[Recognizing and managing side effects of tyrosine kinase inhibitors in chronic myeloid leukemia]. / Effets secondaires des inhibiteurs de tyrosine kinase dans la leucémie myéloïde chronique.

Tyrosine kinase inhibitors (TKI) have emerged as a paradigm-shifting therapeutic approach for the treatment of chronic myeloid leukemia (CML) following their regulatory approval in 2001. These agents have revolutionized the management of CML by significantly improving patient outcomes and enabling them to achieve near-normal life expectancies. Consequently, the utilization of TKI has become increasingly prevalent, accompanied by the recognition and management of their associated adverse effects. Given the expanding patient population receiving TKI therapy, it is imperative that hematologists, as well as general practitioners, assume the responsibility of closely and meticulously monitoring patients' treatment progress while effectively addressing the occurrence of any untoward effects.

Les inhibiteurs de tyrosine kinase (ITK) ont révolutionné la prise en charge de la leucémie myéloïde chronique (LMC) depuis leur autorisation de mise sur le marché en 2001, permettant aux patients d'obtenir une survie comparable à celle de la population générale. À ce jour, plusieurs générations d'ITK sont apparues, avec leurs effets secondaires respectifs. Leur prescription nécessite donc un suivi rapproché et pluridisciplinaire entre l'hématologue et l'interniste hospitalier, mais également le médecin généraliste, qui peut aussi être confronté à ces effets indésirables.

Refined cytogenetic IPSS-R evaluation by the use of SNP array in a cohort of 290 MDS patients.

Genetic testing plays a central role in myelodysplastic neoplasms (MDS) diagnosis, prognosis, and therapeutic decisions. The widely applied cytogenetic revised international prognostic scoring system (IPSS-R) was based on chromosome banding analysis (CBA). However, subsequently developed genetic methodologies, such as single nucleotide polymorphism (SNP) array, demonstrated to be a valid alternative test for MDS. SNP array is, in fact, able to detect the majority of MDS-associated cytogenetic aberrations, by providing further genomic information due to its higher resolution. In this study, 290 samples from individuals with a confirmed or suspected diagnosis of MDS were tested by both CBA and SNP array, in order to evaluate and compare their cytogenetic IPSS-R score in the largest MDS cohort reported so far. A concordant or better refined cytogenetic IPSS-R array-based score was obtained for 95% of cases (277). Therefore, this study confirms the effective applicability of SNP array toward the cytogenetic IPSS-R evaluation and consequently, toward the molecular international prognostic scoring system for MDS (IPSS-M) assessment, which ensures an improved MDS risk stratification refinement. Considering the advent of additional genetic technologies interrogating the whole genome with increased resolutions, counting cytogenetic abnormalities based on their size may result in a simplistic approach. On the contrary, assessing overall genomic complexity may provide additional crucial information. Independently of the technology used, genetic results should indeed aim at ensuring a highly refined stratification for MDS patients.

Role of Bcl-2 inhibition in myelodysplastic syndromes.

Myelodysplasic syndromes (MDS) are diseases occurring mainly in the elderly population. Although hematopoietic stem cell transplantation is the only hope for cure, a majority of the patients suffering from MDS are too old or frail for intensive treatment regimens such as intensive chemotherapy and transplantation. The gold standard for those patients is currently treatment with hypomethylating agents, although real-life data could not reproduce the overall survival rates reported for the pivotal azacitidine phase III study. MDS treatment is often inspired by treatment for acute myeloid leukemia (AML). The new gold standard for elderly and frail patients not able to undergo intensive treatment regimens in AML is the combination of hypomethylating agents with venetoclax, a BCL-2 inhibitor that also showed excellent treatment outcomes in other hematological malignancies. In this review, we explain the rationale for the use of venetoclax in hematological malignancies, study outcomes available so far and the current knowledge of its use in MDS.

Antibody response and intra-host viral evolution after plasma therapy in COVID-19 patients pre-exposed or not to B-cell-depleting agents.

Administration of plasma therapy may contribute to viral control and survival of COVID-19 patients receiving B-cell-depleting agents that impair humoral immunity. However, little is known on the impact of anti-CD20 pre-exposition on the kinetics of SARS-CoV-2-specific antibodies. Here, we evaluated the relationship between anti-spike immunoglobulin G (IgG) kinetics and the clinical status or intra-host viral evolution after plasma therapy in 36 eligible hospitalized COVID-19 patients, pre-exposed or not to B-cell-depleting treatments. The majority of anti-CD20 pre-exposed patients (14/17) showed progressive declines of anti-spike IgG titres following plasma therapy, contrasting with the 4/19 patients who had not received B-cell-depleting agents (p = 0.0006). Patients with antibody decay also depicted prolonged clinical symptoms according to the World Health Organization (WHO) severity classification (p = 0.0267) and SARS-CoV-2 viral loads (p = 0.0032) before complete virus clearance. Moreover, they had higher mutation rates than patients able to mount an endogenous humoral response (p = 0.015), including three patients with one to four spike mutations, potentially associated with immune escape. No relevant differences were observed between patients treated with plasma from convalescent and/or mRNA-vaccinated donors. Our study emphasizes the need for an individualized clinical care and follow-up in the management of COVID-19 patients with B-cell lymphopenia.

Antibody response and intra-host viral evolution after plasma therapy in COVID-19 patients pre-exposed or not to B-cell depleting agents

BackgroundAdministration of plasma therapy may contribute to viral control and survival of COVID-19 patients receiving B-cell depleting agents that hinder the endogenous humoral response. However, little is known on the impact of anti-CD20 pre-exposition and the use of different sources of plasma (convalescent versus vaccinated) on the kinetics of SARS-CoV-2-specific antibodies and viral evolution after plasma therapy. MethodsEligible COVID-19 patients (n = 36), half of them after anti-CD20 targeted therapy, were treated with therapeutic plasma from convalescent (n = 17) or mRNA-vaccinated (n = 19) donors. Each plasma-transfused patient was thoroughly monitored over time by anti-S IgG quantification and whole-genome SARS-CoV-2 sequencing. ResultsThe majority of anti-CD20 pre-exposed patients (15/18) showed progressive declines of anti-S protein IgG titers following plasma therapy, indicating that they mostly relied on the passive transfer of anti-SARS-CoV-2 antibodies. Such antibody kinetics correlated with prolonged infection before virus clearance, contrasting with the endogenous humoral response predominantly present in patients who had not received B-cell depleting agents (15/18). No relevant differences were observed between patients treated with plasma from convalescent and/or vaccinated donors. Finally, 4/30 genotyped patients showed increased intra-host viral evolution and 3/30 included 1 to 4 spike mutations, potentially associated to immune escape. ConclusionsConvalescent and/or vaccinated plasma therapy may provide anti-SARS-CoV-2 antibodies and clinical benefit to B-cell depleted COVID-19 patients. Only a limited number of patients acquired viral mutations prior to clinical recovery, yet our study further emphasizes the need for long-term surveillance for intra-host variant evolution, to guide best therapeutic strategies.

Metabolic Fingerprint of Chronic Obstructive Lung Diseases: A New Diagnostic Perspective.

Chronic obstructive lung disease (COLD) is a group of airway diseases, previously known as emphysema and chronic bronchitis. The heterogeneity of COLD does not allow early diagnosis and leads to increased morbidity and mortality. The increasing number of COLD incidences stresses the need for precision medicine approaches that are specific to the patient. Metabolomics is an emerging technology that allows for the discrimination of metabolic changes in the cell as a result of environmental factors and specific genetic background. Thus, quantification of metabolites in human biofluids can provide insights into the metabolic state of the individual in real time and unravel the presence of, or predisposition to, a disease. In this article, the advantages of and potential barriers to putting metabolomics into clinical practice for COLD are discussed. Today, metabolomics is mostly lab-based, and research studies with novel COLD-specific biomarkers are continuously being published. Several obstacles in the research and the market field hamper the translation of these data into clinical practice. However, technological and computational advances will facilitate the clinical interpretation of data and provide healthcare professionals with the tools to prevent, diagnose, and treat COLD with precision in the coming decades.

Targeted Metabolomic Analysis of Serum Fatty Acids for the Prediction of Autoimmune Diseases.

Autoimmune diseases (ADs) are rapidly increasing worldwide and accumulating data support a key role of disrupted metabolism in ADs. This study aimed to identify an improved combination of Total Fatty Acids (TFAs) biomarkers as a predictive factor for the presence of autoimmune diseases. A retrospective nested case-control study was conducted in 403 individuals. In the case group, 240 patients diagnosed with rheumatoid arthritis, thyroid disease, multiple sclerosis, vitiligo, psoriasis, inflammatory bowel disease, and other AD were included and compared to 163 healthy individuals. Targeted metabolomic analysis of serum TFAs was performed using GC-MS, and 28 variables were used as input for the predictive models. The primary analysis identified 12 variables that were statistically significantly different between the two groups, and metabolite-metabolite correlation analysis revealed 653 significant correlation coefficients with 90% level of significance (p < 0.05). Three predictive models were developed, namely (a) a logistic regression based on Principal Component Analysis (PCA), (b) a straightforward logistic regression model and (c) an Artificial Neural Network (ANN) model. PCA and straightforward logistic regression analysis, indicated reasonably well adequacy (74.7 and 78.9%, respectively). For the ANN, a model using two hidden layers and 11 variables was developed, resulting in 76.2% total predictive accuracy. The models identified important biomarkers: lauric acid (C12:0), myristic acid (C14:0), stearic acid (C18:0), lignoceric acid (C24:0), palmitic acid (C16:0) and heptadecanoic acid (C17:0) among saturated fatty acids, Cis-10-pentadecanoic acid (C15:1), Cis-11-eicosenoic acid (C20:1n9), and erucic acid (C22:1n9) among monounsaturated fatty acids and the Gamma-linolenic acid (C18:3n6) polyunsaturated fatty acid. The metabolic pathways of the candidate biomarkers are discussed in relation to ADs. The findings indicate that the metabolic profile of serum TFAs is associated with the presence of ADs and can be an adjunct tool for the early diagnosis of ADs.

Developing BIOTEL: A Semi-Automated Spreadsheet for Estimating Telomere Length and Biological Age.

Introduction: Telomere length (TL) is causally related to aging and several age-related diseases. Specifically, the abundance of short telomeres and the rate of telomere shortening are strong determinants of cell homeostasis. Thus, tools for analyzing and manipulating TL data can vastly improve research focused on aging. Aim: In this study, we developed a semi-automated worksheet, BIOTEL, to generate individual and group TL statistics and provide a crude estimation of biological age. Results: Data from the Telomere Length Database Project (TLDP) were implemented to the spreadsheet to produce TL statistics. 150 participants were included, and their age was from 21 to 82 years, and the sex distribution ratio was 52.3%: 47.7% (male: female). Initially, we analyzed the fluorescence intensities of telomeres that were measured on metaphase spread leukocytes using three-dimensional (3D) quantitative-fluorescent in situ hybridization (Q-FISH) procedures (3D DNA FISH) with a (C3TA2)3 peptide nucleic acid (PNA) probe. Raw data of fluorescence intensities, demographic data and medical records from the participants were imported into the worksheet. Basic statistical analyses of TL data were provided through BIOTEL, including TL percentiles, specialized charts for TL distribution including the percentage of critically short telomeres (< 3,000 kilobases), individual telomere profiles, and graphs of biological age vs. chronological age. Conclusion: BIOTEL ver. 2.4 is a functional semi-automated worksheet that calculates a wide range of TL statistics, thus a useful tool with applications in research of telomeres and biological age estimation.

Application of metabolomics part II: Focus on fatty acids and their metabolites in healthy adults.

Fatty acids (FAs) play critical roles in health and disease. The detection of FA imbalances through metabolomics can provide an overview of an individual's health status, particularly as regards chronic inflammatory disorders. In this study, we aimed to establish sensitive reference value ranges for targeted plasma FAs in a well­defined population of healthy adults. Plasma samples were collected from 159 participants admitted as outpatients. A total of 24 FAs were analyzed using gas chromatography­mass spectrometry, and physiological values and 95% reference intervals were calculated using an approximate method of analysis. The differences among the age groups for the relative levels of stearic acid (P=0.005), the omega­6/omega­3 ratio (P=0.027), the arachidonic acid/eicosapentaenoic acid ratio (P<0.001) and the linoleic acid­produced dihomo­gamma­linolenic acid (P=0.046) were statistically significant. The majority of relative FA levels were higher in males than in females. The levels of myristic acid (P=0.0170) and docosahexaenoic acid (P=0.033) were significantly different between the sexes. The reference values for the FAs examined in this study represent a baseline for further studies examining the reproducibility of this methodology and sensitivities for nutrient deficiency detection and investigating the biochemical background of pathological conditions. The application of these values to clinical practice will allow for the discrimination between health and disease and contribute to early prevention and treatment.

Using the Scoliometer and a Surface Topography Apparatus to Check if Back Trunk Asymmetry Changes in Children and Adolescents in the Forward Flexion and Standing Erect Positions.

Background The purpose of this study is to evaluate the effects of the forward bending (FB) test versus the standing erect (SE) position on back trunk asymmetry (TA). The Scoliometer in the FB position and the 4D Formetric (4DF; Diers International, Schlangenbad, Germany) readings in the SE position were assessed. Method The angle of trunk inclination (ATI) was measured at the midthoracic, thoracolumbar, and lumbar levels using the Scoliometer in the FB position and the 4DF in the SE position. A total of 134 subjects attending the scoliosis clinic (86 girls and 48 boys), age ranging from seven to 18 years, were assessed. The children and adolescents were divided into three groups according to the severity of TA, symmetric group 1 (0-2 degrees), asymmetry group 2 (2 to 6 degrees), and group 3 having asymmetry of seven or more degrees. Children with leg length discrepancy were excluded from the study. The IBM SPSS v.20 package (IBM Corp., Armonk, NY) was used for analysis. Results At the midthoracic level comparing the Scoliometer to 4DF readings in males in group 1, the Wilcoxon signed ranks test was p=0.451 while for the Spearman's Rho, it was -0.138; in group 2, p=0.184 and Rho=0.204; and in group 3, p=0.109 and Rho=0.500. For females in group 1, p=0.000 while Rho=0.003; in group 2, p=0.008 and Rho=0.000, and in group 3, p=0.003 while Rho=0.642. At the thoracolumbar level in males for group 1, p=0.004 and Rho=-0.517; in group 2, p=0.006 and Rho=0.000; and in group 3, p=0.043 while Spearman's Rho=0.053. For females in group 1, p=0.000 and Rho=-0.095; in group 2, p=0.000 and Rho=-0.171; in group 3, p=0.001 while Rho= -0.081. At the lumbar level for males in group 1 p=0.000 while Rho=0.149; in group 2, p=0.003 and Rho=0.373; while in group 3, p=0.109 and Rho= (-). For females in group 1, p=0.000 while Rho=-0.072; in group 2, p=0.001 and Rho=0.168; and in group 3, p=0.068 while Rho=0.500. Conclusion The results of this study show that the back TA in children and adolescents is not similar in the FB and SE positions. This phenomenon probably is attributed to the complicated trunkal (spinal, thoracic, and pelvic) anatomy, and the results of this study may be used as a useful foundation for further understanding of torso dynamics.

Academic hospital staff compliance with a fecal immunochemical test-based colorectal cancer screening program.

AIM: To measure the compliance of an Academic Hospital staff with a colorectal cancer (CRC) screening program using fecal immunochemical test (FIT). METHODS: All employees of "Attikon" University General Hospital aged over 50 years were thoroughly informed by a team of physicians and medical students about the study aims and they were invited to undergo CRC screening using two rounds of FIT (DyoniFOB(®) Combo H, DyonMed SA, Athens, Greece). The tests were provided for free and subjects tested positive were subsequently referred for colonoscopy. One year after completing the two rounds, participants were asked to be re-screened by means of the same test. RESULTS: Among our target population consisted of 211 employees, 59 (27.9%) consented to participate, but only 41 (19.4%) and 24 (11.4%) completed the first and the second FIT round, respectively. Female gender was significantly associated with higher initial participation (P = 0.005) and test completion - first and second round - (P = 0.004 and P = 0.05) rates, respectively. Physician's (13.5% vs 70.2%, P < 0.0001) participation and test completion rates (7.5% vs 57.6%, P < 0.0001 for the first and 2.3% vs 34%, P < 0.0001 for the second round) were significantly lower compared to those of the administrative/technical staff. Similarly, nurses participated (25.8% vs 70.2%, P = 0.0002) and completed the first test round (19.3% vs 57.6%, P = 0.004) in a significant lower rate than the administrative/technical staff. One test proved false positive. No participant repeated the test one year later. CONCLUSION: Despite the well-organized, guided and supervised provision of the service, the compliance of the Academic Hospital personnel with a FIT-based CRC screening program was suboptimal, especially among physicians.

Risk for childhood leukemia associated with maternal and paternal age.

The role of reproductive factors, such as parental age, in the pathogenesis of childhood leukemias is being intensively examined; the results of individual studies are controversial. This meta-analysis aims to quantitatively synthesize the published data on the association between parental age and risk of two major distinct childhood leukemia types in the offspring. Eligible studies were identified and pooled relative risk (RR) estimates were calculated using random-effects models, separately for childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Subgroup analyses were performed by study design, geographical region, adjustment factors; sensitivity analyses and meta-regression analyses were also undertaken. 77 studies (69 case-control and eight cohort) were deemed eligible. Older maternal and paternal age were associated with increased risk for childhood ALL (pooled RR = 1.05, 95 % CI 1.01-1.10; pooled RR = 1.04, 95 % CI 1.00-1.08, per 5 year increments, respectively). The association between maternal age and risk of childhood AML showed a U-shaped pattern, with symmetrically associated increased risk in the oldest (pooled RR = 1.23, 95 % CI 1.06-1.43) and the youngest (pooled RR = 1.23, 95 % CI 1.07-1.40) extremes. Lastly, only younger fathers were at increased risk of having a child with AML (pooled RR = 1.28, 95 % CI 1.04-1.59). In conclusion, maternal and paternal age represents a meaningful risk factor for childhood leukemia, albeit of different effect size by leukemia subtype. Genetic and socio-economic factors may underlie the observed associations. Well-adjusted studies, scheduled by large consortia, are anticipated to satisfactorily address methodological issues, whereas the potential underlying genetic mechanisms should be elucidated by basic research studies.

Risk Factors for Multiple Myeloma: A Systematic Review of Meta-Analyses.

The epidemiology of multiple myeloma (MM) is an increasingly investigated field, with many controversies. This systematic review aims to synthesize meta-analyses examining risk factors for MM so as to provide a comprehensive, parsimonious summary of the current evidence. Eligible meta-analyses were sought in PubMed adopting a predefined algorithm, without any restriction of publication language; end-of-search date was October 10, 2014. The selection of eligible studies and data extraction were performed by working in pairs, independently and blindly to each other; in case of disagreement, consensus with the whole team was reached. Among the 22 ultimately included meta-analyses, 9 examined occupational factors, 4 assessed aspects of lifestyle (smoking, alcohol, body mass index), 5 evaluated the presence of other diseases, and 4 addressed genetic factors as potential risk factors of MM. A vast compendium of significant associations arose, including farming, occupation as a firefighter, occupation as a hairdresser, exposures to chemicals or pesticides, overweight and obesity, patterns of alcohol intake, pernicious anemia, ankylosing spondylitis, gene promoter methylation, and polymorphisms. In conclusion, MM is a multifactorial disease, encompassing a wide variety of risk factors that span numerous life aspects. Further accumulation of evidence through meta-analyses is anticipated in this rapidly growing field.