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management, or in whom the condition cannot bedifferentiated with certainty from an acute

fulminating ulcerative colitis. When a quickdecision is needed, sections of a carefully takenrectal biopsy may help in differential diagnosis. 1

.

When the small bowel is chiefly affected, thevalue of surgical intervention is doubtful. Perfor-ation of the bowel in this condition is rare and themain dangers to the patient are fluid loss and endo-toxic shock. Severe pseudomembranous colitis isseen more often by the surgeon in view of itsclinical similarity to the toxic dilatation of severeulcerative colitis. The appropriate operation is totalcolectomy with ileostomy, the distal pelvic colonbeing brought out as a mucous fistula so that anileorectal anastomosis can be performed once thecondition has settled. Nevertheless, since bothsmall and large bowel may be affected by thedisease process, even after colectomy problems offluid and electrolyte balance due to high ileostomyoutput may persist for days or weeks.Recent interest in lincomycin and clindomycin

associated colitis should not divert attention fromthe facts that pseudomembranous enterocolitisoccurs in association with other antibiotics, that itmay arise a week or more after the antibiotic hasbeen stopped, and that it also occurs in patientswho have not lately received antimicrobial therapy.The mortality in published series remains high, butmild forms of pseudomembranous enterocolitis

may be part of the spectrum of antibiotic-asso-ciated mild diarrhaeas. The cause of diarrhoea aris-ing during or after an antibiotic course may well beelucidated by direct inspection of the rectalmucosa.

Advanced Breast CancerACCEPTANCE that breast cancer has already

spread by the time most patients come for treat-ment has encouraged trials of systemic therapyadditional to primary local treatment. The objec-tive is to control occult metastatic disease and thus

improve cure and survival rates. Survival is onlypart of the problem. Equally important is thereduced quality of life which is associated with

advancing disease. Severe pain and lack of mobilityon account of bone metastases; acute breathless-ness from involvement of pleura and lung; discom-fort and embarrassment from ulcerating local dis-ease are common afflictions. Methods of palliationinclude radiotherapy, endocrine manipulations(either pharmacological or by ablative surgery),and chemotherapy. Differing schedules of treat-ment are advised and most clinicians have usedthem sequentially and according to the severity ofthe patient’s symptoms. Some workers now believe8. Sinatra, F., Buntain, W. L., Mitchell, C. H., Sunshine, P. J. Pediat. 1976,

88, 304.9. Tedesco, F. J., Barton, R. W., Alpers, D. H. Ann. intern. Med. 1974, 81,

429.

that a more rational approach is to reduce tumourburden by initial aggressive treatment and to fol-low this by some form of maintenance therapy.Whatever the approach, it is important to assess

the effect of treatment accurately by methodswhich allow comparisons between different centres,and which are not bedevilled by the variationswhich can arise from differing optimisms andenthusiasms of the investigators. Various protocolsfor evaluating the response of patients withadvanced breast cancer to therapy have been for-mulatedl-4 but these have been used only in specialstudies and are not uniform in design. In 1974 theBritish Breast Group5 urged that standard criteriashould be used to assess response, and defined aclassification which might be appropriate. Theynoted that this problem was being considered inter-nationally and the report of the findings of the pro-ject team of the U.I.C.C. has now been published b

These two reports stress the importance of (i)obtaining good baseline information about theextent of the disease before the patient receives

treatment; (ii) accurate measurement to assess theprogress of individual tumour deposits; (iii) deter-mining categories of response, which are not

always clearcut; (iv) identifying the time aftertreatment at which response is measured; and (v)a system of external review of the results by thosenot primarily concerned in the study. The U.I.C.C,team also defines in detail the methods by whichthese principles may be achieved in practice andhope that they will become a uniform internationalsystem. While one cannot legislate for an interna-tionally recognised system for assessment of pa-tients with advanced cancer of the breast, the needis clear enough. In future, published reports mustinclude clearly defined and acceptable methods ofassessment of the response to treatment. Objectiveresponse is but one aspect of the effect of treat-ment. Much harder to evaluate, but of equal im-portance, is symptomatic improvement and per-formance. The next task for the cancer groups is to

provide guidelines for assessment of these aspectsof response to treatment.

VITAMIN D AND THE PITUITARY

OuR views of vitamin D metabolism have completelychanged over the past ten years. Vitamin D3 (cholecalci-ferol) is normally formed in the skin from its precursor7-dehydrocholesterol under the action of sunlight. How-ever, we now know that the vitamin itself is largely inac-tive and must be transformed by two metabolic steps

1. Clinical Evalulation in Breast Cancer (edited by J. L. Hayward and R DBulbrook). London, 1966.

2. The Clinical Management of Advanced Breast Cancer: second TenovusWorkshop (edited by C. A. F. Joslin and E. N. Gleave). Cardiff, 1970.

3. Cancer Therapy: prognostic factors and criteria of response (edited by M.J. Staquet). New York, 1975.

4. Breast Cancer Group in Japan. Jap. J. clin. Oncol. 1976, 6, 13.5. British Breast Group, Lancet, 1974, ii, 38.6. Hayward, J. L., Carbone, P. P., Heuson, J.-C., Kumaoka, S., Segaloff, A.,

Rubens, R. D. Eur. J. Cancer, 1977, 13, 89.

841

before exerting its effect. It is first converted in the liver1and gutl to its major circulating form, 25-hydroxychole-calciferol (25 OH D3), and for some years this was

believed to be the final active form of the vitamin. ButFraser and Kodicek3 found that a further hydroxylationtakes place and that this crucial reaction converts

25 OH D3 to an extremely potent steroid hormone. Thishormone, 1,25-dihydroxycholecalciferol (1,25[OH]D),is produced only in the kidney and is the most potentsingle humoral agent regulating calcium metabolism.This new knowledge sparked a rapid expansion inresearch and inspired the organisation of several largeinternational conferences. The latest, largest, and per-haps the most stimulating was held at Asilomar in Cali-fornia in January. The whole sphere of vitamin D wascovered, but the most relevant to clinical medicine werethe papers dealing with plasma assays for 1,25(OH)zD3and those dealing with the physiological regulation ofsecretion of this seco-steroid by the kidney. Practicalplasma assays based on a receptor protein from chick in-testine have been devised 4 and the pioneer assay hasalready been extensively exploited.6 The outstandingfindings are: the very low levels in renal failure and inhypoparathyroidism; the moderate but not invariable in-crease of plasma 1,25(OH)zD3 in hyperparathyroidism;and the striking rise in plasma 1,25(OH)zD3 producedby phosphate deficiency, even in the absence of the para-thyroid gland.The most exciting sections of the meeting were those

dealing with the vexed question of the physiologicalregulation of 1,25(OH)zD3 production. The controver-sies over the role of parathyroid hormone in this regula-tion have enlivened meetings on vitamin D for someyears, but if the arguments have diverted the acolytes,they have confused and perhaps irritated the clinicians.Fortunately, it has been possible to reconcile the differ-ing views during the course of the past year of two andit has become clear that, although parathyroid hormoneis of physiological importance, it is only one of severalregulators of vitamin-D metabolism in the kidney.10Thus, 1,25(OH)2D3 itself, plasma or dietary phosphate,and the circulating levels of plasma calcium are allknown to be important. However, many workers sus-pected that this list was incomplete since it failed to

explain the major changes in calcium absorption whichare seen in normal health. These occur in the growthspurts in childhood, and during pregnancy and lac-tation. None of the known or suggested regulators ofvitamin-D metabolism was really adequate to explain

1. Blunt, J. W., DeLuca, H. F., Schnoes, H. K. Biochemistry, 1968, 7, 3317.2. Tucker, G., Gagnon, R. E., Haussler, M. R. Archs Biochem. Biophys. 1973,

155, 47.3. Fraser, D. R., Kodicek, E. Nature, 1970, 228, 764.4 Brumbaugh, P. F., Haussler, D. R., Bursac, K. M., Haussler, M. R. Bio-

chemistry, 1974, 13, 4091.5 Eisman, J. A., Hamstra, A. J., Kream, B. E., DeLuca, H. F. Archs Biochem.

Biophys. 1976, 176, 235.6 Haussler, M. R., Baylink, D. J., Hughes, M. R., Brumbaugh, P. F., Werge-

dal, J. E., Shen, F. H., Nielsen, R. L., Counts, S. J., Bursac, K. M.,McCain, T. A. Clin. Endocr. 1976, 5, suppl. p. 151s.

7 Garabedian, M., Holick, M. F., DeLuca, H. F., Boyle, I. T. Proc. natn.Acad. Sci. U.S.A., 1972, 69, 1673.

8 Galante, L., Colston, K. W., Evans, I. M. A., Byfield, P. G. H., Matthews,E. W., MacIntyre, I. Nature, 1973, 244, 438.

9 Fraser, D. R., Kodicek, E. Nature New Biol. 1973, 241, 163.10 MacIntyre, I., Colston, K. W., Evans, I. M. A., Lopez, E., MacAuley, S. J.,

Piegnoux-Deville, J., Spanos, E., Szelke, M. Clin. Endocr. 1976, 5, suppl.p. 85S

the changes in D metabolism in these real physiologicalsituations.

But the situation has now dramatically changed as aresult of experiments by MacIntyre, Spanos, and theircolleagues’1 at Hammersmith Hospital in London. Theirinitially surprising findings were that prolactin stimu-lates the chick kidney enzyme which produces the activemetabolite of vitamin D. This inspired a transatlanticcollaborative study12 by the groups at Hammersmithand Tucson which proved that the prolactin-inducedenzyme effects were followed by the anticipated majorincrease of circulating 1,25(OH)2D3. Further, the four-fold enhancement of plasma 1,25(OH)zD3 levels duringlactation, reported at Asilomar, strongly suggests thatthese results can be extended to mammals. And the close

similarity of the aminoacid sequences of growth hor-mone and prolactin makes it very tempting to suggestthat growth hormone will also be found to have a majorinfluence. But in any event, it now seems almost certainthat prolactin, and perhaps growth hormone, are deeplyinvolved with the regulation of D metabolism, and thatthey may even explain the changes in calcium metabo-lism which occur in real life, in contradistinction to theexperimental laboratory.

CIGARETTE SMOKING AND DIABETICRETINOPATHY

THERE is still considerable controversy about the rela-tion between blood-glucose control and long-term dia-betic complications.1 Although most people accept thatgood control from the outset may delay the onset andlessen the gravity of these complications 2 we lack con-clusive evidence that blood-glucose control hampers thedevelopment of retinopathy.4 The American DiabeticAssociation5 states that one of the goals of therapyshould be "a serious effort to achieve levels of blood glu-cose as close to those in the non-diabetic as feasible."Few would argue with this, but such a policy is not

easily put into practice. Long-term assessment of thedegree of hyperglycaemia is very difficult and, despite themost careful and "physiological" use of modern insulins,long-lasting normoglycaemia is hard to secure in most in-sulin-dependent patients.

There is, however, a further factor that seems to beimportant in determining the progression of retinopathyand one which (in theory at least) might readily bemodified or excluded-namely, cigarette smoking. Paet-kau and her colleagues" in Edmonton, Alberta, havestudied the smoking habits of diabetic patients after

observing that many diabetics with proliferative retino-pathy were heavy smokers and that a number of long-standing diabetics with little or no retinopathy werenon-smokers. The Canadian group postulated that

11. Spanos, E., Colston, K. W., Evans, I. M. A., Galante, L. S., MacAuley,S. J., Maclntyre, I. Mol. Cellular Endocr. 1976, 5, 163.

12. Spanos, E., Pike, J. W., Haussler, M. R., Colston, K. W., Evans, I. M. A.,Goldner, A. M., McCain, T. A., Maclntyre, I. Life Sci. 1976, 19, 1751.

1. Cahill, G. F., Jr., Etzwiler, D. D., Freinkel, N. New Engl. J. Med. 1976,294, 1004.

2. Knowles, H. C., Jr. Trans. Am. clin. clim. Ass. 1964, 76, 142.3. Malins, J. M.Jl R. Coll. Physns, 1976, 10, 289.4. Editorial. New Engl.J. Med. 1976, 295, 443.5. Cahill, G. F., Jr., Etzwiler, D. D., Freinkel, N. Diabetes, 1976, 25, 237.6. Paetkau, M. E., Boyd, T. A. S., Winship, B., Grace, M. ibid. 1976, 26, 46.7. The Health Consequences of Smoking: report of the Surgeon General. U.S.

Department of Health, Education and Welfare, Washington D.C., 1971.