1323 itself or of a very closely related molecule, since both bioactive and immunoreactive A.C.T.H. are known to occur in this site.3,4 The sequence A.C.T.H. (4-10) occurs in the &bgr;-lipotropin as well as &bgr;-melanocyte-stimulating hormone (&bgr;-M.S.H.) molecules. The inactivation experiments show, however, that even the sequence A.C.T.H. (1-24) fails to inactivate our antiserum; therefore the immunostaining is unlikely to depend on these molecules. Further, in experiments with metenkephalin as well as gastrin our antiserum did not bind these peptides. Since specific immunostaining persisted after hypophysectomy, the pituitary is very unlikely to be a source of central-nervous-system A.C.T.H..13 The distribution of A.c.T.H.-immunoreactive nerves was in some ways different from, and in others similar to, that of enkephalin nerves.14,15 No staining for A.C.T.H. was seen in, for example, the spinal cord or the medulla oblongata - regions reported to contain both enkephalin nerves and opiate receptors.14,15 However, the distributions overlapped—e.g., in the periventricular thalamic nuclei, the amygdala, and in the periventricular and ventral parts of the hypothalamus. Whether the overlaps reflects any functional interaction between nerves containing A.C.T.H.-like peptides and receptors for opioid peptides such as enkephalin deserves further study. A.c.T.H.-like immunoreactivity was detected also in gastrointestinal and pancreatic endocrine cells. Whereas in dog, cat, and rat the antropyloric mucosa contained immunoreactive cells in the same number and distribution as gastrin cells, in man the immunoreactive cells seemed confined to pancreas and duodenum. Enkephalin immunoreactivity has been reported to occur in the antral gastrin cells.16 Absorption of our antiserum with enkephalin and gastrin, however, did not affect the staining results. The nature of the immunoreactive peptide stored in these cells is unknown. The A.C.T.H. antiserum is specific for the COOH-terminal portion of A.C.T.H. A peptide corresponding to this portion has been isolated from the pituitary intermediate lobe and named corticotropin-like intermediate peptide (C.L.LP.).17,18 C.L.LP. is believed to arise by cleavage of A.C.T.H. (1-39) into a-M.S.H. and A.C.T.H. (18-39) (=C.L.I.P.).17 Its physiological importance is a mystery, since the adrenocortical stimulatory activity resides in the NH2-terminus of A.C.T.H. Recently, however, c.L.l.p. has been noted to be a potent insulin secretagogue. 19 The occurrence of c.L.i.p.-like peptides in gastrointestinal and pancreatic endocrine cells may suggest that C.L.I.P.’S insulin-releasing activity is physiologically important. Studies are under way to establish whether peptides resembling the NH2-terminal portion of A.C.T.H. also occur in the gut and pancreas although, for physiologic reasons, the secretion of adrenal-stimulating peptides from the gut A.C.T.H.

seems

unlikely.

The presence of c.L.i.p.-like molecules in gut and pancreatic endocrine cells may explain why tumours in this region sometimes cause an ectopic Cushing’s syndrome. Interestingly, one tumour, devoid of NH2-terminal A.C.T.H. immunoreactivity, proved to contain numerous cells reactive with the COOH-terminus-specific A.C.T.H. antiserum. Although still very preliminary, this observation indicates that some tumour cells, and perhaps their corresponding normal cells, predominantly contain C.L.i.p.-like peptides. Similar observations have previously been made with radioimmunoassay of a bronchial carcinoid tumour.20

Since I submitted this paper some pertinent new data have emerged. We find that, in the rat, A.C.T.H.immunoreactive antropyloric cells are identical to the gastrin cells (unpublished). Studies with yet another COOH-terminus-specific A.C.T.H. antiserum have, furthermore, produced results identical to those described above. In absorption studies, both antisera were inactivated by highly purified A.C.T.H. (1-39) (Ferring) but not by A.C.T.H. (1-24) (Ciba). Mains and his coworkers2l have reported the occurrence of a large 31 000 dalton peptide that contains the sequence of both A.C.T.H. and enkephalin. The existence of both enkephalin-likel6 and A.C.T.H.-like immunoreactivity in the antral gastrin cells may indicate that these cells, too, manufacture this putative precursor molucule. I thank Dr U.

Lundkvist, Pharmacia, Sweden, for A.C.T.H. antiand Mrs J. B. Lauridsen and Mrs E. Peterson for technical assistance. The work was supported by a grant from the Danish M.R.C.

serum

REFERENCES

1. Guillemin, R., Schally, A. V., Lipscomb, H. S., Andersen, R. N., Long, J. M. Endocrinology, 1962, 70, 471. 2. Schally, A. V., Lipscomb, H. S., Long, J. H., Dear, W. E., Guillemin, R. ibid. 1962, 70, 478. 3. Krieger, D. T., Liotta, A., Brownstein, M. J. Proc. natn. Acad. Sci., U.S.A., 1977. 74, 648. 4. Krieger, D. T., Liotta, A., Brownstein, M. J. Brain Res. 1977, 128, 575. 5. DeWied, D. in The Neurosciences Third Study Program (edited by F. O. Schmitt and F. G. Worden): p. 653. Cambridge, Mass., 1974. 6. Gispen, W. H., Wiegant, V. M., Greven, H. M., DeWied, D. Life Sci. 1976, 17, 645. 7. Terenius, L. J. Pharm. Pharmacol. 1975, 27, 450. 8. Ling, N., Guillemin, R. Proc. natn. Acad. Sci., U.S.A. 1976, 73, 3308. 9. Sternberger, L. Immunocytochemistry. New Jersey, 1974. 10. Håkanson, R., Sundler, F., Larsson, L. -I., Ekman, R., Sjöberg, N. -O. J. Histochem. Cytochem. 1975, 23, 65. 11. Larsson, L. -I., Hirsch, M. A., Hoist, J. J., Ingemansson, S., Kühl, C., Lindkaer Jensen, S., Lundquist, G., Rehfeld, J. F., Schwartz, T. Lancet, 1977, i, 666. 12. Larsson, L. -I., Sundler, F., Håkanson, R., Grimelius, L., Rehfeld, J. F., Stadil, F. J. Histochem. Cytochem. 1974, 22, 419. 13. Bergland, R. M., Davis, S. L., Page, R. B. Lancet, 1977, ii, 276. 14. Simantov, R., Kuhar, M. J., Uhl, G. R., Snyder, S. H. Proc. natn. Acad. Sci., U.S.A., 1977, 74, 2167. 15. Hökfelt, T., Elde, R., Johansson, O., Terenius, L., Stein, L. Neurosci. Letters, 1977,5,25. 16. Polak, J. M., Sullivan, S. N., Bloom, S. R., Facer, P., Pearse, A. G. E. Lancet, 1977, i, 972. 17. Scott, A. P., Ratcliffe, J. G., Rees, L. H., Landon, J., Bennett, H. P. J., Lowry, P. J., McMartin, C. Nature, 1973, 244, 65. 18. Scott, A. P., Lowry, P. J., Bennett, H. P. J., McMartin, C., Ratcliffe, J. G. J. Endocr. 1974, 61, 369. 19. Beloff-Chain, A., Edwardson, J. A., Hawthorn, J. ibid. 1977, 73, 28P. 20. Scott, A. P., Bennett, H. P. J., Lowry, P. J. McMartin, C., Ratcliffe, J. G. ibid. 1972, 55, 36. 21. Mains, R. E., Eipper, B. A., Ling, N. Proc. natn. Acad. Sci. U.S.A. 1977, 74, 3014.

TREATMENT OF CARCINOID LIVER METASTASES BY HEPATIC-ARTERY EMBOLISATION I. M. MODLIN J. ALLISON W. J. JENKINS Departments of Diagnostic Radiology, Surgery and Medicine, Hammersmith Hospital and Royal Postgraduate Medical D.

School, Du Cane Road, London W12

Summary

Two

patients

with

multiple hepatic

car-

cinoid metastases experienced considerable symptomatic relief after the hepatic artery was embolised with fragments of absorbable gelatin sponge administered through a percutaneous arterial catheter. With adequate pharmacological cover the technique is a

safe, effective, and relatively painless treatment for condition which is usually very difficult to manage.

a

1324 INTRODUCTION

MosT patients who present with carcinoid syndrome already have hepatic metastases. Since the primary tumour and metastases usually grow slowly most patients face several years of distressing symptoms. Drugs are rarely completely effective and often have

unpleasant side-effects; surgical procedures such as resection of the hepatic metastases1 or ligation of the hepatic artery2 can provide considerable symptomatic relief, but the mortality-rate is high3.4 and anaesthetic complications are common.3 Since the principal aim of management is the palliation of unpleasant symptoms, it is important to use a method that is as safe, simple, and painless as possible. We describe two patients whose carcinoid metastases were treated by embolisation of the hepatic artery by material injected through a selective hepatic catheter introduced percutaneously via the Fig. 2-Selective hepatic arteriograms in case 2. femoral artery. The efficacy of the pro(A) Before embolisation in case 2 showing extensive abnormal circulation to tumour deposits. cedure was assessed- by the patients’ (B) Case 2, 6 months after complete occlusion with sterispon emboli. Although several vessels and the liver reduction in have become recanalised there is still a clinical condition, liver size, and serial liver-function tests. We are not aware of the technique having been used before in the management of carcinoid

pronounced general

vascularity

is considerably smaller.

disease. METHODS

The patients were given parachlorophenylalanine 500 mg four times a day for 48 hours before the embolisation procedure to reduce the production of 5-hydroxytryptophan and 5-hydroxytryptamine (5-H.T.) during tumour necrosis. Patient 2 was also given cyproheptadine as a peripherally acting 5-H.T. antagonist. The patients were starved for 12 h before the angiography and were given atropine and diazepam premedication. 1 g ofmethylprednisolone was given intravenously 15 min before angiography, and aprotinin (’Trasylol’) was infused at a rate of 50 000 units/h throughout the procedure and for the next 36 h. A 5-day course of tobramycin, metronidazole, and flucloxacillin was started with the premedication. Fentanyl was used for analgesia when required, and methotrimeprazine was available in the event of hypertension. The groin was infiltrated with local anaesthetic and a steerable angiographic

catheter (Muller, U.S.C.I.) was inserted into the femoral artery by the standard Seldinger technique. An initial coeliacaxis arteriogram was performed to demonstrate the vascular anatomy of the liver, and to demonstrate in the late-phase films the patency of the portal vein (an important preliminary step before blocking the hepatic arterial supply). The hepatic artery was then selectively catheterised, and the catheter tip was sited distal to the origin of the gastroduodenal artery. The embolic material used was sterile absorbable gelatin sponge (’Sterispon’), which was cut into fragments varying from 1 mm3 to 5 mm3. The smallest sterispon fragments were injected first in order to obliterate the most peripheral vessels, thereby reducing the chance of collateral pathways subsequently developing. With successive injections larger particles were used to block the main branches of the hepatic artery. The potential liberation of large quantities of vasoactive substances from the infarcted tumours necessitated careful and continuous observation of the cardiovascular system, and frequent examination of the abdomen was also

Fig. 1-Selective arteriograms in case 1 showing hepatic vessels before (A), and after (B), embolisation with sterispon.

1325 necessary since infarction of the gallbladder has been described after ligation of the hepatic artery,3 a complication that fortunately did not occur in our two patients. PATIENTS

Case 1, a 28-year-old Italian labourer, was referred from Bologna (Ospedale Civile di Bozzano) with a gastric carcinoid tumour and massive hepatic metastases. The liver was palpable 16 cm below the costal margin and was irregular and tender. The patient had frequent flushing and sweating attacks and was dyspnoeic because his huge liver elevated the diaphragm. In view of the formidable postoperative problems posed by such a case it was decided to avoid laparotomy and instead to obliterate the hepatic artery by the percutaneous catheter embolisation technique; the procedure was repeated 3

weeks later to deal with collateral and recanalised vessels. Case 2, a 65-year-old engineer, had a left lower pulmonary lobectomy in 1970 for a bronchial carcinoid tumour which had presented with local chest symptoms only. In August, 1976, flushing, wheezy dyspnoea and continuous right upper quadrant pain developed. Examination revealed a large liver (8 cm below the costal margin) which was irregular and exquisitely tender. Percutaneous selective hepatic angiography and embolisation were performed under X-ray fluoroscopic control. 6 months later when upper abdominal pain recurred, the angiogram was repeated and collateral vessels and recanalised vessels were embolised. RESULTS

In both patients the injection of emboli caused slight abdominal discomfort, and in case 2 blood-pressure rose transiently. At the end of the procedure hepatic arterial flow had ceased (fig. 1). The flushing attacks in both patients disappeared immediately and completely, their dyspnoea diminished, and there was a pronounced reduction in liver size during the days after the procedure. During the first fortnight the palpable liver edge decreased from 16 cm to 5 cm below the costal margin in case 1, and this reduction was confirmed by technetium colloid scans. In both patients plasma-bilirubin and ser-

um-glutamic-oxaloacetic-transaminase initially rose sharply and pyrexia and leucocytosis occurred. In case 1 an arteriogram done in Italy 6 weeks after embolisation showed that the hepatic artery was still completely occluded, though one small collateral vessel had appeared from an intercostal artery; in case 2 the repeat angiogram after 6 months demonstrated some recanalisation of the previously blocked hepatic arterial tree, but the vascularity was still very reduced in comparison with the pre-embolisation angiogram (fig. 2). 6 months after his second embolisation procedure this patient remains pain-free with no evidence of dyspnoea, or flushing. The liver is only just palpable below the costal margin, and his 24 h urinary excretion of 5-hydroxyindoleacetic acid remains at one third of its pre-embolisation level.

hepatic-artery ligation have all been used with varying degrees of success. The embolisation technique we describe is performed under local analgesia and can be accomplished by most radiologists with experience of vascular work. The risk of postoperative respiratory complications is very much less than that associated with the other surgical techniques and the procedure causes only slight discomfort. The development, of a collateral circulation to the liver is likely to be slower after embolisation than after surgical ligation of the hepatic artery, because the peripheral hepatic bed can be obliterated by showers of tiny emboli before blocking the main and

artery. Some branches may become recanalised but the procedure, which is easy and safe, may be repeated. There were no serious adverse effects attributable to the sudden release of physiologically active substances from infarcted tumour in our patients. In fact, the humoral manifestations that had troubled them before the procedure disappeared almost immediately after embolisation, and both felt better. They readily agreed to having the procedure repeated. This attitude is encouraging since the comfort and wellbeing of the patient is the main object of palliative treatment. We thank Prof. R. B. Welbourn, Department of Surgery, and Dr V. R. Chadwick, Department of Medicine, for permission to publish details of their patients.

Requests

for

reprints should

life expectancy in most patients with metadeposits in the liver is short, this is not necessarily true for those presenting with carcinoid metastases, which may grow extremely slowly. Since carcinoid deposits also produce unpleasant symptoms as a result of their hormone function, there are strong grounds for attempting to remove or destroy them. Sys-

Although

tumour

temic cytotoxic

therapy, hepatic lobectomy, tumour enucleation, cytotoxic infusions into the hepatic artery,

to

D.J.A., X-ray Depart-

REFERENCES

Zeegen, R., Rothwell-Jackson, R., Sandier, M. Gut, 1969, 10, 617. Murray-Lyon, I. M., Dawson, J. L., Parsons, V. A., Rake, M. O., Blendis, L. M., Laws, J. W., Williams, R. Lancet, 1970, ii, 172. 3. Dery, R. Can. Anœsth. Soc. J. 1971, 18, 245.

1. 2.

4.

McDermott, W. U., Hensle, T. W. Ann. Surg. 1974, 180, 305

PLATELET-MONOAMINE-OXIDASE ACTIVITY PREDICTS RESPONSE TO LITHIUM IN MANIC-DEPRESSIVE ILLNESS

JOHN L. SULLIVAN

JESSE O. CAVENAR, Jr

ALLAN MALTBIE

CHARLES STANFIELD

Laboratory of Clinical Neuropharmacology, Veterans Administration Hospital and Duke University Medical Center, Durham, North Carolina, U.S.A. 27706

Platelet-monoamine-oxidase activity predicts treatment response to lithium in manic-depressive illness. In the treatment-responsive group enzyme activity is similar to that in normal controls, whereas in the treatment-refractory group enzyme activity is significantly less than both control and treat-

Summary

ment-responsive groups. INTRODUCTION

DISCUSSION

static

be addressed

ment, Hammersmith Hospital, Du Cane Road, London W 12 OHS.

PREVIOUS reports indicate a significant reduction in platelet-monoamine-oxidase (M.A.o.) activity in manicdepressive patients.’ Although lithium administration may increase platelet-M.A.o. aciivity2 in manic-depressives, there are no published reports which evaluate the relationship between platelet-M.A.o. activity and response to lithium treatment. The present study examines the possibility of a correlation between enzyme activity and lithium response.