Targeted therapy in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is characterized by the formation of the Philadelphia chromosome and oncogenic signaling by the resulting Bcr-Abl fusion protein. Understanding the molecular basis of CML has led to the development of highly effective targeted therapies that block Bcr-Abl tyrosine kinase activity. Imatinib, the current first-line therapy for CML, induces durable treatment responses in most patients. However, patients may develop imatinib resistance, which is often due to BCR-ABL mutations. With the availability of second generation tyrosine kinase inhibitors, an effective therapeutic option other than stem cell transplantation is available following imatinib failure. Randomized trial data suggest that dasatinib treatment is superior to imatinib dose escalation in patients with imatinib resistance. Nilotinib, a recently approved analogue of imatinib, has also demonstrated encouraging treatment responses in patients with imatinib-resistant CML. Other agents (including bosutinib and INNO-406) are in clinical development. With the potential availability of multiple treatment options for patients with CML, it may be possible to tailor treatment according to individual patient or disease characteristics, for example, BCR-ABL mutations. Future CML treatment may involve combination strategies. Overall, targeted agents have significantly improved the prognosis of patients diagnosed with CML.     

Garlic Potyviruses Are Translocated to the True Seeds through the Vegetative and Reproductive Systems of the Mother Plant

Garlic lost its ability to produce true seeds millennia ago, and today non-fertile commercial cultivars are propagated only vegetatively. Garlic viruses are commonly carried over from one generation of vegetative propagules to the other, while nematodes and arthropods further transmit the pathogens from infected to healthy plants. A recent breakthrough in the production of true (botanical) garlic seeds resulted in rapid scientific progress, but the question of whether viruses are transmitted via seeds remains open and is important for the further development of commercial seed production. We combined morpho-physiological analysis, fluorescence in situ hybridization (FISH), and PCR analysis to follow potyvirus localization and translocation within garlic fertile plants and seeds. Spatial distribution was recorded in both vegetative and reproductive organs. We conclude that garlic potyviruses are translocated to the seeds from the infected mother plant during flower development and post-fertilization, while pollen remains virus-free and does not contribute to seed infection. Therefore, the main practical goal for virus-clean seed production in garlic is the careful maintenance of virus-free mother plants. Although garlic pollen is free of potyviral infection, the male parents’ plants also need to be protected from contamination, since viral infection weakens plants, reducing flowering ability and pollen production.     

Mortality prediction upon hospital admission – the value of clinical assessment: A retrospective,matched cohort study

Accurate prediction of mortality upon hospital admission is of great value, both for the sake of patients and appropriate resources’ allocation. A myriad of assessment tools exists for this purpose. The evidence relating to the comparative value of clinical assessment versus established indexes are scarce. We analyzed the accuracy of a senior physician’s clinical assessment in a retrospective cohort of patients in a crude, general patients’ population and later on a propensity matched patients’ population. In one department of internal medicine in a tertiary hospital, of 9891 admitted patients, 973 (10%) were categorized as prone to death in a 6-months’ duration by a senior physician. The risk of death was significantly higher for these patients [73.1% vs 14.1% mortality within 180 days; hazard ratio (HR) = 7.58; confidence intervals (CI) 7.02‐8.19, P < .001]. After accounting for multiple, other patients’ variables associated with increased risk of mortality, the correlation remained significant (HR = 3.25; CI 2.85‐3.71, P < .001). We further performed a propensity matching analysis (a subgroup of 710 patients, subdivided to two groups with 355 patients each): survival rates were as low as 45% for patients categorized as prone to death compared to 78% in patients who weren’t categorized as such (P < .001). Reliance on clinical evaluation, done by an experienced senior physician, is an appropriate tool for mortality prediction upon hospital admission, achieving high accuracy rates.     

A multi-centre,randomised, double-blind,placebo-controlled clinical trial of methylphenidate in the initial treatment of acute mania (MEMAP study)

Based on many clinical and preclinical findings the ‘vigilance regulation model of mania’ postulates that an unstable regulation of wakefulness is a pathogenetic factor in both mania and Attention Deficit Hyperactivity Disorder (ADHD) and induces hyperactivity and sensation seeking as an autoregulatory attempt to stabilize wakefulness. Accordingly, stimulant medications with their vigilance stabilizing properties could have rapid antimanic effects similar to their beneficial effects in ADHD. The MEMAP study – a multi-center, double-blind, placebo-controlled and randomized clinical trial (RCT) – assessed the antimanic efficacy and safety of a 2.5-day treatment with methylphenidate (20–40 mg/day). Of 157 screened patients with acute mania, 42 were randomly assigned to receive 20–40 mg per day of methylphenidate in one or two applications, or placebo. The primary outcome was the change in Young Mania Rating Scale (YMRS) sum scores from baseline to day 2.5 in the methylphenidate group compared to the placebo group. A group sequential design was chosen to justify early RCT termination based on efficacy or futility at an interim analysis after inclusion of 40 patients. In the interim analysis, the change from baseline in the YMRS total score at day 2.5 was not significantly different between both groups (F(1,37)=0.23; p=0.64). Thus, futility was declared for methylphenidate and the RCT was stopped. In summary, although methylphenidate was well tolerated and safe in the full analysis set, it failed to show efficacy in the treatment of acute mania. Trial registration: clinicaltrials.gov (URL: http://www.clinicaltrials.gov; registration number: NCT01541605).     

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.     

Über den Beugereflex des normalen Menschen

Zusammenfassung Es wird nachgewiesen, daß der Beugereflex beim normalen Menschen durch die in den Antagonisten auftretende Hemmung stets erkannt werden kann. Die Ansicht, daß es sich um ein nur unter pathologischen Umständen auftretendes Phänomen handele ist somit irrig. Die Kontraktion der Agonisten allerdings kann nicht regelmäßig gefunden werden und es bleibt mithin der pathognomonische Sinn des Beugereflexes als klinisches Zeichen unberührt. Die näheren Umstände der Hemmungserscheinung werden beschrieben.Mit 2 Textabbildungen.