Stefano Festa

Molecular pathology and genetics of pancreatic endocrine tumours.

Pancreatic neuroendocrine tumours (PETs) are the second most frequent pancreatic neoplasms. Their poor chemosensitivity, high rate of metastatic disease and relatively long survival make PETs an ideal field to be explored for novel therapies based on specific molecular changes. PETs are generally sporadic but can also arise within hereditary syndromes, such as multiple endocrine neoplasia type 1, von Hippel-Lindau, neurofibromatosis type 1 and tuberous sclerosis complex, which represent a model for sporadic cases too. Among allelic imbalances, main genomic changes involve gain of 17q, 7q and 20q and loss of 11q, 6q and 11p, which identify regions of putative candidate oncogenes or tumour suppressor genes (TSGs), respectively, sometime with potential prognostic significance. Overexpression of Src-like kinases and cyclin D1 (CCND1) oncogene has been described. As for TSGs, P53 (TP53), DPC4/SMAD4 and RB (RB1) are not implicated in PET tumorigenesis, while for p16INK4a (CDKN2A), TIMP3, RASSF1A and hMLH1, more data are available, suggesting a role for methylation as a silencing mechanism. In the last decade, gene expression profile studies, analysis of microRNAs and, more recently, large-scale mutational analysis have highlighted commonly altered molecular pathways in the pathology of PETs. The roles of the mammalian target of rapamycin pathway, and its connection with Src kinases, and the activity of a number of tyrosine kinase receptors seem to be pivotal, as confirmed by the results of recent clinical trials with targeted agents. Mutations of DAXX and ATRX are common and related to altered telomeres but not to prognosis.

Molecular target therapy for gastroenteropancreatic endocrine tumours: Biological rationale and clinical perspectives

Gastroenteropancreatic endocrine tumours (GEP ETs) represent a relatively rare and heterogeneous group of neoplasms whose therapy can be challenging. The poorly differentiated, fast-growing cases are treated with chemotherapy. In the slow-growing ones, biotherapy is usually performed. Several categories of targeted therapies have been studied for their treatment in vitro and in vivo. A critical review of molecular alterations suggests a rationale for targeting angiogenesis, and the phosphatidylinositol 3 kinase (PI(3)K)/AKT/mammalian target of rapamycin (mTOR) pathway. Accordingly, antiangiogenic agents and mTOR inhibitors are presently the most tested agents in phase II and III studies. Bevacizumab, some multitarget inhibitors, and mTOR inhibitors showed promising results in patients with advanced GEP ETs. A limited activity has been reported for imatinib and epidermal growth factor receptor (EGFR) inhibitors. Combinations of molecular targeted therapies with different sites of action, and somatostatin analogues may be relevant to avoid molecular escape pathways. Future trials should include more homogeneous groups of patients and pay more attention to the subgroup with progressive disease.

Acute fulminant hepatitis E virus genotype 3e infection: Description of the first case in Europe

Abstract Hepatitis E virus (HEV) is the most important causative agent of acute hepatitis in developing countries. The disease is usually characterized by a self-limiting, benign course. However, when particular conditions coexist (pregnancy, old age, pre-existing liver disease) it may run an unfavourable course. To date, 4 HEV genotypes have been described. Historically, in the Western world, HEV infection was considered a travel-related disease, however in the last 2 decades a great number of non-travel-related autochthonous cases have been described, more often related to genotype 3 or 4 and in the context of zoonosis. We report the case of an elderly Italian man with an acute fulminant HEV infection genotype 3e that developed in the context of pre-existing liver disease; this is the first case of an unfavourable outcome associated with subgenotype 3e. The potential pathogenicity of this subgenotype together with the influence of host-related risk factors are discussed.

“Mucosal healing” in ulcerative colitis:Between clinical evidence and market suggestion

In recent decades, the prominent role of endoscopy in the management of ulcerative colitis (UC) has been translated into the concept of mucosal healing (MH) as a fundamental therapeutic end-point. This is partially the consequence of growing evidence of a positive prognostic role of MH on the disease course and partially due to market cues indicating a higher rate of MH in patients treated by novel potent biologic agents. The aim of the present review is to clarify the current knowledge of MH in UC, analyzing the definition, the putative prognostic role and the association of MH with the current drugs used to treat UC patients. Because solid data about the management of UC patients based solely on the healing of the mucosa are not yet available, a tailored approach for individual patients thatconsiders the natural history of UC and the presence of prognostic indicators of aggressive disease is desirable. Consequently, unnecessary examinations and treatment would be avoided and restricted to UC patients who require the maximum amount of effort to affect the disease course in the short and long term.

A case of pancreatic small cell neuroendocrine carcinoma associated with SIADH

To the Editor: W e read with interest the recent Pancreas article by Wu et al entitled “When to initialize enteral nutrition in patients with severe acute pancreatitis?” The timing for enteral nutrition initiation in severe pancreatitis is a relevant issue, but we believe that the study design does not allow answering the question. Indeed, this study evaluates essentially the impact of enteral nutrition in comparison to parenteral nutrition because 83% of the patients in “delayed enteral nutrition” group received exclusive parenteral nutrition. However, it is already well established that enteral nutrition was superior to parenteral nutrition to decrease infectious and surgical complications, as well as mortality in severe pancreatitis. On the other hand, the authors used the presence of necrosis to define the expected severity of acute pancreatitis. To date, it is accepted that the systemic inflammatory response syndrome is the better parameter to predict the expected severity of an acute pancreatitis. To assess comparability between the groups, SIRS and organ failure on admission are missing. The main objective of an early enteral nutrition during severe acute pancreatitis is to maintain the integrity of the gut barrier and then to prevent bacterial translocation. The choice made by the authors to use nasojejunal feeding tube placed by endoscopy could be debated. Authors give no information about energy supply within the first 48 hours, but we can assume that some days are necessary to reach the goal of 25 to 30 kcal/kg per day because of delay for the tube placement and the progressive feeding speed (initiated at 20 mL/h). In a recent randomized trial comparing the early nasojejunal tube feeding with an oral diet,

Acute fulminant hepatitis E virus genotype 3e infection: description of the first case in Europe.

We thank Dr Bazarbachi and Dr Haffar for their interest in our article [1]. We agree with them that hepatitis E virus (HEV) infection represents an emerging problem in developed countries, which remains largely overlooked and deserves additional research efforts to better understand its peculiar aspects, especially in the industrialized setting. We appreciate their detailed comments about challenges in diagnosing liver cirrhosis (LC) in the context of acute fulminant hepatitis (AFH), with most of the radiological features overlapping for both conditions. In everyday clinical practice non-invasive imaging techniques play an important role in the diagnosis of LC [2], together with biochemical fi ndings [3]. In particular, several studies have shown a high accuracy (range 66 – 95%), and inter-observer agreement for computed tomography (CT) in the diagnosis of LC, suggesting that CT may be a useful diagnostic test in patients who have contraindications to biopsy [4,5]. Thus, although we acknowledge the possible limitations of the abovementioned studies (most of which do not include AFH patients), the reliability of this non-invasive imaging technique in the diagnosis of LC did support its use for this purpose in our patient. In addition, the clinical management and the diagnostic strategy we followed did consider the advanced age of the patient (79 years), and the coexistence of relevant comorbidities (including severe systemic atherosclerothic disease, previous aortic prosthesis placement, and coagulopathy). These defi ned a high risk for liver transplantation, an option that was accordingly not followed. Consequently, invasive procedures would not have changed our patient ’ s treatment plan, only adding potentially severe procedure-related side effects. Despite pancreatic head enlargement described on CT scan, acute pancreatitis was ruled out, since clinical signs such as abdominal pain were absent and biochemical parameters (amylase and lipase) were within normal limits. In conclusion, we agree with Dr Bazarbachi and Dr Hoffar on the observation that HEV infection should be considered and searched for in cases of acute hepatitis also in the western countries, since the disease is more prevalent than we thought and considering that it can follow a severe course and that possible treatments are available.

A Critical View of Molecularly Target Therapy for Digestive Endocrine Tumours

Enteropancreatic endocrine tumours (EP ETs) are relatively rare neoplasms constituting a heterogeneous nosological category. Most EP ETs present with metastatic disease, are well-differentiated and have a relatively slow growth-rate, with high percentage of stable disease and relative long survival. In those patients with progressive disease biotherapy and chemotherapy have relatively low response rates. In this context, novel therapies are needed, especially for the treatment of progressive, metastatic disease which represents, in this field, the main therapeutic challenge. EP ETs seem an appropriate model for targeting angiogenesis, with solid data from animal and in vitro models. Effects of angiogenesis inhibitors, such as bevacizumab, sunitinib, thalidomide and endostatin seem promising especially in patients with pancreatic tumours. Targeting other tyrosine kinases such as EGFR (with gefitinib) or c-KIT (imatinib) has also been tested, with various degree of response. The mTOR pathway also looks as an interesting pathway to be targeted, with interesting data in some clinical trials. The main limits of the available data are represented by the high heterogeneity of patients and of inclusion criteria. Moreover, few studies included patients with documented progressive disease before treatment, thus making difficult to understand the real efficacy of treatment on spontaneous tumour growth. Future studies should evaluate combination therapies in more homogeneous populations of patients, and include clear definition of the individual progression rate before and after the study entry. An informative review of novel patents and therapeutic targets of enteropancreatic endocrine tumours are also discussed.