Renzo Cestari

Consensus Statements for Management of Barrett's Dysplasia and Early-Stage Esophageal Adenocarcinoma, Based on a Delphi Process

BACKGROUND & AIMS Esophageal adenocarcinoma (EA) is increasingly common among patients with Barretts esophagus (BE). We aimed to provide consensus recommendations based on the medical literature that clinicians could use to manage patients with BE and low-grade dysplasia, high-grade dysplasia (HGD), or early-stage EA. METHODS We performed an international, multidisciplinary, systematic, evidence-based review of different management strategies for patients with BE and dysplasia or early-stage EA. We used a Delphi process to develop consensus statements. The results of literature searches were screened using a unique, interactive, Web-based data-sifting platform; we used 11,904 papers to inform the choice of statements selected. An a priori threshold of 80% agreement was used to establish consensus for each statement. RESULTS Eighty-one of the 91 statements achieved consensus despite generally low quality of evidence, including 8 clinical statements: (1) specimens from endoscopic resection are better than biopsies for staging lesions, (2) it is important to carefully map the size of the dysplastic areas, (3) patients that receive ablative or surgical therapy require endoscopic follow-up, (4) high-resolution endoscopy is necessary for accurate diagnosis, (5) endoscopic therapy for HGD is preferred to surveillance, (6) endoscopic therapy for HGD is preferred to surgery, (7) the combination of endoscopic resection and radiofrequency ablation is the most effective therapy, and (8) after endoscopic removal of lesions from patients with HGD, all areas of BE should be ablated. CONCLUSIONS We developed a data-sifting platform and used the Delphi process to create evidence-based consensus statements for the management of patients with BE and early-stage EA. This approach identified important clinical features of the diseases and areas for future studies.

Long-term endoscopic surveillance of patients with Barrett's esophagus. Incidence of dysplasia and adenocarcinoma: a prospective study.

OBJECTIVE:Barretts esophagus (BE) is a premalignant condition for which regular endoscopic follow-up is usually advised. We evaluated the incidence of esophageal adenocarcinoma (AC) in patients with BE and the impact of endoscopic surveillance on mortality from AC.METHODS:A cohort of newly diagnosed BE patients was studied prospectively. Endoscopic and histological surveillance was recommended every 2 yr. Follow-up status was determined from hospital and registry office records and telephone calls to the patients.RESULTS:From 1987 to 1997, BE was diagnosed in 177 patients. We excluded three with high-grade dysplasia (HGD) at the time of enrollment. Follow-up was complete in 166 patients (135 male, 31 female). The mean length of endoscopic follow-up was 5.5 yr (range 0.5–13.3). Low-grade dysplasia (LGD) was present initially in 16 patients (9.6%) and found during follow-up in another 24 patients. However, in 75% of cases, LGD was not confirmed on later biopsies. HGD was found during surveillance in three patients (1.8%), one with simultaneous AC; two with HGD developed AC later. AC was detected in five male patients during surveillance. The incidence of AC was 1/220 (5/1100) patient-years of total follow-up, or 1/183.6 (5/918) patient-years in subjects undergoing endoscopy. Four AC patients died, and one was alive with advanced-stage tumor. The mean number of endoscopies performed for surveillance, rather than for symptoms, was 2.4 (range 1–10) per patient. During the follow-up years the cohort had a total of 528 examinations and more than 4000 biopsies.CONCLUSION:The incidence of AC in BE is low, confirming recent data from the literature reporting an overestimation of cancer risk in these patients. In our patient cohort, surveillance involved a large expenditure of effort but did not prevent any cancer deaths. The benefit of surveillance remains uncertain.

Predictive Factors of Mortality From Nonvariceal Upper Gastrointestinal Hemorrhage: A Multicenter Study

OBJECTIVES:From an Italian Registry of patients with upper gastrointestinal hemorrhage (UGIH), we assessed the clinical outcomes and explored the roles of clinical, endoscopic, and therapeutic factors on 30-day mortality in a real life setting.METHODS:Prospective analysis of consecutive patients endoscoped for UGIH at 23 community and tertiary care institutions from 2003 to 2004. Covariates and outcomes were defined a priori and 30-day follow-up obtained. Logistic regression analysis identified predictors of mortality.RESULTS:One thousand and twenty patients were included. A total of 46 patients died for an overall 4.5% mortality rate. In all, 85% of deaths were associated with one or more major comorbidity. Sixteen of 46 patients (35%) died within the first 24 h of the onset of bleeding. Of these, eight had been categorized as ASA class 1 or 2 and none of them was operated upon, despite a failure of endoscopic intention to treatment in four. Regression analysis showed advanced age, presence of severe comorbidity, low hemoglobin levels at presentation, and worsening health status as the only independent predictors of 30-day mortality (P < 0.001). The acute use of a PPI exerted a protective effect (OR 0.23, 95% CI 0.09–0.73). Recurrent bleeding was low (3.2%). Rebleeders accounted for only 11% of the total patients deceased (OR 3.27, 95% CI 1.5–11.2).CONCLUSIONS:These results indicate that 30-day mortality for nonvariceal bleeding is low. Deaths occurred predominantly in elderly patients with severe comorbidities or those with failure of endoscopic intention to treatment.

Predicting Mortality in Non-Variceal Upper Gastrointestinal Bleeders: Validation of the Italian PNED Score and Prospective Comparison With the Rockall Score

OBJECTIVES:We sought (i) to validate a new prediction rule of mortality (Progetto Nazionale Emorragia Digestiva (PNED) score) on an independent population with non-variceal upper gastrointestinal bleeding (UGIB) and (ii) to compare the accuracy of the Italian PNED score vs. the Rockall score in predicting the risk of death.METHODS:We conducted prospective validation of analysis of consecutive patients with UGIB at 21 hospitals from 2007 to 2008. Outcome measure was 30-day mortality. All the variables used to calculate the Rockall score as well as those identified in the Italian predictive model were considered. Calibration of the model was tested using the χ2 goodness-of-fit and performance characteristics with receiver operating characteristic (ROC) analysis. The area under the ROC curve (AUC) was used to quantify the diagnostic accuracy of the two predictive models.RESULTS:Over a 16-month period, data on 1,360 patients were entered in a national database and analyzed. Peptic ulcer bleeding was recorded in 60.7% of cases. One or more comorbidities were present in 66% of patients. Endoscopic treatment was delivered in all high-risk patients followed by high-dose intravenous proton pump inhibitor in 95% of them. Sixty-six patients died (mortality 4.85%; 3.54–5.75). The PNED score showed a high discriminant capability and was significantly superior to the Rockall score in predicting the risk of death (AUC 0.81 (0.72–0.90) vs. 0.66 (0.60–0.72), P<0.000). Positive likelihood ratio for mortality in patients with a PNED risk score >8 was 16.05.CONCLUSIONS:The Italian 10-point score for the prediction of death was successfully validated in this independent population of patients with non-variceal gastrointestinal bleeding. The PNED score is accurate and superior to the Rockall score. Further external validation at the international level is needed.

HER-2 overexpression/amplification in Barrett's oesophagus predicts early transition from dysplasia to adenocarcinoma: a clinico-pathologic study.

Barrett’s oesophagus (BO) is the primary precursor lesion for oesophageal adenocarcinoma (ADC). The natural history of metaplasia‐dysplasia‐carcinoma sequence remains largely unknown. HER2/neu oncogene results overexpressed/amplified in preneoplastic lesions and in ADC of the oesophagus and it has been associated with poor prognosis. Our aim was to evaluate the role of HER2 overexpression/amplification in predicting the conversion from precursor lesions to ADC. We retrospectively evaluated by univariate analysis of single variables clinical records and histological specimens of 21 patients with a confirmed diagnosis of BO and/or oesophageal dysplasia. Clinical variables included age, gender, alcohol and smoking intake, presence of symptoms (pyrosis, disphagia) and endoscopic features (length). HER2 status was studied by immunohistochemistry and fluorescence in situ hybridization (FISH) on paraffin‐embedded tissue. The end‐points were the occurrence of progression and the time‐to‐progression (TTP) from the initial histologic lesion to the worst pathological pattern. Median age at diagnosis was 63 years (range 37–84). BO median length was 4.5 cm. Progression occurred in 11 of 21 patients and median TTP was 24 months. HER2 was overexpressed/amplified in 8 of 21 (38%) patients. HER2 overexpression/ amplification and the presence of dysplasia were statistically associated with progression (P= 0.038). This study provides evidence for a possible role of HER2 in the transition from dysplasia to ADC of the oesophagus. This fact could help in identifying patients at high risk of malignant transformation.

Evidence of Epstein-Barr virus infection in ulcerative colitis.

BACKGROUND AND AIM The aetiology of ulcerative colitis is still controversial, however, recent studies have emphasised the possible role of infectious agents or ingested substances and their breakdown products, which might activate immune-mediated mechanisms eventually leading to tissue damage. Aim of this investigation was to ascertain the occurrence and the potential role of Epstein-Barr virus infection in large bowel mucosa of ulcerative colitis patients. PATIENTS AND METHODS Twenty-three biopsies and six total colectomies from 17 patients were analysed for the expression of Epstein-Barr virus proteins and RNAs. Polymerase chain reaction experiments were also carried out to detect Epstein-Barr virus DNA. For comparison, ten biopsies from patients with Crohns disease, ten biopsies from patients with different types of colitis, seven biopsies and five surgical margins of normal colonic mucosa from the small and large bowels were studied (controls). RESULTS Six biopsies and four colectomies from seven ulcerative colitis patients showed scattered lymphocytes expressing nuclear EBER 1-2 and harbouring polymerase chain reaction-amplifiable Epstein-Barr virus-DNA. In some cases, linear viral DNA (typical of lytic Epstein-Barr virus infection) was also found. Epithelial cells were invariably negative in all cases. All control tissues from non-ulcerative colitis patients were also invariably non-reactive. CONCLUSION Evidence of Epstein-Barr virus infection in the mucosal inflammatory cells of ulcerative colitis patients suggests a possible role of this virus in the chronicity of ulcerative colitis.

Haemodynamic effect of triglycyl-lysine-vasopressin (glypressin) on intravascular oesophageal variceal pressure in patients with cirrhosis: A randomized placebo controlled trial

A double-blind random administration of 2 mg glypressin intravenously (i.v.) or placebo was given to 20 volunteer patients suffering from liver cirrhosis with portal hypertension and oesophageal varices. Experimental protocol required two basal intravascular oesophageal variceal pressure (IOVP) measurements, before and after bolus i.v. drug injection. The second measurement was taken as reference to determine whether the treatment was effective. Other measurements were taken 1, 3, 5 and 10 min after drug administration. The fall in IOVP at 3, 5 and 10 min in the patients who had been administered glypressin proved statistically significant (p less than 0.01) with mean percentage variations of -22.3%, -24.4% and -27.9%, respectively. In conclusion, the administration of glypressin in portal hypertensive patients brought about a marked reduction in transmural oesophageal variceal pressure in over 70% of the cases. This decrease may prove to be of clinical importance both as a first line therapy and as a possible aid to emergency sclerotherapy in the presence of active variceal bleeding.

Oesophageal manometry in early and definite systemic sclerosis

The objective of this study was to evaluate the oesophageal dysfunction in patients with “early” systemic sclerosis (SSc), as defined by LeRoy and Medsger, to compare it with that of patients with definite SSc, and to correlate it with other features of the disease. Oesophageal manometry results were retrospectively evaluated in 181 patients classified by the 2001 LeRoy and Medsger criteria and the 1980 American College of Rheumatology (ACR) criteria: group 1: limited SSc: Raynaud’s phenomenon plus specific nailfold capillaroscopy abnormalities and/or autoantibodies; group 2: limited cutaneous SSc not satisfying the ACR criteria (lcSSc ACR−); group 3: lcSSc ACR+; group 4: diffuse cutaneous SSc. Peristaltic abnormalities in the oesophageal body were present in 73 of 125 patients with SSc ACR+ (groups 3 and 4) compared with 13 of 56 with SSc ACR− (groups 1 and 2) (p<0.0001). They were more severe in patients with more advanced disease (1 vs 2; 1 vs 3; 1 vs 4; 2 vs 4; p<0.05) and in patients anti-Scl-70+ than in patients anticentromere positive (p=0.02). Abnormalities of the lower oesophageal sphincter (LES) were present in 35 of 125 patients with SSc ACR+ and 11 of 56 with SSc ACR− (not statistically different). They were correlated with forced vital capacity (FVC) (LES pressure: p=0.0005; LES length: p=0.0004). Abnormalities of the oesophageal body and of the LES were found in 21 and 16% of 46 patients without oesophageal symptoms. Oesophageal manometry can detect abnormalities in a sizeable proportion of patients with “early SSc” not fulfilling the ACR criteria, including asymptomatic patients. The correlation between LES abnormalities and FVC suggests a possible causal relationship between these disease manifestations.

TOPOIIα and HER-2/neu overexpression/amplification in Barrett’s oesophagus, dysplasia and adenocarcinoma

Rossi E, Villanacci V, Bassotti G, Donato F, Festa A, Cengia G, Grisanti S & Cestari R
(2010) Histopathology 57, 81–89
TOPOIIα and HER‐2/neu overexpression/amplification in Barrett’s oesophagus, dysplasia and adenocarcinoma

Different neurotransmitter systems are involved in the development of esophageal achalasia

Clinical and pharmacological evidence suggests that several neurotransmitters are involved in the control of the esophageal motility; in fact, besides the well known cholinergic and sympathetic innervation, Vasoactive Intestinal Polypeptide (VIP)-containing fibers as well as dopamine (DA)-containing nerve endings have been identified within the esophageal wall. Lower Esophageal Sphincter (LES) achalasia is a neuromuscular disorder characterized by the absence of peristalsis in the body of the esophagus and by the failure of the LES to relax in response to swallowing. Stimulation of both VIP receptors and D-2 DA receptors induce a decrease in LES pressure, while D-1 receptors mediates LES contractions. In the present study we show that both VIP and DA system is disregulated in LES achalasia. In particular, this disease is associated not only with the lack of VIP nerves in the LES, but also with a failure in the responsiveness of postsynaptic receptors to VIP stimulation. Furthermore, we demonstrate a selective functional loss of the D-2 DA receptor component, without changes in the D-1 DA receptor mediated responses.