Comprehensive Examination of Cholangiocarcinoma Patients Treated with Novel Targeted Therapies after Extended Molecular Profiling on Liquid Biopsies.

BACKGROUND: Cholangiocarcinoma (CCA) is associated with poor outcomes and limited treatment options, leading to increased use of targeted therapies for its management. Here, we performed one of the largest single-centre reviews evaluating outcomes following personalised targeted agents in CCA patients. METHODS: All consecutive CCA patients receiving systemic therapy between January 2010 and April 2023 at UCLH were included. The primary objective of this study was to evaluate treatment response, survival outcomes and predictors of clinical benefit in CCA patients treated with molecularly guided therapies. Patient demographic factors, disease characteristics and survival outcomes were evaluated using the Kaplan-Meier method and Cox proportional-hazards models. RESULTS: Of the 227 consecutive CCA patients, 162 (71%) had molecular profiling, of whom 56 (35%) were eligible and 55 received molecular-targeted treatment. CCA histological classifications comprised intrahepatic (N = 32), extrahepatic (N = 11), hilar (N = 4) and unknown (N = 9) subtypes. Most patients received targeted agents based on genomic profiling in a second treatment line setting (N = 34). Frequently observed genomic alterations occurred in the FGFR2 (N = 21), IDH1 (N = 7) and BRCA2 (N = 6) genes. Median progression-free survival (PFS) following first-, second- and third-line systemic therapy and overall survival (OS) were 8.44 (95% CI, 7.49-12.78), 5.65 (95% CI, 3.71-7.13), 5.55 (2.79-12.58) and 29.01 (24.21-42.91) months, respectively. CCA subtype and FGFR/BRCA molecular aberration status were not associated with PFS or OS. However, a prior CCA-related surgical history was predictive of OS (p = 0.02). Stratification by best overall response to second-line targeted agents demonstrated an association with PFS (p = 0.002) and OS (p = 0.02). Duration of treatment with second-line targeted therapy was associated with OS (p < 0.001). CONCLUSIONS: Patients receiving targeted therapeutics achieved promising outcomes, especially those attaining a favourable treatment response and those receiving targeted agents for longer periods. Liquid biopsies can reliably provide information on extended molecular profiling to aid patient selection for personalised therapies.

Super-resolution for upper abdominal MRI: Acquisition and post-processing protocol optimization using brain MRI control data and expert reader validation.

PURPOSE: Magnetic resonance (MR) cholangiopancreatography (MRCP) is an established specialist method for imaging the upper abdomen and biliary/pancreatic ducts. Due to limitations of either MR image contrast or low through-plane resolution, patients may require further evaluation with contrast-enhanced computed tomography (CT) images. However, CT fails to offer the high tissue-ductal-vessel contrast-to-noise ratio available on T2-weighted MR imaging. METHODS: MR super-resolution reconstruction (SRR) frameworks have the potential to provide high-resolution visualizations from multiple low through-plane resolution single-shot T2-weighted (SST2W) images as currently used during MRCP studies. Here, we (i) optimize the source image acquisition protocols by establishing the ideal number and orientation of SST2W series for MRCP SRR generation, (ii) optimize post-processing protocols for two motion correction candidate frameworks for MRCP SRR, and (iii) perform an extensive validation of the overall potential of upper abdominal SRR, using four expert readers with subspeciality interest in hepato-pancreatico-biliary imaging. RESULTS: Obtained SRRs show demonstrable advantages over traditional SST2W MRCP data in terms of anatomical clarity and subjective radiologists' preference scores for a range of anatomical regions that are especially critical for the management of cancer patients. CONCLUSIONS: Our results underline the potential of using SRR alongside traditional MRCP data for improved clinical diagnosis.

Quantitative pancreatic MRI: a pathology-based review.

MRI plays an important role in the clinical management of pancreatic disorders and interpretation is reliant on qualitative assessment of anatomy. Conventional sequences capturing pancreatic structure can however be adapted to yield quantitative measures which provide more diagnostic information, with a view to increasing diagnostic accuracy, improving patient stratification, providing robust non-invasive outcome measures for therapeutic trials and ultimately personalizing patient care. In this review, we evaluate the use of established techniques such as secretin-enhanced MR cholangiopancreatography, diffusion-weighted imaging, T 1, T 2* and fat fraction mapping, but also more experimental methods such as MR elastography and arterial spin labelling, and their application to the assessment of diffuse pancreatic disease (including chronic, acute and autoimmune pancreatitis/IgG4 disease, metabolic disease and iron deposition disorders) and cystic/solid focal pancreatic masses. Finally, we explore some of the broader challenges to their implementation and future directions in this promising area.

Pancreatoscopy-Directed Electrohydraulic Lithotripsy for Pancreatic Ductal Stones in Painful Chronic Pancreatitis Using SpyGlass.

OBJECTIVE: Painful chronic pancreatitis is often associated with main duct obstruction due to stones. Approaches to management are challenging, including surgery, extracorporeal shock wave lithotripsy, or endoscopic approaches. Here, we report our experience of pancreatoscopy + electrohydraulic lithotripsy (EHL) for pancreatic duct (PD) stones using SpyGlass. METHODS: We retrospectively audited the use of SpyGlass (Legacy and DS) + EHL. Indication, procedural details, and clinical outcomes were assessed. RESULTS: A total of 118 SpyGlass + EHL procedures for stones were performed, of which 8 (7%) for pancreatic stones, in 6 patients (3 female; mean [standard deviation] age, 45 [7] years). All patients had painful chronic pancreatitis, with radiological evidence of a dilated PD, and main duct stone disease. Surgical options had been considered in all cases. Stone fragmentation and PD decompression were achieved in 83% (n = 5) without complications. Two patients required 2 EHL procedures to achieve clearance. In 1 patient with failed clearance, pancreatoscopy revealed a stone in the adjacent parenchyma and not in PD. All patients with successful EHL had pain relief/marked improvement at clinical review (mean [standard deviation] follow-up, 2.7 [1.1] years). CONCLUSIONS: Pancreatoscopy + EHL may have a valuable role in treating obstructing PD stones, possibly avoiding the need for surgery in some patients.

Acute exacerbation of dysphagia due to foreign body impaction in an oesophageal stricture due to eosinophilic esophagitis.

A 43-year woman with a 4-year history of swallowing difficulty for solids presented with absolute dysphagia, which was only slightly relieved by intravenous relaxant given in the emergency department. Barium swallow showed a smooth polypoid filling defect in the mid-oesophagus, with a hold-up at this level. Gastroscopy showed a narrowed ringed oesophagus with an impacted foreign body. This was extracted with a basket, with relief of the dysphagia. Oesophageal biopsies confirmed the diagnosis of eosinophilic esophagitis.

Current management of cystic echinococcosis: a survey of specialist practice.

BACKGROUND: Cystic echinococcosis (CE) is a significant public health problem worldwide. However, there remains a dearth of evidence guiding treatment in various stages of CE. The 2010 World Health Organization (WHO) Informal Working Group on Echinococcosis (WHO IWGE) guidance is thus based on expert consensus rather than a good evidence base. This study aims to describe the way clinicians worldwide manage CE and to establish whether clinicians follow WHO IWGE guidance. METHODS: Using the online surveying tool SurveyMonkey, a questionnaire was produced detailing 5 clinical cases. Clinicians treating CE were identified and asked how to manage each case through tick-box and short-answer questions. RESULTS: The results showed great variation in practice worldwide. There are practices in common use that are known to be ineffectual, including puncture, aspiration, injection, reaspiration procedures on WHO type 2 cysts, or outdated, including interrupted, rather than continuous, courses of albendazole. A number of unsafe practices were identified such as using scolicidal agents in cysts communicating with the biliary tree and short-course medical therapy for disseminated disease. Most clinicians do not follow the WHO IWGE guidance, but the reasons for this are unclear. CONCLUSIONS: Management of CE varies greatly worldwide. There are key areas of CE for which there is no evidence on which to base guidelines, and randomized controlled trials are needed together with a well-designed international registry to collect data. Further work is required to establish why clinicians do not follow the IWGE guidance, together with better dissemination of future guidance.

Adrenal cancer in neurofibromatosis type 1: case report and DNA analysis.

UNLABELLED: Adrenal cortical carcinoma (ACC) has previously only been reported in eight patients with type 1 neurofibromatosis (NF1). There has not been any clear evidence of a causal association between NF1 gene mutations and adrenocortical malignancy development. We report the case of a 49-year-old female, with no family history of endocrinopathy, who was diagnosed with ACC on the background of NF1, due to a novel germline frame shift mutation (c.5452_5453delAT) in exon 37 of the NF1 gene. A left adrenal mass was detected by ultrasound and characterised by contrast computerised tomography (CT) scan. Biochemical tests showed mild hypercortisolism and androgen excess. A 24-h urinary steroid profile and (18)flouro deoxy glucose PET suggested ACC. An open adrenalectomy was performed and histology confirmed ACC. This is the first reported case with DNA analysis, which demonstrated the loss of heterozygosity (LOH) at the NF1 locus in the adrenal cancer, supporting the hypothesis of an involvement of the NF1 gene in the pathogenesis of ACC. LOH analysis of the tumour suggests that the loss of neurofibromin in the adrenal cells may lead to tumour formation. LEARNING POINTS: ACC is rare but should be considered in a patient with NF1 and adrenal mass when plasma metanephrines are normal.Urinary steroid metabolites and PET/CT are helpful in supporting evidence for ACC.The LOH at the NF1 region of the adrenal tumour supports the role of loss of neurofibromin in the development of ACC.

Cholangiocarcinoma or IgG4-associated cholangitis: how feasible it is to avoid unnecessary surgical interventions?

OBJECTIVE: To evaluate the experience of a tertiary hepatopancreaticobiliary (HPB) center in the diagnostic approach and management of patients with suspicion of cholangiocarcinoma (CCa), focusing on excluding patients with IgG4-associated cholangitis (IAC) from unnecessary major surgical interventions. METHODS: Between January 2008 and September 2010, a total number of 152 patients with suspicion of CCa underwent evaluation through a HPB multidisciplinary team meeting. Patients without tissue diagnosis were managed surgically or medically on the basis of probable presence of IAC as underlying pathology. Serology, immunostaining, and imaging were reviewed and analyzed according to the HISORt (Histology, Imaging, Serology, Other organ involvement, Response to therapy) criteria for IAC. RESULTS: Tissue diagnosis during the diagnostic workup was achieved in 104 patients (68%), whereas the remaining 48 were classified as "highly suspicious for CCa" (n = 35) or as "probable IAC" (n = 13). Among 16 "highly suspicious for CCa" patients who underwent surgery, pathology revealed 2 patients harboring IAC (n = 1) and a benign chronic inflammatory biliary stricture (n = 1), respectively. Among the 13 patients with primarily medical management as "probable IAC," final diagnosis was CCa (n = 3) and IAC (n = 9), while 1 patient had no proven diagnosis. The accuracy of serum IgG4 for diagnosis of IAC reached 60%. Sensitivity and specificity of immunostaining for IAC in biopsy specimens were 56% and 89%, respectively. Imaging features suggesting IAC yielded sensitivity, specificity, and accuracy of 75%, 89%, and 83%, respectively. Initial imaging was revised at the referral institute in 75% of IAC patients (P = 0.009), while an isolated stricture (P = 0.038), a biliary mass (P = 0.006), and normal pancreas on computed tomography (P = 0.01) were statistically significant parameters for distinguishing between CCa and IAC. The mean time for establishing a diagnosis of IAC was 12.4 months (range: 2.5-32 months). CONCLUSIONS: Differential diagnosis between CCa and IAC mandates high index of suspicion and low threshold for referral in high volume institutes. The delayed establishment of diagnosis particularly for CCa needs to be balanced versus avoiding unnecessary surgery for IAC. Imaging features may be most helpful for optimal management.

Endoscopic retrograde cholangiography does not reliably distinguish IgG4-associated cholangitis from primary sclerosing cholangitis or cholangiocarcinoma.

BACKGROUND & AIMS: Distinction of immunoglobulin G4-associated cholangitis (IAC) from primary sclerosing cholangitis (PSC) or cholangiocarcinoma is challenging. We aimed to assess the performance characteristics of endoscopic retrograde cholangiography (ERC) for the diagnosis of IAC. METHODS: Seventeen physicians from centers in the United States, Japan, and the United Kingdom, unaware of clinical data, reviewed 40 preselected ERCs of patients with IAC (n = 20), PSC (n = 10), and cholangiocarcinoma (n = 10). The performance characteristics of ERC for IAC diagnosis as well as the κ statistic for intraobserver and interobserver agreement were calculated. RESULTS: The overall specificity, sensitivity, and interobserver agreement for the diagnosis of IAC were 88%, 45%, and 0.18, respectively. Reviewer origin, specialty, or years of experience had no statistically significant effect on reporting success. The overall intraobserver agreement was fair (0.74). The operating characteristics of different ERC features for the diagnosis of IAC were poor. CONCLUSIONS: Despite high specificity of ERC for diagnosing IAC, sensitivity is poor, suggesting that many patients with IAC may be misdiagnosed with PSC or cholangiocarcinoma. Additional diagnostic strategies are likely to be vital in distinguishing these diseases.

Duodenal web in an adult presenting with acute pancreatitis and acquired megaduodenum: report of a case.

Duodenal webs are a cause of intestinal atresia in infants and surgical repair is the established treatment of choice. However, the late-onset postoperative complications have not been adequately studied, especially in adults who have undergone surgical interventions as infants. This report describes the case of a 65-year-old female patient who presented with consecutive episodes of acute pancreatitis and a history of duodenal atresia repaired by a gastrojejunostomy in early infancy. Imaging studies revealed the presence of megaduodenum and suggested the possibility of impacted stones at the ampulla of Vater. An intact duodenal web at the level of papilla of Vater was revealed during surgery. Excision of the web, tapering of the duodenum and duodenojejunostomy was performed to relieve the obstructive cause of pancreatitis and to restore the intestinal continuity. At the 1-year follow-up, the patient is free of any symptoms, has no diet restrictions, and has increased her body weight as well.

Radical surgery in the presence of biliary metallic stents: revising the palliative scenario.

BACKGROUND: The application of endobiliary self-expandable metallic stents (SEMS) is considered the palliative treatment of choice in patients with biliary obstruction in the setting of inoperable malignancies. In the presence of SEMS, however, radical surgery is the only curative option when the resectability status is revised in case of malignancies or for overcoming complications arising from their application in benign conditions that masquerade as inoperable tumours. The aim of our study was to report our surgical experience with patients who underwent an operation due to revision of the initial palliative approach, whilst they had already been treated with biliary SEMS exceeding the hilar bifurcation. METHODS: Three patients with hilar cholangiocarcinoma that was considered inoperable and one patient with IgG4 autoimmune cholangio-pancreatopathy mimicking pancreatic cancer underwent radical resections in the presence of biliary SEMS. RESULTS: After a detailed preoperative workup, two right trisectionectomies, one left extended hepatectomy and a radical extrahepatic biliary resection were performed. All cases demanded resection and reconstruction of the portal vein. R0 resection was achieved in all the malignant cases. Two patients required multiple biliodigestive anastomoses entailing three and seven bile ducts respectively. There was one perioperative death due to postoperative portal vein and hepatic artery thrombosis, whilst two patients developed grade III complications. At follow-up, one patient died at 13 months due to disease recurrence, whilst the remaining two are free of disease or symptoms at 21 and 12 months, respectively. CONCLUSIONS: Revising the initial palliative approach and operating in the setting of biliary metallic stents is extremely demanding and carries significant mortality and morbidity. Radical resection is the only option for offering cure in such complex cases, and this should only be attempted in advanced hepatopancreaticobiliary centres with active involvement in liver transplantation.

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.

Autoimmune pancreatitis: clinical and radiological features and objective response to steroid therapy in a UK series.

OBJECTIVE: Most cases of autoimmune pancreatitis (AIP) have been reported from Japan. We present data on a UK series, including clinical and radiological features at presentation, and longitudinal response to immunosuppression. METHODS: Over an 18-month period, all patients diagnosed in our center with AIP were studied. Endoscopic biliary stenting was performed as required, and patients were treated with prednisolone, with response assessed longitudinally. In cases of disease relapse following steroid reduction, azathioprine was instituted. RESULTS: Eleven patients met diagnostic criteria for AIP. Diffuse pancreatic enlargement was seen in eight patients (73%), and pancreatic duct strictures in all. Seven patients required biliary stents. Extrapancreatic involvement occurred in all, including intrahepatic stricturing and renal disease. Eight weeks after starting steroids, the median serum bilirubin level had fallen from 38 mumol/L to 11 mumol/L (P= 0.001), and ALT from 97 IU/L to 39 IU/L (P= 0.002). Stents were removed in all cases, with no recurrence of jaundice. Improvements in mass lesions and pancreaticobiliary stricturing occurred in all patients. During a median 18-month follow-up, six patients relapsed, four of whom responded to azathioprine. Two patients discontinued steroids and remained well. CONCLUSIONS: Extrapancreatic disease was an important feature of AIP in this UK series. Initial response to immunosuppressive therapy was excellent, but disease relapse was common. Optimal long-term management remains to be established.

Esophageal cancer staging with endoscopic MR imaging: pilot study.

The authors defined esophageal anatomy and evaluated esophageal cancer staging in a pilot group by comparing endoscopic magnetic resonance (MR) imaging results with pathologic and endoscopic ultrasonographic (US) results when available. A porcine esophagus, one volunteer, and 23 patients suspected of having esophageal cancer were imaged at 0.5 T. MR imaging was successful in 21 patients. Eight of these patients underwent esophagectomy (one after chemotherapy, which invalidated comparison with MR imaging; another did not undergo lymphadenectomy) and one underwent laparoscopy and nodal staging only; eight underwent US. When verified with pathologic staging, endoscopic MR imaging was accurate in six of seven patients (T stage) and five of six patients (N stage; nodal areas too obscured by artifact for comparison in one case). MR imaging and US results concurred in seven of eight (T stage) and five of eight (N stage) patients. No complications were observed. Endoscopic MR imaging is safe and probably comparable to endoscopic US, but with a tendency to overstage the disease.