UK Consensus on Normal Tissue Dose Constraints for Stereotactic Radiotherapy.

Six UK studies investigating stereotactic ablative radiotherapy (SABR) are currently open. Many of these involve the treatment of oligometastatic disease at different locations in the body. Members of all the trial management groups collaborated to generate a consensus document on appropriate organ at risk dose constraints. Values from existing but older reviews were updated using data from current studies. It is hoped that this unified approach will facilitate standardised implementation of SABR across the UK and will allow meaningful toxicity comparisons between SABR studies and internationally.

The endoscopist and malignant and non-malignant biliary obstruction.

Patients with biliary strictures often represent a diagnostic and therapeutic challenge, due to the site and complexity of biliary obstruction and wide differential diagnosis. Multidisciplinary decision making is required to reach an accurate and timely diagnosis and to plan optimal care. Developments in endoscopic ultrasound and peroral cholangioscopy have advanced the diagnostic yield of biliary endoscopy, and novel optical imaging techniques are emerging. Endoscopic approaches to biliary drainage are preferred in most scenarios, and recent advances in therapeutic endoscopic ultrasound allow drainage where the previous alternatives were only percutaneous or surgical. Here we review recent advances in endoscopic practice for the diagnosis and management of biliary strictures. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen.

Validation of a dose warping algorithm using clinically realistic scenarios.

OBJECTIVE: Dose warping following deformable image registration (DIR) has been proposed for interfractional dose accumulation. Robust evaluation workflows are vital to clinically implement such procedures. This study demonstrates such a workflow and quantifies the accuracy of a commercial DIR algorithm for this purpose under clinically realistic scenarios. METHODS: 12 head and neck (H&N) patient data sets were used for this retrospective study. For each case, four clinically relevant anatomical changes have been manually generated. Dose distributions were then calculated on each artificially deformed image and warped back to the original anatomy following DIR by a commercial algorithm. Spatial registration was evaluated by quantitative comparison of the original and warped structure sets, using conformity index and mean distance to conformity (MDC) metrics. Dosimetric evaluation was performed by quantitative comparison of the dose-volume histograms generated for the calculated and warped dose distributions, which should be identical for the ideal "perfect" registration of mass-conserving deformations. RESULTS: Spatial registration of the artificially deformed image back to the planning CT was accurate (MDC range of 1-2 voxels or 1.2-2.4 mm). Dosimetric discrepancies introduced by the DIR were low (0.02 ± 0.03 Gy per fraction in clinically relevant dose metrics) with no statistically significant difference found (Wilcoxon test, 0.6 ≥ p ≥ 0.2). CONCLUSION: The reliability of CT-to-CT DIR-based dose warping and image registration was demonstrated for a commercial algorithm with H&N patient data. ADVANCES IN KNOWLEDGE: This study demonstrates a workflow for validation of dose warping following DIR that could assist physicists and physicians in quantifying the uncertainties associated with dose accumulation in clinical scenarios.

Experience of propofol sedation in a UK ERCP practice: lessons for service provision.

OBJECTIVE: Endoscopic retrograde cholangiopancreatography (ERCP) in the UK has been historically performed under conscious sedation. However, given the increasing complexity of cases, the role of propofol-assisted ERCP (propERCP) is increasing. We describe our experience of propERCP and highlight the importance of this service. DESIGN: Our prospective ERCP database was interrogated between January 2013 and January 2014. Data collection included procedural information, patient demographics, American Association of Anaesthesiologists (ASA) status, Cotton grade of endoscopic difficulty and endoscopic and anaesthetic complications. Comparison was made with patients undergoing conscious sedation ERCP (sedERCP). RESULTS: 744 ERCPs were performed in 629 patients (53% male). 161 ERCPs were performed under propofol. PropERCP patients were younger compared with the sedERCP group (54 vs 66 years, p<0.0001) but ASA grade 1-2 status was similar (84% vs 78%, p=0.6). An increased number of Cotton grade 3-4 ERCPs were performed in the propERCP group (64% vs 34%, p<0.0001). Indications for propERCP included sphincter of Oddi manometry (27%), previously poorly tolerated sedERCP (26%), cholangioscopy (21%) and patient request (8%). 77% of cases were elective, 12% were urgent day-case transfers and 11% were urgent inpatients. 59% of cases were tertiary referrals. ERCP was completed successfully in 95% of cases. Anaesthetic and endoscopic complications were comparable between the two groups (5% and 7% vs 3% and 5%). Where sedERCP had been unsuccessful due to patient intolerance, the procedure was completed successfully using propofol. CONCLUSIONS: PropERCP is safe and is associated with high endoscopic success. The need for propERCP is likely to increase given patient preference and the high proportion of complex procedures being undertaken. All endoscopy units should look to incorporate propofol-assisted endoscopy into aspects of their services.

Self-expandable metal stents for obstructing colonic and extracolonic cancer: European Society of Gastrointestinal Endoscopy (ESGE) Clinical Guideline

This Guideline is an official statement of the European Society of Gastrointestinal Endoscopy (ESGE). This Guideline was also reviewed and endorsed by the Governing Board of the American Society for Gastrointestinal Endoscopy (ASGE). The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system was adopted to define the strength of recommendations and the quality of evidence. Main recommendations The following recommendations should only be applied after a thorough diagnostic evaluation including a contrast-enhanced computed tomography (CT) scan. 1 Prophylactic colonic stent placement is not recommended. Colonic stenting should be reserved for patients with clinical symptoms and imaging evidence of malignant large-bowel obstruction, without signs of perforation (strong recommendation, low quality evidence). 2 Colonic self-expandable metal stent (SEMS) placement as a bridge to elective surgery is not recommended as a standard treatment of symptomatic left-sided malignant colonic obstruction (strong recommendation, high quality evidence). 3 For patients with potentially curable but obstructing left-sided colonic cancer, stent placement may be considered as an alternative to emergency surgery in those who have an increased risk of postoperative mortality, I. e. American Society of Anesthesiologists (ASA) Physical Status ≥ III and/or age > 70 years (weak recommendation, low quality evidence). 4 SEMS placement is recommended as the preferred treatment for palliation of malignant colonic obstruction (strong recommendation, high quality evidence), except in patients treated or considered for treatment with antiangiogenic drugs (e. g. bevacizumab) (strong recommendation, low quality evidence).(AU)

Biliary and hepatic involvement in IgG4-related disease.

BACKGROUND: IgG4-related disease (IgG4-RD) is a multi-systemic disorder. IgG4-related sclerosing cholangitis (IgG4-SC) is the biliary manifestation of the disease, often in association with autoimmune pancreatitis (AIP). Hepatic manifestations of IgG4-RD are less well described within the literature. AIM: To examine and present an overview of IgG4-RD with a focus on the biliary and hepatic manifestations. METHODS: An electronic search using Medline was performed. Search items included 'IgG4 multi-system disease, IgG4 associated cholangitis, IgG4 associated liver disease and autoimmune pancreatitis (AIP)'. RESULTS: IgG4-RD is characterised by an IgG4-positive lymphoplasmacytic tissue infiltrate, storiform fibrosis and an obliterative phlebitis. The HISORt criteria may be used to establish the diagnosis and incorporate a multi-disciplinary approach involving histology, radiology, serum IgG4 levels and response to steroid therapy. IgG4-SC is the commonest extrapancreatic manifestation of type-1 AIP, while the hepatic manifestations remain poorly defined. Important differential diagnoses include primary sclerosing cholangitis, secondary sclerosing cholangitis, cholangiocarcinoma and pancreatic carcinoma. Current treatment regimens remain ill defined although steroid therapy is used first line unless contraindicated. Patients with relapsing disease or multifocal disease should be considered for azathioprine. Available data would also suggest a role for rituximab. CONCLUSIONS: IgG4-related sclerosing cholangitis is a common manifestation of IgG4-related disease which requires a multi-disciplinary approach to establish the diagnosis. Differentiating IgG4-related sclerosing cholangitis from other conditions, both benign and malignant, is challenging, but vital. Steroids remain the mainstay of treatment. Our understanding of the pathogenesis of the hepatic manifestations of IgG4-related disease continues to evolve.

Survey of stereotactic ablative body radiotherapy in the UK by the QA group on behalf of the UK SABR Consortium.

OBJECTIVE: To ascertain the progress being made towards the implementation of stereotactic ablative body radiotherapy (SABR) treatment in the UK, to obtain details of current practice in centres with an active treatment programme and to assess the projected future provision. METHODS: In August 2012, an online questionnaire was sent to all 65 UK radiotherapy institutions. The included questions covered the current number of patients being treated and the intended number of patients for each clinical site; immobilization and motion management methods; CT scanning protocols; target and organ-at-risk delineation; treatment planning; image-guidance and treatment protocols; and quality assurance methods. RESULTS: 48/65 (74%) institutions responded by the end of November 2012, with 15 indicating an active SABR programme. A further four centres indicated that a SABR protocol had been established but was not yet in clinical use. 14 of the 29 remaining responses stated an intention to develop a SABR programme in the next 2 years. CONCLUSION: The survey responses confirm that SABR provision in the UK is increasing and that this should be expected to continue in the next 2 years. A projection of the future uptake would suggest that by the end of 2014, UK SABR provision will be broadly in line with international practice.

Stereotactic ablative radiotherapy in the UK: current status and developments.

Stereotactic ablative radiotherapy (SABR) has developed from the principles and techniques used in the stereotactic radiosurgery treatment of brain metastases. Advances in computer technology, imaging, planning and treatment delivery and evidence from retrospective analysis of single- and multi-institutional early-phase studies have established SABR in the treatment of medically inoperable early lung cancer. Effective multidisciplinary team working is crucial to safe delivery of SABR. The variation in patient selection, radiotherapy planning and delivery techniques has led to a collective approach to SABR implementation across the UK. Centres developing the technique are represented in the UK SABR Consortium, which is supported by the relevant UK professional bodies and represents a platform to develop extracranial SABR across the UK. The uptake of SABR in the UK has been slowed by workforce issues, but at least 15 centres are currently delivering treatment with over 500 patients treated using UK SABR Consortium guidance. A mentoring program is being piloted helping new centres to develop their programs, and over 30 UK centres are expected to be offering SABR treatment by the end of 2014. The use of consistent guidance for patient selection, treatment planning and delivery in the UK gives the opportunity to collect and audit toxicity and outcome across the centres, contributing to the internationally reported SABR experience. Having established this service in the UK, the development of SABR through clinical research is a priority, and with input from the Radiotherapy Trials Quality Assurance Group, the UK is developing a national study program that includes participation in international trials.

Impact of Duodopa on Quality of Life in Advanced Parkinson's Disease: A UK Case Series.

Treatment options in advanced Parkinson's disease (PD) include subcutaneous apomorphine, pallidal or subthalamic nucleus Deep Brain Stimulation (DBS), or levodopa/carbidopa intestinal gel (LCIG/Duodopa). In this study, we describe the outcome of 12 PD patients with PD related complications started on LCIG, with respect to their quality of life measured by a disease specific validated scale-the PDQ39, together with diaries recording time spent "On," "Off," "Dyskinetic," or "Asleep." At the time of latest follow up, improvements were observed in both the PDQ39 Summary index as well as diary reports of PD symptom control following introduction of LCIG, supporting its use in well selected patients. The use of a trial period of LCIG via naso-jejunal administration allows objective evaluation of improvement in PD symptom control in advance of the placement of the more invasive percutaneous jejunostomy procedure. The decision to embark on LCIG, apomorphine or DBS should be supported by input from centres with experience of all 3 approaches. Since LCIG is an expensive option, development of the most appropriate future commissioning of this therapy in the absence of Class 1 evidence requires careful scrutiny of the outcomes of its use in a broad range of published series.

Comparison of adaptive radiotherapy techniques for the treatment of bladder cancer.

OBJECTIVE: Day-to-day anatomical variations complicate bladder cancer radiotherapy treatment. This work quantifies the impact on target coverage and irradiated normal tissue volume for different adaptive strategies. METHODS: 20 patients were retrospectively planned using different three-dimensional conformal radiotherapy treatment strategies for whole-bladder carcinoma: (i) "conventional" treatment used isotropic expansion of the clinical target volume (CTV) by 15 mm to the planning target volume (PTV) for daily treatment; (ii) "plan of the day" used daily volumetric on-treatment imaging [cone beam CT (CBCT)] to select from four available plans with varying superior PTV margins; (iii) "composite" strategies used on-treatment CBCTs from Fractions 1-3 to inform a composite CTV and adapted PTV (5- and 10-mm margins for composite 1 and composite 2, respectively) for subsequent treatment. Target coverage was evaluated from available CBCTs (the first three fractions then the minimum weekly thereafter), and the reduction in the irradiated volume (i.e. within the 95% isodose) was quantified. RESULTS: Plan of the day improved target coverage (i.e. all of the bladder within the 95% isodose throughout the treatment) relative to conventional treatment (p=0.10), while no such benefit was observed with composite 2. Target coverage was reduced with composite 1 relative to conventional treatment. The mean irradiated volume was reduced by 17.2%, 35.0% and 14.6% relative to conventional treatment, for plan of the day, composite 1 and composite 2, respectively (p<0.01 in all cases). No parameters predictive of large changes in bladder volume later in the treatment were identified. CONCLUSIONS: Adaptive techniques can maintain or improve target coverage while allowing for reduced irradiated volume and possibly reduced toxicity. The plan-of-the-day technique appeared to provide the optimal balance between target coverage and normal tissue sparing. ADVANCES IN KNOWLEDGE: This study suggests that plan-of-the-day techniques will provide optimal outcomes for adaptive bladder radiotherapy.

A combination of serum leucine-rich α-2-glycoprotein 1, CA19-9 and interleukin-6 differentiate biliary tract cancer from benign biliary strictures.

BACKGROUND: Biliary tract cancer (BTC) and benign biliary strictures can be difficult to differentiate using standard tumour markers such as serum carbohydrate antigen 19-9 (CA19-9) as they lack diagnostic accuracy. METHODS: Two-dimensional difference gel electrophoresis and tandem mass spectrometry were used to profile immunodepleted serum samples collected from cases of BTC, primary sclerosing cholangitis (PSC), immunoglobulin G4-associated cholangitis and healthy volunteers. The serum levels of one candidate protein, leucine-rich α-2-glycoprotein (LRG1), were verified in individual samples using enzyme-linked immunosorbent assay and compared with serum levels of CA19-9, bilirubin, interleukin-6 (IL-6) and other inflammatory markers. RESULTS: We report increased LRG1, CA19-9 and IL-6 levels in serum from patients with BTC compared with benign disease and healthy controls. Immunohistochemical analysis also demonstrated increased staining of LRG1 in BTC compared with cholangiocytes in benign biliary disease. The combination of receiver operating characteristic (ROC) curves for LRG1, CA19-9 and IL-6 demonstrated an area under the ROC curve of 0.98. In addition, raised LRG1 and CA19-9 were found to be independent predictors of BTC in the presence of elevated bilirubin, C-reactive protein and alkaline phosphatase. CONCLUSION: These results suggest LRG1, CA19-9 and IL-6 as useful markers for the diagnosis of BTC, particularly in high-risk patients with PSC.

Review article: autoimmune pancreatitis - management of an emerging disease.

BACKGROUND: Autoimmune pancreatitis is a steroid-responsive inflammatory pancreatic disease considered to be part of an immunoglobulin G4 (IgG4)-associated systemic disease. AIM: To review the management of autoimmune pancreatitis. METHODS: We conducted a PubMed search using the following key words: autoimmune pancreatitis, IgG4-associated systemic disease, IgG4-associated cholangitis, diagnosis, natural history, treatment. RESULTS: Although there are reports of spontaneous resolution of autoimmune pancreatitis, steroids have been shown to be effective in inducing remission, reducing the frequency of relapse and that of long-term unfavourable events compared to historical controls. There are no randomised data on autoimmune pancreatitis treatment. Oral steroids are used for induction of remission. Reported response results are excellent with variable proportions of patients achieving remission in different studies. After a period of 2-4 weeks, steroids are tapered and usually withdrawn within several months, although long-term maintenance therapy for all autoimmune pancreatitis patients has also been proposed. Disease relapse occurs in more than 40% of patients and can be effectively treated with additional immunosuppression, including azathioprine. CONCLUSIONS: Steroids are effective in inducing remission and in treating relapse in patients with autoimmune pancreatitis. Randomised trials on autoimmune pancreatitis therapy are lacking. To date, questions concerning the timing, choice and duration of long-term immunosuppression remain unanswered.

Endoscopic retrograde pancreatography criteria to diagnose autoimmune pancreatitis: an international multicentre study.

BACKGROUND: Characteristic pancreatic duct changes on endoscopic retrograde pancreatography (ERP) have been described in autoimmune pancreatitis (AIP). The performance characteristics of ERP to diagnose AIP were determined. METHODS: The study was done in two phases. In phase I, 21 physicians from four centres in Asia, Europe and the USA, unaware of the clinical data or diagnoses, reviewed 40 preselected ERPs of patients with AIP (n=20), chronic pancreatitis (n=10) and pancreatic cancer (n=10). Physicians noted the presence or absence of key pancreatographic features and ranked the diagnostic possibilities. For phase II, a teaching module was created based on features found most useful in the diagnosis of AIP by the four best performing physicians in phase I. After a washout period of 3 months, all physicians reviewed the teaching module and reanalysed the same set of ERPs, unaware of their performance in phase I. RESULTS: In phase I the sensitivity, specificity and interobserver agreement of ERP alone to diagnose AIP were 44, 92 and 0.23, respectively. The four key features of AIP identified in phase I were (i) long (>1/3 the length of the pancreatic duct) stricture; (ii) lack of upstream dilatation from the stricture (<5 mm); (iii) multiple strictures; and (iv) side branches arising from a strictured segment. In phase II the sensitivity (71%) of ERP significantly improved (p<0.05) without a significant decline in specificity (83%) (p>0.05); the interobserver agreement was fair (0.40). CONCLUSIONS: The ability to diagnose AIP based on ERP features alone is limited but can be improved with knowledge of some key features.

A novel imaging technique for fusion of high-quality immobilised MR images of the head and neck with CT scans for radiotherapy target delineation.

Uncertainty and inconsistency are observed in target volume delineation in the head and neck for radiotherapy treatment planning based only on CT imaging. Alternative modalities such as MRI have previously been incorporated into the delineation process to provide additional anatomical information. This work aims to improve on previous studies by combining good image quality with precise patient immobilisation in order to maintain patient position between scans. MR images were acquired using quadrature coils placed over the head and neck while the patient was immobilised in the treatment position using a five-point thermoplastic shell. The MR image and CT images were automatically fused in the Pinnacle treatment planning system using Syntegra software. Image quality, distortion and accuracy of the image registration using patient anatomy were evaluated. Image quality was found to be superior to that acquired using the body coil, while distortion was < 1.0 mm to a radius of 8.7 cm from the scan centre. Image registration accuracy was found to be 2.2 mm (+/- 0.9 mm) and < 3.0 degrees (n = 6). A novel MRI technique that combines good image quality with patient immobilization has been developed and is now in clinical use. The scan duration of approximately 15 min has been well tolerated by all patients.

Extrapancreatic manifestations in autoimmune pancreatitis.

It is increasingly recognized that organs beyond the pancreas may be clinically involved in patients with autoimmune pancreatitis (AIP). Other gastrointestinal sites (such as the extrapancreatic biliary tree, liver, and ampulla) appear particularly affected, but involvement of many other organs (including kidneys, lungs, retroperitoneum, and brain) is increasingly reported. A similar histological lesion, characterized by an IgG4-positive lymphoplasmacytic infiltrate, affects both the pancreas and extrapancreatic tissues, strongly suggesting an aetiopathogenic link. In this review we discuss the clinical presentation and disease course, diagnostic features, and management of extrapancreatic involvement in AIP.