Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas).

OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2-200)), 9% had resection beyond 1 year of follow-up (3 years (1-20), size at diagnosis: 25 mm (4-140)) and 39% had no surgery (3.6 years (1-23), 25.5 mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. TRIAL REGISTRATION NUMBER: IRB 00006477.

EUS and EUS-FNA diagnosis of suspected pancreatic cystic neoplasms: Is the sum of the parts greater than the CEA?

BACKGROUND: Carcinoembryonic antigen (CEA) is suggested as the single most useful EUS/EUS-FNA derived test for the diagnosis of mucinous pancreatic cysts. STUDY AIMS: To investigate the yield and diagnostic performance of EUS/EUS-FNA on an intention to diagnose basis and to determine the utility of the recommended CEA and amylase cut-off values. PATIENTS AND METHODS: A retrospective study of a prospectively maintained database of 433 procedures performed in a 10 year period. Diagnostic performance of EUS-FNA was determined in 133 procedures with a definite diagnosis. RESULTS: CEA value was determined in significantly fewer procedures (58.6%) than EUS diagnosis was stated (83.4%; p < 0.0001), cyst fluid appearance recorded (89.4%) or adequate sample for cytology obtained (76.7%; p < 0.005). Median CEA was significantly higher in mucinous cysts than non-mucinous (175 ng/ml vs 3 ng/ml, p < 0.0001) and in malignant cysts compared to benign (8945 ng/ml vs 93 ng/ml, p < 0.001). On an intention-to-diagnose analysis, a CEA cut-off of 110 ng/ml was significantly less accurate (42.8%) than EUS diagnosis (67.7%), cytology (58.6%) or aspirate appearance (66.9%; p < 0.05 for all comparisons). However, the combination of EUS diagnosis, cytology and CEA provided higher sensitivity (91%), specificity (75%) and accuracy (85.7%) than each component test alone (p < 0.05 for all comparisons). Median amylase was significantly higher in benign compared to high-risk mucinous cysts ((11,429IU/L vs. 113IU/L; p < 0.05. CONCLUSION: The combination of EUS, cytology and CEA performed well. Malignant cysts had a higher CEA value than benign cysts. On an intention to diagnose basis a CEA cut-off of 110 ng/ml performed poorly.

What to do for the incidental pancreatic cystic lesion?

BACKGROUND: Incidental pancreatic cysts are identified in 1% of all patients undergoing CT scans of the abdomen for whatever reason. The aim of this review was to provide an overview of the current evidence relating to the investigation and management of these lesions. METHODS: PubMed was searched to identify relevant studies relating to the investigation and management of incidentally discovered pancreatic cystic lesions. RESULTS: Initial investigation of incidentally discovered pancreatic cysts should be with either specific pancreas protocol CT or contrast enhanced MRI with MRCP. The diagnostic yield of these investigations can be increased with the addition of EUS/FNA and cyst fluid analysis in appropriately selected patients. Surgical intervention may be indicated in otherwise fit patients who are identified as having mucinous neoplasms. CONCLUSION: Applying a systematic approach to the investigation of incidentally discovered pancreatic cysts means that in the majority of cases cyst aetiology can be accurately determined and appropriate management plans developed.

Comparison of endoscopic ultrasound and computed tomography in the assessment of pancreatic cyst size using pathology as the gold standard.

BACKGROUND/OBJECTIVES: Accurate assessment of whether a cyst is greater than 3 cm is an essential component when considering resection especially for mucinous lesions. The most accurate method of assessing cyst size is uncertain with many patients undergoing several complimentary imaging modalities. This study aimed to compare the accuracy of endoscopic ultrasound (EUS) with CT scanning in assessing pancreatic cyst size compared to histology. METHODS: Patients referred for EUS of a pancreatic cystic lesion from April 2003 to August 2011. Patient age and gender, lesion size and site were recorded and compared using cyst size at histology compared to EUS and CT recorded within 3 months of surgery. Subgroup analysis was performed with respect to cyst site and proven mucinous lesions. RESULTS: 357 patients were included of which 70 (mean age 60.6 years, 24 males) had undergone surgical resection. The resected cysts were located 30/17/23 in the head/body/tail of the pancreas. Median size at histology was 32 mm compared to 35 mm at EUS (p = 0.47) and 35 mm at CT (p = 0.52). For mucinous lesions alone, median size at histology was 32 mm compared to 33 mm at EUS (p = 0.46) and 35 mm at CT (p = 0.39). EUS and CT had comparable sensitivity, specificity, negative predictive value, positive predictive value and accuracy for all cyst types and locations. CONCLUSIONS: CT and EUS measurements are not significantly different to pathological size following resection of pancreatic cystic lesions. CT and EUS are interchangeable investigations for determining cyst size pre-operatively although EUS has the additional advantage of fluid sampling.

The development and evolution of a tertiary pancreaticobiliary endoscopic ultrasound service: lessons learned.

This article reviews the development of the hepatopancreatobiliary (HPB) endoscopic ultrasound (EUS) service at Freeman Hospital and seeks to identify from our experience learning points for good practice and pitfalls to avoid. The Freeman HPB EUS service has expanded rapidly over the past 10 years in response to the consolidation of cancer care and aligned to the needs of the cancer network. Effective multidisciplinary teamwork and increased subspecialisation by the endosonographers has allowed the efficient use of capacity and development of skills. Mechanisms for monitoring diagnostic performance put in place at the outset of the EUS-fine needle aspiration programme have helped to identify interventions that have led to improved test performance. An excellent working relationship between all stakeholders is critical to the success of such a service as is a preparedness to seek and respond to the views of patients and referrers.

Service provision and training for endoscopic ultrasound in the UK.

Endoscopic ultrasound (EUS) is a standard procedure that plays an important role in the management of both malignant and benign disease. The development of EUS services in the UK has been haphazard and training inconsistent. The British Society of Gastroenterology has charged a working group with the task of laying down a national framework for how such services might be commissioned, structured and regulated; with particular attention to defining how endoscopist skills might be acquired, assessed and maintained. This report lays out a map for this process and its future revision.

Comparison of multislice computed tomography and endoscopic ultrasonography with operative and histological findings in suspected pancreatic and periampullary malignancy.

BACKGROUND: This study compared multislice computed tomography (MSCT) with endoscopic ultrasonography (EUS) in the diagnosis and staging of pancreatic and periampullary malignancy. METHODS: Data were collected prospectively on patients having MSCT and EUS for suspected pancreatic and periampullary malignancy. RESULTS: Eighty-four patients had MSCT and EUS, of whom 35 underwent operative assessment (29 resections). In assessing malignancy, there was no significant difference between MSCT and EUS, and agreement was good (82 per cent, kappa = 0.49); the sensitivity and specificity of MSCT were 97 and 87 per cent, compared with 95 and 52 per cent respectively for EUS (P = 0.264). For portal vein/superior mesenteric vein invasion, MSCT was superior (P = 0.017) and agreement was moderate (72 per cent, kappa = 0.42); the sensitivity and specificity were 88 and 92 per cent for MSCT, and 50 and 83 per cent for EUS. For resectability, there was no significant difference and agreement was good (78 per cent, kappa = 0.51). EUS had an impact on the management of 14 patients in whom MSCT suggested benign disease or equivocal resectability. CONCLUSION: MSCT is the imaging method of choice for pancreatic and periampullary tumours. Routine EUS should be reserved for those with borderline resectability on MSCT.

Endoscopic necrosectomy as primary therapy in the management of infected pancreatic necrosis.

BACKGROUND AND STUDY AIMS: Open pancreatic necrosectomy is the standard treatment for infected pancreatic necrosis but is associated with significant morbidity, mortality, and prolonged hospital stay. Percutaneous or endoscopic necrosectomy are alternative techniques. We evaluated the use of endoscopic necrosectomy for treatment of patients with necrosis that could be accessed through the posterior wall of the stomach. PATIENTS AND METHODS: We retrospectively analyzed the indication, patient status according to acute physiology and chronic health evaluation (APACHE) 2 severity score, and success of endoscopic necrosectomy as primary treatment, in selected patients with localized infected pancreatic necrosis, who presented between May 2002 and October 2004. After the necrosis cavity had been accessed, with the assistance of endoscopic ultrasound, a large orifice was created and necrotic debris was removed using endoscopic accessories under radiological control. Follow-up was clinical and radiological. RESULTS: 13 patients (nine men, four women, mean age 53 years), 11 with positive bacteriology, underwent attempted endoscopic necrosectomy. Median APACHE 2 score on presentation was 8 (range 1-18). Four patients needed intensive therapy unit care and one other patient required (nonventilatory) high-dependency unit care only. Necrosis was successfully treated endoscopically in 12 patients, requiring a mean of 4 endoscopic interventions (range 1-10); one patient required open surgery; two underwent additional percutaneous necrosectomy and one required laparoscopic drainage. Two patients died of complications unrelated to the procedure. The 11 survivors have a median (range) follow-up of 16 (6-38) months. CONCLUSION: Endoscopic necrosectomy is a safe method for treatment of infected pancreatic necrosis. Multiple procedures are usually needed. It may be combined with other methods of surgical intervention. Larger prospective studies will more precisely define its role.

Increase in serum bilirubin levels in obstructive jaundice secondary to pancreatic and periampullary malignancy--implications for timing of resectional surgery and use of biliary drainage.

BACKGROUND: Routine preoperative biliary drainage in cases of jaundice secondary to pancreatobiliary malignancy is associated with a significant risk of complications, failure and stent occlusion. It may be possible to avoid biliary drainage in those patients who are not deeply jaundiced. AIMS: To measure presenting serum bilirubin and its rate of increase in patients with malignant obstructive jaundice. To predict the urgency with which surgery should be performed to avoid preoperative biliary drainage. PATIENTS AND METHODS: Prospective data collection for all pancreatic and periampullary malignancies over a period of 18 months was carried out. Serum bilirubin levels before successful drainage were recorded. Rates of increase in bilirubin and the number of days for bilirubin to reach different thresholds were calculated. RESULTS: Of 111 patients, 66 (59%) had resectable disease on imaging investigations. Median serum bilirubin on presentation was 160 micromol/l. Median increase was 13.1 micromol/l/day or approximately 100 micromol/l/week. The predicted number of days for bilirubin levels to reach a variety of thresholds varied significantly. For a patient presenting with a serum bilirubin of 160 micromol/l, the mean number of days for it to rise to 200 micromol/l, 300 micromol/l, 400 micromol/l and 500 micromol/l was 3, 13, 22 and 31 days, respectively. CONCLUSIONS: There is a variable window of opportunity in jaundiced patients with pancreatic and periampullary malignancy during which surgery may be performed to avoid biliary drainage procedures, depending on the threshold for operating on the jaundiced patient.

The development of new carboxylic acid-based MMP inhibitors derived from a cyclohexylglycine scaffold.

A series of carboxylic acids was prepared based on cyclohexylglycine scaffolds and tested for potency as matrix metalloproteinase (MMP) inhibitors. Detailed SAR for the series is reported for five enzymes within the MMP family, and a number of inhibitors such as compound 18 display low nanomolar potency for MMP-2 and MMP-13, while selectively sparing MMP-1 and MMP-7.

Chemoenzymatic synthesis of functionalized cyclohexylglycines and alpha-methylcyclohexylglycines via Kazmaier-Claisen rearrangement.

The synthesis of homochiral functionalized cyclohexylglycines and alpha-methylcyclohexylglycines via chelated Kazmaier-Claisen rearrangement is described. These were shown to be potent scaffolds for the development of MMP inhibitors.

Effect of L-ornithine-L-aspartate on patients with and without TIPS undergoing glutamine challenge: a double blind, placebo controlled trial.

BACKGROUND AND AIM: An oral glutamine load in cirrhotic patients awaiting liver transplantation was shown to cause a rise in blood ammonia and psychometric abnormalities which were reversed by hepatic transplantation. L-Ornithine-L-aspartate (LOLA) has been shown to reduce ammonia and improve psychometric function in patients with hepatic encephalopathy. The aim of the present study was to assess the effect of LOLA in healthy patients with cirrhosis and no evidence of clinical encephalopathy after challenging the central nervous system by administration of oral glutamine. PATIENTS AND METHODS: Eight cirrhotics (Child's B or C) without transjugular intrahepatic portosystemic shunts (TIPS) and seven with TIPS underwent two oral glutamine (20 g) challenges, receiving LOLA (5 g intravenously) on one occasion and placebo on the other in random order. Psychometric tests, including choice reaction time (CRT) and number connection test, were performed before and after glutamine, together with electroencephalography and blood ammonia. RESULTS: Mean basal ammonia was 27 (SEM 5) micromol/l in non-TIPS and 76 (10) micromol/l in TIPS patients (p<0.05). Basal CRT 2 was 0.643 (0.033) s in non-TIPS and 0.825 (0.076) s in TIPS patients (p<0.02). In non-TIPS patients, ammonia increased to 36 (10) micromol/l when LOLA was administered and to 62 (13) micromol/l with placebo (p<0.02). There was no alteration in psychometric function in non-TIPS patients after glutamine when LOLA was given but when placebo was given, glutamine caused prolongation of CRT (p=0.02). Glutamine did not affect psychometric function in TIPS patients with or without LOLA. CONCLUSION: This study showed that LOLA ameliorated the deleterious psychometric effects of glutamine in Child's grade B and C patients with cirrhosis without TIPS and supports its use in clinical practice in hepatic encephalopathy.

Oral glutamine challenge in cirrhotics pre- and post-liver transplantation: a psychometric and analyzed EEG study.

Latent or sub-clinical hepatic encephalopathy is a recognized complication of cirrhosis and is thought to represent one end of the spectrum of neuropsychiatric impairment, which occurrs as a result of portal-systemic shunting. We studied the psychometric, analyzed electroencephalography (EEG), and venous blood ammonia responses to an oral glutamine challenge in 17 patients with cirrhosis and in 4 normal controls. The cirrhotics were attending for liver transplant assessment and had no clinical evidence of hepatic encephalopathy. The oral glutamine challenge was repeated following liver transplantation. Five of sixteen patients (31%) showed impaired performance on at least one of the baseline psychometric tests. There was a correlation between fasting venous ammonia and choice reaction time (r = .7, P < .01). Following glutamine challenge there was a significant increase in blood ammonia from a mean fasting value ranging between 58 micromol/L to 120 micromol/L (P < .01), between significant prolongation of reaction times of 387 ms to 428 ms (P < .01), and an increase in mean EEG amplitude between 68.5 microV to 78.6 microV (P < .001). Four normal controls who were challenged with glutamine and 6 cirrhotic patients who were challenged with water showed no change in any of these parameters. Following orthotopic liver transplantation (OLT) the eight patients studied had normal baseline psychomotor performance with significant improvements in digit symbol, digit span, information processing, number connection tests (P < .05), and reaction time (P < .005). Posttransplantation, there were no significant changes in blood ammonia, analyzed EEG, or choice reaction time in response to oral glutamine challenge (six patients). We conclude that short lived changes in blood ammonia (in cirrhotics) can cause significant impairment of sensitive tests of brain function and that psychometric performance is improved following OLT.

Synaptosomal glutamate transport in thioacetamide-induced hepatic encephalopathy in the rat.

Dysfunction of excitatory glutamatergic neurotransmission has been implicated in the cause of hepatic encephalopathy. Brain microdialysis studies in various animal models of portal systemic encephalopathy (PSE) and encephalopathy associated with acute liver failure, have established that an increase in extracellular glutamate occurs but the mechanisms of this are unclear. We have measured oxygen consumption, citrate synthase activity (as indices of energy state and mitochondrial content, respectively), calcium-dependent glutamate release, and high-affinity, sodium-dependent glutamate uptake by synaptosomes prepared from rats with thioacetamide-induced encephalopathy. (2 doses of thioacetamide 200 mg/kg with a 24-hour interval). Synaptosomes were prepared either by a modified P2 method (glutamate release study) or by discontinuous sucrose density gradient centrifugation (all other studies). There was no significant difference in synaptosomal oxygen consumption, citrate synthase activity, glutamate release, total synaptosomal glutamate content, or the Kd for glutamate uptake between the encephalopathy group and the controls. However, there was a marked decrease in the maximal velocity of transport (Vmax) for glutamate uptake in synaptosomes from encephalopathic rats, 2.64 versus 4.40 nmol/min/mg (P < .05). The results of this study provide evidence of impaired glutamate uptake in the rat thioacetamide model of hepatic encephalopathy, which could account for the elevated extracellular glutamate seen in the condition.