Predictors of imatinib response in patients with chronic myeloid leukaemia

The majority of patients with chronic myeloid leukaemia (CML) achieve a complete cytogenetic response (CCR) on imatinib. However, we cannot predict which patients will have a suboptimal response. We set out to investigate ways of predicting poor cytogenetic response to imatinib in patients with CML. We examined patients with CML for the possession of particular alleles of the rs2290573 and IL-I P +3953 polymorphisms because these polymorphisms had been linked with the rate of achievement of a major cytogenetic response (MCR). Following the discovery of a polymorphism (K247R) within the P-Ioop of BCR-ABL, we determined its frequency within both CML patients and healthy blood donors, and used in vitro biochemical and cellular assays to test its drug sensitivity. We examined patients with primary cytogenetic resistance to imatinib for the expression of genes associated with drug transport (hOCT 1, MDR 1, ABCG2, ABCCl, ABCA2, ABCC2, ABCC3, ABCC6 and MVP) and compared this to patients who achieved a complete cytogenetic response to imatinib. We used gene expression profiling of CML unselected white cells, and of CML CD34+ cells, to look for genes associated with poor cytogenetic response. We could not find a correlation between the possession of the rs2290573 and IL-I p +3953 polymorphisms, and rate of MCR in our patients. The K247R polymorphism was rare, but 3 out of 5 patients with the arginine allele failed to achieve a major MCR. Despite its position in the P-Ioop, in vitro assays showed K247R to have a drug sensitivity phenotype highly similar to wild type BCR-ABL. Imatini b non-responders had significantly lower pre imatinib gene expression levels of hOCT 1, and significantly higher levels of ABCC3. compared to responders. In addition, in imatinib non-responders we found that the expression level of a variety of drug transport genes changed with time on imatinib, but these changes did not reach statistical significance. Gene expression profiling of CML total white cells revealed that imatinib responders and non-responders had highly similar gene signatures, and that the noise created by different sample source, handling and cell phenotype limited the detection of changes in gene expression. We successfully developed a technique for selecting CD34+ cells from cryopreserved CML mononuclear cells, and preliminary analysis of the CD34+ cell microarray data does not identify any genes that are significantly differentially expressed between cytogenetic responders and non-responders. Possession of the rs2290573 and IL-βI+3953 polymorphisms did not aid prediction of achievement of MCR in our CML popUlation. In patients with CML, possession of the arginine allele of K247R should not be confused with the development of a kinase domain mutation, and the failure of 3 out of 5 patients to achieve a MCR is likely to be a chance finding in a small cohort, but further collection of response data on patients with K247R is required. Differences in drug transport gene expression may influence patients' responses to imatinib, by potentially causing inadequate intracellular imatinib concentrations. Gene expression profiling of CML unselected WBC does not allow prediction of response to imatinib, and work is ongoing to see if the technique proves more useful when using RNA derived from CML CD34+ cells.EThOS - Electronic Theses Online ServiceClinical Training Fellowship, Leukaemia Research Fund : British Journal of Haematology Research Trust : Elimination of Leukaemia FundGBUnited Kingdo

Impact of opioid-free analgesia on pain severity and patient satisfaction after discharge from surgery: multispecialty, prospective cohort study in 25 countries

Background: Balancing opioid stewardship and the need for adequate analgesia following discharge after surgery is challenging. This study aimed to compare the outcomes for patients discharged with opioid versus opioid-free analgesia after common surgical procedures.Methods: This international, multicentre, prospective cohort study collected data from patients undergoing common acute and elective general surgical, urological, gynaecological, and orthopaedic procedures. The primary outcomes were patient-reported time in severe pain measured on a numerical analogue scale from 0 to 100% and patient-reported satisfaction with pain relief during the first week following discharge. Data were collected by in-hospital chart review and patient telephone interview 1 week after discharge.Results: The study recruited 4273 patients from 144 centres in 25 countries; 1311 patients (30.7%) were prescribed opioid analgesia at discharge. Patients reported being in severe pain for 10 (i.q.r. 1-30)% of the first week after discharge and rated satisfaction with analgesia as 90 (i.q.r. 80-100) of 100. After adjustment for confounders, opioid analgesia on discharge was independently associated with increased pain severity (risk ratio 1.52, 95% c.i. 1.31 to 1.76; P < 0.001) and re-presentation to healthcare providers owing to side-effects of medication (OR 2.38, 95% c.i. 1.36 to 4.17; P = 0.004), but not with satisfaction with analgesia (beta coefficient 0.92, 95% c.i. -1.52 to 3.36; P = 0.468) compared with opioid-free analgesia. Although opioid prescribing varied greatly between high-income and low- and middle-income countries, patient-reported outcomes did not.Conclusion: Opioid analgesia prescription on surgical discharge is associated with a higher risk of re-presentation owing to side-effects of medication and increased patient-reported pain, but not with changes in patient-reported satisfaction. Opioid-free discharge analgesia should be adopted routinely

A gene expression signature of CD34+ cells to predict major cytogenetic response in chronic-phase chronic myeloid leukemia patients treated with imatinib

In chronic-phase chronic myeloid leukemia (CML) patients, the lack of a major cytogenetic response (< 36% Ph+ metaphases) to imatinib within 12 months indicates failure and mandates a change of therapy. To identify biomarkers predictive of imatinib failure, we performed gene expression array profiling of CD34+ cells from 2 independent cohorts of imatinib-naive chronic-phase CML patients. The learning set consisted of retrospectively selected patients with a complete cytogenetic response or more than 65% Ph+ metaphases within 12 months of imatinib therapy. Based on analysis of variance P less than .1 and fold difference 1.5 or more, we identified 885 probe sets with differential expression between responders and nonresponders, from which we extracted a 75-probe set minimal signature (classifier) that separated the 2 groups. On application to a prospectively accrued validation set, the classifier correctly predicted 88% of responders and 83% of nonresponders. Bioinformatics analysis and comparison with published studies revealed overlap of classifier genes with CML progression signatures and implicated β-catenin in their regulation, suggesting that chronic-phase CML patients destined to fail imatinib have more advanced disease than evident by morphologic criteria. Our classifier may allow directing more aggressive therapy upfront to the patients most likely to benefit while sparing good-risk patients from unnecessary toxicity

Comparison of diagnoses of early-onset sepsis associated with use of Sepsis Risk Calculator versus NICE CG149: a prospective, population-wide cohort study in London, UK, 2020–2021

Objective We sought to compare the incidence of early-onset sepsis (EOS) in infants ≥34 weeks’ gestation identified &gt;24 hours after birth, in hospitals using the Kaiser Permanente Sepsis Risk Calculator (SRC) with hospitals using the National Institute for Health and Care Excellence (NICE) guidance.Design and setting Prospective observational population-wide cohort study involving all 26 hospitals with neonatal units colocated with maternity services across London (10 using SRC, 16 using NICE).Participants All live births ≥34 weeks’ gestation between September 2020 and August 2021.Outcome measures EOS was defined as isolation of a bacterial pathogen in the blood or cerebrospinal fluid (CSF) culture from birth to 7 days of age. We evaluated the incidence of EOS identified by culture obtained &gt;24 hours to 7 days after birth. We also evaluated the rate empiric antibiotics were commenced &gt;24 hours to 7 days after birth, for a duration of ≥5 days, with negative blood or CSF cultures.Results Of 99 683 live births, 42 952 (43%) were born in SRC hospitals and 56 731 (57%) in NICE hospitals. The overall incidence of EOS (&lt;72 hours) was 0.64/1000 live births. The incidence of EOS identified &gt;24 hours was 2.3/100 000 (n=1) for SRC vs 7.1/100 000 (n=4) for NICE (OR 0.5, 95% CI (0.1 to 2.7)). This corresponded to (1/20) 5% (SRC) vs (4/45) 8.9% (NICE) of EOS cases (χ=0.3, p=0.59). Empiric antibiotics were commenced &gt;24 hours to 7 days after birth in 4.4/1000 (n=187) for SRC vs 2.9/1000 (n=158) for NICE (OR 1.5, 95% CI (1.2 to 1.9)). 3111 (7%) infants received antibiotics in the first 24 hours in SRC hospitals vs 8428 (15%) in NICE hospitals.Conclusion There was no significant difference in the incidence of EOS identified &gt;24 hours after birth between SRC and NICE hospitals. SRC use was associated with 50% fewer infants receiving antibiotics in the first 24 hours of life