O6-Methylguanine-DNA methyltransferase status in neuroendocrine tumours: prognostic relevance and association with response to alkylating agents

Background:

O⁶-Methylguanine-DNA methyltransferase (MGMT) loss of expression has been suggested to be predictive of response to temozolomide in neuroendocrine tumours (NETs), but so far, only limited data are available. We evaluated the prognostic and predictive value of MGMT status, assessed by two molecular methods and immunohistochemistry, in a large series of NETs of different origins.

Methods:

A total of 107 patients, including 53 treated by alkylants (temozolomide, dacarbazine or streptozotocin), were retrospectively studied. In each case, we used methyl-specific PCR (MS-PCR) and pyrosequencing for evaluation of promoter methylation and immunohistochemistry for evaluation of protein status.

Results:

MGMT promoter methylation was detected in 12 out of 99 (12%) interpretable cases by MS-PCR and in 24 out of 99 (24%) by pyrosequencing. O⁶-Methylguanine-DNA methyltransferase loss of expression was observed in 29 out of 89 (33%) interpretable cases. Status of MGMT was not correlated with overall survival (OS) from diagnosis. Progression-free survival and OS from first alkylant use (temozolomide, dacarbazine and streptozotocin) were higher in patients with MGMT protein loss (respectively, 20.2 vs 7.6 months, P<0.001 and 105 vs 34 months, P=0.006) or MGMT promoter methylation assessed by pyrosequencing (respectively, 26.4 vs 10.8 months, P=0.002 and 77 vs 43 months, P=0.026).

Conclusions:

Our results suggest that MGMT status is associated with response to alkylant-based chemotherapy in NETs.     

The antitumoral effect of the long-acting somatostatin analog lanreotide in neuroendocrine tumors

OBJECTIVE: Somatostatin analogs are the first-line drugs for controlling hormone-mediated symptoms of carcinoid tumors. Prospective and retrospective studies have suggested that somatostatin analogs also have antiproliferative activity. The octapeptide lanreotide is available in sustained-release form, obviating the need for daily injections. METHODS: A total of 46 patients were enrolled in this open, prospective, phase II trial. They received lanreotide 30 mg i.m. every 14 days for 6 months when they had symptomatic carcinoid tumors, and lanreotide 30 mg i.m. every 10 days if they had nonsymptomatic tumors. Nonsymptomatic tumors were progressive before the start of the study. Tumor size was assessed every 3 months by means of computed tomography. The assessment was centralized and was made by an external panel. RESULTS: In all, 30 patients had symptomatic neuroendocrine tumors and 16 had asymptomatic neuroendocrine tumors. Five patients in the group with symptomatic tumors and two in the group with nonsymptomatic tumors were considered not to be evaluable. The mean duration of treatment was 12 months in the group with symptomatic tumors and 13 months in the other group. Among the 39 evaluable patients, two objective responses were obtained, giving an objective response rate of 5% (one in the group with symptomatic tumors and one in the other group). Nineteen patients had no significant increase in their tumor size for a mean of 9.5 months. CONCLUSIONS: Lanreotide is safe and well tolerated in patients with carcinoid tumors. It seems to have both symptomatic and antitumoral effects in this setting.     

Calcitonin-producing pancreatic somatostatinoma

A pancreatic somatostatinoma metastatized to the liver was detected in a 70-yr-old woman presenting with chronic diarrhea, steatorrhea, pancreatic insufficiency, diabetes mellitus, and achlorhydria. At immunocytochemistry, most tumor cells stored both somatostatin and calcitoninlike substances. Chromatography of acid extracts of the tumor on G50 Sephadex gave two distinct peaks coeluting with cyclic ovine somatostatin and human calcitonin, respectively, thus ruling out the hypothesis of a single cross-reacting molecule synthetized by the neoplastic cells. When the tumor was extracted at neutral pH, larger molecular forms of the above components were found, which accounted for less than 20% of the total immunoreactivity. Gel permeation of plasma showed that the circulating calcitonin- and somatostatinlike components consisted of three and four different forms, respectively, including components of molecular weights similar to those of the reference peptides. Inhibition curves and immunoadsorption experiments indicated that the large forms were immunologically similar, if not identical, to the corresponding standard preparations. The present case illustrates the occasional ability of neoplastic somatostatin cells of pancreas to synthetize simultaneously components immunologically related to somatostatin and calcitonin. These two inappropriate secretions could account for the symptoms displayed by this patient.     

Somatostatin in mucosa of stomach and duodenum in gastroduodenal disease.

In order to study the distribution of somatostatin in the upper digestive tract in man, biopsies were taken through endoscopy or at surgery from the fundus, antrum, and duodenal bulb in 15 subjects with no gastroduodenal lesion, 12 patients with severe antral and/or fundic atrophy in the sampling area, 28 patients with an active duodenal ulcer, and 14 patients with a nonmalignant gastric ulcer. The specimens were extracted in 2 N acetic acid and tested for somatostatin content with a specific radioimmunoassay. In the control subjects, the somatostatin concentration (nanograms per milligram of wet weight) was 0.60 +/- 0.12 in the fundus, 1.68 +/- 0.33 in the antrum, and 1.35 +/- 0.30 in the duodenal bulb. Atrophy of the gastric mucosa was associated with a reduction of the somatostatin concentration in the fundus and the antrum. No significant variation was observed in the present series of patients with gastric ulcer. Duodenal ulcer was associated with a reduction of the somatostatin concentration in the antrum (P less than 0.02). These results indicate that somatostatin is widely distributed from fundus to duodenal bulb in adult human subjects, and that lower antral concentrations are observed in patients with duodenal ulcer.     

Tissular immunoenzymatic detection of hepatic alphafetoprotein in human hepatomas.

5 human cases of hepatoma have been chosen with respect to their different seric alpha-fetoprotein (alpha-FP) level and histological characters. Cells producing alpha-FP have been studied with specific horseradish-peroxidase-labelled immunoglobulins. Ultrastructural examination shows that alpha-FP is present in the cytoplasm of some tumoral hepatocytes. alpha-FP is also present in the cytoplasm of some rare nontumoral hepatocytes of a nonsecreting hepatoma. Ultrastructural differences are described in tumoral hepatocytes according to the grade of differentiation of the tumoral cell population. alpha-FP production appears to be restricted to moderately differentiated tumoral hepatocytes. These observations led to the hypothesis that production of alpha-FP may transiently develop either during the differentiation of tumoral hepatocytes, or during the new differentiation of nontumoral hepatocytes involved in a proliferative process.     

Effect of jejunal infusion of nutrients on gastrointestinal transit and hormonal response in man

The effects of jejunal infusion of nutrients on gastric emptying and secretion, intestinal transit and hormone release were studied in human volunteers. Two caloric loads, 1.3 and 3.3 kcal/min, of a nutrient solution consisting of 18 percent protein, 27 percent lipids, and 55 percent carbohydrates were tested. These were first used in random order in 6 subjects to assess the effects on intestinal transit. For the study of gastric emptying, jejunal infusion was started 1 h after intragastric instillation of a 490 kcal, 400 ml, homogenized meal. Intestinal transit time and gastric emptying half-time increased with the rate of nutrient infusion into the jejunum. Postprandial gastric secretion was reduced. The two caloric loads induced significant rises of plasma cholecystokinin and gastric inhibitory polypeptide concentrations. Plasma motilin decreased in relation to the jejunal caloric load. The other peptides were essentially not affected by jejunal nutrient infusion in fasting subjects. We conclude that in man, gastric emptying rate, gastric secretion, and intestinal transit are regulated by the presence of nutrients in the jejunum.     

Consequences of antral and duodenal acidification on acid secretion, gastrin response and gastric emptying in duodenal ulcer patients and normal subjects

The present study intended to investigate the effect of antroduodenal acidification on gastric acid secretion and emptying, gastrin and somatostatin release in response to food in healthy subjects as well as in duodenal ulcer patients. Ten duodenal ulcer patients and 9 normal controls were studied twice: the same 400 ml liquid protein meal (proteins: 10 g) was introduced into the stomach; then intragastric pH was either maintained at pH 4.5 or allowed to decrease in response to the meal. Acid secretion was calculated using the intragastric titration method (for which the intragastric pH is fixed at pH 4.5) and using the serial dilution indicator method (which allows antral acidification) respectively. Gastric emptying was estimated according to: a) iterative measurements of intragastric meal residual volume; b) volume passing through the pylorus. These two tests were performed in a random order and during each, plasma gastrin and somatostatin responses to the meal were determined. In healthy subjects, antral acidification following the meal was associated with a significantly lower acid secretion (17.3 +/- 0.9 mmol/h; m +/- SEM) than when the pH was maintained at pH 4.5 (20.2 +/- 1.3; p less than 0.05). Moreover, gastric emptying was slower when the pH was allowed to decrease (t 1/2: 26.2 +/- 1.4 min) than when the pH was constant (t 1/2: 20.5 +/- 2.2 min; p less than 0.05). By contrast, in the duodenal ulcer group, neither acid output nor gastric emptying were significantly different in the two situations.(ABSTRACT TRUNCATED AT 250 WORDS)