Volume 72 - 2009 - Fasc.1 - Case series
Role of vasoactive substances and cellular effectors in the pathophysiology of cirrhotic portal hypertension: the past, the present and the future - Georges Brohée lecture -
In the last decade, knowledge regarding mechanisms involved in the pathogenesis of portal hypertension has taken unprecedented levels. However, many aspects still remain to be elucidated. Portal hypertension is primarily caused by an increase in resistance to portal outflow and secondly by an increase in splanchnic blood flow. In a later phase, these changes lead to a hyperdynamic circulation with increased cardiac output and decreased systemic vascular resistance and perfusion pressure. Regional alterations in vasoreactivity (vasodilation and vasoconstriction) play a central role in the pathophysiology of portal hypertension by contributing to increased intrahepatic resistance, hyperdynamic circulation, and expansion of the collateral circulation. Among vasoactive substances activated in portal hypertension, nitric oxide (NO) is considered as the most important vasodilator. Endothelin-1 and cyclooxygenase-derived prostaglandins are the foremost vasocon- strictor factors. The imbalance between the hyperresponsiveness and overproduction of vasoconstrictors and the hyporesponsive- ness and impaired production of vasodilators are the main respon- sible of the increased vascular one in the sinusoidal area of the liver. In addition to an imbalance in vasoactive substances, a major role has been attributed to activated hypercontractile hepatic stel- late cells which cause vascular remodelling as an adaptive response to the changed balance in vasoactive substances. The present paper aims to elucidate on available knowledge and novel mechanisms gathered over the last years with regard to cirrhotic portal hyper- tension and the increased intrahepatic vascular resistance in particular. (Acta gastroenterol. belg., 2009, 72, 9-16).
Quality assurance and recommendations for quality assessment of screening colonoscopy in Belgium
As population-wide screening for colorectal cancer is adopted by many western countries for all individuals aged 50-75. The success of screening colonoscopy programs is highly dependent on the quality of the procedures. High-quality complete endoscopy with excellent patient preparation and adequate withdrawal time is necessary for effectively reducing colon cancer risk.
In Belgium formal quality assurance programs and principles of credentialing do not exist. The current reimbursement system for colonoscopy does not reward a careful performed examination but rapidly performed examinations at unnecessarily short intervals. There is a clear need for evidence-based quality measures to ensure the quality of screening colonoscopy.
In this guideline review we present an overview of the literature concerning criteria for best practice and important quality indica- tors for colonoscopy. A summary of the latest guidelines is given. Our goal of this update is to provide practical guidelines for endo- scopists performing screening colonoscopy. We hope to provide a broad consensus and an increasing adherence to these recommen- dations. (Acta gastroenterol. belg., 2009, 72, 17-25).
Management of gastro-entero-pancreatic neuroendocrine tumours (GEP NET) : an introduction
Since the discovery of secretin by Bayliss and Starling in 1902 many hormones have been identified in the gut, so that the gastro-intestinal-pancreatic tract can be con- sidered the largest endocrine organ in the human body. Gut endocrine cells constitute a complex regulatory net- work for local control of secretion, absorption, motility, mucosal cell proliferation and differentiation.
Endocrine committed cells in the gut may undergo proliferative changes leading to hyperplastic and dys- plastic lesions and sometimes giving origin eventually to gut or pancreas endocrine tumours, also called neuroen- docrine tumours (NET) (1). They are characterized his- tologically by the intracellular presence of markers of endocrine tissue, such as chromogranin A and neuron- specific enolase, which can be used in the diagnosis of these tumours.
Diagnostic pitfalls in digestive neuroendocrine tumours
Gastro-entero-pancreatic neuroendocrine tumours (GEP NET) represent a rare and highly heterogeneous entity that often is revealed by vague and non-specific symptoms, leading to a delayed diagnosis. Here we will review some of the most regularly observed false positive and false negative cases and provide clues to recog- nize and manage them properly. Particularly, the value of chromo- granin-A as a serum tumour marker and Somatostatin receptor scintigraphy as an imaging test, are reviewed. Indeed, chromo- granin-A and other hormones, such as gastrin, as well as urinary 5- hydroxy-indolic acetic acid (5-HIAA) are often tested to diagnose NET without appraising the clinical situation, leading to extensive work-up on false bases. On the other hand, some tests are per- formed in situations where they do not add additional information (e.g. 5-HIAA in pancreatic or rectal NET) because invariably negative. Somatostatin receptor scintigraphy is an expensive examination, still not reimbursed in Belgium, for which indications must be carefully assessed, knowing its specificity and sensitivity. (Acta gastroenterol. belg., 2009, 72, 29-33).
Carcinoid Heart Disease - a hidden complication of neuroendocrine tumours
Carcinoid heart disease (CHD) develops in serotonin-producing neuroendocrine tumours (NET) due to fibrotic endocardial plaques with associated valve dysfunction leading most often to right-sided heart failure.
The classical carcinoid syndrome usually occurs when serotonin- producing NET metastasize to the liver. Up to 50% of those patients will exhibit carcinoid heart disease.
The pathophysiological process is not yet completely under- stood : serotonin is considered to be a major initiator of the fibrotic process, but other tumour secreted factors may contribute to the pathogenesis. Histopathology reveals intact valvular cusps with superimposed fibrotic plaques, leading to thickening and retraction of the valves, causing valvular dysfunction.
A high index of clinical suspicion to diagnose CHD is needed since symptoms can be rather non-specific. Transthoracic echocar- diography is the gold standard for diagnosis and should probably be performed at the time of diagnosing serotonin-producing NET and then repeated annually. On the other hand, when diagnosing right-heart failure, the presence of CHD and underlying serotonin- producing NET should be taken into account.
Therapeutic options include pharmacotherapy for heart failure, control of the systemic carcinoid disease and in selected individu- als cardiac valve replacement.
The elucidation of the pathologic process is necessary to develop targeted antifibrotic therapeutic agents since CHD seems to be irreversible and associated with poor prognosis. (Acta gastroenterol. belg., 2009, 72, 34-38).
The role of surgery and transplantation in neuroendocrine tumours
Surgery represents the only chance of cure for a patient with a neuroendocrine tumour (NET). The main indications for surgery lie in the risk of developing metastatic disease with increasing tumour diameter and for a functioning NET also in control of the hormonal syndrome. However, only a small minority of patients presents with a potentially resectable primary NET without metastatic disease. An R0-resection is mandatory, which may be achieved in selected cases by tissue sparing surgical techniques.
Most patients unfortunately present with a locally advanced or metastatic disease. For patients with an advanced functioning NET, control of the hormonal syndrome may also represent a sur- gical indication. Various cytoreductive techniques or, in highly selected cases, liver transplantation can be applied. For locally advanced non-functioning tumours, there is an indication for sur- gery in large tumours which tend to create local complications because of bleeding or bowel obstruction. Especially in ileal NETs aggressive surgical therapy is recommended because of prevention of long term complications, which may improve survival. (Acta gastroenterol. belg., 2009, 72, 39-43).
Locoregional and radioisotopic targeted treatment of neuroendocrine tumours
Gastro-entero-pancreatic neuroendocrine tumours (GEP NET) are a heterogeneous group of proliferative disorders whose man- agement dramatically relies on tumour biology. For well-differen- tiated, low-proliferative index tumours, locoregional treatment and targeted radioisotopic therapies offer an attractive and seemingly efficient alternative to palliative surgical resections. Lack of well- designed, prospective, randomized multicentric studies hinders a balanced evaluation of available locoregional treatment methods : embolization, chemo-embolization, radio-embolization.
According to available datas, all techniques achieve a 50-60% radiological response rate and almost 80% of symptomatic relieve for the patients, while their impact on progression-free and overall survival remains not assessable.
Same conclusions can be drawn for radiolabeled targeted thera- pies like MetaiodoBenzylGuanidine (MIBG) and Peptide Receptor Radionuclide Therapy (PRRT), which, provided that their target is expressed by tumour cells, can deliver therapeutic doses of radia- tion to neoplastic tissues.
131I-MIBG has been associated with a 50% symptomatic response rate and mainly haematological toxicities. PRRT with 111In-DiethyleneTriamineentaacetic Acid-Octreotide, [90Y-DOTA0- Tyr3]-Octreotide, or [177Lu-DOTA0-Tyr3]-Octreotate seem to alleviate symptoms in 50% of patients and obtain a radiological response in 30-38%. Renal toxicity, partially preventable, is more frequent than previously thought and result in an annual decrease in glomerular function by 4 to 8% per year.
Forthcoming research in GEP NET should by a majority be designed in randomized, prospective and multicentric fashion. Locoregional disease trials must focus on clinical outcome differ- ences between embolization techniques (embolization, chemoem- bolization and radioembolization) and surgery.
In disseminated disease, studies should assess radiolabeled targeted therapies efficiency when administered along with and compared to new biological and older chemotherapeutic agents. (Acta gastroenterol. belg., 2009, 72, 44-48).
Role of chemotherapy in gastro-entero-pancreatic neuroendocrine tumors : the end of a story ?
Gastroenteropancreatic Neuroendocrine Tumours (GEP NET) are heterogeneous and rare malignancies although their prevalence is increasing. Multiple therapeutic approaches are available to date for their management, including surgery, hormonal and immune radionucleide therapies and chemotherapy. The purpose of this review is to collect, examine, and analyze data available regarding contemporary chemotherapeutic management of GEP NET in order to determine whether or not chemotherapy still takes place in the therapeutic arsenal of GEP NET. We therefore performed a systematic search of all the English-spoken literature regarding GEP NET. Anthracyclins, 5-fluorouracil (5-FU), DTIC and strep- tozotocin are amongst the most commonly used chemotherapeutic agents, usually prescribed in combination. Their efficiency in reducing tumor burden is not always associated with better sur- vival, perhaps due to severe toxicity. Chemotherapy in GEP NET is mainly devoted to poorly differentiated tumours, but also in well differentiated carcinomas either not eligible or resistant to other therapies. Chemotherapy remains therefore useful in specific cases of GEP NET management. However, a new era of antitumoral agents, such as targeted therapies, could eventually replace these old recipes in the near future. (Acta gastroenterol. belg., 2009, 72, 49-53).
The antiproliferative effect of somatostatin analogs : clinical relevance in patients with neuroendocrine gastro-entero-pancreatic tumours
Somatostatin analogs (ssAs) have an important role in the management of patients with neuroendocrine tumours of the gastrointestinal tract and pancreas (GEP NETs). These compounds can control the symptoms induced by the production of hormones and peptides. The antiproliferative effects of ssAs and especially tumour shrinkage are less obvious in patients with GEP NETs than in those with acromegaly. However, based upon phase II experi- ence there is a strong suggestion of a disease stabilizing effect of ssAs in selected patients. Those patients with a progressive, non- functional GEP NET, positive octreotide scintigraphy, a low prolif- eration index and in the absence of surgical options may benefit from a first-line medical therapy with ssAs. The exploration of the mechanisms of this effect are unclear and hampered by the lack of suitable preclinical models.
The better understanding of the tumour biology of GEP NETs, together with the development of new ssAs with better affinity on all somatostatin receptors, represent an unmet medical need. (Acta gastroenterol. belg., 2009, 72, 54-58).
The potential role of targeted therapies in the management of neuroendocrine tumours
The management of gastro-entero-pancreatic neuroendocrine tumours is evolving thanks to new TNM-classification, diagnostic and staging procedures and new therapeutic options. Targeting new pathways, mostly angiogenesis, development of novel agents is under way and opens new perspectives in controlling the evolution of these tumours and possibly changing their management. In parallel, new functional imaging techniques and biomolecular markers will be developed to provide adequate tools for the assess- ment of tumor response according to therapeutic intervention on angiogenesis, proliferation and apoptosis.
This paper reviews the potential role of new investigational targeted agents which will likely become the backbone of future therapy of neuroendocrine tumors. (Acta gastroenterol. belg., 2009, 72, 59-62).
