Treatment Of Ph Research Articles

Targeting STAT5 or STAT5-Regulated Pathways Suppresses Leukemogenesis of Ph+ Acute Lymphoblastic Leukemia.

Combining standard cytotoxic chemotherapy with BCR-ABL1 tyrosine kinase inhibitors (TKI) has greatly improved the upfront treatment of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). However, due to the development of drug resistance through both BCR-ABL1-dependent and -independent mechanisms, prognosis remains poor. The STAT5 transcription factor is activated by BCR-ABL1 and by JAK2-dependent cytokine signaling; therefore, inhibiting its activity could address both mechanisms of resistance in Ph+ ALL. We show here that genetic and pharmacologic inhibition of STAT5 activity suppresses cell growth, induces apoptosis, and inhibits leukemogenesis of Ph+ cell lines and patient-derived newly diagnosed and relapsed/TKI-resistant Ph+ ALL cells ex vivo and in mouse models. STAT5 silencing decreased expression of the growth-promoting PIM-1 kinase, the apoptosis inhibitors MCL1 and BCL2, and increased expression of proapoptotic BIM protein. The resulting apoptosis of STAT5-silenced Ph+ BV173 cells was rescued by silencing of BIM or restoration of BCL2 expression. Treatment of Ph+ ALL cells, including samples from relapsed/refractory patients, with the PIM kinase inhibitor AZD1208 and/or the BCL2 family antagonist Sabutoclax markedly suppressed cell growth and leukemogenesis ex vivo and in mice. Together, these studies indicate that targeting STAT5 or STAT5-regulated pathways may provide a new approach for therapy development in Ph+ ALL, especially the relapsed/TKI-resistant disease.Significance: Suppression of STAT5 by BCL2 and PIM kinase inhibitors reduces leukemia burden in mice and constitutes a new potential therapeutic approach against Ph+ ALL, especially in tyrosine kinase inhibitor-resistant disease. Cancer Res; 78(20); 5793-807. ©2018 AACR.

Effect of alkaline pH on cytotoxicity profile of neem (Azadirachta indica) ethanolic extract against human breast cancer cell line MDA-MB-231

IntroductionNeem (Azadirachta indica) is a well-known medicinal plant used for various pharmacological properties. The present study was designed to investigate dose and pH-dependent in vitro biological activity of ethanolic neem extract. MethodsThe dose-dependent cytotoxic potential of neem ethanolic extract at pH 7.4 as well as that in presence of increasing pH was investigated by trypan blue assay and cytometry based study against human breast cancer cell line MDA-MB-231. Antioxidant potential of neem extract was investigated by DPPH free radical scavenging activity. Antibacterial activity of neem extract was evaluated against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) using agar disc diffusion technique. ResultsResults revealed that an increase in alkaline pH reduced the growth of breast cancer cells. Moreover, combined treatment of neem extract and alkaline pH decreased the growth and survival of cancer cells in a dose and pH-dependent manner. Neem extract at a concentration of 1600 μg/mL and pH 8.6 caused significant mortality in breast cancer cells. A significant increase in antioxidant activity of neem extract was also observed as a function of both pH and dose of neem extract. In addition, the neem extract showed significant antibacterial activity against S. aureus at 200 mg/mL while no appreciable activity was detected against E. coli. ConclusionThe present study has reported the cytotoxic activity of neem extract as a function of alkaline pH for the first time and further investigation is warranted for the effective treatment of cancer.

Liquid Waste Content Based on Chemical Parameters at Animal Slaughterhouse’s Inlet and Outlet

Animal Sluaghterhouse (RPH) liquid waste contains organic matter, suspended solids, and colloid materials such as fat, protein, and cellulose with high concentrations that fall into the category of complex wastewater. RPH X is a RPH that uses Water Waste Treatment Plant (WWTP) in treating wastewater, although it has been equipped with WWTP there are still some problems in RPH X. The purpose of this research is to describe wastewater treatment and content of BOD, COD, TSS, NH3-N, pH and fatty oil at waste water in inlet and outlet of IPAL RPH X, Jember District. This research is a descriptive research. Technique of data collecting done by observation, interview, and laboratory test. The average of wastewater content test result in RPH X Jember Regency at inlet and outlet of IPAL is at safe limit of quality standard according to East Java Governor Regulation Number 72 Year 2013 except COD parameter at inlet that is equal to 277,6 mg / L. The average percentage of content in liquid waste in RPH X decreases from inlet to WWTP outlet except the pH parameter.

Ponatinib in the treatment of chronic myeloid leukemia and philadelphia chromosome positive acute lymphoblastic leukemia.

Philadelphia chromosome, reciprocal translocation between chromosome 9 and 22, leading to a constitutively active fusion protein BCR-ABL1 is the common feature among Philadelphia positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML). The discovery of tyrosine kinase inhibitors (TKIs) has led to significant improvement in the treatment of CML and Ph+ ALL. Ponatinib is a third-generation TKI that is currently approved as per label when no other TKIs are indicated for the treatment of patients with CML and Ph+ ALL after failing treatment with second-generation TKIs or if presence of T315I mutation is discovered. This review summarizes the ponatinib development, approved indications as well as ongoing clinical studies in CML and Ph+ ALL.

Therapeutic targeting of Aurora A kinase in Philadelphia chromosome-positive ABL tyrosine kinase inhibitor-resistant cells.

Abelson murine leukemia viral oncogene homolog (ABL) tyrosine kinase inhibitors (TKIs) have been shown to be effective for treatment of chronic myeloid leukemia (CML) and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia patients. However, resistance to ABL TKIs can develop as a result of breakpoint cluster region-ABL point mutations. Aurora kinases regulate many processes associated with mitosis. In this study, we investigated whether inhibiting Aurora kinase can reduce the viability of Ph+ leukemia cells. Treatment with the Aurora kinase A inhibitor alisertib blocked Ph+ leukemia cell proliferation and Aurora kinase A phosphorylation; it also induced G2/M-phase arrest and increased the intracellular levels of reactive oxygen species. Combined treatment of Ph+ cells with ABL TKIs and alisertib was cytotoxic, with the fraction of senescent cells increasing in a time- and dose-dependent manner. Aurora A gene silencing suppressed cell proliferation and enhanced ABL TKI efficacy. In a mouse xenograft model, co-administration of ponatinib and alisertib enhanced survival and reduced tumor size; moreover, the treatments were well tolerated by the animals. These results indicate that inhibiting Aurora kinase can enhance the cytotoxic effects of ABL TKIs and is, therefore, an effective therapeutic strategy against ABL TKI-resistant cells, including those with the T315I mutation.

PO-028 Effective targeting of NAD+biosynthesis in patient-derived xenograft models of high-risk paediatric acute lymphoblastic leukaemia

IntroductionChildren diagnosed with high-risk acute lymphoblastic leukaemia (ALL) have a dismal prognosis. For those patients who survive treatment, currently used chemotherapeutics are associated with severe health problems, indicating the urgent need for safer and more potent therapeutic strategies. We have therefore investigated the therapeutic potential of a newly developed inhibitor of nicotinamide phosphoribosyltransferase (NAMPT), OT-82, which has previously shown efficacy within a safe therapeutic window against a range of preclinical haematopoietic malignancy models.Material and methodsThe therapeutic potency of OT-82 against high-risk ALL was evaluated in a panel of well characterised paediatric patient-derived xenograft (PDX) models that accurately recapitulate the cellular and molecular features of the original disease and for which in vivo responses to chemotherapeutic agents were significantly correlated with the clinical outcome of the patients from whom the PDX were derived. The PDX panel comprised MLL-rearranged ALL (n=6), B-Cell Precursor ALL (n=9), including Philadelphia chromosome positive (Ph+) and Ph-like ALL, as well as T-cell ALL (n=6) including early T cell precursor ALL. Response to treatment was assessed by event-free survival and stringent objective response criteria modelled after the clinical setting.Results and discussionsOT-82 was well tolerated and demonstrated impressive single agent in vivo activity against the high-risk ALL PDX panel, achieving significant leukaemia growth delay in 95% (20/21) and objective responses in 86% (18/21) of PDX. In addition, OT-82 enhanced the in vivo efficacy of targeted therapy dasatinib, used in the treatment of Ph+ ALL patients, and chemosensitised two highly resistant MLL-rearranged ALL PDX to chemotherapeutic cytarabine. Confirming its action as a NAMPT inhibitor, OT-82 depleted leukaemia cell NAD+ levels thereby decreasing the amount of available ATP and inhibiting the NAD+-requiring DNA damage repair enzyme PARP-1, culminating in apoptosis induction. The previously identified markers for in vitro susceptibility to other NAMPT inhibitors such as baseline NAD+ and NAMPT levels, did not predict in vivo responsiveness of high-risk ALL PDX to OT-82.ConclusionOur study provides evidence that the NAMPT inhibitor OT-82 is a promising new therapeutic strategy for a broad spectrum of high-risk and poor outcome paediatric ALL for which novel therapeutic options are urgently needed.

Down-regulation of CD19 expression inhibits proliferation, adhesion, migration and invasion and promotes apoptosis and the efficacy of chemotherapeutic agents and imatinib in SUP-B15 cells

The survival rate of childhood acute lymphoblastic leukemia (ALL) has increased while that of Philadelphia-positive (Ph+) ALL remains low. CD19 is a B-cell specific molecule related to the survival and proliferation of normal B cells. However, there is little information available on the effects of CD19 on the biological behavior of Ph+ ALL cells. In this study, we explored a lentiviral vector-mediated short hairpin RNA (shRNA) expression vector to stably reduce CD19 expression in Ph+ ALL cell line SUP-B15 cells and investigated the effects of CD19 downregulation on cell proliferation, apoptosis, drug sensitivity, cell adhesion, cell migration and cell invasion in vitro. CD19 mRNA and protein expression levels were inhibited significantly by CD19 shRNA. Down-regulation of CD19 could inhibit cell proliferation, adhesion, migration and invasion, and increase cell apoptosis and the efficacy of chemotherapeutic agents and imatinib in SUP-B15 cells. Moreover, we found that down-regulation of CD19 expression inhibits cell proliferation and induces apoptosis in SUP-B15 cells in a p53-dependent manner. Taken together, our results suggest that lentiviral vector-mediated RNA interference of CD19 gene may be a promising strategy in the treatment of Ph+ ALL.

Ponatinib for Treating Acute Lymphoblastic Leukaemia: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its single technology appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer (Incyte Corporation) of ponatinib (Inclusig®) to submit evidence of its clinical and cost effectiveness for previously treated Philadelphia-chromosome-positive acute lymphoblastic leukaemia (Ph+ ALL) and chronic myeloid leukaemia. This paper focusses on Ph+ ALL. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent evidence review group (ERG). This article presents the critical review of the company's submission by the ERG and the outcome of the NICE guidance. The clinical-effectiveness evidence in the company's submission was derived from a phase II, single-arm, open-label, non-comparative study. Given the lack of comparative evidence, a naïve indirect comparison was performed against re-induction chemotherapy comparing major cytogenetic response and complete remission. Best supportive care (BSC) was assumed to produce no disease response. Despite the limited evidence and potential for biases, this study demonstrated that ponatinib was likely to be an effective treatment for patients with Ph+ ALL. The company submitted a state transition model that analysed the incremental cost effectiveness of ponatinib versus re-induction therapy and BSC for the treatment of Ph+ ALL in patients whose disease is resistant to dasatinib, who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate or who have the threonine-315-isoleucine mutation. This population was further subdivided into those who were suitable for allogeneic stem cell transplant (allo-SCT) and those who were not. The company's revised economic evaluation, following the clarification process, estimated incremental cost-effectiveness ratios (ICERs) in those suitable for allo-SCT of £31,123 per quality-adjusted life-year (QALY) gained for ponatinib compared with re-induction chemotherapy and £26,624 per QALY gained compared with BSC. For those for whom allo-SCT was unsuitable, the company-estimated ICER compared with BSC was £33,954 per QALY gained. Following a critique of the model, the ERG undertook exploratory analyses that, when combined, produced a range in ICERs (due to uncertainty of the most appropriate overall survival function) of dominant (being less expensive and providing more QALYs) to £11,727 per QALY gained compared with re-induction chemotherapy and between £7892 and £31,696 per QALY gained compared with BSC for those in whom allo-SCT was suitable. For those in whom allo-SCT was not suitable, the ERG estimated that ponatinib was dominant. During the consultation period, the company agreed a revised patient access scheme (PAS) that reduced the ICER ranges to £7156 to £29,995 per QALY gained versus BSC and to less than £5000 per QALY gained versus re-induction chemotherapy. In people for whom allo-SCT was unsuitable, ponatinib dominated BSC. The NICE appraisal committee concluded that ponatinib is a cost-effective use of UK NHS resources in the considered population, subject to the company providing the agreed discount in the PAS.

PENGARUH pH EKSTRAKSI TERHADAP RENDEMEN, SIFAT FISIKO-KIMIA DAN FUNGSIONAL KONSENTRAT PROTEIN KACANG GUDE (Cajanus cajan (L.) Millsp.)


 
 
 The purpose of this research are to know the effect of pH extraction on yield, physico-chemical and functional properties of pigeon pea protein concentrate, and also to know the appropriate pH extraction to obtain the best yield and properties of pigeon pea protein concentrate. The research was using Randomized Complete Design with pH extraction treatment which consist of five levels were 9; 9,5; 10; 10,5; and 11. The parameters were observed consist of yield, physical properties (lightness), chemical properties (protein and moisture), and protein’s functional properties (water holding capacity, oil holding capacity, emulsion capacity and stability, and foaming capacity and stability). The result showed that pH extraction gave a significant effect to protein and moisture, and gave very significant effect to yield, lightness (L), water holding capacity, oil holding capacity, emulsion capacity, emulsion stability, foaming capacity and foaming stability of pigeon pea protein concentrate. The best properties of protein concentrate was found at sample which treatment of pH 10 with a yield 17,29% (db), lightness (L) 18,84, protein 86,15% (db), moisture 7,96% (db), water holding capacity 1,96 ml H2O/g solid, oil holding capacity 2,62 ml oil/g solid, emulsion capacity 54,67%, emulsion stability 54,83%, foaming capacity 100%, and foaming stability 38,19%.
 
 

Kinetic models for the electrochemical decolouration of two reactive azo dyes

In this work, the indirect oxidation of two azo dyes (Colour Index Reactive Orange 4 and 13) was performed in an electrochemical batch cell in the presence of chloride as an electrolyte. The effect of different operational parameters on the electrochemical treatment was tested. Kinetic plots consisting of two linear portions were obtained in some experiments. The rate constants and the breaking point between the two linear portions were modelled to evaluate the influence of dye concentration, conductivity and pH. Good correlation between the experimental and the modelled constants and breaking points was observed. Models showed that the dye concentration is the most significant factor in the electrochemical treatment of both dyes, although conductivity and pH were also significant either individually or in interaction with other factors.

Ponatinib: A Third-Generation Inhibitor for the Treatment of CML.

The establishment of imatinib as the standard therapy for CML marked the beginning of a new era of treatment. Due to occurring intolerance and resistance against the drug, the development of new inhibitors was promoted. This led to the second-generation inhibitors dasatinib, nilotinib, and bosutinib. Despite all achieved improvements, first- and second-generation inhibitors are ineffective against the BCR-ABL T315I "gatekeeper" mutation. In order to overcome this issue and to further improve the inhibitory effect, the third-generation inhibitor ponatinib was developed. Various clinical trials have been launched to study the effect of ponatinib in the clinical setting. Based on positive phase 1 and phase 2 trials, ponatinib was approved for the second-line treatment of CML and Ph+ ALL in December 2012 in the USA and in July 2013 in the European Union. The safety data of these trials particularly revealed a dose-dependent, increased risk for serious arterial occlusive events under treatment with ponatinib. Further trials investigate optimized dosing schemes to reduce side effects while maintaining clinical activity in CML and evaluate potential activity of the drug in other malignancies. In conclusion, ponatinib has proved to be a powerful BCR-ABL inhibitor, which exhibits clinical activity both in BCR-ABL wild-type and mutant CML, including the pan-resistant T315I mutation.Ponatinib should be used catiously with respect to increasedcardiovascular risk. Despite previous TKI failure, chronic-phase CML patients can achieve sustained remissions using this drug, offering an important addition to therapeutic options in the treatment for CML.

Pattern of presentation of Graves' disease and response to radioiodine therapy in South African men.

IntroductionTypically hyperthyroidism has been more often associated with the female gender. There is a large female predilection (male:female sex ratio up to 1:10), with little documentation in the literature about wholly male hyperthyroid populations. A male incidence of 0.7 per 100, 000 has been reported for South African men while the women have a relatively higher rate of 0.02. There is no documented evidence between male and female genders in response to treatment of PH with radioactive iodine (RAI), although operational evidence suggests that hyperthyroidism in males is less amenable to RAI treatment (RAIT) than females. This study therefore proposed to evaluate male hyperthyroid patients with Graves' disease (GD) treated at our facility, for factors affecting outcome of RAIT.MethodsThis is a retrospective analysis of records of hyperthyroid patients who were treated with RAI over a 19-year period at a university teaching hospital, in the Western Cape of South Africa.ResultsThe overall cure rate was 76.4% for these male patients. Cure was observed as euthyroidism in 31 patients (15.3%) and hypothyroidism in 129 (63.5%). Age, thyroid uptake, severity of hyperthyroidism, previous antithyroid drug (ATD) usage, administered quantity of RAI, ethnicity and patients' pulse at presentation were not significant in influencing outcome.ConclusionFactors which have been evaluated as affecting outcome of RAIT were unimportant in these patients. Despite the mainly hyperthyroid presentation of the patients, RAIT was so effective that the main type of cure after therapy was hypothyroidism.

Antibacterial Properties of Silicone Membranes after a Simple Two-Step Immersion Process in Iodine and Silver Nitrate Solutions.

Silicone is widely used in packing materials, medical equipment, and separation membranes. Since microbial cells easily adhere to the surface of silicone materials and form biofilms, techniques for incorporating antimicrobial activity into silicone materials are in high demand. This study describes the preparation of silver (Ag)/silicone composite membranes through a simple two-step immersion process, utilizing an iodine solution followed by a silver nitrate solution at room temperature. Scanning electron microscopy (SEM) observations revealed that particles with sizes of several nanometers to several tens of nanometers were present on the silicone membrane surface; these particles were identified as silver iodide using energy-dispersive X-ray spectroscopy (EDS) . The Ag/silicone membrane possessed excellent antibacterial efficacy against Escherichia coli and Staphylococcus aureus, and the antibacterial efficacy (R) against both types of bacteria was R > 4, even after stomacher treatment or acidic treatment of pH 2-6 for 24 h. The mechanical strength of the silicone membrane was also maintained after antibacterial treatment, with Young's modulus values of 7.9±1.2 MPa and 8.3±1.5 MPa for the untreated membrane and Ag/silicone membrane, respectively (p > 0.05) . In addition, the reduction in permeation performance of the Ag/silicone membrane was only 20%, despite the antibacterial treatment on the membrane surface. This antibacterial treatment method of silicone membranes can be conducted at room temperature (25℃) without special equipment, and may be applied to other types of silicone materials.

FDA grants accelerated approval to bosutinib for treatment of newly-diagnosed PH+ CML

FDA grants accelerated approval to bosutinib for treatment of newly-diagnosed PH+ CML

Effects of prolonged exposure to moderate static magnetic field and its synergistic effects with alkaline pH on Enterococcus faecalis

Static magnetic field (SMF) has been shown to biologically affect various microorganisms, but its effects on Enterococcus faecalis, which is associated with multiple dental infections, have not been reported yet. Besides, Enterococcus faecalis was found to be resistant to the alkaline environment provided by a major dental antimicrobial, calcium hydroxide. Therefore, the antibacterial activity of prolonged exposure to moderate SMF (170 mT) and its possible synergistic activity with alkaline pH (pH = 9) were evaluated in the study. The ability to form a biofilm under these conditions was examined by crystal violet assay. Real-time quantitative PCR was performed to evaluate the relative expression of stress (dnaK and groEL) and virulence (efaA, ace, gelE and fsrC) related genes. As the results indicated, cell proliferation was inhibited after 120 h of SMF exposure. What's more, the combined treatment of SMF and alkaline pH showed significantly improved antimicrobial action when compared to single SMF and alkaline pH treatment for more than 24 h and 72 h respectively. However, the ability to form a biofilm was also enhanced under SMF and alkaline pH treatments. SMF can induce stress response by up-regulating the expression of dnaK and elevate virulence gene expression (efaA and ace). These responses were more significant and more genes were up-regulated including groEL, gelE and fsrC when exposed to SMF and alkaline pH simultaneously. Hence, combination of SMF and alkaline pH could be a promising disinfection strategy in dental area and other areas associated with Enterococcus faecalis infections.

A Treatment Protocol with Imatinib and Intensive Chemotherapy for Pediatric Philadelphia Positive Acute Lymphoblastic Leukemia Patients: A Single-Arm, Intergroup Study (EsPhALL 2010-2014)

▪Introduction. Approximately 3-5% of pediatric ALL patients present with the Philadelphia chromosome (Ph+). In the past, Ph+ ALL was associated with a poor prognosis, with long-term event-free-survival (EFS) rates of approximately 30% and most patients allocated to hematopoietic stem cell transplantation (HSCT) in first complete remission (CR1). The COG AALL0031 study showed that continuous high imatinib exposure improved outcome with no increase in toxicity and that HSCT offered no advantage over intensive chemotherapy plus imatinib (Schultz et al, JCO2009). Contemporarily, the EsPhALL 2004-2009 intergroup study of post-induction treatment of Ph+ ALL randomly tested the discontinuous use of imatinib added to BFM ALL high risk chemotherapy after the Induction phase in patients with early response, showing an approximate 10% advantage in long-term DFS. All non-responding patients received imatinib and overall 80% received HSCT in CR1 (Biondi et al, Lancet Oncology 2012). Based on both studies, in 2010 the EsPhALL trial was amended into a single arm study to give all patients, on top of the BFM ALL high risk chemotherapy, imatinib 300/mg/m2/day continuously since day 15 of Induction and to gradually decrease the use of HSCT. We present here the results of this EsPhALL 2010-2014 study.Methods. Ph+ ALL patients aged 1-17 years were enrolled by 10 national study groups (AIEOP, BFM-G/CH, COALL, FRALLE-EORTC, NOPHO, MRC, DCOG, CPH, PINDA, and HKPHOSG), mainly in Europe. MRD was assessed by PCR using IG/TR targets or BCR/ABL1 in hierarchical order, according to Euro-MRD rules. Eligibility to HSCT depended on early response and, after 2012, on MRD at end of Protocol IB (≥ 5 x 10-4) and at the end of consolidation block 3 (any positivity in patients with MRD< 5 x 10-4 at end of IB). Imatinib was recommended throughout the first year after transplant. Patients who continued on chemotherapy received treatment until 24 months after diagnosis.Results. Overall 158 patients were registered from January 2010 to December 2014; 3 were not eligible, leaving 155 evaluable patients. Sixty-two patients (40%) were ≥ 10 years, 73 (47%) had ≥50,000 WBC count at diagnosis, 103 (84%) had p190. 102 (66%) patients achieved both early good response and CR1 at end of IA and were classified as good risk, while the remaining 53 (34%) were at poor risk. CR1 was achieved by 151 patients (97%) at the end of Induction and by the remaining 4 at the end of IB. Overall, 59 patients (38%) underwent HSCT in CR1. Nineteen patients discontinued treatment, 17 during chemotherapy, 15 due to serious adverse events (SAE, of which 9 related to imatinib - mainly infections) and the remaining 2 to MRD increase (1) and to transfer to adult unit (1). Among patients who underwent HSCT in CR1, 2 discontinued imatinib after HSCT, due to MRD increase (1) and gastrointestinal toxicity related to imatinib (1). Overall, 185 SAE were observed in 86 (55%) patients. The most frequent SAE was infection which occurred in 50 (32%) patients. Other toxicities included osteonecrosis (7 patients, 5%) and gastrointestinal disorders (9 patients, 6%). On the complete cohort of 155 patients, with a median follow-up of 57 months (range 1-86), the 5-year EFS and survival were 57.0 (SE 4.1) and 71.8 (SE 3.8), respectively. The 5-year cumulative incidence of relapse was 26.9 (SE 3.7). Overall, 65 events occurred, 46 in 96 patients who received chemotherapy only (32 relapses and 14 deaths in CCR) and 19 in 59 HSCT in CR1 (8 relapses and 11 deaths in CCR). Overall, relapses occurred in the BM (22), BM+CNS (11), BM+eye (1) and CNS (6). All deaths in CCR, except for 1 in chemotherapy and 3 after HSCT, were due to infection. Half of the deaths in CCR (12/25) occurred in 2 unexpected clusters, in HSCT performed in 2010-2011 and in chemotherapy-only patients ≥ 10 years. Further investigations did not reveal any common pattern within the clusters.Conclusions: Addition of imatinib given continuously since day 15 of induction markedly increased CR rate to 97% from 50% of the EsPhALL 2004-2009 study. Moreover, in EsPhALL 2010-2014 only 38% of patients underwent HSCT in CR1 (decreasing from 56% in 2010 to 28% in 2014), compared with 81% in the previous study. In spite of this marked decrease in HSCT, the outcome was similar in the 2 studies: 5-year EFS and survival were 57.0% and 71.8% versus 60.3% and 71.6%, respectively in EsPhALL 2010-2014 versus EsPhALL 2004-2009. DisclosuresCazzaniga:Fondazione Tettamanti onlus: Employment; Italian Association for Cancer Research: Research Funding. Saha:Shire: Research Funding. Schrappe:Medac: Consultancy, Research Funding; SigmaTau: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; JAZZ Pharma: Consultancy, Research Funding; Baxalta: Consultancy, Research Funding.

Upfront treatment with the first and second-generation tyrosine kinase inhibitors in Ph-positive acute lymphoblastic leukemia.

The treatment of Ph-positive acute lymphoblastic leukemia (Ph+ ALL) has entranced tyrosine kinase inhibitors (TKIs) era. Currently both imatinib and dasatinib are registered as the front-line treatment for Ph+ ALL, and the other 2nd-generation TKIs are suggested as an alternative for those who failed the first-line treatment. However, it remains unclear who could benefit from the 2nd-generation TKIs as the first-line treatment for Ph+ ALL. In this study we compared the efficacy and safety of the 1st and 2nd-generation TKIs in the front-line treatment of Ph+ ALL and found a trend toward better disease-free survival (DFS) in the 2nd-generation TKIs group, though no significant difference in early response and long-term survival between the two groups. Furthermore, subgroup analysis showed that if allogeneic hematopoietic stem cell transplantation (allo-HSCT) was incorporated as consolidation, the 2nd-generation TKIs benefited patients with better DFS and overall survival (OS). The two generation TKIs were well tolerated. Higher incidence of acquiring T315I mutation was observed in the patients relapsed on the 2nd-generation TKIs. These findings suggested front-line treatment of Ph+ ALL with the 2nd-generation TKIs might benefit patients with better survival when allo-HSCT was incorporated as consolidation therapy; meanwhile, the higher incidence of T315I mutation in patients relapsed on the 2nd-generation TKIs deserved further attention.

Therapeutic effect and prognostic factors of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Objective To explore the outcome and prognostic factors of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). Methods Forty-nine newly diagnosed adult patients with Ph+ ALL were analyzed retrospectively, and the treatment effect and the impact of different factors on prognosis were explored. Results In 49 patients, there were 24 males and 25 females; the median age was 38 years (range 15-77 years). Hematologic complete remission (CR), major molecular response (MMR) and complete molecular remission (CMR) rate in patients received tyrosine kinase inhibitors (TKI) plus chemotherapy were higher than those in patients received chemotherapy only (96.8% vs. 72.2%, χ2 = 4.308, P = 0.038; 64.5% vs. 16.7%, χ 2 = 10.468, P = 0.001; 25.8% vs. 11.1%, χ 2 = 4.250, P = 0.039). With a median overall survival (OS) of 24 months (3-70 months), the 3-year OS and relapse-free survival (RFS) rates were 32.7% and 21.4%, respectively. The 3-year OS rate and 1-year RFS rate in TKI plus chemotherapy group were 40.3% and 67.8% respectively, which were higher than those in chemotherapy group (11.1% and 11.1%) (χ 2 = 12.725, χ 2 = 17.401, both P < 0.001). The 3-year OS and RFS rates in the allogeneic hematopoietic stem cell transplantation (allo-HSCT) group were higher than those in the group without allo-HSCT (62.5% vs. 25.7%, χ2 = 6.196, P = 0.013; 41.7% vs. 15.0%, χ2 = 8.032, P = 0.005). The 3-year OS and RFS rates in patients achieved MMR after 2 circles treatment were higher than those in the others (45.1% vs. 17.6%, χ2 = 5.446, P = 0.020; 28.9% vs. 11.7%, χ2 = 6.484, P = 0.011). Multivariate analysis showed that received TKI (HR = 0.227, 95% CI 0.094-0.550, P = 0.001) was an independent prognostic factor for OS; received TKI (HR = 0.225, 95% CI 0.082-0.618, P = 0.004) and allo-HSCT (HR = 0.275, 95% CI 0.077-0.983, P = 0.047) were independent prognostic factors for RFS. Conclusions TKI can increase CR, MMR and CMR rates, improve outcome, and give more chance to receive HSCT. In TKI era, allo-HSCT is still the important treatment for Ph+ ALL, especially for patients without MMR. Key words: Leukemia, acute; Philadelphia chromosome; Prognosis; Hematopoietic stem cell transplantation; Imatinib

Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

The incorporation of tyrosine kinase inhibitors (TKIs) into chemotherapy regimens has significantly improved the outcomes of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Second and third generation TKIs with increased potency against BCR-ABL1 and enhanced activity against ABL1 kinase domain mutations have been evaluated in a number of studies showing significant promise. In particular, ponatinib, a potent pan-BCR-ABL1 TKI capable of overcoming the T315I mutation, is of significant interest in the treatment of Ph+ ALL, as a number of reports have shown a high incidence of T315I mutants at relapse.

Pengaruh pH terhadap Produksi Antibakteri oleh Bakteri Asam Laktat dari Usus Itik

This study aimed to determine the effect of pH on the production of antibacterial by lactic acid bacteria. This study uses a completely randomized design factorial 3X 5 (3 X 5 treatment of bacterial isolates pH) with three replications. The first factor consisted of pH 4, pH 5, pH 6, pH 7, pH 8, and the second factor that isolates B2, B7, B8, whereas the parameters consists of a clear zone. The amount of production is determined by the size of the diameter of antibacterial inhibition zone against Salmonella sp. Differences in the production of antibacterial determined based on the results of analysis of variance. The treatment significantly further test BNT at 5% level. The results showed that the effect of media pH test based on the potential for the production of antibacterial effect. The diameter of the largest clear zone produced by B7 isolates at pH 6 was 17.2 mm, 17.1 mm B8 and B2 at pH 7 at 16.7 mm. The smallest diameter of the clear zone produced by B8 at pH 4 was 15.1 mm, B2 at pH 6 there is a clear zone of 12.7 mm and isolate B7 at pH 5 of 11.5 mm Keywords: Antibacterial, Lactic Acid Bacteria, pH, Salmonella sp, Clear zone