- Email: [email protected]
URINARY IMMUNOREACTIVE TRYPSIN IN PANCREATIC CANCER
93 conclusive
(Zl >-2.0)
or
negative for linkage (z, <-2.0).
There was no positive score. Summing of the scores may not be appropriate due to the heterogeneity of dominant hereditary ataxia. Scores for certain families may have z, >+3.02 but none of our pedigrees revealed a similar score. Other markers, on the sixth and other autosomes, may provide more evidence of linkage. In the three pedigrees with recessive ataxia identical haplotypes occurred in affected and unaffected siblings (figure). Mathematical treatment of the data is controversial because the defective gene is not a manifest character in heterozygotes. In the pedigree shown three of the affected individuals share identical haplotypes for HLA (A and B), Bf, and GLO I,
(i.e., 32-15-S-1/1-8-S-2) and 32-15-S-1/9-27-S-2 but has the same
a
fourth reveals clinical illness.
severe
Two entirely normal brothers also have 32-15-S-1/1-8-S-2. The data do not support linkage of the abnormal recessive gene to either the paternal (32-15-S-1) or maternal (1-8-S-2) haplotype. The result indicates that the selected
genetic
markers
are
probably
not
suitable for disease
predic-
tion. Details of all families examined will be
published elsewhere.
Neurology Service, V.A. Medical Center, Albany, N.Y. 12208, U.S.A.
Institute for Human Genetics, University of Hamburg, D-2000 Hamburg 54, West Germany Institute for Transplantations Immunology, Eppendorf University Hospital, Hamburg
A. H. KOEPPEN H. W. GOEDDE L. HIRTH H.-G. BENKMANN
seem to ever
be associated with chronic
pancreatic diseases of what-
origin.
Gastroenterology Department, Mauriziano Hospital, Turin, Italy
*** This letter has been shown follows.-ED. L.
ANGELO ANDRIULLI GUYA MASOERO
to
Dr Lake-Bakaar, whose
reply
SiR,—Dr Andriulli and Dr Masoero conclude that our main claim for the urinary immunoreactive trypsin excretion test was as a screening test for pancreatic cancer. However, despite its title, our paper suggested that a possible value of the test was in the distinction between chronic pancreatitis and cancer of the pancreas. Preliminary results also suggest raised levels in chronic renal failure. The low serum levels of immunoreactive trypsin in chronic pancreatitis overlap with variable levels in cancer of pancreas, and argue in favour of a "proliferation of new diagnostic tests" in an attempt to differentiate betB7een these two common diseases. What is needed is a larger study to confirm or refute our preliminary results. The value of serum immunoreactive trypsin levels, both is well established in fasting and serially after a Lundh meal, several large series, including our own.I Academic Department of Medicine, Royal Free Hospital, London NW3 2QG
G. LAKE-BAKAAR
C. HILLER
ASPIRIN AND PLATELETS URINARY IMMUNOREACTIVE TRYPSIN IN PANCREATIC CANCER
SIR,-Dr Lake-Bakaar and colleagues (Oct. 27, p. 878) suggest urinary excretion of immunoreactive trypsin as a screening test for pancreatic cancer. This conclusion seems overstated since, even though raised trypsin/creatinine clearance ratios were found in all patients with pancreatic cancer, this ratio was also abnormally high in 6 out of 9 patients with acute pancreatitis and in 2 (7%) of the controls. Moreover, no attempt was made to determine this ratio in patients with renal disease, a condition which greatly influences the renal handling and excretion of proteins (e.g., amylase’). Furthermore, the true positive rate (i.e., the number of patients with pancreatic cancer as a percentage of the total number of cases and controls with a positive test) is only 68%, which is very unsatisfactory. It is distressing to recollect the proliferation of new diagnostic tests which subsequently turned out to be no better than tossing a coin.
Using a new radioimmunoassay for immunoreactive trypsin2 (CES-SORIN Biomedica, Saluggia, Vercelli, Italy) which is ten times more sensitive than the one used by Lake-Bakaar et al.,’ we have detected low immunoreactive trypsin levels in the serum of all but 1 patient with pancreatic cancer; our results are at variance with the high levels reported by others4 in this disease, but are supported by the finding that human pancreatic adenocarcinomas do not produce exportable enzymes.5 Immunoreactive trypsin assay is more reliable and less troublesome when done in serum rather than urine. Nevertheless, we do not suggest low circulating values as a new test for pancreatic cancer, since patients with chronic pancreatitis also show abnormal levels.6 Low immunoreactive trypsin levels 1. Andriulli A, et al. Gascroenterology 1979; 77:86. 2. Malvano R, et al. Scand J Gastroenterol (in press). 3. Recchia S, et al. Dan Med Bull 1979; October suppl. 4. Elias E, et al. Lancet 1977; ii: 66. 5. Grant AG, et al. Clin Chim Acta 1978; 90: 75. 6. Andriulli A, et al. Dan Med Bull 1979; October suppl.
SiR,-Professor Masotti and his colleagues (Dec. 8, p. 1213) describe effective platelet cyclo-oxygenase inhibition at a single oral aspirin dose of 3.5mg/kg body-weight with only slight inhibition of vessel-wall prostacyclin (PGI2) production. Higher doses of aspirin significantly inhibited PGI2 production. These workers’ suggestion that administration of higher doses may explain the poor results achieved in clinical trials of aspirin in the prevention of arterial thrombosis seems plausible. Masotti et al. suggest an aspirin dose of 3.5mg/kg every 3 days to induce peak in-vivo inhibition of platelet aggregation. At this dose malondialdehyde (MDA) production at day 3 was 62+8% inhibited. However, results obtained in healthy volunteers may not be applicable to patients. For example, we have observed, in some patients with spontaneous platelet aggregation, 2 h after ingestion of 500 mg aspirin 100% inhibition of MDA production and absence of spontaneous platelet aggregation. However, by day 3 spontaneous platelet aggregation had returned whereas MDA production was still 70% inhibited. Because of the irreversible inhibition of cyclo-oxygenase we expected an accumulative effect of daily low doses of aspirin and have investigated the accumulative inhibitory effect of aspirin on platelet MDA production in eight healthy volunteers. A daily dose of 40 mg aspirin produced an increasing inhibition of MDA production over 3 days with a maximum at the 10th day in all the volunteers. For example, in one typical volunteer inhibition of platelet MDA production (zero on day 0) was 35%, 70%, 85%, and 95% 1, 3, 4, and 10 days, respectively, after the start of aspirin administration at a daily dose of 40 mg. Three volunteers were followed up for a month at this dose of aspirin and had stable suppression of MDA production for the entire period. This does not necessarily mean that the pattern of accumulation of MDA inhibition in patients with arterial thrombosis is the same as it is in healthy volunteers, because such patients are characterised by a high incidence of 1. Lake-Bakaar G, McKavanagh S, Redshaw M, Wood T, Summerfield JA, Elias E. Serum immunoreactive trypsin following a Lundh meal: Its value in the diagnosis of pancreatic disease. JClin Pathol 1979; 32: 1003-08.
(Zl >-2.0)
or
negative for linkage (z, <-2.0).
There was no positive score. Summing of the scores may not be appropriate due to the heterogeneity of dominant hereditary ataxia. Scores for certain families may have z, >+3.02 but none of our pedigrees revealed a similar score. Other markers, on the sixth and other autosomes, may provide more evidence of linkage. In the three pedigrees with recessive ataxia identical haplotypes occurred in affected and unaffected siblings (figure). Mathematical treatment of the data is controversial because the defective gene is not a manifest character in heterozygotes. In the pedigree shown three of the affected individuals share identical haplotypes for HLA (A and B), Bf, and GLO I,
(i.e., 32-15-S-1/1-8-S-2) and 32-15-S-1/9-27-S-2 but has the same
a
fourth reveals clinical illness.
severe
Two entirely normal brothers also have 32-15-S-1/1-8-S-2. The data do not support linkage of the abnormal recessive gene to either the paternal (32-15-S-1) or maternal (1-8-S-2) haplotype. The result indicates that the selected
genetic
markers
are
probably
not
suitable for disease
predic-
tion. Details of all families examined will be
published elsewhere.
Neurology Service, V.A. Medical Center, Albany, N.Y. 12208, U.S.A.
Institute for Human Genetics, University of Hamburg, D-2000 Hamburg 54, West Germany Institute for Transplantations Immunology, Eppendorf University Hospital, Hamburg
A. H. KOEPPEN H. W. GOEDDE L. HIRTH H.-G. BENKMANN
seem to ever
be associated with chronic
pancreatic diseases of what-
origin.
Gastroenterology Department, Mauriziano Hospital, Turin, Italy
*** This letter has been shown follows.-ED. L.
ANGELO ANDRIULLI GUYA MASOERO
to
Dr Lake-Bakaar, whose
reply
SiR,—Dr Andriulli and Dr Masoero conclude that our main claim for the urinary immunoreactive trypsin excretion test was as a screening test for pancreatic cancer. However, despite its title, our paper suggested that a possible value of the test was in the distinction between chronic pancreatitis and cancer of the pancreas. Preliminary results also suggest raised levels in chronic renal failure. The low serum levels of immunoreactive trypsin in chronic pancreatitis overlap with variable levels in cancer of pancreas, and argue in favour of a "proliferation of new diagnostic tests" in an attempt to differentiate betB7een these two common diseases. What is needed is a larger study to confirm or refute our preliminary results. The value of serum immunoreactive trypsin levels, both is well established in fasting and serially after a Lundh meal, several large series, including our own.I Academic Department of Medicine, Royal Free Hospital, London NW3 2QG
G. LAKE-BAKAAR
C. HILLER
ASPIRIN AND PLATELETS URINARY IMMUNOREACTIVE TRYPSIN IN PANCREATIC CANCER
SIR,-Dr Lake-Bakaar and colleagues (Oct. 27, p. 878) suggest urinary excretion of immunoreactive trypsin as a screening test for pancreatic cancer. This conclusion seems overstated since, even though raised trypsin/creatinine clearance ratios were found in all patients with pancreatic cancer, this ratio was also abnormally high in 6 out of 9 patients with acute pancreatitis and in 2 (7%) of the controls. Moreover, no attempt was made to determine this ratio in patients with renal disease, a condition which greatly influences the renal handling and excretion of proteins (e.g., amylase’). Furthermore, the true positive rate (i.e., the number of patients with pancreatic cancer as a percentage of the total number of cases and controls with a positive test) is only 68%, which is very unsatisfactory. It is distressing to recollect the proliferation of new diagnostic tests which subsequently turned out to be no better than tossing a coin.
Using a new radioimmunoassay for immunoreactive trypsin2 (CES-SORIN Biomedica, Saluggia, Vercelli, Italy) which is ten times more sensitive than the one used by Lake-Bakaar et al.,’ we have detected low immunoreactive trypsin levels in the serum of all but 1 patient with pancreatic cancer; our results are at variance with the high levels reported by others4 in this disease, but are supported by the finding that human pancreatic adenocarcinomas do not produce exportable enzymes.5 Immunoreactive trypsin assay is more reliable and less troublesome when done in serum rather than urine. Nevertheless, we do not suggest low circulating values as a new test for pancreatic cancer, since patients with chronic pancreatitis also show abnormal levels.6 Low immunoreactive trypsin levels 1. Andriulli A, et al. Gascroenterology 1979; 77:86. 2. Malvano R, et al. Scand J Gastroenterol (in press). 3. Recchia S, et al. Dan Med Bull 1979; October suppl. 4. Elias E, et al. Lancet 1977; ii: 66. 5. Grant AG, et al. Clin Chim Acta 1978; 90: 75. 6. Andriulli A, et al. Dan Med Bull 1979; October suppl.
SiR,-Professor Masotti and his colleagues (Dec. 8, p. 1213) describe effective platelet cyclo-oxygenase inhibition at a single oral aspirin dose of 3.5mg/kg body-weight with only slight inhibition of vessel-wall prostacyclin (PGI2) production. Higher doses of aspirin significantly inhibited PGI2 production. These workers’ suggestion that administration of higher doses may explain the poor results achieved in clinical trials of aspirin in the prevention of arterial thrombosis seems plausible. Masotti et al. suggest an aspirin dose of 3.5mg/kg every 3 days to induce peak in-vivo inhibition of platelet aggregation. At this dose malondialdehyde (MDA) production at day 3 was 62+8% inhibited. However, results obtained in healthy volunteers may not be applicable to patients. For example, we have observed, in some patients with spontaneous platelet aggregation, 2 h after ingestion of 500 mg aspirin 100% inhibition of MDA production and absence of spontaneous platelet aggregation. However, by day 3 spontaneous platelet aggregation had returned whereas MDA production was still 70% inhibited. Because of the irreversible inhibition of cyclo-oxygenase we expected an accumulative effect of daily low doses of aspirin and have investigated the accumulative inhibitory effect of aspirin on platelet MDA production in eight healthy volunteers. A daily dose of 40 mg aspirin produced an increasing inhibition of MDA production over 3 days with a maximum at the 10th day in all the volunteers. For example, in one typical volunteer inhibition of platelet MDA production (zero on day 0) was 35%, 70%, 85%, and 95% 1, 3, 4, and 10 days, respectively, after the start of aspirin administration at a daily dose of 40 mg. Three volunteers were followed up for a month at this dose of aspirin and had stable suppression of MDA production for the entire period. This does not necessarily mean that the pattern of accumulation of MDA inhibition in patients with arterial thrombosis is the same as it is in healthy volunteers, because such patients are characterised by a high incidence of 1. Lake-Bakaar G, McKavanagh S, Redshaw M, Wood T, Summerfield JA, Elias E. Serum immunoreactive trypsin following a Lundh meal: Its value in the diagnosis of pancreatic disease. JClin Pathol 1979; 32: 1003-08.