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DISTRIBUTION BY SUBSITE OF COLORECTAL CANCER FOUND AT NECROPSY AND (A) RECOGNISED AS UNDERLYING CAUSE OF DEATH (FATAL)OR (B) UNRELATED TO PRIMARY CAUSE OF DEATH (NON-FATAL)

I Distribution bv site (%) I Prevalence (Der 1000 necronsies) at age:

Numbers of cases on which estimates are based are shown in parentheses

latent cancers of the right colon were in people older than 70. Thismay be explained by difficulty with extensive diagnostic procedures(eg, complete colonoscopy and double contrast X-ray) in old peopleand by a less aggressive attitude by clinicians.The prevalence of unsuspected colorectal cancer in our series was

9-6 per 1000, increasing among men from 3-9 in the age group 40-49to 15-9 per 1000 in those aged over 80 and among women from 3 7 to14-3 per 1000, respectively. The prevalences we found are lowerthan the 20-3 per 1000 reported2 for Hawaiian Japanese over 65 (to10-2 per 1000 in our series for those aged 60 plus). For those over 40the prevalence we found is only slightly less than that reported byBerg et aP(12’8 per 1000) in a large series of necropsies in LosAngeles county between 1953 and 1959. Our results are also lowerthan those reported by Lee3 among Chinese in Singapore (13-1 forall over age 14 and 27-6 for those aged 60 plus).

Differences in the prevalence of latent cancers found at necropsyprobably reflect real differences in the frequency of the lesionamong populations as well as differences in the methods ofascertainment of malignant lesions.

Institute of Anatomy and Histopathology,University of Tneste,34125 Trieste, Italy

MAURO DELENDIDANIELA GARDIMAN

Unit of Analytical Epidemiology,International Agency for Research on Cancer,69372 Lyon, France

ELIO RIBOLIANNIE J. SASCO

1. Berg JW, Downing A, Lukes RJ. Prevalence of undiagnosed cancer of the large bowelfound at autopsy Cancer 1970; 25: 1076-80.

2. Stemmermann GN. Unsuspected cancer in elderly Hawaiian Japanese Hum Pathol1982; 13: 1039-44.

3. Lee YS. Incidental carcinoma of the colorectum at autopsy and its effects on theincidence and future trends of colorectal cancers in Singapore. Cancer 1988; 61:1059-64.

4. Berrino F, Vigano G, Gatta G, Crosignani P, Pisani P, Macaluso M. In. Muir C,Waterhouse J, Mack T, Powell J, Whelan S, eds. Cancer incidence in fivecontinents: vol V (IARC Sci Publ no 88) Lyon: International Agency for Researchon Cancer, 1987: 560-65.

ADRENALINE RESPONSE TO HYPOGLYCAEMIAAND INSULIN SPECIES

Sir am baffled that Dr Kerr and his colleagues should believetheir one case report (April 15, p 836) to "suggest that adrenalinesecretion in response to hypoglycaemia may be affected by thespecies of insulin".They give too few details of their investigations of January, 1989,

for valid comparison with the two previous studies. Were the initialglucose levels at the start of the studies similar, or were fructosaminelevels similar? The glucose threshold at which adrenaline"secretion" is triggered is strongly influenced by metabolic

(certainly glycaemic) control, but the published evidence, as well ascommon sense, indicates a period much less than the six weeks ormore for which glycated haemoglobin concentrations give a notionof average glycaemia. Yet their only evidence of "metabolic control"comes from the three haemoglobin Al percentages.

In the absence of measurement of insulin antibodies we mayassume that their patient had substantial concentrations of theseantibodies, raised by use of bovine ultralente (Novo) in 1985-86,

and perhaps reactivated by beef soluble and protamine-like insulinsin 1989. Hence, many insulin variables may have been quitedifferent between the two clamp studies-in particular, the freeinsulin concentrations, the rates of insulin disposal, and the rates ofchange in both free insulin and, especially, glucose concentrations inthe 5 or 10 minutes before the adrenaline determination (plasmaadrenaline concentration has a short half-life).

Hypoglycaemia is not the only stimulus that increases plasmaadrenaline concentration. Anxiety and other emotions may do so,and apparently while there was no increase in pulse rate in August,1988, despite a six-fold increase in plasma adrenaline, heart rate didchange (presumably upwards) in January, 1989. The question ofthe symptomatic response to hypoglycaemia is complicated by itstendency to disappear with increasing duration of diagnoseddiabetes.What is certain is that upsets in glycaemic control (especially

hypoglycaemia) will continue to occur if patients are switched fromnotably antigenic insulins to those much less so (such as the highlypurified porcine and human insulins) without reduction in dose, atleast initially-as surprisingly was done by Kerr et al in August,1986. Difficulties caused by antibody formation can be complicatedby alterations in formulation.With as empirical a business as individual glycaemic control,

there may be patients who fare better on beef and porcine insulinthan on human, and on impure rather than pure insulin

preparations. But it would prima facie seem a sound policy to aim toreplace defective human insulin secretion by insulin preparations ofthe same or closely similar structures (and as little contaminated aspossible); and thus reduce and retard the generation of insulinantibodies. This would seem especially useful for patients startingtreatment with insulin, even if such a policy might not bear muchfruit for several years.

Adrenaline secretion may vary with the rate and extent of

decrease in glycaemia, and with the initial blood-glucoseconcentration, but there is nothing in Kerr and colleagues’ report togive any substantial reason to believe that the species of insulin itselfeither alters the adrenaline response or is a cause of hypoglycaemicunawareness.

Sheikh Rashid Diabetes Unit,Radcliffe Infirmary,Oxford OX2 6HE T. D. R. HOCKADAY

NEONATAL HYPOGLYCAEMIA

SIR,-Your editorial (April 22, p 882) suggests that the bloodglucose be kept above 2-5 mmol/1 in newborn infants. The results ofKoh et al,’ cited in the editorial, are only partly relevant becauseonly five of their patients were newborn (gestational ages notreported) and a neurophysiological effect of a blood glucose as highas 5 mmol/1 was found in only one of them. We have studied ninepreterm infants who had a blood glucose below 1.7 mmol/l in thefirst hours of life, and no effect of hypoglycaemia was found in visualevoked potentials in amplitude integrated Eels We did, however,find an increase in cerebral blood flow at a blood glucose below 1 7mmolll, reflecting a compensatory mechanism and, possibly, stress.

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Although it may seem likely that milder hypoglycaemia imposes astress on the preterm baby it remains to be proved that this can be

prevented without significant side-effects-notably, overhydrationwith its associated risks. There may be important differencesbetween transitory hypoglycaemia shortly after birth and longer-lasting disturbances in blood glucose regulation in older infants.Specialists in neonatal care have, on the basis of descriptiveand retrospective studies, implemented several ill-advised

"improvements" on nature;3 a call for a properly controlled trial ismore appropriate.

Department of Neonataology,Rigshospitalet,2100 Copenhagen Ø, Denmark

GORM GREISENOLE PRYDS

1 Koh THHG, Eyre JA, Aynsley-Green A Neural dysfunction during hypoglycaemiaArch Dis Child 1988; 63: 1386-98.

2 Pryds O, Greisen G, Friis-Hansen B. Compensatory increase of CBF in preterminfants during hypoglycaemia. Acta Paediatr Scand 1988; 77: 632-37

3 Silverman WA. Retrolental fibroplasia: a modem parable New York Grune &

Stratton, 1980

INTERFERON IN LUNGS

SIR,-In her review of the molecular and cellular biology ofhuman interferons (IFNs) Dr Balkwill (May 13, p 1060) mentionsbriefly the possibility of constitutive production of IFNs. Indeed,there is increasing evidence that IFNs are produced in normalhuman tissues in the apparent absence of recognised inducers. 1,2They may serve a physiological role in host defence against virusesand in the regulation of cell proliferation and differentiation.2,3 Thealveolar surface of the lung is the largest surface within the bodywhich is constantly exposed to the external environment. Varioushumoral factors, including immunoglobulins, enzymes, andsurfactant components, have been identified in normal alveolar

epithelial lining fluid,4 which play a role in antimicrobial defence.However, little is known about IFNs in the normal lower

respiratory tract.We have measured IFN-a and IFN-y in serum and in fluid

obtained by washing the lungs of healthy volunteers using thetechnique of bronchoalveolar lavage (BAL). We used commercialimmunoradiometric assays (Abbot Diagnostics and Centocor,respectively). The monoclonal antibodies used in the IFN-a assayrecognise the at and a2 subtypes, which are the most prevalent inconstitutively produced IFN-a mixtures.2 As shown in the figure,none of the sera contained detectable IFN-a and most were also

negative for IFN-y. In contrast, all the cell-free BAL supernatantscontained IFN-a (median 10-63, range 7-31-12-42 U/ml) andIFN-y (median 0-227, range 0-123-0-354 U/ml). Since studies ofthe sequential dilution of lung lining components due to the BALprocedure (4 x 60 ml fluid introduction volumes) suggest that themeasured concentration is less than 7% of the in vivo

concentration,s the IFN concentration in the original alveolarepithelial lining fluid must be much higher than the values werecorded.

Levels of !FN-a and IFN-y in serum and BAL fluid of healthyvolunteers.

The main sources of IFN in the lungs need to be elucidated.T-lymphocytes are thought to be the major producers of

IFN-y,6 and immunocytochemical studies have demonstrated T-lymphocytes in normal lungs, in the alveolar septa and bronchialmucosal tissue.7 Immunocytochemistry has also shown thatalveolar macrophages and other cells in the lungs contain IFN-(x.1The observation that IFN levels in the lungs are far above those inthe serum of healthy volunteers indicates that IFNs are

constitutively produced within the lungs. This may contribute tohost defence by inducing an antiviral state in the respiratoryepithelium8 and enhancing alveolar macrophage antimicrobialfunction.6

Cell Biology Unit,Department of Cardiothoracic Surgery,National Heart and Lung Institute,London SW3 6LY

CHRISTIAN PRIORPATRICIA L. HASLAM

1. Khan NUD, Pulford KAF, Farquharson MA, et al. The distribution ofimmunoreactive interferon-alpha in normal human tissues. Immunology 1989; 66:201-06.

2. Tovey MG, Streuli M, Gresser I, et al. Interferon messenger RNA is producedconstitutively in the organs of normal individuals. Proc Natl Acad Sci USA 1987;84: 5038-42.

3. Toy JL. The interferons. Clin Exp Immunol 1983; 54: 1-13.4. Reynolds HY. Bronchoalveolar lavage. In: Murray JF, Nadel JA. Textbook of

respiratory medicine. Philadelphia: Saunders, 1988: 597-610.5. Davis GS, Giancola MSA, Costanza MC, Low RB. Analyses of sequential

bronchoalveolar lavage samples from healthy human volunteers Am Rev RespirDis 1982; 126: 611-16.

6. Murray HW. Interferon-gamma, the activated macrophage, and host defense againstmicrobial challenge. Ann Intern Med 1988; 108: 595-608.

7. Kradin RL, Divertie MB, Colvin RB, Ramirez J, Ryu J, Carpenter HA, Bhan AK.Usual interstitial pneumonitis is a T-cell alveolitis. Clin Immunol Immunopathol1986; 40: 224-35.

8. Bocci V. Roles of interferon produced in physiological conditions: a speculative review.Immunology 1988; 64: 1-9

PREVENTION OF ACUTE GRAFT-VERSUS-HOSTDISEASE BY MONOCLONAL ANTIBODY TO

INTERLEUKIN-2 RECEPTOR

SiR,—Herve et al reported that monoclonal antibody (MoAb)against interleukin-2 receptor (IL-2R) was effective in establishedgraft-versus-host disease (GVHD) and suggested that the synergyof such an MoAb with cyclosporin should be explored.’ AcuteGVHD is induced by activated mature T lymphocytes. Marrowdepletion of T cells prevented GVHD, but was associated with graftrejection, incomplete donor chimaeras, and increased risks of

relapse.2,3 In mice, the prophylactic use of MoAb against IL-2RMoAB significantly decreased the incidence and severity of GVHDwith a success rate intermediate between that attained by T-celldepletion and the rate in untreated controls.4 We have investigatedthe clinical feasibility of a combination of an anti-IL-2R MoAb withcyclosporin in the prevention of GVHD in 18 recipients of HLAmatched bone marrow transplants (BMT).

17 patients had leukaemias and were conditioned by marrowablative conditioning regimens (cyclophosphamide and total bodyirradiation or busulphan; 1 had severe aplastic anaemia, and wasprepared by cyclophosphamide and thoracoabdominal irradiation).All received standard immunosuppression by short-termmethotrexate and cyclosporin. We used the 33 B3 MoAb(Immunotech), a rat IgG2 which has been extensively studied invitro and which is clinically active in preventing kidney graftrejections 10 mg was given daily following a progressive pattern tostudy interference with engraftment: 4 patients received MoAbwhen the BMT was established (day 15-30), 4 patients were treatedbefore evidence of engraftment (day 10-30), and 10 patients weretreated from day 0 to 30.

Engraftment was achieved in all cases, within a time range similarto that in historical controls. Full donor chimaerism was

documented in the marrow of 10 recipients of sex-mismatchedBMT. No clinical side-effects were observed during the 410infusions. No anti-rat immunisation was detected during and onemonth after the end of the infusions. GVHD did not occur duringanti-IL-2R therapy. GVHD was observed after day 35 in 3/8patients treated for 30 days (all grade 2). With a median follow-up of8 months (range 3-16), 12/18 patients are in remission. This pilot