Asparaginase pharmacokinetics after intensive polyethylene glycol-conjugated L-asparaginase therapy for children with relapsed acute lymphoblastic leukemia.

PURPOSE: Asparaginase therapy is an important component in the treatment of children with acute lymphoblastic leukemia. Polyethylene glycol-conjugated asparaginase (PEG-ASNase) has significant pharmacological advantages over native Escherichia coli asparaginase. We investigated the pharmacokinetics of PEG-ASNase, presence of antibodies to PEG-ASNase, and concentrations of asparagine in serum and cerebrospinal fluid (CSF) in combination chemotherapy for relapsed pediatric acute lymphoblastic leukemia. EXPERIMENTAL DESIGN: Twenty-eight pediatric patients with relapsed medullary (n = 16) and extramedullary (n = 11) acute lymphoblastic leukemia were enrolled at three pediatric institutions and had at least two serum and CSF samples obtained for analysis. Patients received induction therapy (including PEG-ASNase 2500 IU/m2 intramuscularly weekly on days 2, 9, 16, and 23) and intensification therapy (including PEG-ASNase 2500 IU/m2 intramuscularly once on day 7). Serum samples were obtained weekly during induction and intensification. CSF samples were obtained during therapeutic lumbar punctures during induction and intensification. RESULTS: Weekly PEG-ASNase therapy resulted in PEG-ASNase activity of >0.1 IU/ml in 91-100% of patients throughout induction. During intensification, PEG-ASNase on day 7 resulted in PEG-ASNase activity >0.1 IU/ml in 94% and 80% of patients on days 14 and 21, respectively. Serum and CSF asparagine depletion was observed and maintained during induction and intensification in the majority of samples. PEG-ASNase antibody was observed in only 3 patients. CONCLUSIONS: Intensive PEG-ASNase therapy in the treatment of relapsed acute lymphoblastic leukemia reliably results in high-level serum PEG-ASNase activity, and asparagine depletion in serum and CSF is usually achieved. Incorporation of intensive PEG-ASNase in future trials for recurrent acute lymphoblastic leukemia is warranted.     

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.     

Controlled ovarian hyperstimulation: are we monitoring the appropriate sex-steroid hormones?

We prospectively evaluated the behavior of serum 17-hydroxyprogesterone (17-OHP), sex-steroid hormones, and C-reactive protein (CRP) levels in 27 patients during controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). While routine measurement of COH via serum 17-OHP may replace estradiol (E(2)) and progesterone levels, additional studies are needed to elucidate the ceiling level of serum 17-OHP beyond which intervention is required to prevent severe ovarian hyperstimulation syndrome.     

Zur Behandlung der Postanginösen Pyämie Mittels Jugularisunterbindung

Ohne Zusammenfassung     

Radiographic features of gastritis using the biphasic contrast technique

Gastritis is a group of inflammatory disorders that can be diagnosed radiographically. The optimum radiographic examination of the stomach is the biphasic-contrast technique, which includes the use of a medium-dense barium sulfate suspension and a hypotonic agent. Knowledge of the forms of gastritis, a careful application of biphasic-contrast technique, and a perceptive evaluation of information will help the radiologist to detect this entity with great frequency.     

Anteromedial portal versus transtibial drilling techniques in ACL reconstruction: a blinded cross-sectional study at two- to five-year follow-up

Drilling of the femoral tunnel with the transtibial (TT) technique is widely used in bone-patellar tendon-bone (BPTB) anterior cruciate ligament (ACL) reconstruction. Recent studies suggest higher knee stability with the use of the anteromedial portal (AMP). The purpose of this study was to compare functional and clinical outcomes of BPTB ACL reconstruction using the TT or the AMP technique for drilling the femoral tunnel. All ACL reconstructions between January 2003 and April 2006 were approached for eligibility. Forty-seven patients met inclusion criteria (21 TT group and 26 AMP group). Blinded assessments of IKDC score, knee stability and range of motion, one-leg hop test, mid-quadriceps circumference, VAS for satisfaction with surgery, Lysholm and Tegner scores, and SF-12 questionnaire were obtained for both groups. Data on preoperative and postoperative surgical timing were retrospectively reviewed through the charts. The AMP group demonstrated a significantly lower recovery time from surgery to walking without crutches (p < 0.01), to return to normal life (p < 0.03), to return jogging (p < 0.03), to return training (p < 0.03), and to return to play (p < 0.03). Knee stability values measured with KT-1000, Lachman test, pivot-shift sign, and objective IKDC score assessments were significantly better for the AMP compared to TT group (p < 0.002, p < 0.03, p < 0.02, p < 0.015, respectively). No differences were found for VAS for satisfaction with surgery, Lysholm, Tegner, and SF-12 between both groups. The use of the AMP technique significantly improved the anterior-posterior and rotational knee stability, IKDC scores, and recovery time from surgery compared to the TT technique.     

Impaired Fas-induced apoptosis of T lymphocytes in patients with abdominal aortic aneurysms

OBJECTIVE: Homeostasis of the immune system is maintained by apoptotic elimination of potentially pathogenic autoreactive lymphocytes. Emerging evidence shows that Fas-mediated apoptosis is impaired in activated lymphocytes from patients with autoimmune disease. The aim of this work was to assess apoptosis mediated by the cell death receptor Fas in peripheral T lymphocytes from patients with abdominal aortic aneurysms (AAA). METHODS: The apoptotic pathway was triggered by anti-Fas monoclonal antibodies in cultured and activated peripheral T-cell lines from 20 AAA patients with control groups of 15 patients with aortic atherosclerotic occlusive disease (AOD) and 25 healthy individuals. Cell survival and death (apoptosis) rate were assessed. RESULTS: Cross-linkage of Fas receptor exerted a strong apoptotic response on T cells from AOD patients and healthy controls, but a much less pronounced effect on T cells from AAA patients. The evaluation of cell survival rate showed a significantly higher percentage in AAA group (98.9% +/- 10.3%) than in the AOD subjects (58.9% +/- 15.2%) or the healthy group (59.4% +/- 12.9%; P < .001). Apoptosis assessment by annexin V and propidium iodide staining and flow cytometry showed similar results. The defect in AAA group was not due to decreased Fas expression, since Fas was expressed at normal levels. Moreover, it specifically involved the Fas system because cell death was induced in the normal way by methylprednisolone. Complementary DNA sequencing identified no causal Fas gene mutation, but two silent single nucleotide polymorphisms with higher frequency were found in the AAA group. CONCLUSIONS: Fas-induced apoptosis in activated T cells from AAA patients is impaired. This may disturb the normal down-regulation of the immune response and thus provide a new insight into possible mechanisms and routes in the pathogenesis of AAA.     

Routine Laboratory Testing Every 4 Versus Every 6 Weeks for Patients on Maintenance Hemodialysis: A Quality Improvement Project

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Guidance of percutaneous pulmonary biopsies with real-time CT fluoroscopy

OBJECTIVE: Clinical evaluation of computed tomography (CT) fluoroscopy and comparison with conventional CT guidance for monitoring of percutaneous pulmonary biopsy procedures. METHODS: Twenty CT-guided pulmonary biopsy procedures were conducted. The interventions have prospectively been performed either with CT fluoroscopy or with conventional CT guidance. About 120 kV and 50 mA with a frame-rate of eight images per second were used for CT fluoroscopy. Number of pleural needle passages, procedure times, radiation doses and histologic results were analyzed separately for both methods. RESULTS: Compared with conventional CT guidance, CT fluoroscopy was associated with less pleural needle passages (1.8+/-0.6 vs. 1.1+/-0.3; P=0.003, t-test) and procedure times were shorter than for conventional CT guidance (12.7+/-2.2 min vs. 26.7+/-16.4 min; P=0.02). Analysis of estimated patient related radiation exposure and histologic outcome showed no significant difference between conventional and fluoroscopic CT-guided procedures (P>0.05). CONCLUSION: CT fluoroscopy facilitates guidance of percutaneous pulmonary biopsy procedures. Compared with conventional CT assistance, procedure times are decreased and less pleural needle passages are required. While patient-related radiation exposure is similar, operator-related radiation exposure remains a disadvantage associated with CT fluoroscopy.