Elevated cytokine levels are known to downregulate expression and suppress activity of cytochrome P450 enzymes (CYPs). Cytokine‐modulating therapeutic proteins (TPs) used in the treatment of ...inflammation or infection could reverse suppression, manifesting as TP‐drug–drug interactions (TP‐DDIs). A physiologically based pharmacokinetic model was used to quantitatively predict the impact of interleukin‐6 (IL‐6) on sensitive CYP3A4 substrates. Elevated simvastatin area under the plasma concentration–time curve (AUC) in virtual rheumatoid arthritis (RA) patients, following 100 pg/ml of IL‐6, was comparable to observed clinical data (59 vs. 58%). In virtual bone marrow transplant (BMT) patients, 500 pg/ml of IL‐6 resulted in an increase in cyclosporine AUC, also in good agreement with the observed data (45 vs. 39%). In a different group of BMT patients treated with cyclosporine, the magnitude of interaction with IL‐6 was underpredicted by threefold. The complexity of TP‐DDIs highlights underlying pathophysiological factors to be considered, but these simulations provide valuable first steps toward predicting TP‐DDI risk.
Clinical Pharmacology & Therapeutics (2013); 94 2, 260–268. doi:10.1038/clpt.2013.79
Using physiologically based pharmacokinetic modeling, we predicted the magnitude of drug-drug interactions (DDIs) for studies with rifampicin and seven CYP3A4 probe substrates administered i.v. (10 ...studies) or orally (19 studies). The results showed a tendency to underpredict the DDI magnitude when the victim drug was administered orally. Possible sources of inaccuracy were investigated systematically to determine the most appropriate model refinement. When the maximal fold induction (Indmax) for rifampicin was increased (from 8 to 16) in both the liver and the gut, or when the Indmax was increased in the gut but not in liver, there was a decrease in bias and increased precision compared with the base model (Indmax = 8) geometric mean fold error (GMFE) 2.12 vs. 1.48 and 1.77, respectively. Induction parameters (mRNA and activity), determined for rifampicin, carbamazepine, phenytoin, and phenobarbital in hepatocytes from four donors, were then used to evaluate use of the refined rifampicin model for calibration. Calibration of mRNA and activity data for other inducers using the refined rifampicin model led to more accurate DDI predictions compared with the initial model (activity GMFE 1.49 vs. 1.68; mRNA GMFE 1.35 vs. 1.46), suggesting that robust in vivo reference values can be used to overcome interdonor and laboratory-to-laboratory variability. Use of uncalibrated data also performed well (GMFE 1.39 and 1.44 for activity and mRNA). As a result of experimental variability (i.e., in donors and protocols), it is prudent to fully characterize in vitro induction with prototypical inducers to give an understanding of how that particular system extrapolates to the in vivo situation when using an uncalibrated approach.
Nontuberculous mycobacteria (NTM) are the pathogens of concern in people with cystic fibrosis (pwCF) due to their association with deterioration of lung function. Treatment requires the use of a ...multidrug combination regimen, creating the potential for drug-drug interactions (DDIs) with cystic fibrosis transmembrane conductance regulator (CFTR)-modulating therapies, including elexacaftor, tezacaftor, and ivacaftor (ETI), which are eliminated mainly through cytochrome P450 (CYP) 3A-mediated metabolism. An assessment of the DDI risk for ETI coadministered with NTM treatments, including rifabutin, clofazimine, and clarithromycin, is needed to provide appropriate guidance on dosing. The CYP3A-mediated DDIs between ETI and the NTM therapies rifabutin, clarithromycin, and clofazimine were evaluated using physiologically based pharmacokinetic (PBPK) modeling by incorporating demographic and physiological "system" data with drug physicochemical and
parameters. Models were verified and then applied to predict untested scenarios to guide continuation of ETI during antibiotic treatment, using ivacaftor as the most sensitive CYP3A4 substrate. The predicted area under the concentration-time curve (AUC) ratios of ivacaftor when coadministered with rifabutin, clofazimine, or clarithromycin were 0.31, 2.98, and 9.64, respectively, suggesting moderate and strong interactions. The simulation predicted adjusted dosing regimens of ETI administered concomitantly with NTM treatments, which required delayed resumption of the standard dose of ETI once the NTM treatments were completed. The dosing transitions were determined based on the characteristics of the perpetrator drugs, including the mechanism of CYP3A modulation and their elimination half-lives. This study suggests increased doses of elexacaftor/tezacaftor/ivacaftor 200/100/450 mg in the morning and 100/50/375 mg in the evening when ETI is coadministered with rifabutin and reduced doses of elexacaftor/tezacaftor 200/100 mg every 48 h (q48h) and ivacaftor 150 mg daily or a dose of elexacaftor/tezacaftor/ivacaftor 200/100/150 mg q72h when coadministered with clofazimine or clarithromycin, respectively. Importantly, the PBPK simulations provide evidence in support of the use of treatments for NTM in pwCF receiving concomitant dose-adjusted ETI therapy.
Abstract Purpose This study aimed to evaluate the impact on overall survival following palliative surgery to remove the primary lesion in unresectable metastatic small intestinal (SI-NET) and ...pancreatic neuroendocrine tumours (P-NET). Methods A systematic review of the literature and meta-analysis was performed. MEDLINE and Embase databases were searched to identify articles comparing patients undergoing palliative primary tumour resection without metastatectomy vs. no resection. Relevant articles were identified in accordance with PRISMA guidelines. The primary outcome was overall survival. Included studies were evaluated for heterogeneity and publication bias. Results 13 studies met the inclusion criteria, of which 6 presented data suitable for meta-analysis. No randomised controlled trials were identified. Analysis of pooled multivariate hazard ratios demonstrated significantly longer overall survival in patients undergoing resection of both P-NETs (HR 0.43; 95% CI: 0.34 - 0.57, p<0.001) and SI-NETs (HR 0.47; 95% CI: 0.35 - 0.55, p=0.007). The increase in median survival in patients treated surgically relative to non-surgically ranged from 14 to 46 months in P-NET, and 22 to 112 months in SI-NET. The number needed to treat in order that one additional patient was alive at five years, ranged from 3.0 to 4.2, and 1.7 to 7.7 respectively. Conclusions Meta-analysis demonstrates that palliative resection of primary SI-NETs and P-NETs in the setting of unresectable metastatic disease can increase survival. Although these results should be interpreted with caution due to potential selection and publication bias, the data supports consideration of surgery, particularly in patients with low tumour burdens and good functional status.
Background
Percutaneous biopsy is recommended before surgery for suspected retroperitoneal sarcoma (RPS) to confirm the histological diagnosis and guide surgical strategy. The present study aimed to ...establish the diagnostic accuracy of percutaneous core biopsy with respect to histological diagnosis and tumour grade.
Methods
Data on patients with suspected RPS who underwent percutaneous biopsy followed by surgical resection between 2005 and 2016 at one of two tertiary European sarcoma units were reviewed. Histological tumour type and tumour grade on biopsy were correlated with postoperative histology to evaluate diagnostic accuracy.
Results
A total of 239 patients underwent percutaneous core biopsy followed by surgical resection in Milan (163, 68·2 per cent) or Birmingham (76, 31·8 per cent). Diagnostic accuracy varied with histological diagnosis (P < 0·001), but demonstrated overall concordance with final pathology following resection in 67·2 per cent of biopsies (κ = 0·606). The majority of discrepancies occurred in dedifferentiated liposarcoma (DDLPS), owing to under‐recognition of dedifferentiation in this group. Concordance between pathology on biopsy and resection improved to 81·1 per cent when DDLPS and well differentiated liposarcoma were grouped together as liposarcoma. Grade on biopsy was concordant with grade on resection specimen in 60·4 per cent of tumours (κ = 0·640). Diagnosis of high‐grade tumours on biopsy had a high specificity (98 per cent), and moderate positive predictive value (85 per cent) and negative predictive value (78 per cent).
Conclusion
A diagnosis of DDLPS or leiomyosarcoma on percutaneous biopsy is highly reliable. High‐grade sarcomas can be identified with high specificity, which opens the door to a study on neoadjuvant therapy in these patients.
Weak for liposarcoma
Introduction Solitary extramedullary plasmacytoma are rare, solid-mass tumours which appear immunophenotypically similar to multiple myeloma. The diagnosis and management of gastrointestinal ...plasmacytoma is complex and requires multidisciplinary input. This study presents a narrative review of intra-abdominal extramedullary plasmacytoma, illustrated with two case studies. Methods The PubMed database was searched without date restrictions for reports of intra-abdominal extramedullary plasmacytoma to synthesise a narrative review. Electronic records were reviewed at a high-volume, quaternary soft-tissue sarcoma centre to identify patients with histopathologically confirmed extramedullary plasmacytoma affecting the gastrointestinal tract. Results Gastrointestinal extramedullary plasmacytomas can present with mass effect or organ-specific dysfunction. Techniques for tissue diagnosis of extramedullary plasmacytoma vary dependent on location, with a formal diagnosis often being made from a resected specimen. Management can include surgery, radiotherapy, systemic chemotherapy or a combination. No high-quality evidence base exists to guide treatment. Two case studies of operated gastrointestinal extramedullary plasmacytoma are presented at different phases of disease progression, with a resultant impact on survival. Conclusion Intra-abdominal extramedullary plasmacytoma is a rare and heterogeneous condition that lacks consensus guidelines for diagnosis and management. Collaboration between international specialist centres will create better quality evidence for treatment of this cohort.
This observational study aimed to evaluate the impact of intensity of radiological surveillance on survival following resection of retroperitoneal sarcoma.
Retrospective cohort study of patients ...undergoing primary resection of soft tissue sarcoma arising in the retroperitoneum, abdomen or pelvis at a single, high-volume sarcoma centre. Intensity of follow-up regimes up to 5 postoperative years were categorized as ‘European Society for Medical Oncology (ESMO) compliant’ (intense), or ‘non-ESMO compliant’ (less-intense). The primary outcome measure was overall survival (OS). The secondary outcome measures were disease-free survival (DFS) and reoperation rate. Analyses were stratified by high (grade 2 or 3) or low (grade 1) tumour grade.
Of 168 patients, 67.1% had high-grade and 32.9% had low-grade disease. Overall, 40.0% of patients had ESMO-compliant radiological follow-up (high-grade:25.7%, low-grade:66.7%). 41.7% of patients died and 48.2% suffered local or distant recurrence by cessation of follow up. Upon univariable analysis for high-grade tumours, ESMO compliance reduced DFS (p = 0.066) but had no impact on OS. There was no significant difference in the reoperation rate in patients with ESMO-compliant and non-compliant follow-up (p = 0.097). In low-grade tumours, ESMO compliance significantly reduced DFS (p < 0.001), but without effecting OS. In risk-adjusted models for high-grade tumours, ESMO compliant follow-up was associated with reduced OS (HR:3.47, 1.40–8.61, p = 0.007) and no difference in DFS. In low-grade tumours, there was no association between overall ESMO compliance and OS or DFS.
This study did not find a benefit for high-intensity radiological surveillance and overall survival in patients undergoing primary resection for high or low-grade retroperitoneal sarcoma.
Postcholecystectomy syndrome (PCS) Jaunoo, S.S; Mohandas, S; Almond, L.M
International journal of surgery (London, England),
01/2010, Letnik:
8, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract The term postcholecystectomy syndrome (PCS) comprises a heterogeneous group of symptoms and findings in patients who have previously undergone cholecystectomy. Although rare, these patients ...may present with abdominal pain, jaundice or dyspeptic symptoms. Many of these complaints can be attributed to complications including bile duct injury, biliary leak, biliary fistula and retained bile duct stones. Late sequelae include recurrent bile duct stones and bile duct strictures. With the number of cholecystectomies being performed increasing in the laparoscopic era the number of patients presenting with PCS is also likely to increase. We briefly explore the syndrome and its main aetiological theories.
Background
The optimal management of patients with Barrett's‐associated low‐grade dysplasia (LGD) is unclear. The objective of this study was to identify systematically all reports of endoscopic ...treatment of LGD, and to assess outcomes in terms of disease progression, eradication of dysplasia and intestinal metaplasia, and complication rates.
Methods
A systematic review of articles reporting endoscopic treatment of LGD was conducted in accordance with PRISMA guidelines. MEDLINE and Embase databases were searched to identify the relevant literature. Rates of complete eradication of intestinal metaplasia (CE‐IM) and dysplasia (CE‐D) were reported. The pooled incidence of progression to cancer was calculated following endoscopic therapy.
Results
Thirty‐seven studies met the inclusion criteria, reporting outcomes of endoscopic therapy for 521 patients with LGD. The pooled incidence of progression to cancer was 3·90 (95 per cent confidence interval (c.i.) 1·27 to 9·10) per 1000 patient‐years. CE‐IM and CE‐D were achieved in 67·8 (95 per cent c.i. 50·2 to 81·5) and 88·9 (83·9 to 92·5) per cent of patients respectively. The commonest adverse event was stricture formation.
Conclusion
Reports of endoscopic therapy were heterogeneous and follow‐up periods were short. There is a high likelihood of historical overdiagnosis of LGD. Endoscopic therapy, particularly radiofrequency ablation, appears safe and effective at eradicating LGD, but does not eliminate the risk of progression to cancer.
Treatment bedevilled by poor definition of the underlying condition
Although CYP induction is not generally considered to be as clinically relevant as CYP inhibition, there are important examples where induction has caused both therapeutic failure, due to ...insufficient exposure to parent drug, and toxicity, mediated by increased formation of reactive metabolites. Furthermore, while there has been considerable progress in the extrapolation of in vitro data to predict the in vivo consequences of enzyme inhibition, less attention has been given to the quantitative impact of enzyme induction as a mechanism of drug-drug interaction (DDI) and as a component of compound selection and early drug development. We discuss current approaches in the context of a mechanistic framework for the prediction of the extent and time-course of enzyme induction in vivo based on in vitro experimentation. Factors influencing the extent of DDI due to CYP induction are summarised, and areas deficient in information that would allow more accurate prediction within target populations are highlighted.
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