Physiologically Based Pharmacokinetic Modeling To Guide Management of Drug Interactions between Elexacaftor-Tezacaftor-Ivacaftor and Antibiotics for the Treatment of Nontuberculous Mycobacteria.

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 in vitro 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.

The impact of postoperative radiological surveillance intensity on disease free and overall survival from primary retroperitoneal, abdominal and pelvic soft-tissue sarcoma.

AIM: This observational study aimed to evaluate the impact of intensity of radiological surveillance on survival following resection of retroperitoneal sarcoma. METHOD: 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. RESULTS: 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. CONCLUSION: 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.

Diagnostic accuracy of percutaneous biopsy in retroperitoneal sarcoma.

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.

Gastrointestinal manifestations of extramedullary plasmacytoma: a narrative review and illustrative case reports.

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.

Role of palliative resection of the primary tumour in advanced pancreatic and small intestinal neuroendocrine tumours: A systematic review and meta-analysis.

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 22-112 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.

An Update on Non-extremity Soft Tissue Sarcomas.

The management of soft tissue sarcoma is challenging and varied. Centralisation of management in high volume specialist centres has revolutionised outcomes. Surgery remains the mainstay of treatment and is currently the only potentially curative therapy. Retroperitoneal soft tissue sarcoma presents a particular challenge to the surgical oncologist and the concept of extended resection to include surrounding expendable organs taken en bloc with the tumour has now largely been adopted. The use of neoadjuvant and adjuvant therapies for retroperitoneal soft tissue sarcoma is still to be established, although they are employed on a case-specific basis. Guidance on the management of retroperitoneal recurrences and distant metastatic disease is now recognised. The approach to soft tissue sarcoma of the head and neck, trunk and abdominal wall remains largely extrapolated from experience of the management of extremity soft tissue sarcoma. Secondary angiosarcoma of the breast is becoming increasingly more common and presents a particular therapeutic challenge. Continued international collaboration is essential to ensure evolution of the optimal management of this rare group of cancers.

Rapid infrared mapping for highly accurate automated histology in Barrett's oesophagus.

Barrett's oesophagus (BE) is a premalignant condition that can progress to oesophageal adenocarcinoma. Endoscopic surveillance aims to identify potential progression at an early, treatable stage, but generates large numbers of tissue biopsies. Fourier transform infrared (FTIR) mapping was used to develop an automated histology tool for detection of BE and Barrett's neoplasia in tissue biopsies. 22 oesophageal tissue samples were collected from 19 patients. Contiguous frozen tissue sections were taken for pathology review and FTIR imaging. 45 mid-IR images were measured on an Agilent 620 FTIR microscope with an Agilent 670 spectrometer. Each image covering a 140 µm × 140 µm region was measured in 5 minutes, using a 1.1 µm2 pixel size and 64 scans per pixel. Principal component fed linear discriminant analysis was used to build classification models based on spectral differences, which were then tested using leave-one-sample-out cross validation. Key biochemical differences were identified by their spectral signatures: high glycogen content was seen in normal squamous (NSQ) tissue, high glycoprotein content was observed in glandular BE tissue, and high DNA content in dysplasia/adenocarcinoma samples. Classification of normal squamous samples versus 'abnormal' samples (any stage of Barrett's) was performed with 100% sensitivity and specificity. Neoplastic Barrett's (dysplasia or adenocarcinoma) was identified with 95.6% sensitivity and 86.4% specificity. Highly accurate pathology classification can be achieved with FTIR measurement of frozen tissue sections in a clinically applicable timeframe.

A decade of day-case endoscopically guided stent placement in malignant oesophagogastric strictures.

BACKGROUND: Self-expanding metal stents (SEMSs) are the palliative treatment of choice for rapid symptomatic relief in patients with malignant dysphagia. Increasingly endoscopically guided insertion is performed as a day case and without the need for fluoroscopic guidance. This consecutive case series reports 11-year experience of endoscopically guided SEMS insertion in a large UK specialist oesophagogastric unit. METHODS: Patients undergoing stent insertion for malignant dysphagia between 2003 and 2014 were identified from a prospectively maintained database. Data on patient demographics, tumour characteristics, indications, technique of insertion, complications, and need for re-intervention were abstracted and then corroborated by retrospective review of electronic case records. RESULTS: A total of 362 patients with a median age of 76 years underwent primary SEMS insertion under endoscopic guidance. Repeat endoscopic intervention was required in 26 patients within 30 days and 59 patients within 90 days of primary insertion, giving Kaplan-Meier estimated re-intervention rates of 7.7 % and 20.3 %, respectively. Higher tumours were associated with need for repeat intervention (p = 0.014). The most frequent repeat intervention was insertion of a new stent, most commonly for stent migration or tumour overgrowth. Out of 252, 222 (88.1 %) patients referred through a rapid access pathway were stented as day cases, and the 30-day readmission rate in this cohort did not differ significantly from patients stented as inpatients (p = 0.774). Three (0.8 %) patients suffered a perforation, and there was a single procedure-related death. CONCLUSIONS: This large consecutive case series demonstrates that endoscopically guided SEMS insertion in malignant dysphagia can be performed efficiently as a day case with low complication, readmission, and re-intervention rates.

An "all 5 mm ports" technique for laparoscopic day-case anti-reflux surgery: A consecutive case series of 205 patients.

INTRODUCTION: Laparoscopic anti-reflux surgery is conventionally performed using two 10/12 mm ports. While laparoscopic procedures reduce post-operative pain, the use of larger ports invariably increases discomfort and affects cosmesis. We describe a new all 5 mm ports technique for laparoscopic anti-reflux surgery and present a review of our initial experience with this approach. METHODS: All patients undergoing laparoscopic fundoplication over a 35 month period from February 2013 under the care of a single surgeon were included. A Lind laparoscopic fundoplication was performed using an all 5 mm port technique. Data was recorded prospectively on patient demographics, operating surgeon, surgical time, date of discharge, readmissions, complications, need for re-intervention, and reasons for admission. RESULTS: Two hundred and five consecutive patients underwent laparoscopic fundoplication over the study period. The all 5 mm port technique was used in all cases, with conversion to a 12 mm port only once (0.49%). Median operating time was 52 min 185 (90.2%) patients were discharged as day cases. Increasing ASA grade and the presence of a hiatus hernia were associated with the need for overnight stay with admission required in 33% of patients with ASA 3, compared to 4% with ASA 1 (p = 0.001), and 29% of those with a hiatus hernia vs. 5% without (p < 0.001). No port-related complications occurred, and no patients developed recurrence of reflux symptoms. A single patient required mesh repair of a large hiatus hernia. CONCLUSION: The all 5 mm ports approach to laparoscopic anti-reflux surgery is a safe, efficient, and cost-effective technique which facilitates same day discharge and minimises port related complications. National commissioning guidelines in the UK should target quality improvements in anti-reflux surgery based around day-case management. This would improve the service for these patients and culminate in cost savings for the NHS.

Barrett's oesophagus: how should we manage it?

Endoscopic surveillance remains the core management of non-dysplastic Barrett's oesophagus, although questions regarding its efficacy in reducing mortality from oesophageal adenocarcinoma have yet to be definitively answered, and randomised trial data are awaited. One of the main goals of current research is to achieve risk stratification, identifying those at high risk of progression. The recent British Society of Gastroenterology (BSG) guidelines on surveillance have taken a step in this direction with interval stratification on clinicopathological grounds. The majority of Barrett's oesophagus remains undiagnosed, and this has led to investigation of methods of screening for Barrett's oesophagus, ideally non-endoscopic methods capable of reliably identifying dysplasia. Chemoprevention to prevent progression is currently under investigation, and may become a key component of future treatment. The availability of effective endotherapy means that accurate identification of dysplasia is more important than ever. There is now evidence to support intervention with radiofrequency ablation (RFA) for low-grade dysplasia (LGD), but recent data have emphasised the need for consensus pathology for LGD. Ablative treatment has become well established for high-grade dysplasia, and should be employed for flat lesions where there is no visible abnormality. Of the ablative modalities, RFA has the strongest evidence base. Endoscopic resection should be performed for all visible lesions, and is now the treatment of choice for T1a tumours. Targeting those with high-risk disease will, hopefully, lead to efficacious and cost-effective surveillance, and the trend towards earlier intervention to halt progression gives cause for optimism that this will ultimately result in fewer deaths from oesophageal adenocarcinoma.

Endoscopic resection with or without mucosal ablation of high grade dysplasia and early oesophageal adenocarcinoma--long term follow up from a regional UK centre.

BACKGROUND: Endoscopic resection (ER) is emerging as a curative technique in patients with high-grade dysplasia (HGD), intramucosal cancer (IMC), and early submucosal cancer (T1sm1) within Barrett's oesophagus. METHODS: This consecutive case series of 72 patients with HGD or IMC reports outcomes of ER, with or without mucosal ablation, in a single institution after a median of 38 months follow-up between 2004 and 2011. The primary outcome was disease progression to submucosal invasion. Secondary outcomes included disease regression, the effect of ER on staging compared to biopsy and procedure-related complications. RESULTS: 72 patients (mean age 73.0 - range 52.0-93.0) were treated by ER ± ablative therapy with curative intent for HGD (88% patients) or IMC (12%). 38% had one or more severe systemic co-morbidities. A median of 4 (1-11) procedures were undertaken per patient. In addition to ER, 43% of patients were treated with argon plasma coagulation, 17% with radiofrequency ablation, and 11% with photodynamic therapy. 8 (13%) patients with HGD at baseline and 0 (0%) with IMC progressed to invasive carcinoma. The median time to progression was 26.3 and 12.6 months respectively. 51% patients experienced disease regression. Disease staging was upgraded by ER in 27% of patients. DISCUSSION: This case series reports on a minimally invasive technique in an elderly population with multiple co-morbidities, demonstrating disease regression with long-term follow-up. CONCLUSION: ER ± ablation is an effective and potentially curative option for patients with HGD or IMC. The benefit of endoscopic resection for disease staging was clearly demonstrated.

Meta-analysis of endoscopic therapy for low-grade dysplasia in Barrett's oesophagus.

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.

A physiologically based pharmacokinetic modeling approach to predict disease-drug interactions: suppression of CYP3A by IL-6.

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.

Current management of Barrett's oesophagus.

Barrett's oesophagus is one of the most common pre-malignant conditions in the world and its incidence is increasing. The management of this disease is currently the subject of research and debate, with medical, endoscopic and operative intervention all having a therapeutic role.

A 5-year prospective review of posterior partial fundoplication in the management of gastroesophageal reflux disease.

INTRODUCTION: Laparoscopic Nissen fundoplication is the most common surgical procedure performed for gastroesophageal reflux disease (GORD). It is however associated with a number of mechanical complications with as many as one in three patients experiencing troublesome dysphagia or gas bloat. Partial fundoplication, either posterior or anterior, has been advocated in an attempt to reduce these problems. Our aim was to prospectively evaluate laparoscopic posterior partial (Toupet) fundoplication as the primary surgical treatment for GORD. METHOD: Outcomes following Toupet fundoplication performed between October 2002 and October 2007 were recorded prospectively. All patients underwent a 270 degrees posterior partial fundoplication with routine crural repair. All procedures were performed by a single surgeon. Pre-operative investigations included endoscopy, pH studies/manometry and contrast studies. DeMeester acidity scores, percentage reflux time and oesophageal motility were recorded. Pre- and post-operative DeMeester symptom scores (0-9, DSS) and Visick grading were used to assess the outcomes of surgery. RESULTS: 101 Patients were studied. Ages ranged from 17 to 69 years. The median pre-operative DSS of 5 fell to a median of 0 post-operatively. Scores decreased following surgery in all cases. 91 (91%) patients were discharged on the 2nd post-operative day or sooner. 5 (4.9%) patients had prolonged dysphagia (>3 months), and 8 (7.9%) had mild prolonged gas bloat. A single patient had a recurrence of reflux at 2 years and required re-do laparoscopic surgery. There were no conversions to open surgery. CONCLUSIONS: Laparoscopic Toupet fundoplication provides excellent relief of GORD symptoms with a low incidence of post-operative mechanical complications. We would recommend it as the operation of choice for GORD.

Postcholecystectomy syndrome (PCS).

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.

Towards a quantitative framework for the prediction of DDIs arising from cytochrome P450 induction.

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.

Thoracic intradural disc herniation.

Intradural disc herniation is a well-recognized entity in the lumbar region, where over 90% of all intradural herniations are seen.1 By contrast, fewer than 5% occur in either the cervical or thoracic regions.1 We describe a case of a sudden onset neurological deficit caused by an intradural thoracic disc herniation at the T11-T12 level, the intradural nature of which was not diagnosed on preoperative MRI. To the best of our knowledge this is the first description of an intradural disc herniation at this level.