463

Previous studies have demonstrated an association with

consumption of alcoholic beverages.4,5 Increased risks havebeen found particularly among heavy drinkers. 6, Whereassmoking or chewing tobacco has been related to increased riskfor oesophageal cancer in India,8 the association with alcoholconsumption found in Western countries seems to be

independent of tobacco smoking.9,lo In the present study noinformation was available on the use of tobacco and alcohol.

However, differences in such habits could hardly account fora tenfold increase in oesophageal cancer risk amongvulcanisation workers. Stratification for county left therelative risks virtually unchanged, indicating that

geographical variations did not affect our results.In general, oesophageal cancer tends to be located in the

lower or middle third of the oesophagus and is less commonin the upper third. For example, in two studies of oesophagealcancer in Scandinavian men the percentages of tumours in the

upper third of the oesophagus were 8% and 14%

respectively.ll,12 By contrast, no less than 3 of the 8

oesophageal cancers that we found in vulcanisation workerswere in the upper third and none was located entirely in itslower third. In addition, we found a significant increase inlaryngeal cancer in this group.To check the accuracy of the data provided by the cancer-

environment register, different procedures have been used. Ifpersons in the cancer registry cannot be identified in the 1960census, this may be due to incompleteness or inaccuracy ofthe personal identification number used, changes in theidentification numbers after the 1960 census, and

immigration to Sweden since 1960. However, aftercorrection and supplementation of personal identificationnumbers from other registries, only 1 - 2% of the persons inthe cancer registry could not be identified in the census.’3 3

Quality control of a random sample from the cancer-

environment registry disclosed that 0-5% of the hits wereinaccurate, owing to incorrect personal identificationnumbers in either or both of the registers. 14 To evaluate thecompleteness of registration in the cancer registry, data fromthe registry were compared with those from deathcertificates. With this approach, the total loss of cases wasestimated to be 3-4%.15Present occupation and employment as a vulcanisation

worker in the 1960 census does not give information on theduration and level of exposure to vulcanisation products.Furthermore, there may be some errors in the reporting orcoding of occupation in the 1960 census. But these sources oferror would include some persons with little or no exposureto vulcanisation products among the vulcanisation workersand hence lead to underestimation of the relative risk. The

finding of a highly significant tenfold increase in the relativerisk for oesophageal cancer among vulcanisation workerscannot be explained by these sources of error or by factorspreviously known to be related to oesophageal cancer.We thank Dr Barbro Lundh, department of pathology, Huddinge

University Hospital, for examining the slides. This study was supported bygrants from the Swedish Medical Research Council (project no. 6216) and bythe Swedish Work Environment Fund.

Correspondence should be addressed to S. N., Department of SocialMedicine, Huddinge Hospital, S-141 86 Huddmge, Sweden.

REFERENCES

1. Hedenstedt A, Rannug U, Ramel C, Wachtmeister CA. Mutagenicity and metabolismstudies on 12 thiuram and dithiocarbamate compounds used as accelerators in theSwedish rubber industry. Mutat Res 1979, 68: 313-25.

2. Hedenstedt A, Ramel C, Wachtmeister CA. Mutagenicity of rubber vulcanisationgases in Salmonella typhimurium. J Toxicol Environ Health 1981; 8: 805-14.

3. Rothman KJ, Boice JD. Epidemiologic analysis with a programmable calculator.DHEW publication no. (NIH) 79-1649. Washington, D.C.: Government PrintingOffice, 1979.

4. Schoenberg BS, Bailar JC III, Fraumeni JR Jr. Certain mortality patterns of esophagealcancer in the United States, 1930-67. J Natl Cancer Inst 1971; 46: 63-73.

5. Tuyns AJ. Cancer of the esophagus; further evidence of the relation to drinking habitsin France. Int J Cancer 1970; 5: 152-56.

6. Kamionkowski MD, Fleshler B. The role of alcohol intake in esophageal carcinoma.Am J Med Sci 1965; 249: 699-700.

7. Wynder EI, Bross IJA. A study of etiologic factors in cancer of the esophagus. Cancer1961; 14: 389-413.

8. Jayant K, Balakrishnan V, Sanghi LD, Jussawalla DJ. Quantification of the role ofsmoking and chewing tobacco in oral, pharyngeal, and oesophageal cancer. Br JCancer 1977; 35: 232-35.

9. Keller AZ. The epidemiology of esophageal cancer in the west. Prev Med 1980; 9:607-12.

10. Rothman KJ. The proportion of cancer attributable to alcohol consumption. Prev Med1980; 9: 174-79.

11. Appelqvist P. Carcinoma of the oesophagus and gastric cardia. Academic dissertation,medical faculty of the University of Helsinki, 1972. Acta Chir Scand 1972, suppl.430.

12. Cederqvist C, Nielsen J, Berthelsen A, Sand Hansen H. Cancer ofthe oesophagus. ActaChir Scand 1978; 144: 227-31.

13. Wiklund K, Einhorn J, Wennström G, Rapaport E. A Swedish cancer environmentregister available for research. Scand J Work Environ Health 1981; 7: 64-67.

14. Eklund G, Wiklund K. Quality control study of the personal identity in the cancerenvironment registry National Central Bureau of Statistics, statistical review, 1979.Third series, Vol 17, 5, 373-76 and 407-08 Stockholm.

15. Mattson B. Completeness of registration in the Swedish cancer registry. The NationalCentral Bureau of Statistics, Statistical reports, HS 1977.12, Stockholm.

Preventive Medicine

PREVENTION OF PRIMARY LIVER CANCER

Report on a Meeting of a W.H.O. Scientific Group*A W.H.O. Scientific Group on prevention and control of

hepatocellular carcinoma met in Geneva from Jan. 30 to Feb.4, 1983. The meeting was opened by Dr Halfdan Mahler, theDirector-General, who noted that unique opportunities exist,for the first time, to prevent a common human cancer byimmunisation.

Hepatocellular carcinoma is one of the ten commonestcancers in the world and one of the most prevalent cancers indeveloping countries. There are over 250 000 new cases ofliver cancer each year. The evidence linking hepatitis B viruswith primary hepatocellular carcinoma was initially based onepidemiological and geographical observations of a strongassociation between hepatitis B infection and this cancer.’ 1This association is overwhelmingly strengthened by resultsof studies on integration of the viral DNA with the DNA ofthe host genome.2 Integration of viral with cellular DNAprobably precedes transformation by many years, andinfection with hepatitis B virus during the perinatal periodmay well be a critical aetiological factor in liver-cellcarcinoma. 3 Unexpected confirmation of this causalassociation is derived from comparative pathology of

*Report prepared on behalf of the W.H.O. Scientific Group by A. J.ZUCKERMAN (Chairman), SUN TSUNG-TANG (vice-chairman), A. LINSELL(rapporteur), J. STJERNSWARD (chief, cancer unit; secretary).

Participants: G. Ada (Canberra), W. G. van Aken (Amsterdam), R. P.

Beasley (Seattle), N. Bhamarapravati (Bangkok), H. Brummelhuis

(Amsterdam), Chan So Ha (Singapore), P. Coursaget (Dakar), F. Deinhardt(Munich), A. Goudeau (Tours), M. Hilleman (West Point), Khin Maung Tin(Rangoon), S. Lagakos (Boston), Li Ho-min (Beijing), A. Linsell (Geneva),H. C. Loucq (Marnes-la-Coquette), J. E. Maynard (Phoenix), N. C. Nayak(New Delhi), K. Nishioka (Tokyo), G. T. O’Conor (Bethesda), Oon Chong-jin(Singapore), R. Ryder (Banjul), G. C. Schild (London), D. A. Shafritz (NewYork), P. Smith (London), Sun Tsung-tang (Beijing), P. Touré (Dakar), D.Trichopoulos (Athens), O. S. Vyasov (Moscow), G. P. Warwick (U.I.C.C.), M.Yano (Nagasaki), A. J. Zuckerman (London); W.H.O. secretariat-A. Assaad,T. A. Bektimirov, F. T. Perkins, P. Sizaret, K. Stanley, J. Stjernswärd(secretary); W.H.O. regional offices-M. E. Chuwa (Brazzaville), Y. H. Paik(Manila); IARC, Lyon-N. Day, N Munoz, M. Parkin.

464

hepatocellular carcinoma in the eastern woodchuck

(Marmota monax) and by the morphological and serologicalfeatures and molecular virology of hepatitis-B-like viruses inother animals-the Beechey ground squirrel (SpermophilusbeecheYl), certain domesticated ducks (Anas domesticus),4 andprobably black-tailed prairie dogs (Cynonys ludoviccianus), aclose relative of the woodchuck.About 80% of human hepatocellular carcinomas are

considered to be attributable to infection with hepatitis Bvirus. Hepatitis B virus is thus second only to tobacco amongthe known human carcinogens. The age-adjusted incidenceof hepatocellular carcinoma is over 30 new cases per 100 000population each year in some parts of Asia and Africa,whereas it is less than 5 new cases per 100 000 per year inmost countries in Europe, North America, and Australia.Nevertheless, the frequency seems to be rising in most of thelow-incidence countries. This form of cancer is commoner

among males than among females, and its incidence increaseswith age. In high-risk populations the disease occurs inyounger age-groups, and there is a marked increase inincidence in certain ethnic groups. The intermediate stagesbetween infection and the development of liver cancer are theestablishment of persistent infection with the virus, thecarrier state, and, often, chronic liver damage, includingchronic active hepatitis and cirrhosis.Survival and persistence of hepatitis B virus (HBV) in the

population on a global scale is due to a huge reservoir ofcarriers, estimated conservatively to number over 200

million. Prolonged shedding of the virus by a proportion ofcarriers and transmission by various routes account for thefrequency of the infection. In many areas of the world,perinatal infection and infection in early life are extremelyimportant in leading to the carrier state. The timing andmechanism of transmission is, therefore, of great importancein developing intervention strategies by immunisation.

Retrospective investigation of hepatitis B serum markers inmale patients participating in cohort studies in Hawaii, inblood donors in New York, and in Eskimos in Alaska hasrevealed a substantially higher rate of hepatitis B surfaceantigen in those in whom hepatocellular carcinoma

subsequently developed than in the controls. Prospectivestudies among some 22 000 middle-aged Chinese men inTaiwan, of whom 15% were carriers of the surface antigen,have shown a 223-fold excess risk of liver cancer after 75 000

man-years of follow-up, compared with sex-matched and age-matched controls without markers of hepatitis-B virusinfection.5 A study among railway workers in Japan has alsoshown a higher risk among carriers. Other prospectivestudies are in progress in China, Senegal, Singapore, and theUnited States.

Integration of HBV-DNA into one or a discrete number ofsites on the host genome has been reported in almost everytumour in which viral DNA sequences are present. Eachtumour shows a unique restriction-enzyme pattern of

integrated HBV-DNA molecules. In some cases, both freeand integrated viral DNA have been found not only in thetumour tissue, but also in liver tissue adjacent to the tumour.In such patients, the integration pattern in non-malignantliver cells may be the same, similar, or completely differentfrom the integration pattern in the tumour. 6-9 The uniquepattern of a limited number of discrete integration sites

suggests that all or most of the cells in a given liver tumourspecimen are derived from a single progenitor cell which hasbeen stimulated to divide. Integrated HBV-DNA has alsobeen found in tumours from patients with alcoholic cirrhosis

and in the liver of some individuals with no serologicalmarkers of infection with the virus.

Recently, a full-length hepatitis virus RNA transcript wasidentified during the replication cycle of the duck hepatitisvirus. It has been suggested that this transcript serves as anintermediate for replication of this virus via a reverse

transcriptase. Therefore, hepatitis-B-like viruses may havesome properties similar to those of the retroviruses (RNAtumour viruses).1° This is an important new developmentexplaining how integration of HBV-DNA may occur.

Proviral DNA or RNA tumour viruses integrate into the hostchromosomal DNA as part of their normal replication cycle.Whether this reverse-transcriptase activity is the same ordifferent from that observed in the human hepatitis B virusremains to be established.In carriers with or without histological evidence of liver

disease, integration of HBV-DNA may be diffuse in manysites or present in unique sites of the genome. Most of thesepatients have the surface antigen and anti-HBe, and it hasbeen proposed that continued expression of the surfaceantigen in these patients may be the result of integration ofHBV-DNA. However, some patients have HBV-DNA intheir liver without expressing the surface antigen (latentinfection), whereas others also express the surface antigen orthe complete virus (persistent viral infection).The finding of integrated HBV-DNA in patients with

chronic hepatitis and in patients with hepatocellularcarcinoma indicates that elimination of integrated HBV-DNA in persistent carriers is impossible. Prevention,however, may be obtained by protective immunisation

against primary infection, thereby preventing theestablishment of the carrier state.Inactivated 22 nm particle hepatitis B vaccines have been

licensed for use11,12 and so far seem to be safe. Plasma fromhuman hepatitis-B carriers will continue to be the source ofthe 22 nm particle surface antigen for these vaccines and allvaccines to be made in the immediate future. It was agreed atthe meeting that the aim should be to start with purifiedantigen and that some of the potential contaminants can beremoved by physical methods. Some infectious agents maynot be removed by physical methods and thereafter biologicaland/or chemical means must be used to destroy all infectiousagents. The Scientific Group noted that the ultimate

objective of control of hepatitis B by active immunisation andthe implementation of projects to prevent chronic liver

damage and hepatocellular carcinoma could be delayedshould there be an unfortunate accident in which hepatitis Bvaccination led to infection. New hepatitis B vaccines underdevelopment include potent polypeptide micelle vaccines,’ 3and progress is being made with immunogens prepared byDNA-recombinant techniques and, in the longer term withchemically synthesised vaccines. 14

Feasibility studies conducted in several countries with twopreparations of the 22 nm surface antigen particle vaccinehave shown that immunisation of babies, even those withpassively acquired antibody, can prevent natural infectionwith hepatitis B virus and the development of the carrierstate. It is, therefore, now appropriate to plan and initiate anumber of field trials of hepatitis B vaccination in

populations where the prevalence of hepatitis B infection, thecarrier state, and hepatocellular carcinoma are high.Development of "preventive measures specific to cancersthat are preventable in the countries concerned, leading to asignificant reduction in the incidence of these cancers" is oneof the three main targets of the W.H.O. Cancer Control

465

Programme. The present report shows that scientific

knowledge accumulated does allow such measures to be takenand that it would be timely to explore means for their:mplementation.

REFERENCES

1. Szmuness W. Hepatocellular carcinoma and the hepatitis B virus: evidence for a causalassociation. Prog Med Virol 1978; 24: 40-69.

2. Anonymous. Human virus, hepatic cancer. Lancet 1981; ii: 1394-95.3. Zuckerman AJ. Viral hepatitis, the B antigen and liver cancer. Cell 1974; 1: 65-674. Summers J. Three recently described animal virus models for human hepatitis B virus.

Hepatology 1981; 1: 197-83.5. Beasley RP, Hwang L-Y, Lin C-C, Chien C-S. Hepatocellular carcinoma and hepatitis

B virus. Lancet 1981; ii: 1129-33.6. Summers J, O’Connell A, Maupas P, Goudeau A, Coursaget P, Drucker J. Hepatitis B

virus DNA in primary hepatocellular carcinoma. J Med Virol 1978; 2: 207-14.7. Shafritz DA, Shouval D, Sherman HI, Hadziyannis SJ, Kew MC. Integration of

hepatitis B virus DNA into the genome of liver cells in chronic liver disease andhepatocellular carcinoma: studies in percutaneous liver biopsies and post-mortemtissue specimens N Engl J Med 1981; 305: 1067-73.

8. Brechot C, Hadchouel M, Scotto J, et al. State of hepatitis B virus DNA in hepatocytesof patients with hepatitis B surface antigen-positive and -negative liver diseases. ProcNatl Acad Sci USA 1981; 78: 3906-10.

9. Zuckerman AJ. Primary hepatocellular carcinoma and hepatitis B virus. Trans Roy SocTrop Med Hyg 1982; 76: 711-18.

10. Summers J, Mason WS. Properties of the hepatitis B-like viruses related to theirtaxonomic classification. Hepatology 1982; 2 (suppl.): 61S-66S.

11. World Health Organisation Expert Committee on Viral Hepatitis Advances in viralhepatitis Wld Hlth Org Tech Rep Ser no. 602; 1977.

12 World Health Organisation Expert Committee on Biological Standardisation

Requirement for hepatitis B vaccine. Wld Hlth Org Tech Rep Ser no. 658; 1981.13. Skelly J, Howard CR, Zuckerman AJ. Hepatitis B polypeptide vaccine in micelle form

Nature 1981; 290: 51-54.14. Viral hepatitis. An informal WHO meeting Bull Wld Hlth Org 1982; 60: 661-91.

In Wales Once

ENCOUNTERS OF A COLLIERY DOCTOR

"I had supposed that the patients would enter the consulting roomone by one, but I was wrong. The doctors went out to them in thelarge waiting room, where a crowd had assembled. In a corner of thewaiting room was a screen, behind which patients were at leastinvisible. It was here that fractures were set, wounds stitched,fingers lanced, and teeth extracted and from this quarter sensationaland harrowing sounds issued from time to time."So wrote Dr Frank Smith, describing his experiences as a colliery

doctor in a Welsh mining town over 70 years ago. Yet some of hisreminiscences seem to cross the arches of the years, sharing anaffinity with Francis Brett Young, A. J. Cronin, and those of us whoworked as assistants in large towns in the ’50s. The packed low-amenity surgeries; the long round of house calls; the interruptedmeals and the disturbed nights; the poor pay and the vast

experience; and the deadly animosity of opposing practices. Even tothe overcrowded street which was a community unto itself. His wasGwynfa Terrace. "There is not an empty house in the street andnever has been since it was built. It is useless to try to hide eithervirtues or vices under a bushel in Gwynfa Terrace for the

neighbours sift your character to the very bottom. There is buzz oftalk from early morning until late at night." Every doctor used tohave a Gwynfa Terrace (mine was Harmony Row in Govan) and likeFrank Smith’s, they were rich in characters, problems, incidents,and illness. The visiting general practitioner was as much a part ofthe landscape as the police, the sanitary inspector, and the insuranceman.

"This is a jolly good post," said his first principal. "I offer you200 a year, with rooms, coal and gas. Nothing like it in all

England?" Frank Smith stayed in the valleys for seven years, but hisaffection for the people; the crowded, bustling, dirty mining town;and the bleak, pit-scarred countryside remained with him all his life.It is a book to be given to young doctors to let them know how it usedto be, and to older general practitioners to remind them of howthings have changed and yet, in some ways, remained the same.

1. The Surgery at Aberffrwd. By Francis Maylett Smith. Edited by Denis Hayes Crofton.Hythe, Kent: Volturna Press. 1983. Pp 173 £5 90.

National Health Service

A FURTHER INQUIRY INTO EFFICIENCY

THE appointment of Mr Roy Griffiths, Managing Director ofSainsburys, to head yet another inquiry into the running of theN .H.S. is deeply disturbing. It is not only that Mr Griffiths and histeam of three businessmen have been given only until June toprepare their report, or that the inquiry will concentrate on staffinglevels and related resources, or the probability that their findingswill not be made public,2 though each of these features is disturbingenough. The very wide group of people who carry some degree ofresponsibility for the organisation of the N.H.S., from porters toregional administrators, should of course be constantly learninghow to do their jobs better and how best to adapt services to achanging world. However, an atmosphere of confidence andopenness to learning is not generated by a hasty and secretinvestigation. Worse, much administrative time will be divertedfrom completing the current reorganisation of the N.H.S. andrunning the service-and given the lack of relevant experience of theinvestigators and the conditions under which they will be working,the report itself is almost certain to be damaging.Ministers who came into office having absorbed hostile and ill-

informed views of the N.H.S. from Fleet Street and the back-woodsmen of medical politics should surely by now be aware thatthe overall performance of the N.H.S. is outstandingly cost-

effective when compared-as it ought to be-with health care inother countries. For example, the staffing levels are far from

extravagant, the proportion of G.N.P. spent on health care in theUnited Kingdom is still strikingly low for an industrialised countryand our administrative overheads run at around 5%3 compared with21% in the U.S.A. The problems of the N.H.S. should be seen inperspective: many of them are basically the result of the poorperformance of the British economy. Do ministers need remindingof the comparative performance of British industry and commerce-the apparently omniscient and omnicompetent private sector?When it is recalled that a diligent Royal Commission reported in

1979, that Mr Fowler’s colleague, Sir Keith Joseph, was responsiblefor the first major reorganisation of the N.H.S. only nine years ago(and which involved private-sector management consultants), andthat an equally disruptive reorganisation, ostensibly to correct themajor errors of 1974, has not yet been completed, theannouncement of another newcomer’s inquiry into efficiency makesthe Secretary of State for Social Services look like the boy who keptdigging up his plants to see whether they were growing.There are many people, from members of authorities and

community health councils to all kinds of members of staff, whohave much experience of the problems of organising health care andwho have constructive ideas which could improve the N.H.S. Giventime and copious briefing, Mr Griffiths and his colleagues mightalso develop some useful contributions-though their experienceequips them much better to produce proposals for the wastelands ofBritish industry and commerce. However, such contributions-even for industry and commerce-would be taken more seriously ifthey were offered in response to invitations by the relevant staff andin circumstances which permitted the separation of the wheat fromthe chaff.How should the staff of the N.H.S. react to this latest inquiry? If

administrators and health authorities were to object, most of thepress would probably characterise their resistance as a defensive andguilty reaction. However, if the medical profession were to make itclear individually and collectively that this inquiry is unnecessary,misguided, and potentially dangerous, the morale of those with

1. Deitch R. Commentary from Westminster A new inquiry into N.H.S. staffing andefficiency. Lancet 1983, i: 369

2. Sherman J, Black T, Halpern S Manpower checkout Health and Social Services J Feb.17, 1983, p. 196

3 Laurance J Managing medicine. New Society Feb 10, 1983, p 223.4. Lalonde M. Beyond a new perspective. Am J Pub Health 1977; 67: 4.