Staphylococcus aureus biofilm formation at the physiologic glucose concentration depends on the S. aureus lineage

<p>Abstract</p> <p>Background</p> <p>Since bacteria embedded in biofilms are far more difficult to eradicate than planktonic infections, it would be useful to know whether certain <it>Staphylococcus aureus </it>lineages are especially involved in strong biofilm formation. For this reason, <it>in vitro </it>biofilm formation of 228 clinical <it>S. aureus </it>isolates of distinct clonal lineages was investigated.</p> <p>Results</p> <p>At 0.1% glucose, more than 60% of the <it>S. aureus </it>strains associated with multilocus sequence typing (MLST) clonal complex (CC)8 produced large amounts of biomass, compared to 0-7% for various other clonal lineages. Additionally, <it>S. aureus </it>bloodstream isolates associated with MLST CC8 and CC7 had similar biofilm forming capacities as their commensal counterparts. Furthermore, strong biofilm formation could not be attributed to a specific accessory gene regulator (<it>agr</it>) genotype, as suggested previously. The <it>agr </it>genotypes were strictly associated with the clonal lineages. Moreover, strong biofilm formation was not related to slime formation. Congo red agar (CRA) screening is therefore not useful as a qualitative screening method for biofilm formation.</p> <p>Conclusion</p> <p>The adherence to polystyrene surfaces under physiologic glucose concentration (0.1%) was dependent on the clonal lineage. Strains associated with MLST CC8 were markedly more often classified as strong biofilm former at glucose concentrations of 0%, 0.1% and 0.25%.</p> <p>The present study reveals that the MLST CC8 associated genetic background was a predisposing factor for strong biofilm formation <it>in vitro</it>, under all tested glucose concentrations.</p

Exploring the impact of patient-specific clinical features on osimertinib effectiveness in a real-world cohort of patients with EGFR mutated non-small cell lung cancer

Osimertinib is prescribed to patients with metastatic non-small cell lung cancer (NSCLC) and a sensitizing EGFR mutation. Limited data exists on the impact of patient characteristics or osimertinib exposure on effectiveness outcomes. This was a Dutch, multicenter cohort study. Eligible patients were ≥18 years, with metastatic EGFRm+ NSCLC, receiving osimertinib. Primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and safety. Kaplan-Meier analyses and multivariate Cox proportional hazard models were performed. In total, 294 patients were included. Primary EGFR-mutations were mainly exon 19 deletions (54%) and p.L858R point mutations (30%). Osimertinib was given in first-line (40%), second-line (46%) or beyond (14%), with median PFS 14.4 (95% CI: 9.4-19.3), 13.9 (95% CI: 11.3-16.1) and 8.7 months (95% CI: 4.6-12.7), respectively. Patients with low BMI (&lt;20.0 kg/m2) had significantly shorter PFS/OS compared to all other subgroups. Patients with a high plasma trough concentration in steady state (Cmin,SS; &gt;271 ng/mL) had shorter PFS compared to a low Cmin,SS (&lt;163 ng/mL; aHR 2.29; 95% CI: 1.13-4.63). A significant longer PFS was seen in females (aHR = 0.61, 95% CI: 0.45-0.82) and patients with the exon 19 deletion (aHR = 0.58, 95% CI: 0.36-0.92). A trend towards longer PFS was seen for TP53 wild-type patients, while age did not impact PFS. Patients with a primary EGFR exon 19 deletion had longer PFS, while a low BMI, male sex and a high Cmin,SS were indicative for shorter PFS and/or OS. Age was not associated with effectiveness outcomes of osimertinib.</p

Durvalumab after chemoradiotherapy in patients with stage III non-small-cell lung cancer: real-world outcomes versus clinical trial results

Aim: We investigated the effectiveness of durvalumab post-concurrent CRT (cCRT) and post-sequential CRT (sCRT) versus cCRT and sCRT alone and compared these outcomes with the PACIFIC trial. Methods: Four cohorts of stage III NSCLC patients who received CRT were included: cCRT with and without durvalumab, sCRT with and without durvalumab. PFS and OS were analyzed using Cox regression. Results: Durvalumab improved PFS (cCRT: aHR = 0.69, sCRT: aHR = 0.71) and OS (cCRT: aHR = 0.71, sCRT: aHR = 0.32), although not all results were significant. PFS was longer in the real-world than in the trial, while OS did not differ. Conclusion: Durvalumab after CRT improved the survival outcomes. The difference between PFS in our study and the trial may be due to differences in follow-up methods. Plain language summary We assessed a medicine called durvalumab on patients with non-small cell lung cancer who received chemoradiotherapy in a real-world setting. We compared their outcomes with those from a clinical trial. Patients who received two types of chemoradiotherapy with or without durvalumab were included, and their progression-free survival (PFS) and overall survival (OS) outcomes were analyzed. We found that patients treated with durvalumab had better PFS and OS than those treated without durvalumab. PFS was longer in the real-world than in the clinical trial, but OS was similar. The difference in PFS may be due to differences in measuring PFS

A Systematic Evaluation of Cost-Saving Dosing Regimens for Therapeutic Antibodies and Antibody-Drug Conjugates for the Treatment of Lung Cancer

Background: Expensive novel anticancer drugs put a serious strain on healthcare budgets, and the associated drug expenses limit access to life-saving treatments worldwide. Objective: We aimed to develop alternative dosing regimens to reduce drug expenses. Methods: We developed alternative dosing regimens for the following monoclonal antibodies used for the treatment of lung cancer: amivantamab, atezolizumab, bevacizumab, durvalumab, ipilimumab, nivolumab, pembrolizumab, and ramucirumab; and for the antibody-drug conjugate trastuzumab deruxtecan. The alternative dosing regimens were developed by means of modeling and simulation based on the population pharmacokinetic models developed by the license holders. They were based on weight bands and the administration of complete vials to limit drug wastage. The resulting dosing regimens were developed to comply with criteria used by regulatory authorities for in silico dose development. Results: We found that alternative dosing regimens could result in cost savings that range from 11 to 28%, and lead to equivalent pharmacokinetic exposure with no relevant increases in variability in exposure. Conclusions: Dosing regimens based on weight bands and the use of complete vials to reduce drug wastage result in less expenses while maintaining equivalent exposure. The level of evidence of our proposal is the same as accepted by regulatory authorities for the approval of alternative dosing regimens of other monoclonal antibodies in oncology. The proposed alternative dosing regimens can, therefore, be directly implemented in clinical practice.</p

A polymorphism in the regulatory region of PRNP is associated with increased risk of sporadic Creutzfeldt-Jakob disease

Background: Creutzfeldt-Jakob disease (CJD) is a rare transmissible neurodegenerative disorder. An important determinant for CJD risk and phenotype is the M129V polymorphism of the human prion protein gene (PRNP), but there are also other coding and non-coding polymorphisms inside this gene.Methods: We tested whether three non-coding polymorphism located inside the PRNP regulatory region (C-101G, G310C and T385C) were associated with risk of CJD and with age at onset in a United Kingdom population-based sample of 131 sporadic CJD (sCJD) patients and 194 controls.Results: We found no disease association for either PRNP C-101G or PRNP T385C. Although the crude analysis did not show a significant association between PRNP G310C and sCJD (OR: 1.5; 95%CI = 0.7 to 2.9), after adjusting by PRNP M129V genotype, it resulted that being a C allele carrier at PRNP G310C was significantly (p = 0.03) associated with a 2.4 fold increased risk of developing sCJD (95%CI = 1.1 to 5.4). Additionally, haplotypes carrying PRNP 310C coupled with PRNP 129M were significantly overrepresented in patients (p = 0.02) compared to controls. Cases of sCJD carrying a PRNP 310C allele presented at a younger age (on average 8.9 years younger than those without this allele), which was of statistical significance (p = 0.05). As expected, methionine and valine homozygosity at PRNP M129V increased significantly the risk of sCJD, alone and adjusted by PRNP G310C (OR MM/MV = 7.3; 95%CI 3.9 to 13.5 and OR VV/MV = 4.0; 95%CI 1.7 to 9.3).Conclusions: Our findings support the hypothesis that genetic variations in the PRNP promoter may have a role in the pathogenesis of sCJD

Lack of association between PRNP 1368 polymorphism and Alzheimer's disease or vascular dementia

<p>Abstract</p> <p>Background</p> <p>Polymorphisms of the prion protein gene (<it>PRNP</it>) at codons 129 and 219 play an important role in the susceptibility to Creutzfeldt-Jakob disease (CJD), and might be associated with other neurodegenerative disorders. Several recent reports indicate that polymorphisms outside the coding region of <it>PRNP </it>modulate the expression of prion protein and are associated with sporadic CJD, although other studies failed to show an association. These reports involved the polymorphism <it>PRNP </it>1368 which is located upstream from <it>PRNP </it>exon 1. In a case-controlled protocol, we assessed the possible association between the <it>PRNP </it>1368 polymorphism and either Alzheimer's disease (AD) or vascular dementia (VaD).</p> <p>Methods</p> <p>To investigate whether the <it>PRNP </it>1368 polymorphism is associated with the occurrence of AD or VaD in the Korean population, we compared the genotype, allele, and haplotype frequencies of the <it>PRNP </it>1368 polymorphism in 152 AD patients and 192 VaD patients with frequencies in 268 healthy Koreans.</p> <p>Results and conclusion</p> <p>Significant differences in genotype, allele and haplotype frequencies of <it>PRNP </it>1368 polymorphism were not observed between AD and normal controls. There were no significant differences in the genotype and allele frequencies of the <it>PRNP </it>1368 polymorphism between Korean VaD patients and normal controls. However, in the haplotype analysis, haplotype Ht5 was significantly over-represented in Korean VaD patients. This was the first genetic association study of a polymorphism outside the coding region of <it>PRNP </it>in relation to AD and VaD.</p

Drug-drug interactions with tyrosine-kinase inhibitors

In their Review, Roelof van Leeuwen and colleagues1 recommend various dose adjustments during concomitant use of tyrosine-kinase inhibitors and drugs that inhibit or induce cytochrome P450 3A4 (CYP3A4).1 Most information is taken from the US Food and Drug Administration (FDA)'s drug label or the European Medicines Agency (EMA)'s Summary of Product Characteristics. However, we could not find support for their advice regarding concomitant use of pazopanib and strong CYP3A4 inducers such as carbamazepine. They suggested to gradually increase the pazopanib dose in 200 mg steps depending on patient's tolerance,1 whereas both the FDA and EMA recommend that concomitant use should be avoided, and that the dose of pazopanib should not exceed 800 mg.2 and 3 We are unaware of clinical evidence for safety and efficacy of dose enhancement. By contrast, concomitant use and enhancement might result in carbamazepine toxic effects, because pazopanib can also act as a CYP3A4 inhibitor,2, 3 and 4 whereas carbamazepine is not only a CYP3A4 inducer, but also a CYP3A4 substrate with a narrow therapeutic index. We wonder which evidence supports the dosing guidelines that have been recommended by the authors.1 The Department of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (employers of FV) has received unrestricted research funding from the Netherlands Organisation for Health Research and Development, the Dutch Health Insurance Board, the Royal Dutch Association for the Advancement of Pharmacy, the private–public funded Top Institute Pharma (EU Innovative Medicines Initiative, EU 7th Framework Program), the Dutch Medicines Evaluation Board, the Dutch Ministry of Health, and industry (GlaxoSmithKline, Pfizer, and others)

Administration of crizotinib via jejunostomy tube:A case report

Crizotinib is an orally available tyrosine kinase inhibitor, approved for treatment of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangement-positive non-small cell lung cancer (NSCLC). According to the product leaflet, crizotinib capsules should be swallowed whole, and should not be crushed, dissolved or opened. However, this manner of administration is not always possible. At present, literature is lacking regarding the absorption of crizotinib via percutaneous endoscopic jejunostomy (PEJ) tube. We report a case of a patient with ALK+ NSCLC who was administered crizotinib via PEJ tube. An adequate steady state crizotinib trough concentration was reached, resulting in a metabolic response. Safety for the caregiver was ensured since the administration of crizotinib was made without crushing or opening the capsule. This case supports the option for providing crizotinib via PEJ tube in patients who have ALK+ NSCLC and are unable to swallow whole capsules. This option might also apply to the administration of other ALK inhibitors