Olaparib treatment significantly improved objective response rate (primary end point) and progression-free survival versus nonplatinum chemotherapy in patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer in the open-label phase III SOLO3 trial (ClinicalTrials.gov identifier: NCT02282020). We report final overall survival (OS; prespecified secondary end point), post hoc OS analysis by number of previous chemotherapy lines, and exploratory BRCA reversion mutation analysis. Two hundred sixty-six patients were randomly assigned 2:1 to olaparib tablets (300 mg twice daily; n = 178) or physician's choice of single-agent nonplatinum chemotherapy (pegylated liposomal doxorubicin, paclitaxel, gemcitabine, or topotecan; n = 88). OS was similar with olaparib versus chemotherapy (hazard ratio [HR], 1.07 [95% CI, 0.76 to 1.49]; P = .71, median 34.9 and 32.9 months, respectively, full analysis set). OS with olaparib was favorable in patients with two previous chemotherapy lines (HR, 0.83 [olaparib v chemotherapy] [95% CI, 0.51 to 1.38]; median 37.9 v 28.8 months); however, a potential detrimental effect was seen in patients with at least three previous chemotherapy lines (HR, 1.33 [95% CI, 0.84 to 2.18]; median 29.9 v 39.4 months). BRCA reversion mutations might have contributed to this finding. No patient randomly assigned to olaparib with a BRCA reversion mutation detected at baseline (6 of 170 [3.5%]) achieved an objective tumor response.

• MeSH
• Deoxycytidine analogs & derivatives   administration & dosage   MeSH
• Progression-Free Survival MeSH
• Adult MeSH
• Doxorubicin analogs & derivatives   administration & dosage   MeSH
• Phthalazines * therapeutic use   adverse effects   administration & dosage   MeSH
• Gemcitabine MeSH
• Middle Aged MeSH
• Humans MeSH
• Neoplasm Recurrence, Local * drug therapy   MeSH
• Ovarian Neoplasms * drug therapy   genetics   mortality   pathology   MeSH
• Paclitaxel administration & dosage   MeSH
• Poly(ADP-ribose) Polymerase Inhibitors * therapeutic use   adverse effects   MeSH
• Piperazines * therapeutic use   adverse effects   administration & dosage   MeSH
• Polyethylene Glycols administration & dosage   MeSH
• BRCA1 Protein genetics   MeSH
• BRCA2 Protein genetics   MeSH
• Antineoplastic Combined Chemotherapy Protocols * therapeutic use   adverse effects   MeSH
• Aged MeSH
• Topotecan administration & dosage   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

Pegunigalsidase alfa, a PEGylated α-galactosidase A enzyme replacement therapy (ERT) for Fabry disease, has a longer plasma half-life than other ERTs administered intravenously every 2 weeks (E2W). BRIGHT (NCT03180840) was a phase III, open-label study in adults with Fabry disease, previously treated with agalsidase alfa or beta E2W for ≥3 years, who switched to 2 mg/kg pegunigalsidase alfa every 4 weeks (E4W) for 52 weeks. Primary objective assessed safety, including number of treatment-emergent adverse events (TEAEs). Thirty patients were enrolled (24 males); 23 previously received agalsidase beta. Pegunigalsidase alfa plasma concentrations remained above the lower limit of quantification throughout the 4-week dosing interval. Thirty-three of 182 TEAEs (in 9 patients) were considered treatment-related; all were mild/moderate. No patients developed de novo anti-drug antibodies (ADAs). In the efficacy analysis (n = 29), median (inter-quartile range) eGFR change from baseline over 52 weeks was -1.9 (-5.9; 1.8) mL/min/1.73 m2 (n = 28; males [n = 22]: -2.4 [-5.2; 3.2]; females [n = 6]: -0.7 [-9.2; 2.0]). Overall, median eGFR slope was -1.9 (-8.3; 1.9) mL/min/1.73 m2/year (ADA-negative [n = 20]: -1.2 [-6.4; 2.6]; ADA-positive [n = 9]: -8.4 [-11.6; -1.0]). Lyso-Gb3 concentrations were low and stable in females, with a slight increase in males (9/24 ADA-positive). The BRIGHT study results suggest that 2 mg/kg pegunigalsidase alfa E4W is tolerated well in stable adult patients with Fabry disease. Due to the low number of patients in this study, more research is needed to demonstrate the effects of pegunigalsidase alfa given E4W. Further evidence, outside of this clinical trial, should be factored in for physicians to prolong the biweekly ERT intervals to E4W. TAKE-HOME MESSAGE: Treatment with 2 mg/kg pegunigalsidase alfa every 4 weeks could offer a new treatment option for patients with Fabry disease.

• MeSH
• alpha-Galactosidase * administration & dosage   therapeutic use   MeSH
• Adult MeSH
• Enzyme Replacement Therapy * methods   MeSH
• Fabry Disease * drug therapy   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Polyethylene Glycols administration & dosage   MeSH
• Recombinant Proteins * administration & dosage   therapeutic use   MeSH
• Drug Administration Schedule MeSH
• Aged MeSH
• Sphingolipids blood   MeSH
• Trihexosylceramides blood   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH

The utilization of 3D printing- digital light processing (DLP) technique, for the direct fabrication of microneedles encounters the problem of drug solubility in printing resin, especially if it is predominantly composed of water. The possible solution how to ensure ideal belonging of drug and water-based printing resin is its pre-formulation in nanosuspension such as nanocrystals. This study investigates the feasibility of this approach on a resin containing nanocrystals of imiquimod (IMQ), an active used in (pre)cancerous skin conditions, well known for its problematic solubility and bioavailability. The resin blend of polyethylene glycol diacrylate and N-vinylpyrrolidone, and lithium phenyl-2,4,6-trimethylbenzoylphosphinate as a photoinitiator, was used, mixed with IMQ nanocrystals in water. The final microneedle-patches had 36 cylindrical microneedles arranged in a square grid, measuring approximately 600 μm in height and 500 μm in diameter. They contained 5wt% IMQ, which is equivalent to a commercially available cream. The homogeneity of IMQ distribution in the matrix was higher for nanocrystals compared to usual crystalline form. The release of IMQ from the patches was determined ex vivo in natural skin and revealed a 48% increase in efficacy for nanocrystal formulations compared to the crystalline form of IMQ.

• MeSH
• Printing, Three-Dimensional * MeSH
• Administration, Cutaneous MeSH
• Imiquimod * chemistry   administration & dosage   MeSH
• Needles * MeSH
• Skin Absorption MeSH
• Skin metabolism   MeSH
• Drug Delivery Systems instrumentation   MeSH
• Microinjections instrumentation   MeSH
• Nanoparticles * chemistry   administration & dosage   MeSH
• Polyethylene Glycols chemistry   administration & dosage   MeSH
• Povidone chemistry   MeSH
• Solubility * MeSH
• Drug Liberation MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH

Koloskopické vyšetření je klíčová metoda pro prevenci, diagnostiku i léčbu onemocnění tlustého střeva. Součástí koloskopického vyšetření je příprava střeva před samotným zákrokem, spočívající ve vyprázdnění střeva pomocí perorálně užívaných lavážujících látek a s tím související přechodná změna diety. Tato příprava může u pacientů s diabetes mellitus vést k rozkolísání glykemie a riziku hypoglykemie. Kazuistika popisuje případ pacienta s diabetes mellitus 1. typu léčeného pomocí hybridního uzavřeného okruhu, který v rámci přípravy na koloskopické vyšetření využíval na základě dat z kontinuální monitorace glykemie sáčky s 5 gramy sacharózy k doplnění energie a stabilizaci glykemie. Glykemie se v průběhu přípravy pohybovaly

Colonoscopy is a key method for preventing, diagnosing, and treating colon diseases. The colonoscopic examination includes preparing the colon before the procedure, which involves emptying the bowel with orally administered lavage agents and the associated temporary change in diet. This preparation can lead to glycemic fluctuations and the risk of hypoglycemia in patients with diabetes mellitus. This case report describes the case of a patient with type 1 diabetes mellitus treated with a hybrid closed-loop system who used 5 grams of sucrose sachets during colonoscopic preparation to replenish energy and stabilize glucose based on continuous glucose monitoring data. Glycemia during preparation kept within recommended values 3.9-10.0 mmol/l.

• MeSH
• Defecation drug effects   MeSH
• Diabetes Mellitus, Type 1 * complications   MeSH
• Hypoglycemia prevention & control   MeSH
• Colonoscopy * adverse effects   MeSH
• Colorectal Neoplasms prevention & control   MeSH
• Diabetes Complications prevention & control   MeSH
• Blood Glucose analysis   MeSH
• Middle Aged MeSH
• Humans MeSH
• Polyethylene Glycols administration & dosage   MeSH
• Preoperative Care methods   MeSH
• Glycemic Control methods   MeSH
• Sucrose administration & dosage   MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Publication type
• Case Reports MeSH

Interferon-based therapies, such as ropeginterferon alfa-2b have emerged as promising disease-modifying agents for myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET). Current ET treatments aim to normalize hematological parameters and reduce the thrombotic risk, but they do not modify the natural history of the disease and hence, have no impact on disease progression. Ropeginterferon alfa-2b (trade name BESREMi®), a novel, monopegylated interferon alfa-2b with an extended administration interval, has demonstrated a robust and sustained efficacy in polycythemia vera (PV) patients. Given the similarities in disease pathophysiology and treatment goals, ropeginterferon alfa-2b holds promise as a treatment option for ET. The ROP-ET trial is a prospective, multicenter, single-arm phase III study that includes patients with ET who are intolerant or resistant to, and/or are ineligible for current therapies, such as hydroxyurea (HU), anagrelide (ANA), busulfan (BUS) and pipobroman, leaving these patients with limited treatment options. The primary endpoint is a composite response of hematologic parameters and disease-related symptoms, according to modified European LeukemiaNet (ELN) criteria. Secondary endpoints include improvements in symptoms and quality of life, molecular response and the safety profile of ropeginterferon alfa-2b. Over a 3-year period the trial assesses longer term outcomes, particularly the effects on allele burden and clinical outcomes, such as disease-related symptoms, vascular events and disease progression. No prospective clinical trial data exist for ropeginterferon alfa-2b in the planned ET study population and this study will provide new findings that may contribute to advancing the treatment landscape for ET patients with limited alternatives. TRIAL REGISTRATION: EU Clinical Trials Register; EudraCT, 2023-505160-12-00; Registered on October 30, 2023.

• MeSH
• Adult MeSH
• Thrombocythemia, Essential * drug therapy   MeSH
• Interferon alpha-2 * therapeutic use   adverse effects   MeSH
• Interferon-alpha * therapeutic use   adverse effects   MeSH
• Clinical Trials, Phase III as Topic MeSH
• Middle Aged MeSH
• Humans MeSH
• Multicenter Studies as Topic MeSH
• Polyethylene Glycols * therapeutic use   adverse effects   administration & dosage   MeSH
• Prospective Studies MeSH
• Recombinant Proteins * therapeutic use   adverse effects   administration & dosage   MeSH
• Aged MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial Protocol MeSH

• MeSH
• Medical History Taking MeSH
• Defecation physiology   MeSH
• Diagnosis, Differential MeSH
• Child MeSH
• Fecal Incontinence classification   MeSH
• Humans MeSH
• Manometry methods   MeSH
• Polyethylene Glycols administration & dosage   MeSH
• Laxatives administration & dosage   classification   MeSH
• Age Factors MeSH
• Constipation * diagnosis   diet therapy   etiology   drug therapy   pathology   therapy   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Publication type
• Review MeSH

BACKGROUND AND OBJECTIVES: The pharmacokinetics of polyethylene glycol-conjugated asparaginase (PEG-ASNase) are characterized by an increase in elimination over time, a marked increase in ASNase activity levels from induction to reinduction, and high inter- and intraindividual variability. A population pharmacokinetic (PopPK) model is required to estimate individual dose intensity, despite gaps in monitoring compliance. METHODS: In the AIEOP-BFM ALL 2009 trial, two PEG-ASNase administrations (2500 U/m2 intravenously) during induction (14-day interval) and one administration during reinduction were administered in children with acute lymphoblastic leukemia. ASNase activity levels were monitored weekly. A PopPK model was used for covariate modeling and external validation. The predictivity of the model in case of missing data was tested for observations, as well as for the derived parameters of the area under the concentration time curve (AUC0-∞) and time above different thresholds. RESULTS: Compared to the first administration in induction (1374 patients, 6069 samples), the initial clearance and volume of distribution decreased by 11.0% and 15.9%, respectively, during the second administration during induction and by 41.2% and 28.4% during reinduction. Furthermore, the initial clearance linearly increased for children aged > 8 years and was 7.1% lower for females. The model was successfully externally validated (1253 patients, 5523 samples). In case of missing data, > 52% of the predictions for observations and > 82% for derived parameters were within ± 20% of the nominal value. CONCLUSION: A PopPK model that describes the complex pharmacokinetics of PEG-ASNase was successfully externally validated. AUC0-∞ or time above different thresholds, which are parameters describing dose intensity, can be estimated with high predictivity, despite missing data. ( www.clinicaltrials.gov , NCT01117441, first submitted date: May 3, 2010).

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy   MeSH
• Asparaginase administration & dosage   pharmacokinetics   MeSH
• Models, Biological * MeSH
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Area Under Curve MeSH
• Polyethylene Glycols administration & dosage   pharmacokinetics   MeSH
• Child, Preschool MeSH
• Antineoplastic Agents administration & dosage   pharmacokinetics   MeSH
• Tissue Distribution MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial MeSH
• Multicenter Study MeSH
• Validation Study MeSH

BACKGROUND: Therapeutic drug monitoring (TDM) can identify patients with subtherapeutic asparaginase (ASNase) activity [silent inactivation (SI)] and prospectively guide therapeutic adaptation. However, limited intra-individual variability is a precondition for targeted dosing and the diagnosis of SI. METHODS: In the AIEOP-BFM acute lymphoblastic leukemia (ALL) 2009 trial, 2771 children with ALL were included and underwent ASNase-TDM in a central laboratory in Münster. Two biweekly administrations of pegylated ASNase during induction and a third dose during reinduction or the high-risk block, which was administered several weeks later, were monitored. We calculated (1) the incidence of SI; and (2) the predictivity of SI for SI after the subsequent administration. ASNase activities monitored during induction were categorized into percentiles at the respective sampling time points. These percentiles were used to calculate the intra-individual range of percentiles as a surrogate for intrapatient variability and to evaluate the predictivity of ASNase activity for the subsequent administration. RESULTS: The overall incidence of SI was low (4.9%). The positive predictive value of SI identified by one sample was ≤21%. Confirmation of SI by a second sample indicated a high positive predictive value of 100% for biweekly administrations, but not for administration more than 17 weeks later. Sampling and/or documentation errors were risks for misdiagnosis of SI. High intra-individual variability in ASNase activities, with ranges of percentiles over more than 2 quartiles and low predictivity, was observed in approximately 25% of the patients. These patients were likely to fail dose individualization based on TDM data. CONCLUSIONS: To use TDM as a basis for clinical decisions, standardized clinical procedures are required and high intra-individual variability should be taken into account. Details of the treatment are available in the European Clinical Trials Database at https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-004270-43/DE.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy   MeSH
• Asparagine blood   MeSH
• Asparaginase administration & dosage   blood   therapeutic use   MeSH
• Child MeSH
• Infant MeSH
• Humans MeSH
• Inactivation, Metabolic physiology   MeSH
• Adolescent MeSH
• Drug Monitoring methods   MeSH
• Polyethylene Glycols administration & dosage   therapeutic use   MeSH
• Child, Preschool MeSH
• Dose-Response Relationship, Drug MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

The colloidal stability, in vitro toxicity, cell association, and in vivo pharmacokinetic behavior of liposomes decorated with monomethoxy-poly(ethylene glycol)-lipids (mPEG-lipids) with different chemical features were comparatively investigated. Structural differences of the mPEG-lipids used in the study included: (a) surface-anchoring moiety [1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), cholesterol (Chol), and cholane (Chln)]; (b) mPEG molecular weight (2 kDa mPEG45 and 5 kDa mPEG114); and (c) mPEG shape (linear and branched PEG). In vitro results demonstrated that branched (mPEG114)2-DSPE confers the highest stealth properties to liposomes (∼31-fold lower cell association than naked liposomes) with respect to all PEGylating agents tested. However, the pharmacokinetic studies showed that the use of cholesterol as anchoring group yields PEGylated liposomes with longer permeance in the circulation and higher systemic bioavailability among the tested formulations. Liposomes decorated with mPEG114-Chol had 3.2- and ∼2.1-fold higher area under curve (AUC) than naked liposomes and branched (mPEG114)2-DSPE-coated liposomes, respectively, which reflects the high stability of this coating agent. By comparing the PEGylating agents with same size, namely, linear 5 kDa PEG derivatives, linear mPEG114-DSPE yielded coated liposomes with the best in vitro stealth performance. Nevertheless, the in vivo AUC of liposomes decorated with linear mPEG114-DSPE was lower than that obtained with liposomes decorated with linear mPEG114-Chol. Computational molecular dynamics modeling provided additional insights that complement the experimental results.

• MeSH
• Biological Availability MeSH
• Cholanes administration & dosage   chemistry   pharmacokinetics   MeSH
• Cholesterol administration & dosage   chemistry   pharmacokinetics   MeSH
• Phosphatidylethanolamines administration & dosage   chemistry   pharmacokinetics   MeSH
• HeLa Cells MeSH
• Humans MeSH
• Lipids MeSH
• Liposomes MeSH
• Molecular Weight MeSH
• Mice, Inbred BALB C MeSH
• Mice MeSH
• Drug Carriers pharmacokinetics   MeSH
• Polyethylene Glycols administration & dosage   chemistry   pharmacokinetics   MeSH
• Surface Properties MeSH
• Drug Compounding methods   MeSH
• Molecular Dynamics Simulation MeSH
• Drug Stability MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

Asparaginase-associated pancreatitis is a life-threatening toxicity to childhood acute lymphoblastic leukemia treatment. To elucidate genetic predisposition and asparaginase-associated pancreatitis pathogenesis, ten trial groups contributed remission samples from patients aged 1.0-17.9 years treated for acute lymphoblastic leukemia between 2000 and 2016. Cases (n=244) were defined by the presence of at least two of the following criteria: (i) abdominal pain; (ii) levels of pancreatic enzymes ≥3 × upper normal limit; and (iii) imaging compatible with pancreatitis. Controls (n=1320) completed intended asparaginase therapy, with 78% receiving ≥8 injections of pegylated-asparaginase, without developing asparaginase-associated pancreatitis. rs62228256 on 20q13.2 showed the strongest association with the development of asparaginase-associated pancreatitis (odds ratio=3.75; P=5.2×10-8). Moreover, rs13228878 (OR=0.61; P=7.1×10-6) and rs10273639 (OR=0.62; P=1.1×10-5) on 7q34 showed significant association with the risk of asparaginase-associated pancreatitis. A Dana Farber Cancer Institute ALL Consortium cohort consisting of patients treated on protocols between 1987 and 2004 (controls=285, cases=33), and the Children's Oncology Group AALL0232 cohort (controls=2653, cases=76) were available as replication cohorts for the 20q13.2 and 7q34 variants, respectively. While rs62228256 was not validated as a risk factor (P=0.77), both rs13228878 (P=0.03) and rs10273639 (P=0.04) were. rs13228878 and rs10273639 are in high linkage disequilibrium (r2=0.94) and associated with elevated expression of the PRSS1 gene, which encodes for trypsinogen, and are known risk variants for alcohol-associated and sporadic pancreatitis in adults. Intra-pancreatic trypsinogen cleavage to proteolytic trypsin induces autodigestion and pancreatitis. In conclusion, this study finds a shared genetic predisposition between asparaginase-associated pancreatitis and non-asparaginase-associated pancreatitis, and targeting the trypsinogen activation pathway may enable identification of effective interventions for asparaginase-associated pancreatitis.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma complications   drug therapy   genetics   MeSH
• Alleles MeSH
• Asparaginase administration & dosage   adverse effects   MeSH
• Models, Biological MeSH
• Child MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease MeSH
• Genetic Variation * MeSH
• Genetic Association Studies MeSH
• Genotype MeSH
• Polymorphism, Single Nucleotide MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Pancreatitis etiology   MeSH
• Polyethylene Glycols administration & dosage   adverse effects   MeSH
• Child, Preschool MeSH
• Antineoplastic Agents administration & dosage   adverse effects   MeSH
• Trypsin genetics   MeSH
• Trypsinogen genetics   MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH