68Ga-labelled peptides for diagnosis of neuroendocrine tumours

On the basis of available literature, the aim of this paper is to describe the advantages and limitations of ⁶⁸Ga-DOTA peptide PET/CT imaging for the assessment of neuroendocrine tumours (NET) and to examine potential future perspectives. The introduction of new PET tracers labelled with ⁶⁸Ga has changed the diagnostic approach to NET. While in the past decades the gold standard imaging modality for NET detection was the somatostatin analogue tracers labelled with ¹¹¹In, several advantages now emerge by using both labelled somatostatin analogues with ⁶⁸Ga and PET/CT tomography for image acquisition, leading to a larger use of these tracers in clinical practice. There is an increasing number of reports showing the higher accuracy of ⁶⁸Ga-DOTA peptide PET/CT for the detection of NET lesions as compared to morphological imaging procedures and somatostatin receptor scintigraphy. The use of ⁶⁸Ga-DOTA peptides offers the possibility to non-invasively evaluate NET cells for the presence of somatostatin receptor expression, with direct therapeutic implications. Last but not least, the use of ⁶⁸Ga-DOTA peptides also leads to several practical advantages including the relatively easy and economic synthesis process and the fact that ⁶⁸Ga labelling can be performed in centres without an on-site cyclotron.     

Surgical treatment of neuroendocrine tumours of the pancreas

Gastro-entero-pancreatic (GEP) endocrine tumours can originate from various pancreatic islet cells, from endocrine cells of the gastric and duodenal mucosa, or from APUD cells of neuroectodermal origin in the gastrointestinal tract. They are benign when smaller than 2 cm, but larger tumours are generally malignant. Surgery is the only method for the curative treatment of GEP tumours. A diagnosed and localised tumour is an absolute indication for radical surgery. Conservative medical treatment may be indicated only in an inoperable condition, but in this case tumour reduction surgery is suggested. In the last 15 years 22 patients with pancreatic neuroendocrine tumours were treated without any mortality. Except for two of them, the surgical therapy was curative.     

Proliferative activity of well differentiated neuroendocrine tumours of the gut

Neuroendocrine tumours of the gastrointestinal tract are relatively uncommon neoplasms with, in spite of their characteristic morphology, relatively unpredictable biological behaviour. In some sites, notably the appendix, these tumours are largely benign whereas at other localisations, such as the small bowel, metastases occur and the outcome is less favourable. Given the lack of discriminative power of histological parameters, immunohistochemical parameters have been proposed. Of these the Ki-67 index, as an indicator of proliferative activity, has shown some promise. In order to assess their proliferative activity and the potential contribution of this parameter to defining biological behaviour, we performed Ki-67 immunostaining of a series of 64 well differentiated neuroendocrine tumours of the gut (stomach, small bowel, appendix, colon and rectum). Ki-67 labeling index, based upon counting of up to 5000 cells, ranged between 0 and 6.1%. No difference was found according to age, gender, size, location or TNM classification. Ki-67 labeling index of midgut endocrine tumours of long term surviving patients did not differ from patients that died. We conclude that Ki-67 labeling index as an indicator of proliferative activity of well differentiated neuroendocrine tumours of the digestive tract does not correlate with size nor site nor stage. Even though only small numbers of tumours could be analysed, which hampered appropriate statistical analysis, it seems unlikely that proliferative activity has potential as an independent prognostic parameter for this type of tumour.     

Serum pancreastatin levels predict response to hepatic artery chemoembolization and somatostatin analogue therapy in metastatic neuroendocrine tumors

INTRODUCTION: Neuroendocrine tumors often metastasize to the liver and present with disabling hormonal symptoms. Hepatic artery chemoembolization (HACE) combined with somatostatin therapy, pre-embolization, peri-embolization and post-embolization, at doses to control symptoms, is an aggressive approach that can relieve hormonal symptoms with minimal morbidity and mortality. METHODS: Chemoembolization was performed using 30 mg of adriamycin, 50 mg of mitomycin, 12 ml of hexabrix, 10 ml of ethiodol, and 360-500-microm particles. Pancreastatin, a split product of chromogranin A, was measured pre-HACE and post-HACE in all patients. RESULTS: Forty-three chemoebolization procedures were performed in 34 symptomatic patients from December 1995 to August 1999. Seventeen patients had intestinal primaries (50%), seven had pancreatic primaries (20%), five had bronchial primaries (15%), and five had unknown primaries (15%). Systemic pancreastatin levels were improved or stable in 31 patients (78%). Symptoms were improved in these 31 patients (78%). Systemic serotonin levels were improved or stable in 24 patients (60%). Radiographic improvement or stability was seen in 18 patients (45%). Procedural related morbidity included pain, fevers, nausea, vomiting, and transient elevations of liver function studies in 75-100% of patients. There was one procedural related mortality (2%). Less than 20% improvement in pancreastatin levels from baseline was associated with death in five of five patients (100%). This was not observed with serotonin levels. CONCLUSION: Measurement of serum pancreastatin levels is an easy and useful method to predict success in patients who undergo HACE plus somatostatin therapy for metastatic neuroendocrine tumors to the liver. This therapeutic approach is effective in relieving symptoms in 78% of patients, with minimal major morbidity or mortality.     

Prognostic value of nucleolar organizer regions in neuroendocrine tumours of the lung

The value of the number and size of the nucleolar organizer regions (NORs) as prognostic indicators in human neuroendocrine lung tumours was evaluated in a quantitative study of 57 cases, including 33 small cell carcinomas (SCLCs), 9 well-differentiated neuroendocrine carcinomas (WDNECs) and 15 classic carcinoids. NORs were visualized on paraffin sections by an argyrophilic technique (AgNOR) and measured by automatic image analysis. In each case, the mean number and area of AgNORs were evaluated; the results were compared with clinical follow-up and survival. AgNOR values for both number and area were significantly higher in SCLCs than in WDNECs and carcinoids. WDNECs had insignificantly higher AgNOR values than carcinoids. Among SCLCs, AgNOR values of the oat cell subtype and the intermediate cell subtype did not differ significantly. Regardless of the histological tumour type, AgNOR values strongly correlated with prognosis, with more and larger AgNORs indicating a more progressive clinical course. In the present study we demonstrate for the first time that the biological behaviour of neuroendocrine lung tumours is correlated with the number and size of AgNORs. Thus the measurement of AgNORs may serve as an additional prognostic indicator in these neoplasms, particularly in the separation of SCLCs from WDNECs with a more favourable prognosis.     

Polyclonal carcinoembryonic antigen staining in the cytologic differential diagnosis of primary and metastatic hepatic malignancies.

In order to assess the utility of immunocytochemical staining of bile canaliculi with a polyclonal antiserum to carcinoembryonic antigen (pCEA) in the differentiation of primary hepatocellular carcinomas from metastatic malignancies, pCEA staining was performed on fine needle aspiration specimens from hepatic lesions in 60 patients. The original cytologic diagnoses were hepatocellular carcinoma in 22 patients, metastatic neoplasm or cholangiocarcinoma in 27 patients and benign hepatocytes in 11 cases. The cytologic diagnoses of malignancy were confirmed by surgical excision, autopsy or clinical investigations in 82% of the patients. Follow-up data, supported by pCEA staining, reversed the original cytologic diagnosis in three cases. Bile canalicular pCEA staining was identified in 18 of 22 cases of hepatocellular carcinoma and in all 11 benign hepatocellular aspirates. All 27 cases of metastatic malignancy or cholangiocarcinoma were negative for canalicular pCEA staining, although 11 cases exhibited cytoplasmic staining. Interpretation of pCEA staining was not affected by the intermingling of malignant cells and benign hepatocytes. Predictive values were 100% for a positive test and 87% for a negative test. These findings indicate that staining with pCEA antiserum is a useful adjunct in the differential cytologic diagnosis of malignant hepatic lesions.     

Endotoxin-mediated necrosis and regression of established tumours in the mouse

Summary The fractional distribution of cardia output was measured in tumour-bearing mice treated with 50 g intravenous endotoxin, and correlated with ultrastructural changes in tumour morphology.The proportion of the cardiac output going to the tumour decreased to less than 50% of its original value by 2 h and to 10%–30% by 6 h after giving endotoxin. Because endotoxin decreases absolute cardiac output, the actual perfusion of the tumour will be considerably less than these figures suggest.The decrease in perfusion correlated closely with changes in vascular morphology. Venous congestion on the tumour edge started within 1 h of giving endotoxin and by 3 h, endothelial damage and platelet aggregates were visible. At this time, all cells, tumour, connective tissue and infiltrate in the tumour centre were dead or damaged.By 24–48 h a conspicuous infiltrate of neutrophils and macrophages was present on the edge of the tumour and many of these cells were closely related to tumour cells.We suggest that the haemorrhagic necrosis may be caused by vascular obstruction leading to hypoxia and that the subsequent regression is mediated by activated macrophages and perhaps by neutrophils.     

Expression of class III beta-tubulin in neuroendocrine tumours of gastrointestinal tract

Class III b-tubulin is presented as a specific marker for the cells of neuronal origin as well as for the tumours originating from these cells. Its expression is considered one of the earliest events that appear in the cells revealing neuronal differentiation. Using monoclonal antibody TU-20 in an immunohistochemical analysis, we studied the expression of class III b-tubulin in gastrointestinal carcinoid tumours. Paraffin-embedded, formalin-fixed tissue sections from 49 tumour samples obtained from following locations: stomach (4 cases), small intestine (8 cases), appendix (18 cases), rectum (3 cases), pancreas (5 cases), liver metastases (7 cases) and lymph node metastases (4 cases) were used in the study. In 41 of the 49 tumour samples (83.7%), positive staining for class III b-tubulin was detected, while 8 tumour samples (16.3%) were negative. Expression of class III b-tubulin was prominent in all three rectal carcinoids and in three atypical carcinoids located in small intestine. Pancreatic neuroendocrine tumours revealed either weak immunostaining (2 cases), or were negative for this marker (3 cases). The intensity of class III b-tubulin immunolabelling was not related to the degree of tumour differentiation. The results of this study suggest that class III b-tubulin could be a perspective marker for gastrointestinal neuroendocrine tumours. Moreover, the differences in its expression could also elucidate some aspects of histogenetic relationships of neuroendocrine tumours of gastrointestinal tract.     

Telemedicine may help change the face of medical care in Eastern Canada

Pilot projects in eastern Canada that use personal computers and telephone lines to link patients and rural physicians with specialists in urban centres indicate that telemedicine may be a cost-effective adjunct to clinical medicine. Dermatology, radiology, cardiology and oncology are among the areas that have been tested in Nova Scotia. Although physicians say telemedicine may have many useful applications, such as providing efficient continuing medical education for doctors in remote communities, they say it must respect traditional referral patterns.     

Electron microscopy for the diagnosis of tumours.

The role of leukocyte transfusions in the prevention and treatment of infections in adults with granulocytopenia was investigated. Leukocytes were obtained from healthy volunteers by continuous-flow centrifugation. Histocompatibility antigen (HLA)-matched leukocytes were used to assess the prophylactic value of leukocyte transfusions. Seven patients with acute myelogenous leukemia received HLA-matched leukocytes during the period of maximal granulocytopenia associated with initial remission induction therapy; 20 concurrently treated patients who did not receive leukocyte transfusions were the control group. The patients receiving HLA-matched leukocytes had significantly fewer (P = 0.043) infectious episodes (not bacteriologically proven) during the study period, and remission occurred in 5 of the 7, compared with 10 of the 20 controls. In addition, 52 series of two or more ABO-compatible transfusions were given to 50 patients with proven infection or elevated temperature presumed due to infection and a granulocyte count of less than 0.5 X 10(9)/L. Response, indicated by a decrease in temperature, occurred in 23 patients. Leukocyte transfusions thus have an important adjuvant role in the management of patients with severe granulocytopenia.