Giampiero Macarri

Italian consensus guidelines for the diagnostic work-up and follow-up of cystic pancreatic neoplasms.

This report contains clinically oriented guidelines for the diagnostic work-up and follow-up of cystic pancreatic neoplasms in patients fit for treatment. The statements were elaborated by working groups of experts by searching and analysing the literature, and then underwent a consensus process using a modified Delphi procedure. The statements report recommendations regarding the most appropriate use and timing of various imaging techniques and of endoscopic ultrasound, the role of circulating and intracystic markers and the pathologic evaluation for the diagnosis and follow-up of cystic pancreatic neoplasms.

Regulation of ERK/JNK/p70S6K in two rat models of liver injury and fibrosis

BACKGROUND/AIMS The regulation of three major intracellular signalling protein kinases was investigated in two models of liver injury leading to hepatic fibrosis, dimethylnitrosamine administration (DMN) and bile duct ligation (BDL). METHODS Extracellular signal-regulated kinases (ERK)1/2, c-Jun terminal kinase (JNK) and p70S6-kinase (p70(S6K)) were studied in vivo in the whole liver, in liver sections and in isolated hepatocytes, cholangiocytes and hepatic stellate cells (HSC). RESULTS In the whole liver, activation of these kinases occurred with a different kinetic pattern in both models of liver injury. By immunohistochemistry and Western blot in isolated cells, phosphorylated kinases were detected in proliferating cells (i.e. hepatocytes and cholangiocytes after DMN and BDL, respectively), in addition to stellate-like elements. ERK1/2, JNK and p70(S6K) activation was associated with hepatocytes proliferation after DMN, while JNK activation was not associated with cholangiocytes proliferation after BDL. In HSC isolated from injured livers, protein kinases were differentially activated after BDL and DMN. Kinases activation in HSC in vivo preceded cell proliferation and alpha-smooth muscle actin appearance, a marker of HSC transformation in myofibroblast-like cells, and collagen deposition. CONCLUSIONS Our findings indicate that these kinases are coordinately regulated during liver regeneration and suggest that their modulation could be considered as a future therapeutic approach in the management of liver damage.

Intracellular pH regulation and Na+/H+ exchange activity in human hepatic stellate cells: effect of platelet-derived growth factor, insulin-like growth factor 1 and insulin

BACKGROUND/AIMS The Na+/H+ exchanger is involved in rat hepatic stellate cell (HSC) proliferation induced by platelet-derived growth factor (PDGF). We therefore evaluated in human HSC: (1) the mechanisms of intracellular pH regulation; (2) the relationship between Na+/H+ exchange activation and cell proliferation induced by PDGF, insulin-like growth factor 1 (IGF-1) and insulin. METHODS/RESULTS pH(i) regulation was mainly dependent on the activity of the Na+/H+ exchanger, which was evaluated by measuring pH(i) recovery from an acute acid load. PDGF (25 ng/ml) gradually increased the activity of the Na+/H+ exchanger which peaked at 18 h and remained stable until the 24th h. IGF-1 (10 nmol/l), but not insulin (100 nmol/l), slightly but significantly increased the activity of the Na+/H+ exchanger. Amiloride (100 micromol/l) and 20 micromol/l 5-N-ethyl-N-isopropyl-amiloride completely inhibited HSC proliferation (evaluated by measurement of bromodeoxyuridine incorporation) induced by PDGF and IGF-1, but did not affect proliferation of HSC induced by insulin. Finally, IGF-1 did not modify the activity of the Na+/Ca2+ exchanger. CONCLUSIONS The Na+/H+ exchanger is involved in HSC proliferation induced by PDGF and IGF-1, whereas the proliferative effect of insulin is mediated by intracellular pathways which are Na+/H+ exchange-independent.

Primary biliary cirrhosis: modalities of injury and death in biliary epithelium.

BACKGROUND/AIM Despite the number of studies on primary biliary cirrhosis, contrasting data remain concerning modalities of cholangiocyte death. Liver biopsies obtained from 40 patients with anti mitochondrial antibody-positive primary biliary cirrhosis, at various stages of the disease, were examined, and special attention was paid to the expression of subcellular damage and evidence of apoptosis. METHODS Liver sections were stained with haematoxylin/eosin or Sirius red. Ductular mass was evaluated on sections after cytokeratin 7 staining. Apoptosis was evaluated on haematoxylin/eosin stained material or after processing for terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling assay. In 16 patients, part of the biopsy was processed for electron microscopy. Twenty histologically normal liver biopsies were used for control purposes. RESULTS According to Scheuers classification, 29 patients were classified as stage I-II, and 11 as stage III-IV. A strong staining of bile ducts was evident after immunohistochemistry for cytokeratin 7, often associated with ductular metaplasia in lobular zone 1. Cytokeratin 7-positive cells occupied 3.0+/-1.3% of liver mass as compared to 0.25+/-0.03% in controls. Ductular metaplasia accounted for 1.4+/-0.07% of all cytokeratin 7-positive cells. Regardless of staging, apoptotic bodies were seen only exceptionally in epithelial wall of bile ducts, whereas cholangiocyte damage leading to extensive lytic necrosis appeared responsible for most of the bile duct mass loss, as also confirmed by ultrastructural studies. A few terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling-positive nuclei were occasionally associated with the inflammatory infiltrate and evidence of apoptosis in hepatocytes was frequent, especially in zone 1. CONCLUSION Regardless of staging, lytic necrosis and not apoptosis accounts for most of the bile duct loss in primary biliary cirrhosis. Furthermore, ductular metaplasia appears as a late event with highly variable pattern being observed between patients.

A simplified clinical risk score predicts the need for early endoscopy in non-variceal upper gastrointestinal bleeding

BACKGROUND Pre-endoscopic triage of patients who require an early upper endoscopy can improve management of patients with non-variceal upper gastrointestinal bleeding. AIMS To validate a new simplified clinical score (T-score) to assess the need of an early upper endoscopy in non variceal bleeding patients. Secondary outcomes were re-bleeding rate, 30-day bleeding-related mortality. METHODS In this prospective, multicentre study patients with bleeding who underwent upper endoscopy were enrolled. The accuracy for high risk endoscopic stigmata of the T-score was compared with that of the Glasgow Blatchford risk score. RESULTS Overall, 602 patients underwent early upper endoscopy, and 472 presented with non-variceal bleeding. High risk endoscopic stigmata were detected in 145 (30.7%) cases. T-score sensitivity and specificity for high risk endoscopic stigmata and bleeding-related mortality was 96% and 30%, and 80% and 71%, respectively. No statistically difference in predicting high risk endoscopic stigmata between T-score and Glasgow Blatchford risk score was observed (ROC curve: 0.72 vs. 0.69, p=0.11). The two scores were also similar in predicting re-bleeding (ROC curve: 0.64 vs. 0.63, p=0.4) and 30-day bleeding-related mortality (ROC curve: 0.78 vs. 0.76, p=0.3). CONCLUSIONS The T-score appeared to predict high risk endoscopic stigmata, re-bleeding and mortality with similar accuracy to Glasgow Blatchford risk score. Such a score may be helpful for the prediction of high-risk patients who need a very early therapeutic endoscopy.

Management of serous cystic neoplasms of the pancreas

Pancreatic serous cystadenomas are uncommon benign tumours that are often found incidentally on routine imaging examinations. Radiological imaging techniques alone have proven to be suboptimal to fully characterize cystic pancreatic lesions. Endoscopic ultrasound, with the addition of fine-needle aspiration in difficult cases, has showed greater diagnostic accuracy than conventional imaging techniques. The best management strategy of these neoplasms is still debated. Surgery should be limited only to symptomatic and highly selected cases and most of the patients should only be strictly monitored. In the current paper, we provide an updated overview on pancreatic serous cystadenomas, focusing our attention on epidemiology, clinical characteristics and diagnostic evaluation; finally, we also discuss different management strategies and areas for future research.

Endoscopic ultrasound-guided tissue acquisition of pancreatic masses with core biopsy needles using wet suction technique

We read with great interest the recent review by Villa et al. entitled, “Endoscopic ultrasound-guided fine needle aspiration: The wet suction technique”[1] about a novel sampling method for endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) of pancreatic solid lesions. In brief, this technique includes removing the stylet and flushing the needle with saline to replace the column of air with water, and then the needle is passed into the lesion and the suction applied with a 10cc prevacuum syringe[2] or with a 10cc syringe prefilled with 3 mL of normal saline.[3]

Endoscopic Ultrasonography May Select Subjects Having Asymptomatic Chronic Pancreatic Hyperenzymemia Who Require a More Strict Follow-up.

Objectives We have previously shown that at least 50% of patients with asymptomatic chronic pancreatic hyperenzymemia (ACPH) may develop morphological pancreatic alterations. Endoscopic ultrasonography (EUS) may detect small lesions, and its sensitivity seems to be higher than other imaging techniques. The aim of this study was to evaluate whether EUS may modify the management of patients having ACPH. Methods In 2 referral centers for pancreatic disease, a retrospective analysis of prospectively enrolled patients with ACPH was conducted. Results Seventy-three patients with ACPH were enrolled for the purpose of this study. Endoscopic ultrasonography was performed as the last examination in 45 subjects who resulted negative at previous imaging studies (abdominal ultrasound, computed tomography, magnetic resonance imaging associated with cholangiopancreatography). Using EUS in 7 subjects, abnormalities were found in the following: 3 branch-duct intraductal papillary mucinous neoplasms, 1 duodenal diverticulum, 1 annular pancreas, 1 findings suggestive of chronic pancreatitis, and 1 undefined cyst (<5 mm). Conclusions Endoscopic ultrasonography is able to detect alteration not found by other imaging technique in 15.5% of patients with ACPH and may be useful to select those patients who require a more strict follow-up.

Biliary plastic stent does not influence the accuracy of endoscopic ultrasound-guided sampling of pancreatic head masses performed with core biopsy needles

OBJECTIVE While the presence of biliary stent significantly decreases the accuracy of endoscopic ultrasound (EUS) for pancreatic head cancer staging, its impact on the EUS-guided sampling accuracy is still debated. Furthermore, data on EUS-fine needle biopsy (EUS-FNB) using core biopsy needles in patients with pancreatic mass and biliary stent are lacking. The aim of this study was to evaluate the influence of biliary stent on the adequacy and accuracy of EUS-FNB in patients with pancreatic head mass. METHODS All patients who underwent EUS-guided sampling with core needles of solid pancreatic head masses causing obstructive jaundice were retrospectively identified in a single tertiary referral center. Adequacy, defined as the rate of cases in which a tissue specimen for proper examination was achieved, with and without biliary stent, was the primary outcome measure. The diagnostic accuracy and complication rate were the secondary outcome measures. RESULTS A total of 130 patients with pancreatic head mass causing biliary obstruction were included in the study: 74 cases of them were sampled without stent and 56 cases with plastic stent in situ. The adequacy was 96.4% in the stent group and 90.5% in the group without stent (p=0.190). No significant differences were observed for sensitivity (88.9% vs. 85.9%), specificity (100% for both groups), and accuracy (89.3% vs. 86.5%) between those with and without stent, respectively. The accuracy was not influenced by the timing of stenting (<48h or ≥48h before EUS). No EUS-FNB related complications were recorded. CONCLUSION The presence of biliary stent does not influence the tissue sampling adequacy, the diagnostic accuracy and the complication rate of EUS-FNB of pancreatic head masses performed with core biopsy needles.

Pancreatic disorders in inflammatory bowel disease

An increased incidence of pancreatic disorders either acute pancreatitis or chronic pancreatitis has been recorded in patients with inflammatory bowel disease (IBD) compared to the general population. Although most of the pancreatitis in patients with IBD seem to be related to biliary lithiasis or drug induced, in some cases pancreatitis were defined as idiopathic, suggesting a direct pancreatic damage in IBD. Pancreatitis and IBD may have similar presentation therefore a pancreatic disease could not be recognized in patients with Crohns disease and ulcerative colitis. This review will discuss the most common pancreatic diseases seen in patients with IBD.