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specimens of adrenal and pancreas. The help of the manyphysicians who provided specimens and clinical information is

gratefully acknowledged. We thank the British DiabeticAssociation for a research grant to D. R. G.,: and Dr T. D.Kellock of the Central Middlesex Hospital for helpfuldiscussions.

Requests for reprints should be addressed to R. L.

REFERENCES

1. Lancet, 1974, ii, 1549.2. Perlman, L. V. Ann. intern. Med. 1961, 55, 796.3. Solomon, N., Carpenter, C. J. C., Bennett, I. L., Harvey, A. M.

Diabetes, 1965, 14, 300.4. Ungar, B., Stocks, A. E., Martin, F. I. R., Whittingham, S., Mackay,

I. R. Lancet, 1968, ii, 415.5. Nerup, J. in Immunity and Autoimmunity in Diabetes Mellitus

(edited by P. A. Bastenie and W. Gepts); p. 149. Amsterdam, 1974.6. Irvine, W. J., Clarke, B. F., Scarth, L., Cullen, D. R., Duncan,

L. J. P. Lancet, 1970, ii, 163.7. Nerup, J., Binder, C. Acta endocr. Copenh. 1973, 72, 279.8. Gepts, W. Diabetes, 1965, 14, 619.9. Nerup, J., Andersen, O. O., Bendixen, G., Egeberg, J., Gunnarsson,

R., Kromann, H., Poulsen, J. E. Proc. R. Soc. Med. 1974, 67, 506.10. MacCuish, A. C., Jordan, J., Campbell, C. J., Duncan, L. J. P.,

Irvine, W. J. Diabetes, 1974, 23, 693.11. Bottazzo, G. F., Florin-Christensen, A., Doniach, D. Lancet, 1974,

ii, 1279.12. Mancini, A. M., Zampa, G. A., Vecchi, A., Costanzi, G. ibid. 1965,

i, 1189.13. MacCuish, A. C., Barnes, E. W., Irvine, W. J., Duncan, L. J. P.

ibid. 1974, ii, 1529.14. Bloom, A., Hayes, T. M., Gamble, D. R. (in preparation).15. Gamble, D. R. Postgrad. med. J. 1974, 50, suppl. 3, p. 538.16. Lendrum, R., Walker, G. Gut (in the press).17. Roitt, I. M., Doniach, D. W.H.O. Manual of Autoimmune

Serology. Geneva, 1969.18. Gamble, D. R., Taylor, K. W. Br. med. J. 1969, iii, 631.19. Gamble, D. R. in Proceedings of a workshop-conference on The

Genetics of Diabetes. Berlin (in the press).20. Melin, K., Ursing, B. Nord. Med. 1958, 60, 1715.21. Forrest, J. M., Menser, M. A., Burgess, J. A. Lancet, 1971. ii, 332.22. Landing, B. H., Pettit, M. D., Wiens, R. L., Knowles, H., Guest,

G. M. J. clin. Endocr. Metab. 1963, 23, 119.23. Goldstein, D. E., Drash, A., Gibbs, J., Blizzard, R. M. J. Pediat.

1970, 77, 304.

INCREASED INCIDENCE OF MALIGNANCY

DURING CHRONIC RENAL FAILURE

ARTHUR J. MATASCARL M. KJELLSTRAND

RICHARD L. SIMMONSTHEODORE J. BUSELMEIER

JOHN S. NAJARIANDepartments of Surgery and Medicine,University of Minnesota, Minneapolis,

Minnesota 55455, U.S.A.

Summary The incidence of cancer in 646 dialysis/transplant patients before uræmia

developed, during the period of progressive uræmia,and post-transplantation was compared. 10 tumours

(3 breast, 2 kidney, 1 leukæmia, 1 lung, 1 insulinoma,1 thyroid, 1 cervix in situ) developed in 9 patientsduring the period of progressive uræmia, a significantincrease over the expected number in the age-matchedgeneral population. 6 of these patients have receivedtransplants and have no evidence of recurrent disease6 months to 4 years post-transplantation. 11 de-novotumours have developed in 530 transplant recipients(4 cervix in situ, 2 skin, 2 reticulum-cell sarcoma, 1

lip, 1 dysgerminoma, 1 colon)—a significant increaseover the age-matched general population. The can-cers in the uræmic patients are relatively common typesof mesenchymal tumours while the cancers in the trans-plant recipients are epithelial and lymphoproliferative.

This difference may reflect the presence of the graftin the transplant patient or may be due to differentpatterns of immunosuppression in these two popula-tions.

Introduction

AN increased incidence of cancer has been reportedin transplant recipients on immunosuppressivetherapy.l.2 The pathogenesis of this increase has beenattributed to a loss of immunosurveillance 1·3·4 Anadditional immunosuppressive factor which maycontribute to the increased cancer incidence is theuraemic status of the pre-transplant patient. Uraemiacan adversely affect immunocompetence,5.6 but therehave been no reports of an increased incidence ofcancer in pre-transplant ureemic patients. We haverecorded cases of cancer in dialysis/transplant patientsbefore uraemia developed, during the period of pro-gressive urxmia (serum-creatinine >25 mg. per 100

ml.), and after transplantation.

FindingsThe charts of all patients admitted to the trans-

plant/dialysis service since 1963 for evaluation of

end-stage renal failure were reviewed to determinethe incidence of cancer before the onset of renal

disease, during the progression of uraemia, and aftertransplantation. Since 1968 we have been treating allpatients with end-stage renal failure by dialysis or

transplantation regardless of disease. 7 The patientswere 530 transplant recipients, 38 patients awaitingtransplantation, and 78 patients on chronic hxmo-dialysis (total 646). Patients who had a malignancy(e.g., Wilms tumour, bilateral hypernephroma, acuteleuksemia, or multiple myeloma) and who requireddialysis for acute renal failure related to the primarymalignancy were not included.

Before Onset of Renal DiseaseIn this group of 646 patients, 3 tumours had devel-

oped before the onset of renal disease (table i). Noevidence of recurrent cancer has appeared in thesepatients.

During Progressive UraemiaIn contrast, in this same group of 646 patients, 9

had a tumour diagnosed in the relatively brief timethat they were uraemic (6-36 months) (table 11). Themean duration of known uraemia (serum-creatinine>2’5 mg. per 100 ml.) pre-transplantation was 20months in this group. This incidence (1032 per100,000 ursemic-patient years) is seven times (P<0.02) the expected yearly incidence in the age-matchedgeneral population (148 per 100,000) in the ConnecticutCancer Registry.8 The average age at the time of

diagnosis was 43 (range 23-54) and the tumours (tableII) are the ones that might be expected in this age-group. After treatment of their malignancies, 6

patients have been transplanted and 5 of the 6 are

doing well 6 months to 4 years post-transplantation.1 of these patients (patient 11) developed a de-novocarcinoma in-situ of the uterine cervix 21 years aftertransplantation. She remains well 18 months aftertotal abdominal hysterectomy. The sixth trans-

planted patient died of disseminated cytomegalovirusinfection; no residual disease or metastases were found

884

at necropsy. 1 patient died on dialysis, and the

remaining 2 (patients 9 and 12) are awaiting trans-plantation. Thus, of 6 patients receiving transplantsafter treatment of their tumour, none have shownrecurrence of their disease.

After TransplantationThere have been 11 cases of de-novo malignancy

in the 530 transplant recipients. This incidence (796per 100,000 post-transplant years) is also a significantincrease over the reported yearly incidence in the age-

matched general population (102 per 100,000) (p<0’01).8 There is no significant difference between thenumber of tumours developing in the pre-transplanturaemic period and the post-transplant period.The average age of the patient developing malig-

nancy post-transplantation was 32 years (range 9-62years) and the tumour developed an average of 28

years post-transplant (range 4 months-5 years). 8 ofthe 11 patients are doing well after treatment; 2patients with reticulum-cell sarcomas died from theirtumours and 1 patient with cured ovarian dysgermin-

TABLE I-CANCBRS DEVELOPING BEFORE uRsmiA IN 646 PATIENTS

TABLE 11---CANCER DEVELOPING IN 646 URAMIC PATIENTS AFTER THE ONSET OF CHRONIC RENAL FAILURE (SERUM-CREATININE>2-5 mg./lOO ml.)

TABLE III-DE-NOVO CANCER IN 530 TRANSPLANT RECIPIENTS

885

oma died after rejection of her kidney (no residualtumour was found at necropsy 9).

Discussion

A statistically significant increase of cancer in thepatient with end-stage renal failure has not previouslybeen reported. It is likely that before the advent ofhaemodialysis, ursemic patients did not live longenough for neoplasia to develop. Maher et al.10

reported only a 30% 3-month survival of patientsafter the serum-creatinine reached 10 mg. per 100 ml.if dialysis was not instituted.Penn and Starzl collected 8 cases of malignancy

in patients with chronic renal failure from trans-

plant/dialysis centres. In addition, they reported on12 renal neoplasms in uraemic patients, 9 of whichwere incidental findings at pre-transplant nephrec-tomy (2 of these are patients 5 and 6 in table n).9% of 241 de-novo malignancies in transplantpatients collected by Penn were diagnosed in the first4 months post-transplant, suggesting that they mayhave been present at the time of transplantation 1’A more accurate measure of the incidence of cancer

in the uraemic patient might be obtained by deter-mining the incidence in large series of patients onchronic hsemodialysis, but neither the EuropeanDialysis Registry (personal communication) nor theAmerican National Dialysis Registry (personal com-munication) has such data. The European DialysisRegistry did, however, report that 6% of home-

dialysis deaths and 2% of hospital-dialysis deaths in1972 were due to cancerp suggesting that progressiveincurable cancer is a relatively common problemin the long-term dialysis patient. Unfortunately,patients with malignancy which led to renal failureare probably included in these statistics.A possible error in any report of this type is patient

selection. The general belief that immunosuppres-sion exacerbates previous cancers and that trans-

plantation is contraindicated in patients with a recenthistory of cancer may result in relatively few patientswith urxmia and cancer presenting themselves at atransplant centre. On the other hand, our reputationfor transplanting " high risk " patients 13 may lead toan excessive referral of patients with treated cancer;however, this factor probably plays little part, since,of the 10 malignancies found during uraemia, 8 werediagnosed and treated by us and only 2 were referredhere after treatment of their neoplasm.An increased incidence of cancer in the post-

transplant patient receiving immunosuppressivetherapy has previously been reported.l,2,l1 This in-crease has been attributed to loss of immuno-surveillance,l reactivation of oncogenic viruses,14-17 orchronic immunostimulationY--2o 75 % of tumours

reported in the transplant recipient have been carci-nomas of the skin, lip, or cervix and lymphoreticu-lar tumours, with lymphoreticular tumours showingthe greatest increase in incidence.2 2 In contrast, theuraemic patient seems to develop malignancies morecommon to the general population.Uraemia is immunosuppressive, notably with

respect to cell-mediated immunity.5,6 However, theuramic patient differs from the transplanted patientin that chronic immunostimulation by the graft is

absent. Chronic antigenic stimulation seems to beespecially important in the pathogenesis of lympho-reticular malignancies in the immunodepressedlaboratory animal.18-20 In addition, latent oncogenicviruses are reactivated when animals are immuno-depressed and simultaneously immunostimulated byan allogeneic graft.14.17

-

Another possible factor contributing to the differ-ence in histological types of cancer seen in uraemicand transplant patients may be that there are differentpatterns of immunosuppression in these two popula-tions. Some support for this concept can be foundfrom observations of the neoplasms that arise in

patients with primary immunodeficiency diseases.For example, lymphomas and leukxmia comprise100% of the malignancies that have developed in

patients with Bruton’s agammaglobulinsmia and 92%of reported malignancies in Wiskott-Aldrich syn-drome, but only 54% of reported neoplasms in patientswith common variable immunodeficiency. In con-

trast, epithelial tumours comprise 39% of tumoursthat have been documented in patients with commonvariable immunodeficiency but have yet to be reportedin association with either Bruton’s agammaglobulin-xmia or the Wiskott-Aldrich syndrome.21

Furthermore, recording practices must be taken intoaccount. It may be that certain major cancers are

more frequently reported to a registry than the moreminor superficial malignancies. On the other hand, itis possible that in the large closely observed series,superficial cancers are over-reported in comparisonto the general population. For example, in the twolargest series reporting an increased incidence of skincancer after transplantation, all patients are followedclosely and biopsies are taken from all suspicious skinlesions.11,22 The incidence of cancer is then comparedto the incidence in the general population as reportedto cancer registries. However, many tumour registriesonly obtain information from hospital records, andthus the true incidence of lesions not requiring hospitaladmission is likely to be greater than that recorded.8

This work was supported by grant AM 13083 from the U.S.Public Health Service.

Requests for reprints should be addressed to R. L. S., Box185, University of Minnesota Hospitals, Minneapolis, Minnesota55455, U.S.A.

Addendum

We have lately encountered three more cases of

malignancy in 250 additional uraemic patients-carcinoma of the common bileduct, gastric carcinoma,and basal-cell carcinoma of the skin, after 8 months,6 years, and 5 years of progressive renal failure.

REFERENCES

1. Penn, I., Starzl, T. E. Transplantation, 1972, 14, 407.2. Hoover, R., Fraumeni, J. F. Lancet, 1973, ii. 55.3. Burnet, F. M. Progr. exp. Tumor Res. 1970, 13, 1.4. Thomas, L. in Cellular and Humoral Aspects of the Hypersensitive

State (edited by H. S. Lawrence); p. 529. New York, 1959.5. Merrill, J. P. Cancer Res. 1968, 28, 1449.6. Wilson, W. E. C., Kirkpatrick, C. H., Talmage, D. W. Ann. intern.

Med. 1965, 62, 1.7. Kjellstrand, C. M., Simmons, R. L., Buselmeier, T. J., Najarian,

J. S. in Transplantation (edited by J. S. Najarian and R. L.Simmons); p. 418. Philadelphia, 1972.

886

8. Doll, R., Payne, P., Waterhouse, J. (editors). Cancer Incidence inFive Continents. Berlin, 1966.

9. Simmons, R. L., Kelly, W. D., Tallent, M. B., Najarian, J. S.New Engl. J. Med. 1970, 283, 190.

10. Maher, J. F., Nolph, K. D., Bryan, C. W. Ann. intern. Med. 1974,81, 43.

11. Penn, I. Transplant. Proc. (in the press).12. Gurland, H. J., Brunner, F. P., Deln, H. V., Harler, H., Parsons,

F. M., Scharer, K. Proc. Eur. Dialysis Transplant. Ass. 1973, 10,xvii.

13. Simmons, R. L., Kjellstrand, C. M., Buselmeier, T. J., Najarian,J. S. Archs Surg. 1971, 103, 290.

14. Hirsch, M. S., Ellis, D. A., Black, P. H., Monaco, A. P., Wood,M. L. Science, 1973, 180, 500.

15. Hirsch, M. S., Phillips, S. M., Salnik, C., Black, P. H., Schwartz,R. S., Carpenter, C. B. Proc. natn. Acad. Sci. U.S.A. 1972, 69,1069.

16. Melief, C. J. M., Datta, S., Louie, S., Schwartz, R. S. Unpublished.17. Wood, M. L., Hirsch, M. S., Monaco, A. P. Transplant. Proc.

(in the press).18. Schwartz, R. S., Beldotti, L. Science, 1965, 149, 1511.19. Walford, R. C. ibid. 1966, 152, 78.20. Metcalf, D. Acta Un. int. Cancer, 1963, 19, 657.21. Kersey, H., Spector, B. D., Good, R. A. Adv. Cancer Res. 1973,

18, 211.22. Marshall, V. C. Transplantation, 1974, 17, 272.

DIRECT INHIBITION OF GASTRIC ACID BY

GROWTH-HORMONE RELEASE-INHIBITING

HORMONE IN DOGS

A. A. J. BARROS D’SA S. R. BLOOM

J. H. BARON

Departments of Surgery and Medicine, Royal PostgraduateMedical School and Hammersmith Hospital, London W12

Summary To find out if growth-hormone release-inhibiting hormone (G.H.-R.I.H.) had any

direct action on gastric acid production independentof its effect on gastrin release, cyclic G.H.-R.I.H. was

infused at a rate of 20 &micro;g. per kg. per hour into dogswith gastric fistul&aelig;. Gastric acid output fell sharplyin response to three stimuli of acid production&mdash;ameal and pentagastrin and histamine infusions. Thefact that acid output was inhibited during pentagastrinadministration suggests that G.H.-R.I.H. has a directaction on the gastric parietal cell.

Introduction

GROWTH-HORMONE release-inhibiting hormone (G.H.-R.I.H.), a fourteen aminoacid ovine hypothalamichormone, inhibits the release not only of growthhormone but also of thyroid-stimulating hormone,2 insulin,3 glucagon,4 and gastrin.5 In a single patientwith Zollinger-Ellison syndrome administration ofG.H.-R.I.H. lowered the plasma-gastrin and almost

completely inhibited gastric acid production.’ Becausethere had been no reports of any direct action of G.H.-R.I.H. on non-endocrine tissue, this inhibition of acidsecretion seemed most easily explained as a result ofthe inhibition of gastrin production by the gastrinoma.However, G.H.-R.I.H. might also have a direct inhibi-tory action on the gastric parietal cells besides itsaction in inhibiting the release of gastrin from the Gcells. Experiments were, therefore, designed in dogsto test whether G.H.-R.I.H. had any direct action on

gastric acid production independent of its action ongastrin release.

Methods

Four ,dogs with previously fashioned gastric nstulsewere each studied on four occasions after an overnightfast. The effect of a 2-hour G.H.-R.i.H. or control salineinfusion on the 3-hour gastric acid response to a standardmeal was studied in random order using the constant

intragastric pH titration technique.6 G.H.-R.I.H. was in-fused in the second hour of a 3-hour infusion of histamine

acid phosphate (0’5 &micro;g. per kg. per minute). During bothpentagastrin and histamine tests the gastric juice was col-lected in 15-minute fractions and the volume, pH, andtitratable acidity (to pH 7) were measured. Highly purecyclic G.H.-R.i.H. was used (Bachem Ltd.) and was infusedin 09% saline at a rate of 20 &micro;g. per kg. per hour.

Results

G.H.-R.i.H. inhibited gastric acid production to allthree stimuli. The effect on meal-stimulated acid isshown in fig. 1. During the 2-hour infusion gastric

Fig. 1&mdash;Effect on gastric acid of G.H.-R.I.H. (0 - - C)) or salineinfused intravenously for 2 hours after a meat meal.

Gastric acid was titrated intragastricaUy.6 Results are shown asmean&plusmn;S.E.M.

acid was totally inhibited in every dog with somereturn of secretion after stopping the infusion. Thedramatic inhibition of pentagastrin-stimulated acid

production (97 &plusmn;1%) is shown in fig. 2. Gastricacid production fell swiftly in the first half-hour ofthe G.H.-R.I.H. infusion to reach nearly basal levelsat the end of the hour, but during the third hour ofthe pentagastrin recovery was,,seen, though this wassomewhat delayed. The inhibition of histamine.stimulated gastric acid secretion was less complete(fig. 3) but still highly significant, since during thelast 30 minutes of G.H.-R.I.H. infusion the secretion ofacid was reduced by 71 % (S.E.M. 11 %, n<0.01) com-

pared with the last 30 minutes before G.H.-R.I.H.

Recovery of acid secretion to almost pre-G.H.-R.I.H.levels was seen by the end of the 3rd hour. No