Standardization of evaluation method and prognostic significance of histological response to preoperative chemotherapy in high-grade non-round cell soft tissue sarcomas.

BACKGROUND: Preoperative chemotherapy is widely applied to high-grade localized soft tissue sarcomas (STSs); however, the prognostic significance of histological response to chemotherapy remains controversial. This study aimed to standardize evaluation method of histological response to chemotherapy with high agreement score among pathologists, and to establish a cut-off value closely related to prognosis. METHODS: Using data and specimens from the patients who had registered in the Japan Clinical Oncology Group study, JCOG0304, a phase II trial evaluating the efficacy of perioperative chemotherapy with doxorubicin (DOX) and ifosfamide (IFO), we evaluated histological response to preoperative chemotherapy at the central review board. RESULTS: A total of 64 patients were eligible for this study. The percentage of viable tumor area ranged from 0.1% to 97.0%, with median value of 35.7%. Regarding concordance proportion between pathologists, the weighted kappa coefficient (κ) score in all patients was 0.71, indicating that the established evaluation method achieved substantial agreement score. When the cut-off value of the percentage of the residual tumor area was set as 25%, the p-value for the difference in overall survival showed the minimum value. Hazard ratio of the non-responder with percentage of the residual tumor < 25%, to the responder was 4.029 (95% confidence interval 0.893-18.188, p = 0.070). CONCLUSION: The standardized evaluation method of pathological response to preoperative chemotherapy showed a substantial agreement in the weighted κ score. The evaluation method established here was useful for estimating of the prognosis in STS patients who were administered perioperative chemotherapy with DOX and IFO. TRIAL REGISTRATION: UMIN Clinical Trials Registry C000000096. Registered 30 August, 2005 (retrospectively registered).

Eco-Friendly, Simple, Fast, and Sensitive UPLC-MS/MS Method for Determination of Pexidartinib in Plasma and Its Application to Metabolic Stability.

Pexidartinib is the first drug approved by the U.S. Food and Drug Administration specifically to treat the rare joint tumor tenosynovial giant cell tumor. In the current study, a validated, selective, and sensitive UPLC-MS/MS assay was developed for the quantitative determination of pexidartinib in plasma samples using gifitinib as an internal standard (IS). Pexidartinib and IS were extracted by liquid-liquid extraction using methyl tert-butyl ether and separated on an acquity BEH C18 column kept at 40 °C using a mobile phase of 0.1% formic acid in acetonitrile: 0.1% formic acid in de-ionized water (70:30). The flow rate was 0.25 mL/min. Multiple reaction monitoring (MRM) was operated in electrospray (ESI)-positive mode at the ion transition of 418.06 > 165.0 for the analyte and 447.09 > 128.0 for the IS. FDA guidance for bioanalytical method validation was followed in method validation. The linearity of the established UPLC-MS/MS assay ranged from 0.5 to 1000 ng/mL with r > 0.999 with a limit of quantitation of 0.5 ng/mL. Moreover, the metabolic stability of pexidartinib in liver microsomes was estimated.

Therapeutic drug monitoring in oncology: International Association of Therapeutic Drug Monitoring and Clinical Toxicology consensus guidelines for imatinib therapy.

Although therapeutic drug monitoring (TDM) is an important tool in guiding drug dosing for other areas of medicine including infectious diseases, cardiology, psychiatry and transplant medicine, it has not gained wide acceptance in oncology. For imatinib and other tyrosine kinase inhibitors, a flat dosing approach is utilised for management of oral chemotherapy. There are many published studies examining the correlation of blood concentrations with clinical effects of imatinib. The International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) determined that there was a need to examine the published literature regarding utility of TDM in imatinib therapy and to develop consensus guidelines for TDM based on the available data. This article summarises the scientific evidence regarding TDM of imatinib, as well as the consensus guidelines developed by the IATDMCT.

Patient-reported outcomes for monitoring symptomatic toxicities in cancer patients treated with immune-checkpoint inhibitors: A Delphi study.

BACKGROUND: Immune-related adverse events (IrAEs) associated with the use of immune checkpoint inhibitors (ICIs) may not be fully covered by existing measures like the PRO-CTCAE™. Selecting PRO-CTCAE™ items for monitoring symptomatic adverse events is hindered by the heterogeneity and complexity of IrAEs, and no standardised selection process exists. We aimed to reach expert consensus on the PRO-CTCAE™ symptom terms relevant for cancer patients receiving ICIs and to gather preliminary expert opinions about additional symptom terms reflecting ICI symptomatic toxicities. Additionally, we gathered expert consensus about a core set of priority symptom terms for prospective surveillance and monitoring. DESIGN: This Delphi study involved an international panel of experts (n = 6 physicians; n = 3 nurses, n = 1 psychiatrist and n = 1 patient advocates). Experts prioritised the relevance and importance of symptom terms to monitor in patients treated with ICIs. RESULTS: Experts reached a consensus on the relevance of all (n = 80) PRO-CTCAE™ Symptom Terms. Consensus on the importance of these symptom terms for prospective monitoring in patients receiving ICIs was reached for 81% (n = 65) of these terms. Additional symptoms terms (n = 56) were identified, with a consensus that 84% (47/56) of these additional symptom terms should also be considered when monitoring symptomatic IrAEs. CONCLUSION: This study identified a prioritised list of symptom terms for prospective surveillance for symptomatic IrAEs in patients receiving ICI treatment. Our results indicate the need to strengthen the validity of PRO measures used to monitor patients receiving ICIs. While these results provided some support for the content validity of the PRO CTCAE™ and resulted in a preliminary set of salient symptomatic adverse events related to the use of ICIs, broader international agreement and patient involvement are needed to further validate our initial findings.

The First WHO International Standard for Adalimumab: Dual Role in Bioactivity and Therapeutic Drug Monitoring.

The expanded availability of adalimumab products continues to widen patient access and reduce costs with substantial benefit to healthcare systems. However, the long-term success of these medicines is highly dependent on maintaining consistency in quality, safety and efficacy while minimizing any risk of divergence during life-cycle management. In recognition of this need and demand from global manufacturers, the World Health Organization (WHO) Expert Committee on Biological standardization established the WHO 1st International standard (IS) for Adalimumab (coded 17/236) in October 2019 with a defined unitage ascribed to each of the individual bioactivities evaluated in the study namely, TNF-α binding, TNF-α neutralization, complement dependent cytotoxicity and antibody-dependent cellular cytotoxicity. For development of the IS, two candidate standards were manufactured as per WHO recommendations. Analysis of extensive datasets generated by testing of a common set of samples including the candidate standards by multiple stakeholders including regulatory agencies using their own qualified assays in a large international collaborative study showed comparable biological activity for the tested candidates for the different activities. Use of a common standard significantly decreased the variability of bioassays and improved agreement in potency estimates. Data from this study clearly supports the utility of the IS as an important tool for assuring analytical assay performance, for bioassay calibration and validation, for identifying and controlling changes in bioactivity during life-cycle management and for global harmonization of adalimumab products. In addition, in a separate multi-center study which included involvement of hospital and clinical diagnostic laboratories, the suitability of the adalimumab IS for therapeutic drug monitoring assays was examined by analysis of data from testing of a common blind coded panel of adalimumab spiked serum samples representative of the clinical scenario along with the IS and in-house standards in diverse immunoassays/platforms. Both commercially available and in-house assays that are routinely used for assessing adalimumab trough levels were included. Excellent agreement in estimates for adalimumab content in the spiked samples was observed regardless of the standard or the method with inter-laboratory variability also similar regardless of the standard employed. This data, for the first time, provides support for the extended applicability of the IS in assays in use for therapeutic drug monitoring based on the mass content of the IS. The adalimumab IS, in fulfilling clinical demand, can help toward standardizing and harmonizing clinical monitoring assays for informed clinical decisions and/or personalized treatment strategies for better patient outcomes. Collectively, a significant role for the adalimumab IS in assuring the quality, safety and efficacy of adalimumab products globally is envisaged.

Factors associated with reduced infliximab exposure in the treatment of pediatric autoimmune disorders: a cross-sectional prospective convenience sampling study.

BACKGROUND: Inadequate systemic exposure to infliximab (IFX) is associated with treatment failure. This work evaluated factors associated with reduced IFX exposure in children with autoimmune disorders requiring IFX therapy. METHODS: In this single-center cross-sectional prospective study IFX trough concentrations and anti-drug antibodies (ADAs) were measured in serum from children diagnosed with inflammatory bowel disease (IBD) (n = 73), juvenile idiopathic arthritis (JIA) (n = 16), or uveitis (n = 8) receiving maintenance IFX infusions at an outpatient infusion clinic in a tertiary academic pediatric hospital. IFX concentrations in combination with population pharmacokinetic modeling were used to estimate IFX clearance. Patient demographic and clinical data were collected by chart review and evaluated for their relationship with IFX clearance. RESULTS: IFX trough concentrations ranged from 0 to > 40 µg/mL and were 3-fold lower in children with IBD compared to children with JIA (p = 0.0002) or uveitis (p = 0.001). Children with IBD were found to receive lower IFX doses with longer dosing intervals, resulting in dose intensities (mg/kg/day) that were 2-fold lower compared to children with JIA (p = 0.0002) or uveitis (p = 0.02). Use of population pharmacokinetic analysis to normalize for variation in dosing practices demonstrated that increased IFX clearance was associated with ADA positivity (p = 0.004), male gender (p = 0.02), elevated erythrocyte sedimentation rate (ESR) (p = 0.02), elevated c-reactive protein (CRP) (p = 0.001), reduced serum albumin concentrations (p = 0.0005), and increased disease activity in JIA (p = 0.009) and IBD (p ≤ 0.08). No significant relationship between diagnosis and underlying differences in IFX clearance was observed. Multivariable analysis by covariate population pharmacokinetic modeling confirmed increased IFX clearance to be associated with anti-IFX antibody positivity, increased ESR, and reduced serum albumin concentrations. CONCLUSIONS: Enhanced IFX clearance is associated with immunogenicity and inflammatory burden across autoimmune disorders. Higher systemic IFX exposures observed in children with rheumatologic disorders are driven primarily by provider drug dose and interval selection, rather than differences in IFX pharmacokinetics across diagnoses. Despite maintenance IFX dosing at or above the standard recommended range for IBD (i.e., 5 mg/kg every 8 weeks), the dosing intensity used in the treatment of IBD is notably lower than dosing intensities used to treat JIA and uveitis, and may place some children with IBD at risk for suboptimal maintenance IFX exposures necessary for treatment response.

Determination of the Peptide AWRK6 in Rat Plasma by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) and Its Application to Pharmacokinetics.

AWRK6 was a synthesized peptide developed based on the natural occurring peptide dybowskin-2CDYa, which was discovered in frog skin in our previous study. Here, a quantitative determination method for AWRK6 analysis in rat plasma by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) was established and validated following U.S. FDA guidelines. A combination of plasma precipitation and liquid-liquid extraction was applied for the extraction. For pharmacokinetics study, the rats were administrated with AWRK6 via intraperitoneal and intravenous injection. The prepared plasma samples were separated on an ODS column and analyzed by tandem MS using precursor-to-product ion pairs of m/z: 533.4→84.2 for AWRK6 and m/z: 401.9→101.1 for internal standard Polymyxin B sulfate in multiple reaction monitoring mode. AWRK6 concentrations in rat plasma peaked at about 1.2 h after intraperitoneal injections at 2.35, 4.7 and 9.4 mg/kg bodyweight. The terminal half-life was around 2.8 h. The absolute bioavailability of AWRK6 was 50% after 3 doses via injection, and the apparent volume of distribution was 4.884 ± 1.736 L. The obtained determination method and pharmacokinetics profiles of AWRK6 provides a basis for further development, and forms a benchmark reference for peptide quantification.

Fingerstick Glucose Monitoring in Veterans Affairs Nursing Home Residents with Diabetes Mellitus.

BACKGROUND/OBJECTIVE: Guidelines recommend less intensive glycemic treatment and less frequent glucose monitoring for nursing home (NH) residents. However, little is known about the frequency of fingerstick (FS) glucose monitoring in this population. Our objective was to examine the frequency of FS glucose monitoring in Veterans Affairs (VA) NH residents with diabetes mellitus, type II (T2DM). DESIGN AND SETTING: National retrospective cohort study in 140 VA NHs. PARTICIPANTS: NH residents with T2DM and older than 65 years admitted to VA NHs between 2013 and 2015 following discharge from a VA hospital. MEASUREMENTS: NH residents were classified into five groups based on their highest hypoglycemia risk glucose-lowering medication (GLM) each day: no GLMs; metformin only; sulfonylureas; long-acting insulin; and any short-acting insulin. Our outcome was a daily count of FS measurements. RESULTS: Among 17,474 VA NH residents, mean age was 76 (standard deviation (SD) = 8) years and mean hemoglobin A1c was 7.6% (SD = 1.5%). On day 1 after NH admission, 49% of NH residents were on short-acting insulin, decreasing slightly to 43% at day 90. Overall, NH residents had an average of 1.9 (95% confidence interval (CI) = 1.8-1.9) FS measurements on NH day 1, decreasing to 1.4 (95% CI = 1.3-1.4) by day 90. NH residents on short-acting insulin had the most frequent FS measurements, with 3.0 measurements (95% CI = 2.9-3.0) on day 1, decreasing to 2.6 measurements (95% CI = 2.5-2.7) by day 90. Less frequent FS measurements were seen for NH residents receiving long-acting insulin (2.1 (95% CI = 2.0-2.2) on day 1) and sulfonylureas (1.7 (95% CI = 1.5-1.8) on day 1). Even NH residents on metformin monotherapy had 1.1 (95% CI = 1.1-1.2) measurements on day 1, decreasing to 0.5 (95% CI = 0.4-0.6) measurements on day 90. CONCLUSION: Although guidelines recommend less frequent glucose monitoring for NH residents, we found that many VA NH residents receive frequent FS monitoring. Given the uncertain benefits and potential for substantial patient burdens and harms, our results suggest decreasing FS monitoring may be warranted for many low hypoglycemia risk NH residents.

A best-worst scaling experiment to identify patient-centered claims-based outcomes for evaluation of pediatric antipsychotic monitoring programs.

OBJECTIVE: This article employs a best-worst scaling (BWS) experiment to identify the claims-based outcomes that matter most to patients and other relevant parties when evaluating pediatric antipsychotic monitoring programs in the United States. DATA SOURCES: Patients and relevant parties, with pediatric antipsychotic oversight and treatment experience, completed a BWS experiment, including policymakers (n = 31), foster care alumni (n = 28), caseworkers (n = 23), prescribing clinicians (n = 32), and caregivers (n = 18). STUDY DESIGN: Respondents received surveys with a scenario on antipsychotic monitoring programs and ranked 11 candidate claims-based outcomes as most and least important for program evaluation. DATA ANALYSIS: Stratified by respondent group, best-worst scores were calculated to identify the relative importance of the claims-based outcomes. A conditional logit examined whether candidate outcomes for safety, quality, and unintended consequences were preferred over reduction in antipsychotic treatment, the outcome used most often to evaluate antipsychotic monitoring programs. PRINCIPAL FINDINGS: Safety indicators (eg, antipsychotic co-pharmacy, cross-class polypharmacy, higher than recommended doses) ranked among the top three candidate outcomes across respondent groups and were an important complement to antipsychotic treatment reduction. Foster care alumni prioritized "antipsychotic treatment reduction" and "increased psychosocial treatment." Caseworkers, prescribers, and caregivers prioritized "increased follow-up after treatment initiation." Potential unintended consequences of an antipsychotic monitoring program ranked lowest, including increased use of other psychotropic medication classes (as a substitute), increased psychiatric hospital stays, and increased emergency room utilization. Results of the conditional logit model found only caregivers significantly preferred other indicators over antipsychotic treatment reduction, preferring improvements in follow-up care (5.78) and psychosocial treatment (4.53) and reduction in prescriptions of higher than recommended doses (3.64). CONCLUSIONS: The BWS experiment supported rank ordering of candidate claims-based outcomes demonstrating the opportunity for future studies to align outcomes used in antipsychotic monitoring program evaluations with community preferences, specifically by diversifying metrics to include safety and quality indicators.

Comparison of Two Analytical Methods for Busulfan Therapeutic Drug Monitoring.

BACKGROUND AND OBJECTIVES: Busulfan (Bu) is an old drug, but is still well recommended as an alkylating agent during conditioning therapy, before hematopoietic stem cell transplantation. Although its dose administration is standardized and based on patient weight, therapeutic drug monitoring is required in order to maintain its exposure [as area under the concentration-time curve (AUC) from 0 to infinity AUC0-∞] within a narrow therapeutic range and, if necessary, to adjust the dose with as short a lead time as possible. The aim of the study is to evaluate the agreement (as calculated AUC) between a gold standard analytical method and a new one that is faster and easier. METHODS: We analyzed 221 plasma samples from 37 children (0.25-16 years; 4-62.5 kg) and 11 adults (21-59 years; 45-80 kg), corresponding to 52 AUC values (ng h/mL). The drug exposure was calculated, simultaneously, by two validated analytical methods. The reference method was a high-performance liquid chromatography (HPLC) assay combined with an ultraviolet detector (UV). The test method had a triple quadrupole mass spectrometer (MS) as detector; the clean-up procedures of the samples were different and faster. RESULTS: The agreement between the two methods (reference and test) was evaluated in terms of Bu exposure differences based on Lin's concordance correlation coefficient (CCC) and represented by the Bland-Altman plot. The CCC between the AUC of the two methods was excellent (0.868; 95% CI: 0.802-0.935). The precision of the measures (expressed by Pearson's italic "r") was 0.872, and the accuracy (accounted by the bias correction factor) was 0.996. CONCLUSIONS: We can conclude that the HPLC-MS/MS assay represents a very good alternative to the reference.

Evaluation of Hepatitis B Reactivation Among Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors.

Hepatitis B reactivation (HBVr) in cancer patients is a well-established complication due to chemotherapy-induced immunosuppression. Studies have reported HBVr associated with immunosuppressive medications, such as rituximab, methotrexate, and high dose steroids. There are different risks for different types of chemotherapy with rituximab carrying one of the highest risks for hepatitis B reactivation. Tyrosine kinase inhibitors (TKIs) are the standard of care in patients with chronic myeloid leukemia (CML). The risk of HBVr in chronic myeloid leukemia has been reported in many studies, but to this date, there are no clear guidelines or recommendations regarding screening and monitoring of HBV in CML patients receiving TKIs. We conducted this review to identify the risk of HBVr in patients with CML who are treated with tyrosine kinase inhibitors. We recommend testing for HBV status in patients who are to be treated with TKIs and to consider giving prophylaxis in those who are positive for HBsAg at baseline. More studies are needed to assess the risk of reactivation in patients with Hepatitis B core antibody positive receiving TKIs. Currently, monitoring such patients for reactivation may be the best strategy.

Sensitive Analysis of Idarubicin in Human Urine and Plasma by Liquid Chromatography with Fluorescence Detection: An Application in Drug Monitoring.

A new approach for the sensitive, robust and rapid determination of idarubicin (IDA) in human plasma and urine samples based on liquid chromatography with fluorescence detection (LC-FL) was developed. Satisfactory chromatographic separation of the analyte after solid-phase extraction (SPE) was performed on a Discovery HS C18 analytical column using a mixture of acetonitrile and 0.1% formic acid in water as the mobile phase in isocratic mode. IDA and daunorubicin hydrochloride used as an internal standard (I.S.) were monitored at the excitation and emission wavelengths of 487 and 547 nm, respectively. The method was validated according to the FDA and ICH guidelines. The linearity was confirmed in the range of 0.1-50 ng/mL and 0.25-200 ng/mL, while the limit of detection (LOD) was 0.05 and 0.125 ng/mL in plasma and urine samples, respectively. The developed LC-FL method was successfully applied for drug determinations in human plasma and urine after oral administration of IDA at a dose of 10 mg to a patient with highly advanced alveolar rhabdomyosarcoma (RMA). Moreover, the potential exposure to IDA present in both fluids for healthcare workers and the caregivers of patients has been evaluated. The present LC-FL method can be a useful tool in pharmacokinetic and clinical investigations, in the monitoring of chemotherapy containing IDA, as well as for sensitive and reliable IDA quantitation in biological fluids.

Co-trimoxazole induced hyperkalemia and potassium monitoring in hospitalized patients.

Background Co-trimoxazole is an antibiotic combination used for the treatment of Pneumocystis jirovecii pneumonia, amongst others. Co-trimoxazole is known to increase serum potassium. For this reason, Dutch guidelines advise serum potassium monitoring in high-risk patients. Objective This study aimed to determine average serum potassium rise after administration of intravenous co-trimoxazole in hospitalized patients, compared to intravenous ceftriaxone. This study also aimed to determine adherence to Dutch guidelines by measuring the incidence of serum potassium monitoring in these patients. Setting Data was collected retrospectively from patients in five departments of the Canisius Wilhelmina Hospital, a teaching hospital in Nijmegen, the Netherlands. Method Data was collected and compared from patients that received intravenous co-trimoxazole (n = 66) and intravenous ceftriaxone (n = 132) in the period of November 2008-November 2017. For each patient using co-trimoxazole, two patients using ceftriaxone were included in a paired fashion. Baseline and follow-up potassium were collected, if available. Additionally, it was tested if serum potassium was measured around the initiation of antibiotic therapy. Main outcome measure Changes in serum potassium where obtainable in 30 patients using cotrimoxazole and 40 patients using ceftriaxone. When compared to ceftriaxone, administration of intravenous co-trimoxazole was associated with a significant mean increase in serum potassium (+0.55 mmol/l, 95% CI 0.29-0.80, p < 0.001). After correction for confounders (baseline potassium, estimated glomerular filtration rate 30 ≤ 60, the presence of haematological malignancies and the usage of corticosteroids), this effect shrunk noticeably, but remained significant (+0.28 mmol/l, 95% CI 0.03-0.53, p = 0.031). Results The incidence of hyperkalemia at follow-up was 20% in the cotrimoxazole group, compared to 5% in the ceftriaxone group. Despite this, serum potassium was often not measured in patients using intravenous cotrimoxazole, being 76% at baseline and 55% in the period of 48-120 h after antibiotic therapy initiation, compared to 87% and 34% in the ceftriaxone group respectively. Conclusion Adherence to Dutch guidelines was poor as serum potassium monitoring was often not performed. As intravenous co-trimoxazole usage is associated with a significant increase in mean serum potassium, monitoring is strongly recommended.

Practical Laboratory Tools for Monitoring of BCR-ABL1 Transcripts and Tyrosine Kinase (TK) Domain Mutations in Chronic Myeloid Leukemia Patients Undergoing TK Inhibitor Therapy: A Single-Center Experience in Thailand.

OBJECTIVE: The genetic hallmark of CML is known as the appearance of t(9;22)(q34.1;q11.2) (BCR-ABL1) which is present in more than 95% of cases. Here, we demonstrated practical laboratory tools for monitoring of BCR-ABL1 transcripts in chronic myeloid leukemia patients undergoing TK inhibitor therapy. METHODS: Real time quantitative PCR and direct sequencing were performed for monitoring of BCR-ABL1 transcripts in 245 treated CML. RESULTS: At month 3 after first time point of monitoring, we found that 89% (218/245), 2% (5/245), and 9% (22/245) of patients are determined as optimal, warning, and failure response, respectively. The responses to TKI were slightly decreased at months 6 as following 73% optimal (180/245), 18% warning (43/245), and 9% failure response (22/245). Additionally, responses to TKI were gradually decreased at month 12 after first time point of monitoring as following 65% optimal (160/245), 13% warning (31/245), and 22% failure (54/245). We could detect 20% (49/245) of patients positive for BCR-ABL1 TKD mutations. Interestingly, one third (17 of 49) of TKD mutated cases were positive for compound/polyclonal mutation patterns. While major molecular response were observed in the majority of patients without TKD mutation, resistant to TKI were detected in patients with T315I mutation (n = 9; % mean IS = 8.1510, % median IS = 9.7000), compound/polyclonal mutations with T315I (n = 9; % mean IS = 13.0779, % median IS = 5.404), and other TKD mutations (n = 14; % mean IS = 8.1416, % median IS = 1.060), respectively. Conlusion: These practical laboratory techniques provided a more comprehensive understanding of CML progression during drug therapy and could be of benefit in earlier prognosis.

[Direct oral anticoagulants: In which indications? Which one to prescribe? For or against their use in frail patients and in atypical cases? Which monitoring and management haemorrhage complications?] / Anticoagulants oraux directs : dans quelles indications ? Lequel prescrire ? Pour ou contre chez les personnes fragiles et dans les situations atypiques ? Quelle surveillance et gestion des accidents hémorragiques ?

Since their approval, the direct oral anticoagulants have been widely used in the management of venous thromboembolism, for stroke and systemic embolism prevention in non valvular atrial fibrillation, and in venous thromboembolism prophylaxis after surgical hip or knee replacement. Because they are easy to use, with oral fixed doses and no biological monitoring need, they are more and more prescribed. New indications are rising in cancer associated thrombosis in France beyond the 6 first months of treatment, and to prevent cardiovascular events after an acute coronary syndrome, or in stable coronary or peripheral arterial disease in Europe. The efficacity and safety of direct oral anticoagulants in frail patients or in unusual pathological contexts are not entirely known, but further data are coming and will probably bring new answers.

Development of a precise quantitative method for monitoring sirolimus in whole blood using LC/ESI-MS/MS.

Sirolimus is used on patients after solid organ transplantation and on lymphangioleiomyomatosis (LAM) patients, and therapeutic drug monitoring is required in clinical practice. We have previously reported an accurate method for quantitative determination of sirolimus, but its sample preparation step was complicated. In this study, we developed a modified liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) method for sirolimus quantification. A supported liquid extraction cartridge was used to purify sirolimus from whole blood and ion suppression was mostly prevented. The validation results met the acceptance criteria. This method was compared with the antigen conjugated magnetic immunoassay (ACMIA) and our previously reported method, using whole blood samples from LAM patients. Comparison of the Bland-Altman plots of the currently developed method and the previous method revealed no significant difference between the two methods (mean bias, -2.02%; 95% CI, -7.81-3.78). The values obtained using ACMIA were significantly higher than those obtained using the current method by 13.87% (95% CI, 6.49-21.25) owing to cross-reactivity. The degrees of cross reactivities in LAM patients and in organ transplant patients were similar, and our LC/ESI-MS/MS method precisely measured the blood concentrations of sirolimus.

Population pharmacokinetics of busulfan in Saudi pediatric patients undergoing hematopoietic stem cell transplantation.

Background Busulfan is an antineoplastic drug that is used widely as part of a conditioning regimen in pediatric patients undergoing hematopoietic stem cell transplantation. It has a narrow therapeutic index and highly variable pharmacokinetics; therefore therapeutic drug monitoring is recommended to optimize busulfan dosing. Objective To study the population pharmacokinetics of busulfan in Saudi pediatric patients to optimize its dosing. Settings King Abdullah Specialist Children's Hospital in Riyadh, Saudi Arabia. Methods This pharmacokinetic observational study was conducted between January 2016 and December 2018. All pediatric patients receiving IV busulfan and undergoing routine therapeutic drug monitoring were included. Population pharmacokinetics modeling was conducted using Monolix2019R1. Pharmacokinetic data of busulfan in children. Results The study included 59 patients and 513 samples. The mean ± SD age was 6.10 ± 3.17 years, and the dose administered was 0.994 ± 0.15 mg/kg. The mean ± SD Cmax and area under the curve (AUC) were 900.60 ± 402.8 ng/mL and 1031.14 ± 300.75 µM min, respectively. Based on our simulations, the European Medicines Agency recommended dose were adequate for most patient's groups to achieve the conventional target of an AUC0-tau of 900-1350 µM min. For patients in the lower weight group < 9 kg, higher doses were need at 1.2 mg/kg. With regards to the newly proposed target of AUC 78-101 mg h/mL, all of the doses we tested had low probability of achieving it. Conclusions Most of our patients had less than a proportional increase in busulfan concentration suggesting autoinduction. The high interindividual variability and autoinduction make dose adjustments challenging and AUC at steady state difficult to predict from the first dose. One approach to improve dose predictions is to use Bayesian dosing software. Based on our simulations, the European Medicines Agency recommended doses were adequate for most patient groups, except those in the lower (< 9 kg) and higher weight groups (> 34 kg).

When is it OK to Stop Anti-Programmed Death 1 Receptor (PD-1) Therapy in Metastatic Melanoma?

Systemic therapy for metastatic melanoma has been revolutionized over the past decade with the development of highly effective immune checkpoint inhibition, specifically anti-Programmed Death 1 receptor (PD-1) therapy. However, even though one-third of patients will have durable response to single-agent or combination therapy, the optimal duration of therapy is unknown. Identifying the optimal duration of therapy is important, as exposure to anti-PD-1 therapy increases the risk of developing immune-mediated toxicities that can have significant morbidity and are, at times, fatal. It has long been understood that patients with complete responses to high-dose interleukin-2 and ipilimumab typically maintain their responses after a brief treatment course; thus, it is important to better understand the data to help understand the optimal management of melanoma patients treated with anti-PD-1 therapy. The clinical data with anti-PD-1-based therapy and published data on the duration of therapy suggest that patients may not require a full 2 years of anti-PD-1 therapy and that the risk of toxicity may be mitigated by further understanding the mechanisms and kinetics of response to therapy. Although novel markers to help guide therapeutic decision making are under investigation, there is an ongoing need to improve our tools to monitor response to therapy and disease activity.