The role of tumor markers in the diagnosis and management of gastrointestinal cancer.
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Biomedical subjects
Publications and source records attributed to S Domschke.
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Duodenal acidification is known to inhibit gastric H+ secretion while stimulating pancreatic HCO-3 secretion, but the mechanisms of these effects have not been fully explained. This study was designed to determine the role of endogenous and exogenous secretin in gastric inhibition and pancreatic stimulation by an acidified liver extract (LE) meal in conscious dogs prepared with chronic gastric and pancreatic fistulas pretreated with normal serum (control) or anti-secretin serum. In control tests, plasma gastrin and gastric H+ secretion showed a marked rise with LE meals at pH ranging from 7.0 to 4.0, but significantly declined at pH 3.0 and 2.0. Plasma secretin and pancreatic secretion started to rise with LE meals at pHs below 4.5, and both reached peaks at pH 2.0. Exogenous secretin infused at graded doses suppressed plasma gastrin and gastric H+ responses to LE meals at doses of 1.0 and 2.0 U/kg-h, but increased, dose-dependently, plasma secretin and pancreatic HCO-3 starting with a dose of 0.03 U/kg-h. Following the administration of anti-secretin serum, the effects of exogenous secretin on plasma gastrin and secretin levels as well as on gastric and pancreatic secretion were almost completely abolished. The increase in plasma secretin and pancreatic HCO-3 responses to LE meals at pH below 4.5 were also abolished by anti-secretin serum, but the suppression of plasma gastrin level and the inhibition of gastric H+ responses to LE meals at lower pH (3.0 and 2.0) remained virtually unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)
The pharmacokinetics of high-dose metoclopramide (10 mg/kg body wt. in five infusions of 2 mg/kg body wt. each) was studied in 11 patients (5 females, 6 males) in two groups: group A with and group B (consisting of five patients) without forced diuresis. When the drug was infused, forced diuresis had no influence on the pharmacokinetics of metoclopramide (serum level after the 1st infusion was 851 +/- 361 ng/ml in group A versus 840 +/- 348 ng/ml in group B; after the 5th infusion it was 2,005 +/- 588 ng/ml in group A versus 2,463 +/- 1,350 ng/ml in group B). There were significant differences in the 24-h serum levels (582 +/- 308 ng/ml in group A versus 379 +/- 170 ng/ml in group B; P less than 0.05) and in the elimination half life (8.5 +/- 2.6 h in group A versus 6.1 +/- 1.1 h in group B; P less than 0.05). The results demonstrate that the dosage regimen originally suggested by Gralla for cytostatic drugs, with forced diuresis for high-dose metoclopramide therapy, may also be applied, with no dosage reduction, with to other cytostatic drugs which do not require forced diuresis.
Tumour-associated antigen CA 19-9 was determined in serum from 166 patients (30 without gastro-intestinal disease, 32 with liver cirrhosis, 9 with choledocholithiasis, 65 with acute or chronic pancreatitis and 30 with malignant tumors in the region of pancreas and bile passages). The specificity of CA-19-9 as tumour marker was 97% in patients without gastro-intestinal disease, but in those with liver cirrhosis or choledocholithiasis it was only 56% and 44%, respectively. In particular, cholestasis reduced specificity. Acute pancreatitis in its initial attack gave false-positive CA 19-9 values in 27% of cases, repeated bouts in chronic recurrent pancreatitis in as many as 50%. In chronic pancreatitis the specificity was 90%. Malignant tumours of pancreas and bile ducts were diagnosed with a sensitivity of 80%. Determination of CA 19-9 in pure pancreatic secretion failed to differentiate between the control group (30), chronic pancreatitis (21) and carcinoma of the pancreas (22).
In 11 persons with normal pancreas function and 21 patients with chronic pancreatitis serum levels of insulin and C-peptide were measured under basal conditions and after maximal stimulation with glucose-tolbutamide-glucagon. Patients with the highest excretory deficiency in the secretin-pancreozymin test had the most marked impairment in endocrine function. In patients with manifest diabetes the exocrine capacity was reduced to an average of 10% of normal. The endocrine parameters correlated linearly with the exocrine ones, most markedly C-peptide reserve with pancreatic enzyme secretion.
Therapeutic pancreatic duct occlusion (PDO) is applied to preserve endocrine pancreatic function by atrophizing and thus eliminating chronically inflamed exocrine pancreatic parenchyma. So far, efficient and lasting elimination of exocrine parenchyma is brought about only by intraoperative PDO upon partial duodenopancreatectomy. While partial duodenopancreatectomy itself reduces endocrine pancreatic function by about 40%, intraoperative PDO does not further impair endocrine function. Endocrine function is not affected at all by endoscopic PDO, which has to be improved, however, concerning its eliminatory effect on exocrine pancreatic parenchyma.
In 29 patients (48 courses of chemotherapy), a randomized double-blind crossover study was undertaken to establish the antiemetic effectiveness of a combination of metoclopramide at a moderately high dose (5 mg/kg body weight) with 1 g methylprednisolone (treatment A) as compared with metoclopramide monotherapy (5 mg/kg body weight; treatment B). With cisplatin doses of 60 mg/m2, a good antiemetic effect (0-1 vomiting episodes in 24 h) was observed in 9 out of 10 patients under treatment A as well as under treatment B. With a cisplatin dose of 120 mg/m2, treatment A produced a good antiemetic effect in 9 out of 11 patients (82%), while treatment B produced such an effect in only 3 out of 11 patients (27%; p less than 0.5). The results obtained permit the following conclusions to be made: At doses of cisplatin of up to 60 mg/m2, the antiemetic effect produced by metoclopramide (5 mg/kg body weight) given alone is adequate. At doses of cisplatin of 120 mg/m2 and more, high-dose methylprednisolone has a good additive antiemetic effect vis-à-vis metoclopramide (5 mg/kg body weight). The antiemetic effect of this combination corresponds approximately to the antiemetic effect produced with high-dose metoclopramide (10 mg/kg body weight) administered alone.
The therapeutic effectiveness of a conventional (Pankreon-Granulat) and an acid-protected (Kreon) porcine pancreatic enzyme preparation, and an acid-stable fungal enzyme preparation (Nortase) in the treatment of severe pancreatogenic steatorrhoea was investigated. The study comprised 17 patients with chronic pancreatitis and exocrine pancreatic insufficiency with (A) or without (B) a previous Whipple's procedure (B II resection + partial duodenopancreatectomy). With all three enzyme preparations, a significant (p less than 0.05) reduction in the total faecal fat excretion/day was achieved. In therapy group A, this reduction was, on average, 58% for Kreon (100,000 U lipase/day), 67% for Pankreon-Granulat (360,000 U lipase/day) and 54% for Nortase (75,000 U lipase/day), the respective figures for therapy group B being 58%, 52% and 46% at identical dosages. Thus, in both groups, the effect produced by the conventional porcine pancreatic enzyme preparation and the acid-protected porcine or the acid-stable fungal enzyme preparation was largely equivalent, although the latter two preparations were administered at only 1/4 of the dosages of the former preparation. On the basis of the respective average reduction in total faecal fat excretion and average number of stools/day, it would appear that in patients with chronic pancreatitis and prior Whipple's procedure, Pankreon-Granulat should be administered for enzyme replacement while in patients with an intact upper gastrointestinal tract, Kreon should be administered, in the treatment of steatorrhoea in chronic pancreatitis.
To further elucidate the pathophysiological role of peptide hormones in duodenal ulcer (DU) disease, several endocrine, paracrine and neurocrine peptides were determined radioimmunologically in biopsies of gastroduodenal mucosa obtained endoscopically in 8 subjects without upper gastrointestinal disease, and in 8 duodenal ulcer patients. The DU patients had a BAO of 6.6 +/- 1.9 and a PAO of 41.8 +/- 6.1 mEq/h. In DU patients, a lack of the acid and gastrin-release inhibiting agent somatostatin was found neither in antral nor in fundic mucosa (185 +/- 60 vs 83 +/- 19 pmol/g tissue wet weight in controls). Basal and peak acid outputs of DU patients were positively correlated with fundic somatostatin concentrations (p less than 0.01). While gastrin levels were not significantly elevated in the antrum of DU patients, the mucosal content of potentially releasable gastrin of the duodenal bulb and the descending duodenum was higher than in controls (p less than 0.01). In the whole duodenum, CCK-like immunoreactivity was also more abundant in DU patients than in controls, whereas GIP and motilin did not exhibit characteristic profiles. Presumably as a reactive phenomenon, the mucosal levels of the peptidergic neurotransmitters VIP and substance P were markedly increased in the proximal duodenum of DU patients.
In 93 patients with known exocrine pancreatic function (secretin-pancreozymin test), NMR spectrometry and chloroform-methanol extraction of quantitatively collected, homogenized and lyophilized stools provided significantly correlated results with respect to stool fat concentration (r = 0.872) and total stool fat excretion/day (r = 0.983). In 83% of 24 patients with total stool fat excretion/day of more than 15 g (chloroform-methanol extraction), the indication for enzyme replacement was also established by stool fat concentrations of more than 35% determined by NMR spectrometry, irrespective of whether stool fat was measured in total stools or in 3 consecutive unhomogenized samples. In the remaining (17%) patients total stool fat excretion/day was only slightly elevated (16-21 g). Interestingly, in only 58% of patients actually needing enzyme replacement, did the secretin-pancreozymin test reveal a reduction of stimulated enzyme secretion to below 15% of the lower normal limit. The results indicate that NMR spectrometry of lyophilized samples of 3 consecutive unhomogenized stools is suitable for stool fat quantitation and for establishing the indication for enzyme replacement in chronic pancreatitis.
The degree of correlation between exocrine pancreatic function and endocrine secretory capacity was examined in 13 chronic pancreatitis patients with secondary diabetes mellitus, 8 chronic pancreatitis patients without diabetes, and 11 healthy subjects. The two parameters were studied under maximal stimulation (volume-corrected secretin-pancreozym test and glucose-tolbutamide-glucagon provocation, respectively). A close, linear correlation was found between all endocrine variables and pancreatic acinar function (e.g. rs = 0.77 for chymotrypsin output and C-peptide release; p less than 0.0001). The correlation was less strong with pancreatic bicarbonate output (e.g. rs = 0.49 for C-peptide release; p less than 0.05). In our patients, secondary overt diabetes occurred in chronic pancreatitis when protease outputs were, on an average, reduced to about 10% of the mean maximal protease output of normal subjects.
Endoscopic examination of the colon was performed in 405 patients (125 without, 217 with benign, and 63 with malignant colorectal diseases), and the serum levels of the tumour-associated antigens CEA and CA 19-9 were determined. On comparing both markers, the specificity of CA 19-9 (96% correctly normal values) was found to be higher in benign colorectal diseases than that of CEA (92% with a cut-off limit of 5 ng/ml for CEA). On the other hand, the sensitivity of CA 19-9 in colorectal carcinomas was only about 25% and thus much lower than that of CEA (52% correctly pathological values). The sensitivity of both markers was particularly low in the initial stages of carcinoma (in Dukes A: CEA 20%, CA 19-9 0%). If the cut-off limit for CEA was raised to 10 ng/ml, the specificity was increased to 99%, whereas the sensitivity was markedly reduced to 25%. The diagnostic accuracy of CEA in colorectal carcinomas was not surpassed by CA 19-9. There was no obvious advantage in simultaneous determination of CEA and CA 19-9.
Ingestion of the plant fiber guar in therapeutic dosage (20 g/d) in 20 healthy probands led to a highly significant (P less than 0.01) inhibition of lipolytic and a clearly less effective (0.05 greater than P greater than or equal to 0.01) inhibition of proteolytic exocrine pancreatic function. Plant fibers with a highly significant in-vivo inhibition of lipolytic exocrine pancreatic function such as guar gum should thus not be administered to patients with exocrine pancreatic insufficiency and steatorrhoea. However, they should be considered as additional measures in drug treatment of hypertriglyceridaemia.
A 43-year-old female suffering from ulcerative colitis did not improve under therapy with sulfasalazine. Following withdrawal of sulfasalazine and its replacement by systemic steroids and metronidazole++ she went into clinical and endoscopic remission. A second trial with sulfasalazine was, again, followed by a rapid and sever relapse of the colitis. On discontinuation of sulfasalazine therapy, gross inflammation resolved immediately. This adverse reaction to sulfasalazine has been reported previously in only four cases. The pathophysiology of this event is unknown.
In man, convincing data have been obtained in short-term observations that some drugs can cause acute gastroduodenal damage including gastritis and erosions. Useful clinical and epidemiological studies on the relationship between these acute lesions and peptic ulceration, and between the chronic ingestion of these drugs and peptic ulceration or massive upper gastrointestinal haemorrhage are, however, rare. Even for the most widely used and studied greatest offender--acetylsalicylic acid (ASA)--an association with major bleeding or gastric ulceration could only be established for frequent and heavy ASA intake. The percentage of those ASA users who will experience such a serious event each year is about 0.01 to 0.05 per cent. By the use of special (e.g. enteric-coated) ASA formulations and other precautions, this low rate may be further reduced. Although for most of the other non-steroidal anti-inflammatory drugs (NSAIDs), anecdotal reports on putative drug-related major gastric bleeding or peptic ulceration exist, the ulcerogenicity of these drugs has not yet been conclusively proven in controlled studies. Some of the newer NSAIDs seem at normal dosage to be far less damaging than traditional ASA or indomethacin. Glucocorticoids might enhance ulcer risk to a minor extent when administered at high dosage for prolonged periods to susceptible individuals. Chronic moderate alcohol consumption by itself does not seem to increase the liability to peptic ulceration. With highly concentrated alcoholic beverages, gastric bleeding from acute lesions may, however, be occasionally precipitated under certain circumstances, such as when unbuffered ASA is taken concomitantly. Smoking of cigarettes is associated, and perhaps causally related, with an increased incidence of gastric and duodenal ulcerations, impaired ulcer healing, and more frequent ulcer recurrences. Duodenal ulcer patients in particular should be advised to stop smoking.
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