), has been found to be linked to risk of development of chronic myeloid leukaemia (CML). Imatinib, as its first-line therapy, exhibits striking activity in both chronic and accelerated phases of the condition. However, numerous clinical trials have shown that many patients become refractory or experience relapses. Thus, development of new, hopefully effective Imatinib-based treatment strategies, are still needed., Materials and Methods: Effects of recombinant adiponectin protein, in enhancing Imatinib anti-tumour activities, in K562 and MEG-01 CML cells, were examined in vitro and in vivo. Forty-eight consecutive newly diagnosed adult patients with Bcr-Abl-positive CML, in the early chronic phase (ECP), were enrolled in the study. Imatinib efficacy, plasma adiponectin levels and their correlations were analysed., Results: Data presented here indicate that adiponectin enhanced Imatinib efficacy in vitro and in vivo. Furthermore, this augmented effect was due to inhibition of Bcr-Abl tyrosine kinase activity in an AdipoR1-dependent way, while AdipoR2 was not involved. Most importantly, additional clinical data revealed that adiponectin plasma levels in CML ECP patients, correlated with Imatinib efficacy., Conclusions: Adiponectin enhanced Imatinib anti-tumour activity in human chronic myeloid leukaemia cells and its serum levels were associated with Imatinib efficacy, in early chronic phase patients., (© 2015 John Wiley & Sons Ltd.)

Objective: Altered differentiation is a common feature of haematopoietic malignancies with poor prognosis. CAAT/enhancer binding protein alpha (C/EBPα) is a key transcription factor that regulates myeloid differentiation. This study is aimed to know the prognostic value of CAAT/enhancer binding protein alpha expression and correlate its expression with response to imatinib therapy., Methods: We quantified the expression of C/EBPα gene in 126 chronic myeloid leukaemia samples (82 from newly diagnosed and 44 from imatinib-resistant patients) and 20 control samples. C/EBPα mRNA level was measured by real-time quantitative polymerase chain reaction using the ΔΔCT method., Results: C/EBPα expression level was significantly lower in the imatinib-resistant group than in the pretreatment and control group (P = 0.0398). Low CAAT/enhancer binding protein alpha levels in the imatinib-resistant group were significantly associated with advanced phase (P = 0.04), with more peripheral blasts (P = 0.0001), high BCR-ABL levels (P = 0.018) and T315I and P-loop mutations (P = 0.0002). In the pretreatment group, low expression showed association with high EUTOS risk score (P = 0.03) and possible partial cytogenetic response (P = 0.010)., Conclusions: Our results suggest that low expression of CAAT/enhancer binding protein alpha might have a role in the response to imatinib and progression of disease in patients with chronic myeloid leukaemia., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Gastrointestinal stromal tumours (GISTs) of the rectum often require radical surgery to achieve complete resection. This study investigated the management and outcome of surgery for rectal GISTs and the role of imatinib., Methods: A cohort study was undertaken of patients identified from a database at one tertiary sarcoma referral centre over a continuous period, from January 2001 to January 2013., Results: Over 12 years, 19 patients presented with a primary rectal GIST. Median age was 57 (range 30-77) years. Neoadjuvant imatinib was used in 15 patients, significantly reducing mean tumour size from 7·6 (95 per cent c.i. 6·1 to 9·0) to 4·1 (2·8 to 5·3) cm (P < 0·001). Nine of these patients underwent surgical resection. Imatinib therapy enabled sphincter-preserving surgery to be undertaken in seven patients who would otherwise have required abdominoperineal resection or pelvic exenteration for tumour clearance. Neoadjuvant imatinib treatment also led to a significant reduction in mean(s.d.) tumour mitotic count from 16(16) to 4(9) per 50 high-power fields (P = 0·015). Imatinib was used only as adjuvant treatment in two patients. There were three deaths, all from unrelated causes. Eleven of the 13 patients who underwent resection were alive without evidence of recurrence at latest follow-up, with a median disease-free survival of 38 (range 20-129) months and overall survival of 62 (39-162) months., Conclusion: The use of neoadjuvant imatinib for rectal GISTs significantly decreased both tumour size and mitotic activity, which permitted less radical sphincter-preserving surgery., (© 2015 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Duodenal gastrointestinal tumors represent an extremely rare subset of stromal tumors arising from interstitial cells of Cajal. In the last 30 years the comprehension of the pathophysiology and natural history of this previously misunderstood clinical entity, in association with developments in endoscopy, imaging technology, and immunohistochemistry has resulted in novel diagnostic and treatment approaches. This is a comprehensive review of the current data of the literature on the various aspects of the diagnosis and treatment of these tumors. The duodenum is the less commonly involved site for these tumors in the digestive tract. Endoscopy and computed tomography can usually establish the diagnosis, confirmed by immunohistochemical staining and occasionally molecular genetic analysis. Endoscopic ultrasound with fine needle aspiration has been recently found to be the gold diagnostic standard with high sensitivity and specificity rates, diagnosing GIST in up to 80% of patients. Due to the complex anatomy of the pancreatico-duodenal region optimal therapeutic strategy of duodenal GISTs are challenging. Nevertheless surgical resection with microscopically clear resection margins seems to be the only potentially curative treatment for non-metastatic primary GISTs of the duodenum. Imatinib mesylate plays a key role in the management of GISTs both as neoadjuvant therapy and in patients with recurrent and metastatic disease. Meanwhile, the advances in the comprehension of the pathophysiology and natural history of this previously misunderstood clinical entity as well as the treatment of these tumors may render feasible, in the near future, the advent of newer and more effective treatment options., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

In this study, we randomly compared high doses of the tyrosine kinase inhibitor imatinib combined with reduced-intensity chemotherapy (arm A) to standard imatinib/hyperCVAD (cyclophosphamide/vincristine/doxorubicin/dexamethasone) therapy (arm B) in 268 adults (median age, 47 years) with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The primary objective was the major molecular response (MMolR) rate after cycle 2, patients being then eligible for allogeneic stem cell transplantation (SCT) if they had a donor, or autologous SCT if in MMolR and no donor. With fewer induction deaths, the complete remission (CR) rate was higher in arm A than in arm B (98% vs 91%; P = .006), whereas the MMolR rate was similar in both arms (66% vs 64%). With a median follow-up of 4.8 years, 5-year event-free survival and overall survival (OS) rates were estimated at 37.1% and 45.6%, respectively, without difference between the arms. Allogeneic transplantation was associated with a significant benefit in relapse-free survival (hazard ratio [HR], 0.69; P = .036) and OS (HR, 0.64; P = .02), with initial white blood cell count being the only factor significantly interacting with this SCT effect. In patients achieving MMolR, outcome was similar after autologous and allogeneic transplantation. This study validates an induction regimen combining reduced-intensity chemotherapy and imatinib in Ph+ ALL adult patients and suggests that SCT in first CR is still a good option for Ph+ ALL adult patients. This trial was registered at www.clinicaltrials.gov as #NCT00327678., (© 2015 by The American Society of Hematology.)

In this issue of Blood, Chalandon et al report the results of a prospective randomized study comparing standard vs less-intensive chemotherapy, both combined with imatinib, for patients with newly diagnosed Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL). They show that the less-intensive therapy reduces early mortality without impairing efficacy, resulting in a significantly higher hematologic complete remission (CR) rate and an equivalent major molecular response (MMolR) rate.

Significance: Chronic myeloid leukemia (CML) involves the malignant transformation of hematopoietic stem cells, defined largely by the Philadelphia chromosome and expression of the breakpoint cluster region-Abelson (BCR-ABL) oncoprotein. Pharmacological tyrosine kinase inhibitors (TKIs), including imatinib mesylate, have overcome limitations in conventional treatment for the improved clinical management of CML., Recent Advances: Accumulated evidence has led to the identification of a subpopulation of quiescent leukemia progenitor cells with stem-like self renewal properties that may initiate leukemogenesis, which are also shown to be present in residual disease due to their insensitivity to tyrosine kinase inhibition., Critical Issues: The characterization of quiescent leukemia progenitor cells as a unique cell population in CML pathogenesis has become critical with the complete elucidation of mechanisms involved in their survival independent of BCR-ABL that is important in the development of novel anticancer strategies. Understanding of these functional pathways in CML progenitor cells will allow for their selective therapeutic targeting. In addition, disease pathogenesis and drug responsiveness is also thought to be modulated by epigenetic regulatory mechanisms such as DNA methylation, histone acetylation, and microRNA expression, with a capacity to control CML-associated gene transcription., Future Directions: A number of compounds in combination with TKIs are under preclinical and clinical investigation to assess their synergistic potential in targeting leukemic progenitor cells and/or the epigenome in CML. Despite the collective promise, further research is required in order to refine understanding, and, ultimately, advance antileukemic therapeutic strategies.

Few patients in remission of Ph-positive chronic myelogenous leukemia (CML) develop Ph-negative MDS/AML, usually with clonal cytogenetic abnormalities. Isolated Ph-negative myeloid sarcoma (MS) is presented here as a form of such disorder, different from Ph-positive MS establishing CML relapse in blastic phase. We describe 11-year-old male who developed Ph-negative isolated MS with NPM1 mutation, remaining in complete molecular remission of Ph-positive chronic myeloid leukemia treated with allo-HSCT in first chronic phase and with imatinib and donor lymphocyte infusion in molecular relapse. The possible mechanisms of the tumor formation are reviewed with stress on importance of comprehensive molecular/cytogenetic evaluations., (© 2015 Wiley Periodicals, Inc.)

The prognosis of advanced gastrointestinal stromal tumors (GISTs) was dramatically improved in the era of imatinib. Cytoreduction surgery was advocated as an additional treatment for advanced GISTs, especially when patients having poor response to imatinib or developing resistance to it. However, the efficacy and benefit of cytoreduction were still controversial. Likewise, the sequence between cytoreduction surgery and imatinib still need evaluation. In this study, we tried to assess the feasibility and efficiency of cytoreduction in advanced GISTs. Furthermore, we analyzed the impact of timing of the cytoreduction surgery on the prognosis of advanced GISTs. We conducted a prospective collecting retrospective review of patients with advanced GISTs (metastatic, unresectable, and recurrent GISTs) treated in Chang Gung memorial hospital (CGMH) since 2001 to 2013. We analyzed the impact of cytoreduction surgery to response to imatinib, progression-free survival (PFS), and overall survival (OS) in patients with advanced GISTs. Moreover, by the timing of cytoreduction to imatinib, we divided the surgical patients who had surgery before imatinib use into early group and those who had surgery after imatinib into late. We compared the clinical response to imatinib, PFS and OS between early and late cytoreduction surgical groups. Totally, 182 patients were enrolled into this study. Seventy-six patients underwent cytoreduction surgery. The demographic characteristics and tumor presentation were similar between surgical and non-surgical groups. The surgical group showed better complete response rate (P <  .001) and partial response rate (P = 0.008) than non-surgical group. The 1-year, 3-year, and 5-year PFS were significantly superior in surgical group (P = 0.003). The 1-year, 3-year, and 5-year OS were superior in surgical group, but without statistical significance (P = 0.088). Dividing by cytoreduction surgical timing, the demographic characteristics and tumor presentation were comparable in early and late groups. The late cytoreduction group presented higher R0 resection rate (59.1% vs 31.5%, P = 0.025). However, the PFS and OS were comparable in both groups.Combining imatinib with cytoreduction increased the response rate to imatinib and prolonged PFS in patients with advanced GISTs. Moreover, early and late cytoreduction surgery was comparable in prognosis, although late cytoreduction revealed higher complete resection rate.

A 78-year-old male, who had CKD and chronic heart failure, was referred to our hospital for evaluation of leukocytosis. His bone marrow contained 12% blast cells and chromosome analysis showed the Ph chromosome as well as other changes. The patient was diagnosed with the accelerated-phase CML because FISH and RT-PCR disclosed BCR/ABL fusion signals and minor BCR/ABL, respectively. Imatinib was administered, but the CML was resistant to this treatment. We gave him nilotinib employing a reduced and intermittent administration protocol because of the progression of anemia and heart failure. The patient achieved PCyR in 8 months, but, 12 months later, his WBC count increased and 83% of the cells were blasts. Because the probable diagnosis was the blast crisis of CML, we switched from nilotinib to dasatinib. However, leukocytosis worsened and he died of pneumonia. It was later revealed that he had a normal karyotype and both FISH and RT-PCR analysis of BCR/ABL were negative. His final diagnosis was Ph negative AML developing from Ph positive CML in PCyR. Since there were no dysplastic changes indicative of MDS, it was assumed that the AML was not secondary leukemia caused by the tyrosine kinase inhibitor but, rather, de novo AML.

Platelet-derived growth factor (PDGF) is implicated in the pathogenesis of pulmonary arterial hypertension (PAH). Imatinib, a PDGF-receptor tyrosine kinase inhibitor, improved hemodynamics, but serious side effects and drug discontinuation are common when treating PAH. A drug delivery system using nanoparticles (NPs) enables the reduction of side effects while maintaining the effects of the drug. We examined the efficacy of imatinib-incorporated NPs (Ima-NPs) in a rat model and in human PAH-pulmonary arterial smooth muscle cells (PASMCs). Rats received a single intratracheal administration of PBS, FITC-NPs, or Ima-NPs immediately after monocrotaline injection. Three weeks after monocrotaline injection, intratracheal administration of Ima-NPs suppressed the development of pulmonary hypertension, small pulmonary artery remodeling, and right ventricular hypertrophy in the rat model of monocrotaline-induced PAH. We also examined the effects of imatinib and Ima-NPs on PDGF-induced proliferation of human PAH-PASMCs by (3)H-thymidine incorporation. Imatinib and Ima-NPs significantly inhibited proliferation after 24 hours of treatment. Ima-NPs significantly inhibited proliferation compared with imatinib at 24 hours after removal of these drugs. Delivery of Ima-NPs into lungs suppressed the development of MCT-induced PAH by sustained antiproliferative effects on PAS-MCs.

Background: The aim of this study was to compare the T lymphocyte subsets of chronic myelogenous leukemia (CML) patients who had a complete cytogenetic response (CCyR) after treatment with imatinib (IM) or homoharringtonine (HHT)., Methods: T and Th lymphocyte subsets in CCyR patients treated with HHT (n = 15) or IM (n = 16) were assayed with flow cytometry., Results: It was found that there were no differences in T lymphocyte subset proportions at the time of achieving CCyR0 and also no difference in the CD8+T cell proportions at the 12th month after CCyR (CCyR12), between the 2 groups. The values of CD3+T, CD4+T, CD8+T, CD4+T/CD8+T, Th1 and Th2 cells were 54.21% ± 6.12% vs. 44.32% ± 4.85%, 29.83% ± 5.53% vs. 22.27% ± 3.22%, 24.66 ± 4.91 vs. 25.41% ± 5.72% , 1.11 ± 0.23 vs. 0.92 ± 0.19, 10.23% ± 4.24% vs. 8.34% ± 3.45% and 11.12% ± 3.91% vs. 13.67% ± 4.78%, respectively in the HHT group and IM group at CCyR12, which meant that the proportions of CD3+T, CD4+T and Th1 cells and the ratio of CD4+T to CD8+T cells were higher and the CD8+T and Th2 cell proportions were lower in the HHT group than in the IM group., Conclusions: HHT has a weaker immunodepression effect on T lymphocyte subsets compared with IM.

Purpose: Metastatic gastrointestinal stromal tumour (GIST) is generally an incurable disease with variable response to imatinib. We aimed to develop prognostic nomograms to predict overall survival (OS) and progression-free survival (PFS) for patients treated with imatinib., Methods: Nomograms were developed in a training cohort (n=330) of patients treated in a randomised trial (EORTC-ISG-AGITG 62005 phase III study) using Cox regression models, and validated in patients (n=236) treated in routine clinical care from six referral centres. Nomogram performance was assessed by calculating the c statistic. A classification based on the nomograms' scores was generated to group patients according to risk., Results: Nomogram risk factors for OS and PFS were size of the largest metastasis, tumour genotype, primary tumour mitotic count, haemoglobin and blood neutrophil count at commencement of imatinib. The nomograms predicted survival with a c statistic of 0.75 (training) and 0.62 (validation) for OS, and 0.69 (training) and 0.62 (validation) for PFS. When tested in the validation cohort, the nomograms discriminated well the high and intermediate risk from low risk patients (hazard ratio [HR] for OS 3.83, 95% confidence interval [CI] 1.71-8.56; and 2.48, 95% CI 1.12-5.50; for PFS 2.84, 95% CI 1.66-4.87; and 1.45, 95% CI 0.87-2.41, respectively)., Conclusion: The nomograms predicted the risk of GIST progression and death with good discrimination of risk groups, and may be of value for patient counselling and risk stratification., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Objectives: In Brazil, imatinib mesylate is supplied as the first-line therapy for chronic myeloid leukemia in the chronic phase through the public universal healthcare program, Sistema Único de Saúde (SUS). We studied the socio-demographic factors that influenced therapy success in a population in the northeast region of Brazil., Methods: Patients with chronic myeloid leukemia from the state of Piauí were treated in only one reference center. Diagnosis was based on WHO 2008 criteria. Risk was assessed by Sokal, Hasford and EUTOS scores. Patients received 400 mg imatinib daily. We studied the influence of the following factors on the achievement of complete cytogenetic response within one year of treatment: age, clinical risk category, time interval between diagnosis and the start of imatinib treatment, geographic distance from the patient's home to the hospital, years of formal education and monthly income., Results: Among 103 patients studied, the median age was 42 years; 65% of the patients had 2-9 years of formal education, and the median monthly income was approximately 100 US$. Imatinib was started in the first year after diagnosis (early chronic phase) in 69 patients. After 12 months of treatment, 68 patients had a complete cytogenetic response. The Hasford score, delay to start imatinib and years of formal education influenced the attainment of a complete cytogenetic response, whereas income and the distance from the home to the healthcare facility did not., Conclusion: Patients require additional healthcare information to better understand the importance of long-term oral anticancer treatment and to improve their compliance with the treatment.

Dermatofibrosarcoma protuberans (DFSP) is a rare, plaque-like tumor of the cutaneous tissue occurring more on the trunk than the extremities and neck. More than 95% of DFSP present anomalies on the 17q22 and 22q13 chromosomal regions leading to the fusion of COL1A1 and PDGFB genes. Surgery is the optimal treatment for DFSP, but less effective in locally advanced or metastatic patients, as is the case with chemotherapy and radiotherapy. The aim of this study was to assess retrospectively the therapeutic activity and safety of imatinib on 22 Chinese patients with locally inoperative or metastatic DFSP at a single institution.In the collected data of 367 Chinese patients with DFSP, we analyzed retrospectively 22 patients with locally advanced or metastatic DFSP, all of whom received imatinib therapy at 1 center from January 2009 to October 2014. Patients were administered with imatinib at an initial dose of 400 mg and escalated to 800 mg daily after they developed imatinib resistance. The median follow-up time was 36 months, and the median treatment time was 15 months.The results showed that 10 locally advanced DFSP patients and 12 metastatic DFSP patients received imatinib therapy. Apart from 1 patient who developed primary imatinib resistance, 15 patients achieved partial remission (PR), and 6 patients achieved stable disease (SD). Both fibrosarcomatous DFSP and classic DFSP patients demonstrated similar response to imatinib. Median PFS was estimated to be 19 months. Median overall survival (OS) has not been reached, and estimated 1- and 3-year OS rates were 95.5% (21/22) and 77.3% (17/22), respectively. Four out of 10 patients with primarily unresectable DFSP received complete surgical resection after neoadjuvant treatment of imatinib.Imatinib therapy is well tolerated with a safety profile and is the therapy of choice in locally inoperative or metastatic DFSP. Neoadjuvant treatment of locally advanced or metastatic DFSP with imatinib improves surgical outcomes and may facilitate resection of difficult tumors.

Purpose: Here, we studied whether amplicon next-generation deep sequencing (NGS) could improve the detection of emerging BCR-ABL1 kinase domain mutations in chronic phase chronic myeloid leukemia (CML) patients under tyrosine kinase inhibitor (TKI) treatment and discussed the clinical relevance of such sensitive mutational detection., Methods: For NGS data evaluation including extraction of biologically relevant low-level variants from background error noise, we established and applied a robust and versatile bioinformatics approach., Results: Results from a retrospective longitudinal analysis of 135 samples of 15 CML patients showed that NGS could have revealed emerging resistant mutants 2-11 months earlier than conventional sequencing. Interestingly, in cases who later failed first-line imatinib treatment, NGS revealed that TKI-resistant mutations were already detectable at the time of major or deeper molecular response. Identification of emerging mutations by NGS was mirrored by BCR-ABL1 transcript level expressed either fluctuations around 0.1 %(IS) or by slight transcript level increase. NGS also allowed tracing mutations that emerged during second-line TKI therapy back to the time of switchover. Compound mutants could be detected in three cases, but were not found to outcompete single mutants., Conclusions: This work points out, that next-generation deep sequencing, coupled with a robust bioinformatics approach for mutation calling, may be just in place to ensure reliable detection of emerging BCR-ABL1 mutations, allowing early therapy switch and selection of the most appropriate therapy. Further, prospective assessment of how to best integrate NGS in the molecular monitoring and clinical decision algorithms is warranted.

Treatment with a tyrosine kinase inhibitor (TKI) targeting BCR-ABL1 is currently the standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CML-CP). In this study, we present results of the ENESTchina (Evaluating Nilotinib Efficacy and Safety in Clinical Trials-China) that was conducted to investigate nilotinib 300 mg twice daily vs imatinib 400 mg once daily in a Chinese population. ENESTchina met its primary end point with a statistically significant higher rate of major molecular response (MMR; BCR-ABL1 ≤0.1% on the International Scale) at 12 months in the nilotinib arm vs the imatinib arm (52.2% vs 27.8%; P < .0001), and MMR rates remained higher with nilotinib vs imatinib throughout the follow-up period. Rates of complete cytogenetic response (0% Philadelphia chromosome-positive [Ph+] metaphases by standard cytogenetics) were comparable and ≥80% by 24 months in both arms. The estimated rate of freedom from progression to accelerated phase/blast crisis at 24 months was 95.4% in each arm. The safety profiles of both drugs were similar to those from previous studies. In conclusion, rates of MMR at 12 months were superior with nilotinib vs imatinib in Chinese patients with newly diagnosed Ph+ CML-CP. This trial was registered at www.clinicaltrials.gov as #NCT01275196., (© 2015 by The American Society of Hematology.)

To explore the factors for achieving early molecular responses (EMR; BCR-ABL1 ≤10% at 3 months, ≤1% at 6 months) by imatinib (IM), baseline characteristics including individual BCR-ABL1 transcript level, dose intensity, and IM trough level on day 29 were analyzed in 286 chronic phase chronic myeloid leukemia patients. Distinct predictive factors for achieving EMR at 3 months and 6 months were noted. Blast count at diagnosis and IM trough level on day 29 were significantly associated with an achievement of 3-month EMR. Early decline of BCR-ABL1 transcript, low Sokal risk, and mean daily dose (≥350mg/day) by 6 months were associated with an achievement of 6-month EMR. Understanding the predictive factors for EMR may provide additional information to guide clinical decisions on the changing therapies at each landmark., (Copyright © 2015. Published by Elsevier Ltd.)

Imatinib was administrated to a 38-year-old woman with chronic myeloid leukemia(CML). A major molecular response (MMR)(≤5 copies/0.5 μgRNA in Amp-CML detected using the transcription mediated amplification/hybridization protection assay(TMA/HPA)method)was achieved in 18 months. She maintained MMR for 10 months, and wished to become pregnant. Imatinib was stopped intentionally because she wished to plan a pregnancy, but we prescribed interferon alpha (IFN-a)due to the likelihood of the CML recurring after pregnancy. The nausea caused by IFN-a was improved by administrating it during the night, and she gave birth to a healthy baby by a normal delivery, whilst maintaining MMR. In this case, IFN-a treatment gave good clinical results, the patient's prognosis was improved, and she could maintain a good quality of life. We consider this to be an informative example of IFN-a therapy for CML during pregnancy.

Background: Chronic myelogenous leukaemia (CML) is a hematopoietic stem cell disease with a relatively stable clinical course. Survival has increased with addition of Tyrosine Kinase inhibitors (TKI's). Its conversion into blast crises (BC) heralds an accelerated clinical course that is less responsive to treatment and has high mortality., Methods: Clinical records of 20 patients with CML who transformed to BC in two years between January 2012 and December 2013 were reviewed., Results: Out of total 240 patients, 20 (8.3%) transformed to blast crisis; among them 75% were males and 25% females. Mean age was 37.9 years (24-58 years) and 19 patients were positive for t (9; 22) (q34; q11) translocation at the time of transformation. The mean initial blood cell count was 204 (range: 33 to 526). Imatinib was offered in 76% of patients. The average duration between diagnosis and transformation to blast crises was 201 days (range: 24-333 days). Eight patients (40%) were transformed to acute myeloid leukaemia (AML) and 12 (60%) had acute lymphoblastic leukaemia (ALL). These patients were treated with standard AML/ALL type induction chemotherapy except one who died early. During the study period, 11 patients died. Median survival for whole group was 55 days. On bivariate and multivariate linear regression analyses mortality was not, significantly associated with the duration between diagnosis and development of blast crises or the type of treatment received., Conclusion: Treatment of BC remains a challenge, particularly in under resourced areas where allogeneic hematopoietic stem cell transplantation (Allo-SCT) facility is sparse. Outcomes remain dismal in majority of these patients.

Background: The prognosis about duodenal GISTs is debatable. The purpose of this study is to compare the characteristics and the prognostic factors in patients with gastrointestinal stromal tumor (GIST) located in the duodenum with those located in the small intestine., Methods: One hundred-one patients with GIST located in the duodenum (n = 40), or small intestine (n = 61) underwent resection between 1996 and 2010. We analyzed clinicopathologic features, surgical outcomes, and prognostic factors., Results: Five-year survival rate in patients with GIST located in the duodenum and small intestine were 66.6 and 80.8%, respectively (p = 0.018). After survival analysis, high mitotic count and tumor rupture were identified as independent adverse prognostic factors. Advanced T stage and absence of adjuvant imatinib treatment were adverse prognostic factors with marginal statistical significance. The rate of progressive disease was significantly higher in patients with duodenal GISTs (36.8%) than in those with small intestinal GIST (29.6%) (p = 0.024)., Conclusions: The clinicopathologic findings of duodenal GIST differ from those of small intestinal GIST. Patients with duodenal GIST have a worse prognosis than those with small intestinal GIST. Aggressive treatment including surgical resection should be considered for duodenal GIST, even if the risk is relatively low.

Introduction: Although it has now been accepted that imatinib is a valid treatment for gastrointestinal stromal tumour (GIST) patients in the adjuvant setting, information on its clinical efficacy in improving the prognosis for patients with colorectal GISTs is limited., Methods: The clinical and follow-up records of 42 colorectal GIST patients who underwent surgical resection at our institution between January 2004 and December 2013 were reviewed retrospectively. The effect of postoperative imatinib treatment on recurrence free survival and overall survival time was analysed with the Kaplan-Meier method and the multivariate Cox proportional hazards model., Results: Sixteen patients were assigned to imatinib treatment (imatinib group) after surgical tumour resection while twenty-six patients did not receive any adjuvant treatment (control group). The one, three and five-year recurrence free survival rates were 100%, 90% and 77% respectively. This was significantly higher than in the control group (92%, 53% and 36%) (logrank test, p=0.012). The one, three and five-year overall survival rates were 100%, 91% and 68% in the imatinib group compared with 96%, 77% and 39% in the control group (logrank test, p=0.021). Analysis with the multivariate Cox regression model yielded similar results on the efficacy of adjuvant imatinib in prolonging both recurrence free survival (hazard ratio [HR]: 0.23, 95% confidence interval [CI]: 0.07-0.80) and overall survival (HR: 0.20, 95% CI: 0.05-0.91)., Conclusions: Adjuvant imatinib therapy seems to be effective in decreasing the risk of tumour occurrence and prolonging the overall survival time in colorectal GIST patients.

Introduction: It is believed that the reason of the leukemic clone cell resistance to treatment with tyrosine kinase inhibitors during chronic myeloid leukemia (CML) is mutations in the genome of an early bone marrow progenitor cells that are CD34-positive. Such cells, regardless of treatment, acquire ability to proliferation and differentiation. This leads to the re-expansion of the CD34(+) cells., Aim: to determine the CD34 antigen expression in bone marrow and peripheral blood cells in CML patients with different response to imatinib therapy using the results of hematopoietic cells culturing and the data of flow cytometry., Methods: Bone marrow aspirate from 39 patients who were treated with imatinib was studied with cytogenetic, flow cytometry and culture methods in vitro., Results: In patients with an optimal response to imatinib therapy the number of colonies was 1.8 times lower than the number of those in the group of patients with a suboptimal response to therapy. In turn, in patients with failure of imatinib therapy the number of colonies was the highest and was 2.1 times higher than the patients with optimal response. The results of cytometric studies have shown that the number of CD34(+) cells in bone marrow was significantly higher compared to the number of CD34(+) cells in peripheral blood cells and increased with the acquisition of leukemic cells the resistance to imatinib. There was a direct correlation between the number of colonies and clusters in semisolid agar in vitro and the number of CD34(+) cells in the bone marrow of patients., Conclusions: The correlation between the number of CD34(+) cells and the number of cell aggregates in semisolid agar in vitro indicates the prognostic value of the method for determining CD34(+) cells in the patient bone marrow. The parallel increase of their number in the peripheral blood will allow developing express methods for the detection of individual patient response to imatinib therapy.

Introduction: Priapism is rare-presenting feature in male patients with chronic myeloid leukemia (CML). Several hypotheses for pathogenesis have been described. Management has been controversial; some authors described resolution following priapism-specific interventions, and others recommended addition of CML-specific therapy or even CML-specific therapy alone., Aim: In this report, we describe presentation and management of a man with refractory priapism that was the first presenting manifestation of CML. We also report, for the first time, the pathology sections of the sinusoidal tissue in such cases. Literature is reviewed for similar cases and their outcome., Methods: A 21-year-old male patient presented with painful priapism that started 6 days earlier and failed aspiration-irrigation. CBC revealed marked leucocytosis. Oncology care diagnosed CML, and treatment with Imatinib was commenced with prior semen cryopreservation. Following remission, a penile prosthesis was implanted, assisted by optical corporotomy. Sinusoidal tissue biopsy was stained by hematoxylin/eosin (H&E) and CD34., Main Outcome Measures: Pathology sections of cavernous tissue following CML-induced priapism., Results: The penile implant survived without complications. H&E examination of the sinusoidal tissue biopsy revealed leukemic infiltration associated with vascular endothelial damage. CD34 staining showed the mixed picture of leukemic infiltrates, intact vascular endothelium with lumena showing leukemic cells, alternating with destroyed vessels, and no vascular lumena and ruminants of endothelial cells., Conclusion: Priapism can be the first manifestation of previously undetected CML. The pathological picture of sinusoidal tissue in such cases is presented. In the case at hand, a complete blood picture was helpful in early diagnosis of CML and early initiation of targeted chemotherapy along with the corporal irrigation/aspiration or shunt surgery. It is therefore recommended to have a CBC examined at presentation of any case of ischemic priapism of unknown etiology, early initiation of CML therapy along with aspiration/irrigation, preferably cryopreserving a semen sample before CML therapy., (© 2015 International Society for Sexual Medicine.)