Guido Missale

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.

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.

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.

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.

Evidence for the presence of both D-1 and D-2 dopamine receptors in human esophagus

Clinical and pharmacological evidence suggested that dopamine is involved in the control of esophageal motility. The present study was designed to determine whether or not dopamine receptors are present in human esophagus. With this aim we measured adenylate cyclase activity as a biochemical index of dopamine receptor function in esophageal specimens taken from five patients during surgery for upper esophageal carcinoma. The selective D-1 agonist fenoldopam stimulated cAMP formation in the lower esophageal sphincter, but not in the esophageal body; this effect was prevented by the selective D-1 antagonist SCH 23390 and by d-butaclamol. Bromocriptine, a selective D-2 stimulator, inhibited adenylate cyclase activity in the lower esophageal sphincter, an effect blocked by the D-2 antagonist (-)sulpiride. No effects of bromocriptine were found in the esophageal body. These data indicate that both D-1 and D-2 receptors are present in the lower esophageal sphincter, but not in esophageal body and emphasize the role of dopamine in the regulation of esophageal function.

Opposing roles for D-1 and D-2 dopamine receptors in the regulation of lower esophageal sphincter motility in the rat

In the present study we have identified biochemically DA receptors in rat Lower Esophageal Sphincter (LES) and have identified their role in the control of the sphincter motility. Dopamine (DA) both stimulated and inhibited cyclic AMP formation in rat LES; the pharmacological characterization of these effects indicated that they were mediated by D-1 and D-2 receptors, respectively. The results obtained with LES helical strips showed that DA plays both inhibitory and stimulatory effects on the sphincter function; the pharmacological characterization with selective D-1 and D-2 agonists and antagonists strongly suggested that D-1 receptors are involved in LES contraction, while D-2 receptors mediate the relaxation of the sphincter. The same results were obtained by measuring intraluminal LES pressure in anesthetized rats. The selective D-1 agonist fenoldopam (40 micrograms/kg, i.v.) increased the LES pressure; on the other hand bromocriptine (10 micrograms/kg, i.v.), which preferentially interacts with D-2 receptors, induced a decrease of the resting LES pressure.

Intestinal metaplasia in Barrett's oesophagus: An essential factor to predict the risk of dysplasia and cancer development

BACKGROUND To date, there is still uncertainty on the role of specialized intestinal metaplasia in the carcinogenic process of Barretts oesophagus (BE); this fact seems of importance for planning adequate surveillance programs. AIMS To predict the risk of progression towards dysplasia/cancer based on typical morphological features by evaluating the importance of intestinal metaplasia in BE patients. METHODS 647 cases with a histological diagnosis of BE, referred to the Endoscopy Unit of a tertiary centre between 2000 and 2012 were retrospectively identified, and divided into two groups according to the presence/absence of intestinal metaplasia. For each patient, all histological reports performed during a follow-up of 4-8 years were analyzed. RESULTS Overall, 537 cases (83%) with intestinal metaplasia and 110 cases (17%) without intestinal metaplasia were included. During the follow-up period, none of the patients without intestinal metaplasia developed dysplasia/cancer nor progressed to metaplasia, whereas 72 patients with intestinal metaplasia (13.4%) showed histological progression of the disease. CONCLUSION The histological identification of intestinal metaplasia seems to be an essential factor for the progression towards dysplasia and cancer in BE patients.

Immunocytochemical Assessment of p53 Protein to Detect Malignancy in Increased Cell-Yield Brush Cytology from the Biliopancreatic Tree

Background Malignancies arising from the biliopancreatic tree are often diagnostic challenges for the gastroenterologist and the pathologist, especially when strictures without masses are present. Aim To evaluate the diagnostic yield of p53 immunocytology for the detection of malignancies in material obtained by biliopancreatic tree brushing by means of an increased cell-yield procedure. Patients and Methods Cytologic specimens obtained from biliary and pancreatic tree brushing in 24 patients with biliary strictures suspected for malignancy were assessed by conventional Papanicolau staining and p53 immunocytochemistry. Results Papanicolau staining detected 67% and p53 87% of the malignancies in the study group. p53 immunocytology displayed excellent sensitivity, specificity, and diagnostic accuracy. Conclusions p53 immunocytology may represent a useful diagnostic tool in the detection of malignancies from biliary and pancreatic tree brushing, especially when using an increasing cell-yield procedure.

Lack of interference between small bowel capsule endoscopy and implantable cardiac defibrillators: an ‘in vivo’ electrophysiological study

Background Capsule endoscopy is a widely performed procedure for small bowel investigation. Once swallowed by the patient, the capsule transmits images to an external recorder over a digital radiofrequency communication channel. Potential electromagnetic interferences with implantable cardiac devices have been postulated. Clinical studies on the safety of capsule endoscopy in patients with cardiac defibrillators are lacking. Objective The aim of this study was to assess potential mutual electromagnetic interferences between capsule and defibrillators. Methods This study used the Given M2A video capsule system. Ten different types of defibrillators were tested in a clinical setting. Before capsule ingestion, defibrillator electrical therapies were switched off. During capsule endoscopy patients were monitored with cardiac telemetry. At the end of capsule endoscopy the following defibrillator’s parameters were analysed: change in device settings; inappropriate shocks; inappropriate anti-tachycardia therapy; inappropriate sensing or pacing; noise detection; device reset; programming changes; permanent electrical damages. Any technical problem related to capsule image transmission was recorded. Results Neither defibrillator malfunction nor interference in sensing or pacing was recorded; conversely, no capsule malfunction potentially caused by defibrillators was registered. Conclusion Our results suggest that capsule endoscopy can be safely performed in patients with cardiac defibrillators.