ABL mutations in late chronic phase chronic myeloid leukemia patients with up-front cytogenetic resistance to imatinib are associated with a greater likelihood of progression to blast crisis and shorter survival: a study by the GIMEMA Working Party on Chronic Myeloid Leukemia.

PURPOSE: Point mutations within the ABL kinase domain of the BCR-ABL gene have been associated with clinical resistance to imatinib mesylate in chronic myeloid leukemia (CML) patients. To shed further light on the frequency, distribution, and prognostic significance of ABL mutations, we retrospectively analyzed a homogeneous cohort of late chronic phase CML patients who showed primary cytogenetic resistance to imatinib. PATIENTS AND METHODS: Using denaturing high-performance liquid chromatography (D-HPLC) and sequencing, we screened for ABL mutations in a total of 178 bone marrow and/or peripheral blood samples from 40 late chronic phase CML patients homogeneously treated with imatinib 400 mg/d, who did not reach a major cytogenetic response at 12 months. RESULTS: Mutations were found in 19 of 40 patients (48%). Mutations were already detectable by D-HPLC at a median of 3 months from the onset of therapy. The presence of a missense mutation was significantly associated with a greater likelihood of subsequent progression to accelerated phase/blast crisis (P = .0002) and shorter survival (P = .001). Patients carrying mutations falling within the P-loop seemed to have a particularly poor outcome in terms of time to progression (P = .032) and survival (P = .045). CONCLUSION: Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.     

Experience with comprehensive pharmacogenomic multi-gene panel in clinical practice: a retrospective single-center study

AimTo assess the prevalence of actionable pharmacogenetic interventions in patients who underwent pharmacogenetic testing with a multi-gene panel.MethodsWe retrospectively reviewed single-center electronic health records. A total of 319 patients were enrolled who underwent pharmacogenomic testing with the RightMed test panel using TaqMan quantitative real-time PCR method and copy number variation analysis to determine the SNPs in the 27 target genes.ResultsActionable drug-gene pairs were found in 235 (73.7%) patients. Relevant guidelines on genotype-based prescribing were available for 133 (56.7%) patients at the time of testing. Based on the patients’ genotype, 139 (43.6%) patients were using at least one drug with significant pharmacogenetic interactions.ConclusionTwo out of three patients had at least one drug-gene pair in their therapy. Further studies should assess the clinical effectiveness of integrating pharmacogenomic data into patients’ electronic health records.

The field of pharmacogenetics has been booming in the past decades, with research being focused on studying novel genetic variants that impact drug metabolism or pharmacological effect, which ultimately affects the patient’s response to a given dose of medication. Pharmacogenetics examines gene-drug interactions that change pharmacokinetic and/or pharmacodynamic properties of a drug (1). It is impossible to implement any of the principles of personalized medicine without determining the patients'' pharmacogenetic profile before starting a new therapy (2).Several professional organizations, namely, Clinical Pharmacogenetics Implementation Consortium (CPIC) and Dutch Pharmacogenetics Working Group (DPWG), provide comprehensive and understandable guidelines on genotype-based drug prescribing (3,4). Pharmacogenomic prescribing guidelines are growing in number and are available for various drug classes including the cardiovascular drugs, drugs affecting the central nervous system, gastrointestinal drugs, drugs that treat infectious and malignant diseases, immunosuppressives, analgesics, and other (5,6).Several companies specialize in pharmacogenetic panels, making it easily accessible for patients and clinicians of various specialties to obtain the test results in a matter of days or weeks. These commercial tests are developed by industry stakeholders and can be implemented in various settings during the diagnostic or treatment process (7,8). They are comprehensive and include a number of genes that are important for the pharmacologic profile across drug groups, or targeted for a certain category of drugs, ie, psychiatric, analgesics, oncologic drugs, etc. Data on the rate of utilization and clinical utility of such tests are lacking. A recent study found that from 2013 until 2017 only 5712 insured US patients performed pharmacogenetic testing of at least one gene (9). The field of pharmacogenomics is still in its early stages. One of the principal problems is the education of health care providers responsible for ordering and interpreting the test results. In a recent survey, 84.3% of doctors from seven European countries deemed pharmacogenomics relevant for their practice, however 65.7% did not order a pharmacogenomic test in the last year (10). Potential implementation of pharmacogenomics in the clinical practice should be complemented with a clinical decision support tool integrated into the patient’s electronic health record (11,12). In Croatia, pharmacogenomic testing has been available for over a decade, with multiple studies examining population genetics and cost-effectiveness of pharmacogenomic guided therapies (13,14). However, commercial panel-based tests targeting multiple genes known to influence drug response is a new concept that was implemented in 2018 at St. Catherine Hospital in Zagreb (8,15,16).The aim of this retrospective study was to assess the proportion of patients with actionable pharmacogenetic interventions in a single center from 2018 to 2021 who had undergone pharmacogenetic testing of 27 genes by using a commercial gene panel.     

LTA and FAU-X Iron-Enriched Zeolites: Use for Phosphate Removal from Aqueous Medium

Hydrothermally synthesized Linde type A (LTA) and faujasite X (FAU-X) zeolites are low-cost and environmentally benign inorganic carriers for environmental applications. In this study, (oxy)hydroxides were incorporated onto LTA and FAU-X zeolites to promote the phosphate adsorption. The performance of LTA-Fe and FAU-X-Fe was evaluated through batch adsorption assays. A complete evaluation was performed to recover phosphate from synthetic wastewater. The effect of pH, concentration, equilibrium, and kinetic parameters on phosphate adsorption and its further reuse in sorption–desorption cycles were evaluated. LTA-Fe and FAU-X-Fe are effective for adsorption of phosphate at neutral (e.g., pH 7.0 ± 0.2) and in a broad range of phosphate concentrations. Higher ratios of adsorption capacities were obtained by synthetic zeolites enriched with iron in comparison to their parent forms. The phosphate adsorption occurred through hydrogen bonding and complexation reactions between protonated iron hydroxyl groups and phosphate anions. The phosphate monolayer adsorption was followed by diffusion through the internal pores and 80% of the equilibrium adsorption was reached within 50 min. The LTA-Fe and FAU-X-Fe can be used for phosphate recovery from wastewater treatment plants. The use of LTA-Fe and FAU-X-Fe in a tertiary wastewater treatment stage could allow to reduce the phosphate–phosphorous content, reaching the regulatory levels (equal 1 mg L⁻¹ total phosphorous). The phosphate adsorption using LTA-Fe and FAU-X-Fe does not require pH adjustment, and it is endothermic. The reusability of both iron zeolites is limited, and they can be finally disposed for soil amendment applications.     

Neoadjuvant chemotherapy plus radical surgery in locally advanced cervical cancer during pregnancy: a case report

Management of cervicocarcinoma during pregnancy is influenced by gestational age, stage of disease, and patient's desire to maintain her pregnancy. We report a case of a pregnant patient with locally advanced cervicocarcinoma successfully treated by neoadjuvant chemotherapy, followed by caesarean section and radical surgery.     

Reactive vaccination as control strategy for an outbreak of invasive meningococcal disease caused by Neisseria meningitidis C:P1.5-1,10-8:F3-6:ST-11(cc11), Bergamo province,Italy, December 2019 to January 2020

In Italy, serogroup C meningococci of the clonal complex cc11 (MenC/cc11) have caused several outbreaks of invasive meningococcal disease (IMD) during the past 20 years. Between December 2019 and January 2020, an outbreak of six cases of IMD infected with MenC/cc11 was identified in a limited area in the northern part of Italy. All cases presented a severe clinical picture, and two of them were fatal. This report is focused on the microbiological and molecular analysis of meningococcal isolates with the aim to reconstruct the chain of transmission. It further presents the vaccination strategy adopted to control the outbreak. The phylogenetic evaluation demonstrated the close genetic proximity between the strain involved in this outbreak and a strain responsible for a larger epidemic that had occurred in 2015 and 2016 in the Tuscany Region. The rapid identification and characterisation of IMD cases and an extensive vaccination campaign contributed to the successful control of this outbreak caused by a hyperinvasive meningococcal strain.     

How Diet and Physical Activity Modulate Gut Microbiota: Evidence,and Perspectives

Gut microbiota plays a significant role in the maintenance of physiological homeostasis, contributing to human health. Nevertheless, some factors (sex, age, lifestyle, physical activity, drug-based therapies, diet, etc.) affect its composition and functionality, linked to pathologies and immunological diseases. Concerning diet, it interacts with microorganisms, leading to beneficial or detrimental outcomes for the health of host. On the other hand, physical activity is known to be useful for preventing and, sometimes, treating several diseases of cardiovascular, neuroendocrine, respiratory, and muscular systems. This paper focuses on diet and physical activity presenting the current knowledge about how different diets (Western, ketogenic, vegan, gluten free, Mediterranean) as well as different types of exercise (intensive, endurance, aerobic) could shape gut microbiota.     

Buccal micronucleus cytome assay in primary school children: A descriptive analysis of the MAPEC_LIFE multicenter cohort study

Background

Recent data support the hypothesis that genetic damage occurring early in life during childhood can play an important role in the development of chronic diseases in adulthood, including cancer.