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- Menden, MP, et al.
(författare)
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Community assessment to advance computational prediction of cancer drug combinations in a pharmacogenomic screen
- 2019
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 2674-
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Tidskriftsartikel (refereegranskat)abstract
- The effectiveness of most cancer targeted therapies is short-lived. Tumors often develop resistance that might be overcome with drug combinations. However, the number of possible combinations is vast, necessitating data-driven approaches to find optimal patient-specific treatments. Here we report AstraZeneca’s large drug combination dataset, consisting of 11,576 experiments from 910 combinations across 85 molecularly characterized cancer cell lines, and results of a DREAM Challenge to evaluate computational strategies for predicting synergistic drug pairs and biomarkers. 160 teams participated to provide a comprehensive methodological development and benchmarking. Winning methods incorporate prior knowledge of drug-target interactions. Synergy is predicted with an accuracy matching biological replicates for >60% of combinations. However, 20% of drug combinations are poorly predicted by all methods. Genomic rationale for synergy predictions are identified, including ADAM17 inhibitor antagonism when combined with PIK3CB/D inhibition contrasting to synergy when combined with other PI3K-pathway inhibitors in PIK3CA mutant cells.
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| 6. |
- Litjens, Carlijn H. C., et al.
(författare)
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Prediction of Moxifloxacin Concentrations in Tuberculosis Patient Populations by Physiologically Based Pharmacokinetic Modeling
- 2022
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Ingår i: Journal of clinical pharmacology. - : John Wiley & Sons. - 0091-2700 .- 1552-4604. ; 62:3, s. 385-396
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Tidskriftsartikel (refereegranskat)abstract
- Moxifloxacin has an important role in the treatment of tuberculosis (TB). Unfortunately, coadministration with the cornerstone TB drug rifampicin results in suboptimal plasma exposure. We aimed to gain insight into the moxifloxacin pharmacokinetics and the interaction with rifampicin. Moreover, we provided a mechanistic framework to understand moxifloxacin pharmacokinetics. We developed a physiologically based pharmacokinetic model in Simcyp version 19, with available and newly generated in vitro and in vivo data, to estimate pharmacokinetic parameters of moxifloxacin alone and when administered with rifampicin. By combining these strategies, we illustrate that the role of P-glycoprotein in moxifloxacin transport is limited and implicate MRP2 as transporter of moxifloxacin-glucuronide followed by rapid hydrolysis in the gut. Simulations of multiple dose area under the plasma concentration-time curve (AUC) of moxifloxacin (400 mg once daily) with and without rifampicin (600 mg once daily) were in accordance with clinically observed data (predicted/observed [P/O] ratio of 0.87 and 0.80, respectively). Importantly, increasing the moxifloxacin dose to 600 mg restored the plasma exposure both in actual patients with TB as well as in our simulations. Furthermore, we extrapolated the single dose model to pediatric populations (P/O AUC ratios, 1.04-1.52) and the multiple dose model to children with TB (P/O AUC ratio, 1.51). In conclusion, our combined approach resulted in new insights into moxifloxacin pharmacokinetics and accurate simulations of moxifloxacin exposure with and without rifampicin. Finally, various knowledge gaps were identified, which may be considered as avenues for further physiologically based pharmacokinetic refinement.
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- Caspers, Irene A., et al.
(författare)
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The impact of sex on treatment and outcome in relation to histological subtype in patients with resectable gastric cancer : Results from the randomized CRITICS trial
- 2024
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Ingår i: Journal of Surgical Oncology. - : John Wiley & Sons. - 0022-4790 .- 1096-9098. ; 129:4, s. 734-744
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Tidskriftsartikel (refereegranskat)abstract
- Background and ObjectiveThis study aims to investigate the impact of sex on outcome measures stratified by histological subtype in patients with resectable gastric cancer (GC).MethodsA post-hoc analysis of the CRITICS-trial, in which patients with resectable GC were treated with perioperative therapy, was performed. Histopathological characteristics and survival were evaluated for males and females stratified for histological subtype (intestinal/diffuse). Additionally, therapy-related toxicity and compliance were compared.ResultsData from 781 patients (523 males) were available for analyses. Female sex was associated with a distal tumor localization in intestinal (p = 0.014) and diffuse tumors (p < 0.001), and younger age in diffuse GC (p = 0.035). In diffuse GC, tumor-positive resection margins were also more common in females than males (21% vs. 10%; p = 0.020), specifically at the duodenal margin. During preoperative chemotherapy, severe toxicity occurred in 327 (63%) males and 184 (71%) females (p = 0.015). Notwithstanding this, relative dose intensities were not significantly different between sexes.ConclusionsPositive distal margin rates were higher in females with diffuse GC, predominantly at the duodenal site. Females also experience more toxicity, but this neither impacts dose intensities nor surgical resection rates. Clinicians should be aware of these different surgical outcomes when treating males and females with GC.
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- van Laarhoven, Constance J H C M, et al.
(författare)
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Carotid tortuosity is associated with extracranial carotid artery aneurysms.
- 2022
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Ingår i: Quantitative imaging in medicine and surgery. - : AME Publishing Company. - 2223-4292 .- 2223-4306. ; 12:11, s. 5018-5029
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Tortuous arteries may be associated with carotid dissection. The intima disruption caused by a carotid dissection is a possible cause of extracranial carotid artery aneurysms (ECAAs). The aim was to investigate if carotid tortuosity is also associated with ECAA in patients without presence or history of a carotid artery dissection.METHODS: A retrospective case-control study was performed including 35 unilateral ECAA patients (cases) and 105 age- and sex-matched controls. Tortuosity was expressed as tortuosity-index (TI), curvature, and torsion measured on computed tomography angiography (CTA) data in 3Mensio Vascular and MATLAB by two independent investigators. Primary comparison was tortuosity in ipsi- versus contralateral carotid artery within the cohort of ECAA patients. Secondary comparison was tortuosity with ipsilateral carotid arteries in control patients. All observations were assessed on inter- and intra-operator reproducibility.RESULTS: Carotid tortuosity was comparable within the cohort of ECAA patients (Spearman correlation 0.76, P<0.001), yet distinctively higher in comparison with unilateral controls. After adjustment for patient characteristics, presence of ECAA was associated with TI (β 0.146, 95% CI: 0.100-0.192). All tortuosity observations showed excellent inter- and intra-operator reproducibility.CONCLUSIONS: Carotid tortuosity seems to be a risk factor for development of ECAA. Surveillance of individuals with increased carotid tortuosity therefore potentially ensures prompt diagnosis and treatment of ECAA. However, future research should investigate if persons with an increased tortuosity do indeed develop ECAA.
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- van Laarhoven, Constance J. H. C. M., et al.
(författare)
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Systematic Review of the Co-Prevalence of Arterial Aneurysms Within the Vasculature
- 2021
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Ingår i: European Journal of Vascular and Endovascular Surgery. - : Elsevier. - 1078-5884 .- 1532-2165. ; 61:3, s. 473-483
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Forskningsöversikt (refereegranskat)abstract
- Objective: Aneurysms are considered focal manifestations of a systemic vascular condition, and various studies report co-prevalence of aneurysms in different vascular beds. Insight into profiles of patients at risk of multiple aneurysms is lacking, and few clinical algorithms exist if additional screening is indicated. This systematic review assessed the co-prevalence of aneurysms in different vascular beds and analysed putative risk factors for multiple aneurysms. Methods: Medline, Embase, and Cochrane libraries were searched up to February 2020 for studies reporting co-prevalence of aneurysms in different vascular beds using the keywords: "aneurysm", "co-prevalence", or synonyms. All studies were reviewed by two authors independently. Studies were excluded if they described concomitant treatment of multi-aneurysms, or if the aneurysm was reported solely bilateral, post-dissection, mycotic, traumatic, iatrogenic, or caused by a connective tissue disease. Radar plots were used to indicate studies that found an association between the investigated features and aneurysm co-prevalence against those that did not. Results: Thirty-two studies met the inclusion criteria, describing in total 16 353 patients of whom 2 015 had at least one additional aneurysm. The weighted co-prevalence was 16.9% (95% confidence interval [CI] 11.8-22.6), I-2 > 90%. At least 19 combinations of aneurysms were described, mostly derived from retrospective studies. Seventeen of 32 (53%) studies described concurrent aneurysms in patients with an abdominal aortic aneurysm. Predominantly positive associations were found for higher age, hypertension, stenotic disease, presence of multiple (at least three) aneurysms, and primary aneurysm size. Conclusion: Approximately one in six patients with a primary aneurysm harbours an additional aneurysm, increasing to one in four if the patient has a popliteal artery aneurysm. Higher age, hypertension, stenotic disease, presence of multiple (at least three) aneurysms, and primary aneurysm size were predictive of aneurysm co-prevalence. These clinical predictors may assist when deciding whether a patient with a primary aneurysm needs to be screened for additional aneurysms.
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