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ABSTRACT: Somatostatin analogs (SA) are the standard of care for controlling symptoms of patients with functional gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs). SA control symptoms in more than 70% of patients with carcinoid syndrome. Similar results are obtained in patients with functional, hormone-secreting, pancreatic NETs. The use of SA as antiproliferative agents has been established only recently. Retrospective studies have shown stabilization of tumor growth in >50% of patients with progressive disease. The results of a recent randomized phase III trial (PROMID) demonstrated that the median time to progression in patients with midgut carcinoid tumors treated with octreotide LAR (Long-Acting-Repeatable, Novartis, Basel, Switzerland) was more than twice as long compared to that of patients treated with placebo. The results of a phase III study of lanreotide versus placebo in nonfunctional NETs are not yet available. More studies are needed to determine whether combining SA with novel targeted treatments will result in enhanced antiproliferative activity compared to treatment with a SA alone. Studies are ongoing using pan-receptor agonists (eg, pasireotide) and chimeric dimers, which possess features of somatostatin and dopamine agonists (dopastatins) and are thought to enhance symptom control by binding multiple receptors (somatostatin and dopamine receptors). Somatostatin receptor antagonists are also currently being developed for clinical use. Peptide receptor radionuclide therapy (PRRT), consisting of yttrium-90 and lutetium-177 isotopes conjugated with SA appear to be efficacious in advanced NETs. Randomized studies are needed to definitively establish the safety and efficacy of this strategy compared to other available treatments, and to determine which radiolabeled isotopes or combinations are most effective.
Seminars in Oncology 02/2013; 40(1):56-68. · 3.50 Impact Factor
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ABSTRACT: The development of valvular heart disease in patients with carcinoid syndrome is thought to be related to the secretion of vasoactive substances by a tumor. We sought to identify modifiable risk factors for the development of carcinoid heart disease because this may help define strategies to attenuate the disease process. Two hundred fifty-two patients with carcinoid syndrome were prospectively followed with serial echocardiograms at 6-month intervals. Clinical characteristics, biochemical markers, and radiologic markers were measured at set intervals. An echocardiographic scoring system was applied. Patients were defined as having progression of carcinoid heart disease if the echocardiographic score increased by ≥25%. After a median follow-up of 29 months, 44 patients developed carcinoid heart disease or had progression of existing valvular dysfunction. At time of progression of carcinoid heart disease compared to the previous 6 months, there was a significant increase in median levels of 5-hydroxyindoleacetic acid (5-HIAA; 791 vs 460.5 μmol/24 hours) and flushing episodes (4.5 vs 2 episodes per day). Independent predictors of the development or progression of carcinoid heart disease were a 5-HIAA level ≥ 300 μmol/24 hours and ≥ 3 episodes of flushing per day. 5-HIAA levels of ≥ 300 to 599, 600 to 899, and > 900 μmol/24 hours conferred 2.74, 3.16, and 3.40 times the risk of progression of carcinoid heart disease, respectively. In conclusion, a 5-HIAA level ≥ 300 μmol/24 hours and ≥ 3 flushing episodes per day are predictors of the development or progression of carcinoid heart disease.
The American journal of cardiology 02/2011; 107(8):1221-6. · 3.58 Impact Factor
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ABSTRACT: Synchronous malignant neoplasms in a single patient are well documented in the literature. It is also recognized that there is increasing incidence of synchronous non-neuroendocrine neoplasm in patients with neuroendocrine tumor (NET). We present a case, of a patient with synchronous colorectal cancer and pancreatic NET, both cancers presenting with liver metastasis. By using 18F-FDG PET and 68Ga-DOTATATE PET imaging, we showed 2 different tumor types within the liver, which was subsequently confirmed on liver biopsy. This case report shows the utility of molecular imaging using different PET peptides. These newer modalities are useful in understanding the biology of the NET and in determining the best patient management.
Journal of clinical gastroenterology 01/2011; 45(1):e8-11. · 2.21 Impact Factor
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ABSTRACT: The development of carcinoid heart disease causes significant valvular dysfunction, eventually leading to symptomatic right heart failure and impaired survival. Data regarding cardiovascular surgery are limited. We sought to identify outcomes, risks and complications of valve surgery for carcinoid heart disease.
Twenty-two patients with carcinoid heart disease underwent cardiac valve surgery between 2006 and 2010. Patients were considered for surgery if (1) they had stable carcinoid tumour, (2) they had severe valvular dysfunction and (3) were symptomatic and (4) they had no other significant co-morbidities. Three patients underwent tricuspid valve replacement alone, 15 patients underwent tricuspid and pulmonary valve replacement, two patients underwent tricuspid, pulmonary and mitral valve replacement and two patients underwent quadruple valve replacement.
Overall 30-day mortality was 18%. Causes of death were right ventricular dysfunction (two patients), carcinoid crises (one patient) and pneumonia (one patient). Four patients required permanent pacemaker for complete heart block. Of those that survived initial surgery, median follow-up was 26 months (interquartile range 8-42); 1- and 2-year survival rates were 56% and 44%, respectively. There was no significant difference in survival between those patients in the New York Heart Association (NYHA) class I/II, mild/moderate right ventricular dilatation or N-terminal brain natriuretic peptide (NT-proBNP) <1245 pg ml(-1) compared with those in NYHA class III/IV, severe right ventricular enlargement or NT-proBNP > 1245 pg ml(-1), respectively. Long-term causes of death were related to advanced metastatic carcinoid tumour. No patient required re-operation for bioprosthetic degeneration.
Valve surgery for carcinoid heart disease is of higher risk compared with most other forms of valvular surgery. However, in those that survive the operation significant improvement in functional class occurs. Most long-term complications were related to the tumour itself rather than cardiac complications.
European journal of cardio-thoracic surgery: official journal of the European Association for Cardio-thoracic Surgery 12/2010; 40(1):168-72. · 2.40 Impact Factor
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ABSTRACT: Carcinoid heart disease is a rare form of valvular heart disease. We sought describe the spectrum of carcinoid heart disease identified by echocardiography and cardiac MRI.
Two hundred fifty-two patients with carcinoid syndrome underwent a range of investigations including 2D transthoracic echocardiography, 3D transthoracic echocardiography and transesophageal echocardiography, and cardiac MRI. Fifty-two patients had evidence of carcinoid heart disease. Involvement of the tricuspid, pulmonary, mitral, and aortic valves were found in 47 (90%), 36 (69%), 15 (29%), and 14 (27%), respectively. Myocardial metastases were found in 2 (3.8%) patients. Several patterns of disease were identified depending on the extent and severity to which each leaflet and its associated subvalvular apparatus was affected. Thirteen of 15 (87%) patients with left-sided carcinoid involvement had a patent foramen ovale. Three patients with severe degree of shunting had severe valvular regurgitation. Patients with mild/moderate degree of shunting had mild or moderate valvular regurgitation. Three-dimensional transthoracic echocardiography/transesophageal echocardiography provided detailed anatomic information particularly for the tricuspid and pulmonary valves. Cardiac MRI allowed complementary assessment of valvular heart disease and delineation of myocardial metastases. Gallium-68 octreotide positron emission tomography identified neuroendocrine metastases.
Carcinoid heart disease is a heterogeneous disease with a wide spectrum of echocardiographic findings. A multimodality approach is needed in patients with this complex pathology.
Circulation Cardiovascular Imaging 11/2009; 3(1):103-11. · 5.94 Impact Factor
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ABSTRACT: A 48-year-old man presented with diarrhea, flushing, abdominal pain and weight loss of 10 kg over a 6-month period. He subsequently developed dyspnea on exertion.
Physical examination, laboratory tests, CT of the abdomen, liver biopsy, echocardiography, immunohistochemistry staining of the biopsy specimen for neuroendocrine markers including chromogranin A, synaptophysin and protein gene product 9.5, and (111)In-pentetreotide scintigraphy (Octreoscan).
Carcinoid tumor of midgut origin with large segment 3 liver metastasis. Carcinoid syndrome and carcinoid heart disease.
Symptomatic relief with somatostatin analog therapy and subsequent resection of the segment 3 liver metastasis. Tricuspid and pulmonary valve replacement.
Nature Reviews Clinical Oncology 08/2009; 6(7):429-33. · 11.96 Impact Factor
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ABSTRACT: We sought to investigate whether N-terminal pro-brain natriuretic peptide (NT-pro-BNP) can be used as a biomarker for the detection of carcinoid heart disease (CHD); 200 patients with carcinoid syndrome were screened for CHD using transthoracic echocardiography. A carcinoid score was formulated to quantify severity of CHD. NT-pro-BNP was measured in all patients before echocardiography. Patients were categorised into New York Heart Association class. CHD was present in 39 patients (19.5%). NT-pro-BNP was significantly higher in those with CHD (median 1,149 pg/ml) than in those without CHD (median 101 pg/ml, p <0.001). The sensitivity and specificity of NT-pro-BNP at a cut-off level of 260 pg/ml for detection of CHD were 0.92 and 0.91, respectively. NT-pro-BNP positively correlated both with carcinoid score (r = 0.81, p <0.001) and New York Heart Association class (p <0.001). The number of patients screened to diagnose 1 case of CHD decreased from 5.1 to 1.4. In conclusion, NT-pro-BNP seems to be an excellent biomarker of CHD. A high negative predictive value may allow it to provide a screening test for CHD.
The American Journal of Cardiology 10/2008; 102(7):938-42. · 3.37 Impact Factor
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ABSTRACT: Parathyroid hormone-related peptide (PTHrP) was discovered in 1987 as the tumour product responsible for humoral hypercalcaemia of malignancy (HHM). Pancreatic neuroendocrine tumours (NETs) are uncommon malignancies with an incidence of 1:100,000 population. PTHrP-secreting NETs are rare but are being recognised as a cause of HHM in NETs. We describe the largest series to date and the management of these rare tumours.
One male and 4 female patients were seen in our unit from 1998 to 2006. The average duration of follow-up was 86 months from initial diagnosis. All patients had a histologically confirmed diagnosis of pancreatic NET, all of which were low-grade tumours. PTHrP assay was performed in 4 of 5 cases and was elevated in these patients.
Initial management involved surgery in 2 of 5 cases, whilst 2 cases underwent chemotherapy and 1 case was commenced on interferon-alpha. We discuss the further therapies that all patients underwent and the complexities that arose in managing disease progression as well as resistant hypercalcaemia.
PTHrP-secreting tumours should be considered in the differential diagnosis of patients with NETs who present with hypercalcaemia and a disproportionately low PTH. PTHrP tumours may well be underestimated as the assay is difficult to perform and may not be requested. In hypercalcaemic patients the standard management acutely includes intravenous fluids, diuretics and intravenous bisphosphonate. In the further management, somatostatin analogue therapy is the first medical option to consider and we discuss the role of other therapies.
Neuroendocrinology 09/2008; 89(1):48-55. · 2.38 Impact Factor
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ABSTRACT: In-pentetreotide scan (OctreoScan) is a widely available agent with high sensitivity for imaging neuroendocrine tumours. Negative In-pentetreotide poses diagnostic as well as therapeutic problems in terms of staging and consideration of targeted radionuclide therapy.
To assess the role of Tc-depreotide in patients with negative or weakly positive OctreoScan (Krenning score< or =1; measured on a scale range 0-4). To determine the usefulness of Tc-depreotide scintigraphy for highlighting lesions that may be missed by OctreoScan and/or CT/MRI imaging.
Prospective analysis of 25 patients with neuroendocrine tumours, with negative or weakly positive In-pentetreotide scans, who were consecutively enrolled to undergo In-pentetreotide and Tc-depreotide imaging. The results were compared with either CT or MRI scans.
Histology was available for 20 of 25 patients: of these 40% had high-grade tumours (cellular proliferation marker Ki-67 score >20%), a further 35% had intermediate-grade tumours (Ki-67 2-20%), and the remaining 25% had low-grade tumours (Ki-67 <2%). Fifty-two percent of patients had completely negative and 48% had weakly positive OctreoScan results. Thirty-two percent of these same patients had significantly positive Tc-depreotide scans (Krenning score> or =2), with the histology demonstrating intermediate-grade or high-grade tumours.
Tc-depreotide imaging has low sensitivity but is useful in a one-third of OctreoScan-negative patients, displaying significantly better uptake than In-pentetreotide in this patient group. It aids diagnosis by highlighting lesions not seen by OctreoScan and/or CT/MRI imaging, and can possibly identify a group of patients amenable to therapy with radionuclide agents, such as SOM230, targeting somatostatin receptor subtypes 2, 3 and 5.
Nuclear Medicine Communications 05/2008; 29(5):436-40. · 1.40 Impact Factor
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ABSTRACT: Carcinoid heart disease (CHD), reported in 50% to 70% of patients with carcinoid syndrome, is thought to be related to the production of 5-hydroxytryptamine by the tumor. The development of new therapeutic modalities designed to reduce tumor hormone production may have altered the development of CHD. Currently, echocardiography is performed when clinical suspicion of CHD exists. The aim of this study was to establish the prevalence of CHD in the setting of modern treatment regimens and delineate whether a screening program for CHD is needed. One hundred fifty patients with carcinoid syndrome were screened for CHD by transthoracic echocardiography. The functional status of patients was classified according to New York Heart Association class. Thirty patients (20%) were found to have CHD. Of those with CHD, 14 (47%) had left- and right-sided valvular lesions. Patent foramen ovale was present in all patients with left-sided CHD. Forty-three percent of patients were in New York Heart Association class I, 40% in class II, 13% in class III and 3% in class IV. Eight patients (27%) with moderate or severe valvular lesions were in class I. Thirty-seven percent of patients with CHD had no physical signs. In conclusion, the presence of symptoms or abnormalities on clinical examination has a low sensitivity for the presence of CHD. Therefore, screening with echocardiography, even in patients who are asymptomatic, should be advocated.
The American Journal of Cardiology 03/2008; 101(3):378-81. · 3.37 Impact Factor
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ABSTRACT: In patients with advanced neuroendocrine tumours, surgery is curative in only a minority of cases, whilst the anti-tumour effect of somatostatin analogues, despite efficient symptom control, is limited. Systemic chemotherapy has been proved to be effective only in certain tumour types. Although metastatic midgut carcinoids and well-differentiated gastrointestinal carcinoids are relatively insensitive to chemotherapy, pancreatic neuroendocrine tumours show a response rate of around 40% to streptozotocin-based combinations, particularly with fluorouracil and doxorubicin. Poorly differentiated tumours respond even better, especially to a combination of cisplatin and etoposide. In patients with predominant liver disease, ischaemia of tumour lesions induced by vascular occlusion by particle embolization or chemoembolization may be considered. This may have clinical and biochemical responses up to 80%, and objective responses up to 60%, in disease which is progressive despite previous treatments. Potential adverse effects and short duration of response should be taken into account.
Bailliè re s Best Practice and Research in Clinical Endocrinology and Metabolism 04/2007; 21(1):131-44. · 4.12 Impact Factor
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ABSTRACT: Goblet cell appendiceal carcinoids represent rare tumors that exhibit histologic features of both adenocarcinomas and neuroendocrine tumors. We present the long-term results of a series of 15 patients, focusing on clinical manifestations, diagnosis, and management.
Eight male and seven female patients (median age, 52.8 years) were included. Final diagnosis was confirmed by histology. Patients were evaluated clinically, biochemically, and radiologically every four months. Median follow-up was 30 months.
The majority of patients (7/15) presented with symptoms compatible with acute appendicitis. Right hemicolectomy was performed in all except one, who subsequently developed metastases. Three patients had metastases at previous diagnosis. Plasma chromogranin-A was slightly elevated in two of them, while urinary 5-hydroxy-indol-acetic acid was normal. (111)Indium-labeled octreotide scintigraphy was positive only in two of the four patients with metastases. Ki67 index was greater than 20 percent in all of them, while in only one with local tumor. Combination chemotherapy with either cisplatin plus etoposide or with 5-fluorouracil, cisplatin, and streptozotocin was administered to all patients with metastases resulting in temporary stabilization of disease. Twelve patients are alive, while three died of their disease 9, 13, and 14 months after diagnosis.
The diagnostic value of chromogranin-A, urinary 5-hydroxy-indol-acetic acid, and (111)Indium-labeled octreotide scintigraphy seems to be limited in these tumors. Ki67 index appears to predict tumor behavior. Right hemicolectomy may reduce the risk of developing metastases. Chemotherapy may have efficacy in metastatic disease, however, more data are required to determine this and the optimal regimen.
Diseases of the Colon & Rectum 04/2007; 50(3):315-22. · 3.13 Impact Factor
