Management of ponatinib dosing in chronic myeloid leukemia patients.

Ponatinib (Iclusig®, Takeda/Incyte) is a third-generation highly-potent-pan-inhibitor of tyrosine kinases, active in all single resistance ABL kinase mutations including the T315l mutation. It is approved to treat of chronic myeloid leukemia (CML) in every phase of disease-resistant or intolerant to second-generation tyrosine kinase inhibitors (2GTKIs) and for whom imatinib is not clinically appropriate as well as for patients with T315I mutation. The drug is also indicated for Ph+ acute lymphoblastic leukemia (ALL). The approved starting dose for ponatinib is 45 mg once daily. Available data revealed ponatinib dose-dependent increased risk of cardiovascular toxicity. There is still no consensus about the optimal, initial dose of ponatinib and its management during therapy. It is crucial to start treatment with the risk-adjusted dose and assess the benefit-risk profile of ponatinib dosing. Evaluation of dosing modification should be considered during treatment, mainly if toxicity occurs. Our study summarizes current knowledge and recommendations about the choice of starting dose of ponatinib and management of ponatinib dosing during the treatment.

Correction: Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Anesthetic Management During Pediatric Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy With Cisplatin in a Small Child: A Case Report and Systematic Literature Review.

Cytoreductive surgery (CS) and hyperthermic intraperitoneal chemotherapy (HIPEC) present a challenging task for anesthesia providers. Anesthesia management may be complicated by hyperthermia, fluid shifts, and distinct inflammatory response. Only a few reports dealing with the anesthesia management of pediatric CS and HIPEC have been published. We report a case of a 2-year-old child with a relapse of an alveolar rhabdomyosarcoma of the uterus and peritoneal carcinomatosis treated with CS and HIPEC. For children, careful temperature measurement, intraoperative prevention of hyperthermia, and sufficient volume management are important, as well as postoperative pediatric intensive care with experience CS and HIPEC patients.

Standardisation and consensus guidelines for minimal residual disease assessment in Philadelphia-positive acute lymphoblastic leukemia (Ph + ALL) by real-time quantitative reverse transcriptase PCR of e1a2 BCR-ABL1.

Minimal residual disease (MRD) is a powerful prognostic factor in acute lymphoblastic leukemia (ALL) and is used for patient stratification and treatment decisions, but its precise role in Philadelphia chromosome positive ALL is less clear. This uncertainty results largely from methodological differences relating to the use of real-time quantitative PCR (qRT-PCR) to measure BCR-ABL1 transcript levels for MRD analysis. We here describe the first results by the EURO-MRD consortium on standardization of qRT-PCR for the e1a2 BCR-ABL1 transcript in Ph + ALL, designed to overcome the lack of standardisation of laboratory procedures and data interpretation. Standardised use of EAC primer/probe sets and of centrally prepared plasmid standards had the greatest impact on reducing interlaboratory variability. In QC1 the proportion of analyses with BCR-ABL1/ABL1 ratios within half a log difference were 40/67 (60%) and 52/67 (78%) at 10-3 and 36/67 (53%) and 53/67 (79%) at 10-4BCR-ABL1/ABL1. Standardized RNA extraction, cDNA synthesis and cycler platforms did not improve results further, whereas stringent application of technical criteria for assay quality and uniform criteria for data interpretation and reporting were essential. We provide detailed laboratory recommendations for the standardized MRD analysis in routine diagnostic settings and in multicenter clinical trials for Ph + ALL.

LMA Protector™ Airway: first experience with a new second generation laryngeal mask.

BACKGROUND: The LMA Protector™ Airway (The Laryngeal Mask Company Ltd., Teleflex Incorporated, Athlone, Ireland) is a new supraglottic airway promising a better seal, an improved drainage of gastric secretions and the opportunity of a simplified fiberscopy-guided tracheal intubation. The aim of this study was to present a primary evaluation of the LMA Protector in a clinical setting. METHODS: After informed consent 50 patients, scheduled for minor/moderate surgery in supine position, were recruited. Pharyngeal seal pressures were examined in neutral position of the patients' head and in maximum passive extension of the neck. Additionally, the fiberscopic view on the glottis was graduated and the feasibility of fiberscope guided tracheal intubation through the device was evaluated. RESULTS: The median pharyngeal seal pressure of the LMA Protector in neutral position of the head was 34 cmH2O. Passive extension of the neck did not cause a reduction of the pharyngeal seal (median pharyngeal seal pressure: 34.7 cmH2O; P<0.039). The LMA Protector was applicable for fiberscopic tracheal intubation but is not reliable for blind tracheal intubation. CONCLUSIONS: The LMA Protector provides a high pharyngeal seal. Uncommon for laryngeal masks its pharyngeal seal is not affected by the extension of the patient's neck. As a second generation supraglottic airway which is also suitable for simplified fiberscopic guided tracheal intubation, the LMA Protector could be considered as a supraglottic airway of the third generation.

Mechanistic insights into allosteric regulation of the A2A adenosine G protein-coupled receptor by physiological cations.

Cations play key roles in regulating G-protein-coupled receptors (GPCRs), although their mechanisms are poorly understood. Here, 19F NMR is used to delineate the effects of cations on functional states of the adenosine A2A GPCR. While Na+ reinforces an inactive ensemble and a partial-agonist stabilized state, Ca2+ and Mg2+ shift the equilibrium toward active states. Positive allosteric effects of divalent cations are more pronounced with agonist and a G-protein-derived peptide. In cell membranes, divalent cations enhance both the affinity and fraction of the high affinity agonist-bound state. Molecular dynamics simulations suggest high concentrations of divalent cations bridge specific extracellular acidic residues, bringing TM5 and TM6 together at the extracellular surface and allosterically driving open the G-protein-binding cleft as shown by rigidity-transmission allostery theory. An understanding of cation allostery should enable the design of allosteric agents and enhance our understanding of GPCR regulation in the cellular milieu.

Effects of Particle Size and Surface Chemistry on the Dispersion of Graphite Nanoplates in Polypropylene Composites.

Carbon nanoparticles tend to form agglomerates with considerable cohesive strength, depending on particle morphology and chemistry, thus presenting different dispersion challenges. The present work studies the dispersion of three types of graphite nanoplates (GnP) with different flake sizes and bulk densities in a polypropylene melt, using a prototype extensional mixer under comparable hydrodynamic stresses. The nanoparticles were also chemically functionalized by covalent bonding polymer molecules to their surface, and the dispersion of the functionalized GnP was studied. The effects of stress relaxation on dispersion were also analyzed. Samples were removed along the mixer length, and characterized by microscopy and dielectric spectroscopy. A lower dispersion rate was observed for GnP with larger surface area and higher bulk density. Significant re-agglomeration was observed for all materials when the deformation rate was reduced. The polypropylene-functionalized GnP, characterized by increased compatibility with the polymer matrix, showed similar dispersion effects, albeit presenting slightly higher dispersion levels. All the composites exhibit dielectric behavior, however, the alternate current (AC) conductivity is systematically higher for the composites with larger flake GnP.

Treatment and outcome of 2904 CML patients from the EUTOS population-based registry.

The European Treatment and Outcome Study (EUTOS) population-based registry includes data of all adult patients newly diagnosed with Philadelphia chromosome-positive and/or BCR-ABL1+ chronic myeloid leukemia (CML) in 20 predefined countries and regions of Europe. Registration time ranged from 12 to 60 months between January 2008 and December 2013. Median age was 55 years and median observation time was 29 months. Eighty percent of patients were treated first line with imatinib, and 17% with a second-generation tyrosine kinase inhibitor, mostly according to European LeukemiaNet recommendations. After 12 months, complete cytogenetic remission (CCyR) and major molecular response (MMR) were achieved in 57% and 41% of patients, respectively. Patients with high EUTOS risk scores achieved CCyR and MMR significantly later than patients with low EUTOS risk. Probabilities of overall survival (OS) and progression-free survival for all patients at 12, 24 and 30 months was 97%, 94% and 92%, and 95%, 92% and 90%, respectively. The new EUTOS long-term survival score was validated: the OS of patients differed significantly between the three risk groups. The probability of dying in remission was 1% after 24 months. The current management of patients with tyrosine kinase inhibitors resulted in responses and outcomes in the range reported from clinical trials. These data from a large population-based, patient sample provide a solid benchmark for the evaluation of new treatment policies.

Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale.

Molecular monitoring of chronic myeloid leukemia patients using robust BCR-ABL1 tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO) BCR-ABL1 reference panel was developed (MR(1)-MR(4)), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR(4.5) level. The secondary panel was calibrated to IS using digital PCR with ABL1, BCR and GUSB as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of BCR-ABL1 assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR(4.5) sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms.

The EUTOS population-based registry: incidence and clinical characteristics of 2904 CML patients in 20 European Countries.

This population-based registry was designed to provide robust and updated information on the characteristics and the epidemiology of chronic myeloid leukemia (CML). All cases of newly diagnosed Philadelphia positive, BCR-ABL1+ CML that occurred in a sample of 92.5 million adults living in 20 European countries, were registered over a median period of 39 months. 94.3% of the 2904 CML patients were diagnosed in chronic phase (CP). Median age was 56 years. 55.5% of patients had comorbidities, mainly cardiovascular (41.9%). High-risk patients were 24.7% by Sokal, 10.8% by EURO, and 11.8% by EUTOS risk scores. The raw incidence increased with age from 0.39/100,000/year in people 20-29 years old to 1.52 in those >70 years old, and showed a maximum of 1.39 in Italy and a minimum of 0.69 in Poland (all countries together: 0.99). The proportion of Sokal and Euro score high-risk patients seen in many countries indicates that trial patients were not a positive selection. Thus from a clinical point of view the results of most trials can be generalized to most countries. The incidences observed among European countries did not differ substantially. The estimated number of new CML cases per year in Europe is about 6370.

Laboratory recommendations for scoring deep molecular responses following treatment for chronic myeloid leukemia.

Treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors has advanced to a stage where many patients achieve very low or undetectable levels of disease. Remarkably, some of these patients remain in sustained remission when treatment is withdrawn, suggesting that they may be at least operationally cured of their disease. Accurate definition of deep molecular responses (MRs) is therefore increasingly important for optimal patient management and comparison of independent data sets. We previously published proposals for broad standardized definitions of MR at different levels of sensitivity. Here we present detailed laboratory recommendations, developed as part of the European Treatment and Outcome Study for CML (EUTOS), to enable testing laboratories to score MR in a reproducible manner for CML patients expressing the most common BCR-ABL1 variants.

Toric vs aspherical control intraocular lenses in patients with cataract and corneal astigmatism: a randomized clinical trial.

IMPORTANCE: Spectacle independence is becoming increasingly important in cataract surgery. Not correcting corneal astigmatism at the time of cataract surgery will fail to achieve spectacle independency in 20% to 30% of patients. OBJECTIVE: To compare bilateral aspherical toric with bilateral aspherical control intraocular lens (IOL) implantation in patients with cataract and corneal astigmatism. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, hospital-based, randomized clinical trial was conducted. The participants included 86 individuals with bilateral cataract and bilateral corneal astigmatism of at least 1.25 diopters (D) who were randomized to receive either bilateral toric (n = 41) or bilateral control (n = 45) IOL implantation. INTERVENTIONS: Bilateral implantation of an aspherical toric IOL or an aspherical control IOL. MAIN OUTCOMES AND MEASURES: Spectacle independency for distance vision, uncorrected distance visual acuity, refractive astigmatism, contrast sensitivity, wavefront aberrations, and refractive error-related quality-of-life questionnaire. RESULTS: Preoperatively, mean (SD) corneal astigmatism was 2.02 (0.95) D and 2.00 (0.84) D in the toric and control groups, respectively. Four patients (5%) were lost to follow-up. At 6 months postoperatively, 26 (70%) of the patients in the toric group achieved an uncorrected distance visual acuity of 20/25 or better compared with 14 (31%) in the control group (P < .001; odds ratio, 5.23; 95% CI, 2.03-13.48). Spectacle independency for distance vision was achieved in 31 patients (84%) in the toric group compared with 14 patients (31%) in the control group (P < .001; odds ratio, 11.44; 95% CI, 3.89- 33.63). Mean refractive astigmatism was -0.77 (0.52) D and -1.89 D (1.00) D, respectively. Vector analysis of toric IOLs showed a mean magnitude of error of +0.38 D, indicative of overcorrection. No significant differences were found in contrast sensitivity, higher-order aberrations, or refractive error-related quality of life. CONCLUSIONS AND RELEVANCE: In patients with cataract and corneal astigmatism, bilateral toric IOL implantation results in a higher spectacle independency for distance vision compared with bilateral control IOL implantation. No significant differences were identified in contrast sensitivity, higher-order aberrations, or refractive error-related quality of life following both treatments. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01075542.

Cataract surgery with toric intraocular lens implantation in keratoconus: a case report.

PURPOSE: We report 2 cases in which cataract extraction with a foldable acrylic toric intraocular lens (IOL) implantation was used to correct (irregular) corneal astigmatism in patients with keratoconus and cataract. METHODS: Case 1 was a 78-year-old man with cataract and keratoconus in the left eye. He underwent phacoemulsification with a toric IOL [Acrysof SN60T9; cylinder power: 6.0 diopters (D)] implantation. Case 2 was a 64-year-old woman with bilateral cataract and keratoconus. She underwent phacoemulsification with toric IOL implantation in the right (Acrysof SN60T9; cylinder power: 6.0 D) and left eyes (Acrysof SN60T5; cylinder power: 3.0 D). Postoperative follow-up in both cases was 6 months. RESULTS: In case 1, the uncorrected visual acuity increased from 20/400 to 20/50. The refractive cylinder decreased from -6.0 to -1.5 D, which is a reduction of 75%. In case 2, the uncorrected visual acuity increased from 20/400 to 20/130 in the right eye and from 20/400 to 20/30 in the left eye. Refractive astigmatism decreased by 70% in both eyes. No IOL misalignment or other complications occurred. CONCLUSIONS: Cataract extraction with toric IOL implantation can be used to correct (irregular) astigmatism and to improve visual functioning in patients with mild to moderate amounts of stable keratoconus and cataract.

Low redetachment rate due to encircling scleral buckle in giant retinal tears treated with vitrectomy and silicone oil.

BACKGROUND: The goal of this study was to identify risk factors for redetachment and to assess long-term anatomic and functional results of pars plana vitrectomy (PPV) for retinal detachment associated with giant retinal tears (GRT). SUBJECTS AND METHODS: In a retrospective study the authors analyzed 30 eyes which were operated with PPV for GRT retinal detachment in their clinic between March 1998 and August 2003. RESULTS: Redetachment rate after one vitrectomy procedure in this series of 30 eyes was 30% (n = 9), and ultimately, the retina was attached in 29 (96.7%) eyes. After multivariate analysis the absence of an encircling scleral buckle (P = 0.008) was significantly associated with redetachment. Visual acuity improved in 54% of the eyes. CONCLUSION: Vitrectomy with an encircling scleral buckle seems to be a preferred treatment for complicated retinal detachments due to GRT.

Effects of ethanol on adenosine 5'-triphosphate-gated purinergic and 5-hydroxytryptamine receptors.

This report of the proceedings of a symposium presented at the 2005 annual meeting of the Research Society on Alcoholism highlights the actions of ethanol on purinergic (P2XRs) and 5-hydroxytryptamine3 (5-HT3Rs) receptors. Both P2XRs and 5-HT3Rs, are modulated by pharmacologically relevant concentrations of ethanol, with inhibition or stimulation of P2XR subtypes and stimulation of 5-HT3Rs, respectively. With regard to ethanol-modulatory actions, these 2 distinctly different receptor classes have been studied to a much lesser extent than other LGICs. The organizers and chairs were Daryl L. Davies and Tina K. Machu. John J. Woodward discusses the molecular pharmacology and physiology of P2XRs and 5-HT3Rs and sets the stage for a detailed investigation into the ethanol sensitivity of these channels by the invited speakers. Daryl L. Davies discusses the results from recent electrophysiological studies conducted in his and Dr. Woodward's laboratories, highlighting the actions of ethanol on P2XR subtypes. Jiang-Hong Ye discusses results from recent studies using loose-patch and whole-cell recordings on purinergic receptors expressed on neurons from the ventral tegmental area (VTA) in rats. Tina K. Machu discusses electrophysiological studies conducted in her and Dr. David Lovinger's laboratories on nonpore lining residues of the second transmembrane domain (TM2) of the 5-HT3A receptor. Li Zhang presents data demonstrating that F-actin cytoskeletons play a critical role in 5-HT3 receptor clustering in hippocampal neurons. Collectively, the presentations provided strong evidence that P2X and 5-HT3 receptors are important targets for ethanol action.

Ethanol differentially affects ATP-gated P2X(3) and P2X(4) receptor subtypes expressed in Xenopus oocytes.

P2X receptors are cation-selective, ligand-gated ion channels activated by synaptically released, extracellular adenosine 5'-triphosphate (ATP). ATP-gated currents are inhibited by ethanol when tested in dorsal root ganglion and CA1 neurons. Recently, we reported differences in sensitivity to ethanol inhibition between homomeric P2X(2) and P2X(4) receptors expressed in Xenopus oocytes, which suggested that subunit composition of native P2X receptors determines their ethanol sensitivity. The present study extended the investigation to P2X(3) receptors. The effects of ethanol and zinc ions (Zn(2+)) were tested on homomeric P2X(3) and P2X(4) receptors expressed in Xenopus oocytes using two-electrode voltage clamp. Ethanol potentiated ATP-gated P2X(3) receptor currents in a concentration dependent manner. In contrast, ethanol inhibited P2X(4) receptor function. Ethanol did not directly alter receptor function, nor did it alter the Hill coefficient or maximal ATP response (E(max)) in either P2X(3) or P2X(4) receptors. Ethanol increased the maximal response to Zn(2+) ATP-gated currents in P2X3 receptors which suggests that ethanol and Zn(2+) act on different sites. The differences in ethanol response of P2X(3) and P2X(4) receptors set the stage for future investigations that will use chimeric P2X receptors or other molecular manipulations of P2X structure to investigate the molecular sites and mechanisms of action of ethanol.

Laparoscopic removal of retroperitoneal accessory spleen in patient with relapsing idiopathic thrombocytopenic purpura 30 years after classical splenectomy.

The clinical success of therapeutic splenectomy for idiopathic thrombocytopenic purpura depends on the complete removal of all functional splenic tissue. Among reasons for poor response to splenectomy, failure to remove accessory spleens is mentioned. We present our experience with laparoscopic removal of accessory spleen from retroperitoneal space in a patient with relapse of ITP 30 years after classical splenectomy. A 45-year-old female patient underwent in 1972 classical splenectomy for ITP. Progressive decline in thrombocyte count was observed 7 years ago. Scintigraphy, CT, and ultrasound revealed residual splenic tissue. A laparoscopic approach was proposed. Four trocars placed along left costal margin were used. After dissection of all the adhesions behind the pancreatic tail deep in the retroperitoneal space a round structure 4 cm in diameter, macroscopically resembling splenic tissue, was found. The accessory spleen was removed intact. The patient recovered well; 2 months later steroids were discontinued while the thrombocyte level was 251 x 10(9)/L. Identification of accessory spleen seems to be major intraoperative problem. We believe that accessory spleen can be safely removed laparoscopically, avoiding a major open procedure, and a satisfactory postoperative result could be expected.

[Harvesting bone marrow from the posterior superior iliac crest for transplantation]. / Pobieranie szpiku kostnego z talerzy biodrowych da celów transplantacyjnych.

The purpose of bone marrow cells harvesting is to isolate haemopoietic stem cell for the transplantation, by means of multiple punctures from the posterior iliac crest under general anaesthesia. This method is the alternative procedure for collecting circulating peripheral blood progenitor cells performed with continuous-flow cell separators. The aim of the both procedures is the collection of progenitor cells for transplantation in the number enabling reconstitution of marrow function after myeloablative therapy. The bone marrow cell harvesting is a safe measure: the infrequent complication related to general anaesthesia may occur and the simultaneous or subsequent blood transfusion is usually required.

[Molecular basis of chronic myelogenous leukemia and significance of diagnostic methods based on BCR-ABL gene amplification]. / Molekularne podloze przewleklej bialaczki szpikowej i znaczenie metod diagnostycznych opartych o amplifikacje genu BCR-ABL.

Chronic myelogenous leukemia is characterized by an abnormal 22nd chromosome known as a Philadelphia chromosome, which can be detected in 95% of patients with CML. Molecular equivalent of this aberration is a BCR-ABL translocation resulting in chimeric gene formation. A BCR-ABL chimeric gene plays a key role in the hematopoietic cells proliferation regulation. RT-PCR can be used in diagnosis of CML, to detect chimeric BCR-ABL gene, and to reveal the type of translocation what could have prognostic importance, and in monitoring of minimal residual disease, confirming the eradication of pathological cells clone after treatment and identifying the group of patients with best prognosis and best overall survival. RT-PCR in monitoring of minimal residual disease after allo- or autologous hemopoietic cells transplantation can early reveal relapse of the disease. Detection of molecular relapse is an important prognostic factor and may implicate induction of treatment which should prevent haematological relapse of the disease.

[Autologous hemopoietic stem cell transplantation in treatment of chronic myelogenous leukemia]. / Autotransplantacja hemopoetycznych komórek macierzystych w leczeniu przewleklej bialaczki szpikowej.

Chronic myelogenous leukemia in more than 90% of patients is associated with the abnormal Philadelphia chromosome, which results in aberrant BCR-ABL chimeric gene expression. The mean overall survival on standard chemotherapy (which is not curative) ranges between 54-72 months. Selected patients with CML can be cured by allogeneic hemopoietic stem cell transplantation. Only 30% of patients has an optimal HLA-identical sibling donor. It is possible to find well-matched unrelated donor for another 20-30% of patients, however matched-unrelated donor transplantation is still associated with relative high risk of complications and cannot be used in elderly patients. Interferon alpha treatment in monotherapy or in combination with ARA-C can induce a cytogenetical and molecular remission in selected group of patients, which benefits with significantly prolonged survival. Nevertheless the cost of this treatment is high and long period of therapy is required to assess its efficacy. In patients lacking matched related or unrelated donors for allogeneic transplantation, autologous stem cell transplantation could be the alternative method of treatment. Discussed in the paper method of mobilization and transplantation of Philadelphia-negative peripheral-blood progenitor cells collected during early phase of bone marrow regeneration after "mobilizing" chemotherapy (mini-ICE) enables to achieve a complete or major cytogenetical response in about 77% of patients. There is only minimal morbidity and no transplant-related mortality. This procedure and the post-transplant immunotherapy (IFN alpha, interleukin-2) can considerably suppress the pathological clone and significantly prolong the overall survival in CML patients not eligible for allogeneic transplantation.