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` Researeh Reports on 2-6 Tobacco and Health Vol. 6 No. 1 March-April 1963 IN THIS ISSUE Viruses and Cancer, p. 1 British Emigrants, p. 3 Tuberculosis Scars, p. 4 TM.r. 4 dM.+ttr .t .ptals r.p.rdYy t.r.aae awn a./ YedU. t:MrM. .gdof tar..w e a widdr p.Wleta.d, Mrt tw a».Mle. 4 oW.e te adari.b'whidt Mdlwla tlrM dl/aly .rtal.a. .aM fW p.MisdMs nqwb as.a .f tYw .oNri.& . Special report from Houston . . . Scientists Discuss Viruses and Cancer Research findings lending support to the theory that viruses may be in- volved in human cancer were reported by scientists throughout the world at the 17th Annual Symposium on Fund- amental Cancer Research sponsored by the University of Texas M.D. Ander- son Hospital and Tumor Institute at Houston, Feb. 20•22. The session, whose theme was "Viruses, nucleic acids, and cancer," drew more than 1,000 registrants who discussed such topics as the structure of viruses, viral replication, cell changes following viral infection, avian viruses and neoplasia, biological aspects of tumor induction by viruses, interrelationship of viruses, and cell protection against viral action. Several participants noted that while no virus has yet been detected in a human cancer, sufficient experi- mental evidence is available to support the viral theory of human cancero- genesis. Dr. Maurice R. Hilleman of the Merck Institute for Therapeutic Re- search, West Point, Pa., said "the past decade has seen a rapid accumulation of a vast body of information relat- ing to malignancies in animals which lends inferential support to the virus theory for causation of cancer. "In fact, there is much to suggest that some human cancer may be the result of infection with ordinary `every day' viruses (smallpox, chickenpox, mumps, etc.) with no need for the unique or the exotic," said Dr. Hille- man, co-discoverer of the SV40 virus, the first virus of primate origin to cause malignancy in an experimental animal. Hilleman said he and associates had for the first time purified "interferon," a protein substance released from in- fected cells which has the ability to inhibit virus production in other sus- ceptible cells. Several other scientists discussed interferon. One reported that interferon had been shown to stop tumor production by the Rous sar- coma virus. Other highlights of the meeting were summed up in a news confer- ence by the chairman, Dr. Leon Dmochowski, chief of the section of virology and electron microscopy at M.D. Anderson Hospital and Tumor Institute : (Continued on page 2) Statistics 'Disappointing' In Chronic Disease Work "Classical" statistical methods which worked well in identifiying the causes of acute infectious diseases "have been disappointing" in the search for the causes of chronic dis- eases such as lung cancer, three Cin- cinnati epidemiologists conclude.' Drs. Theodor D. Sterling, John J. Phair and Jagdish Rustagi, of the University of Cincinnati College of Medicine, show that in past studies, "Depending solely upon methods of manipulation of numbers, smoking appeared to increase the risk of death (Continued on page 4) •"New developments in chronic disease epi- demiolo~: Competing risks and eligibility." American Industrial Nyltene Association Journal, November-December 1962. Autopsy Study Fails To Support Smoking Tie To Vascular Ills A study of findings in nearly 1000 autopsies indicates "that if an associ- ation exists between smoking practices and the development of arteriosclero- sis or lesions resulting therefrom, it is at best tenuous and inconclusive," two New York pathologists report.' The published statistical linkage of heavy cigarette smoking to coronary artery disease probably reflects more distinct clinical symptoms of the dis- ease in heavy smokers rather than a cause and effect relationship, said Drs. Sigmund L. Wilens and-Cassius M. Plair, who studied 989 consecutive autopsies on men performed at the New York Veterans Administration Hospital between 1958-1961. "The relation between cigarette smoking and heart attacks could be an indirect or even a fortuitous one," -they said. The pathologists found evidence of distinct myocardial infarcts in approx- imately 20% of non•smokers, 25% of heavy smokers, 23% of moderate smokers, 25eJo of light smokers, 27~Jo of pipe and cigar smokers and in 20~Jo (Continued on page 4) •"Cigarette smoking and arteriosclerosis." Science, November 30, 1962. Study of 13,307 Death Records Finds ... Lung Cancer Deaths 20% Overstated Errors in recording cancer deaths by specific sites are "sufficiently large" to "warrant skepticism of the value of the death record for studies which compare individual environmental factors with subsequent cause of death," report Drs. Herbert L. Lom- bard, Evelyn Potter Huyck and Leonid S. Snegireff of Boston.' This observation resulted from their •"An a~praisal of the cancer death record." Proceediaxs of the Nadoaol Academy of Sciences, December 1962. study of the 1946-1958 death records of the Massachusetts Cancer Registry, which comprises the accumulated life- time records of nearly all the patients of the 30 state cancer clinics. They found that the deaths as recorded showed a better than 20 percent over- statement of actual number of deaths from primary cancer of the lung. This was only partially offset by an 8.4 per cent understatement, because of primary lung cancer deaths that were (Continued on page 3) TIMN 0115607 T200090

Fletcher and Garland ... Experts Differ on Royal College Report One of the authors of the Royal Col- lege of Physicians' report on Smok- ing and Health has come to its defense in a letter to the New England Journal of .tiledicine.' The Journal also pub- lishes a reply by a previous critic of the report, San Francisco radiologist Dr. L. H. Garland. In his letter, Dr. C. M. Fletcher, of London. England, charges that Dr. Garland "appears to confuse the un- controlled evidence about outdated medical and surgical procedures now looked upon as `largely erroneous in concept and in application' with the meticulous statistical work that has gone to show the association between cigarette smoking and lung cancer. This is a failure to distinguish black from white in respect to scientific evi- dence. He is also a very careless reader. He criticizes the report . . . in respect to its observations on the rela- tions of cigarette smoking to chronic bronchitis and peptic ulcer . . ." Dr. Fletcher concludes: "Dr. Garland also submits that 'the scientific evidence that cigarette smok- ing is a hazard to peptic ulcer is ten- uous if not paradoxic.' It is only paradoxic if one fails to make the correct comparison and fails to dis- tinguish gastric from peptic ulcer. "If the report on smoking and health did seriously misrepresent any of the evidence this should be pointed out, but strictures like those of Dr. Garland, based on a failure to read the report and to consider the facts, suggest a bias that no good doctor should permit when he is dealing with the major problem of public health presented by cigarette smoking." `Serious Flaws' Dr. Garland replies: "The report of the Royal College on smoking has been read in its entirety and more than once. Its tenor and con- clusions had been adumbrated during its 36 months' gestation and were not unexpected in the light of past cor- respondence with its distinguished composer . . . "What Dr. Fletcher seems to forget or overlook is the fact that 'the metic- ulous statistical work' on which the association of cigarette smoking and lung cancer is based is not regarded as without serious flaws. Reference to the many publications of such dis- •"Smoke vs. Fire " Letters, New England lournal o/ Medicine, Dec. 6, 1962 . tinguished statisticians as C. Wilson, J. Berkson, J. Yerushalmy and R. Fisher will quickly validate this point ... "Having lived through the era when it was preached as gospel that 'every gastric ulcer should be excised to pre- vent its becoming cancerous' (Ochs- ner) and 'every colon polyp is to be regarded as premalignant (Buie), one must not object to skepticism at the reportedly unqualified evil nature of cigarettes. "The British report skims over the general air• pollutants problem, and gives short shrift to possible viral fac- tors. Lung cancer is one of our major medical tragedies, but let us keep it in perspective: in the latest year for which United States Vital Statistics are available, recorded deaths due to primary lung cancer accounted for only 1.8 percent of all reported deaths in the United States." Houston: Special Report (Continued /rorn page 1) 1. Important knowledge of the structure of viruses at the molecular level is being obtained. There seems to be a fundamental "unity in struc- ture" between all viruses - plant, in- sect, animal and man - though they may differ in size and other charac- teristics. 2. Heretofore it had been believed that only deoxyribonucleic acid (DNA) was cancerogenic in experi- mental work. Now it has been shown that ribonucleic acid (RNA) viruses may produce cancer. (Dr. J. Huppert of France reported he took an RNA preparation from leukemic chickens, injected it into other chickens and induced leukemia in them.) Major strides are being made in chemical analysis of the differences between normal DNA ("the blueprint of life") and the DNA that is cancerogenic. 3. More knowledge is being ob- tained about how viruses replicate in the cells they infect. Viruses can pro- duce new enzymes to help their own synthesis. Knowledge of the many mechanisms involved will be important in future chemotherapy. 4. Reports on avian tumors are im- portant because it is now firmly es- tablished that tumor viruses from chickens can induce various types of cancer in mammals such as mice, rats, Tobacco and Health Published by THE TOBACCO INSTITUTE, INC. Address correspondence to: Editorial Office Tobacco and Health 150 East 42nd Street New York 17, N. Y. guinea pigs, hamsters and rabbits. "To say this three years ago would have been heresy." 5. The human adenovirus 12, which produces cancer when injected into new-born hamsters, now has been shown to induce cancers in mice. Adenovirus 18, another human virus responsible for common respiratory disorders, has been shown to induce cancers in rats as well as in hamsters. (Dr. John Trentin of Baylor Uni- versity, who first reported the work with adenovirus 12 in hamsters, said in an interview that he and others now are using this virus in experimental work with monkeys.) Co-sponsors of the meeting were the National Cancer Institute, the Texas State Department of Health, the Amer- ican Cancer Society's Texas Division and the University of Texas Postgrad- uate School of Medicine. Full pro- ceedings of the meeting are to be published. Peptic Ulcers Often Found In Lung Cancer Autopsies Peptic ulcers are more frequently found at autopsy with carcinomas of the lung than with other carcinomas, and this difference may be significant, two Veterans Administration patholo- gists report.' In autopsies of 107 patients with bronchogenic carcinoma at the VA West Side Hospital, Chicago, Drs. Simon J. Ramah and Bernhard Cho- met found that 22 also showed gastric or duodenal ulcers, an incidence of 21 percent. In 201 cases of cancer of other organs (excluding cancer of the stomach ), they found 21 instances (10 percent) of associated peptic ulcers. Of the ulcers associated with lung cancer, they note, 15 were chronic and ,wven were acute. Other workers have reported simi- lar associations, the Chicago patholo- gists said. •"Bronchogenic carcinoma and peptic ul- cer." Cancer, November-December 1962. M 2 TIMN 0115608 T200091

When Britons Go to Australia ... Lung Cancer Risks Drop After Move Men and women who emigrate to Australia from Great Britain show higher lung cancer mortality rates than Australian-born men and women, but lower lung cancer mortality rates than are found in England and Wales. The differences do not appear to be due to differences in smoking habits, according to Dr. Geoffrey Dean of Eastern Cape Provincial Hospital, Port Elizabeth, South Africa.' Dr. Dean said his findings, similar to those he previously had reported for his home country, are "consistent with the hypothesis that the contribu- tion of air pollution to lung cancer has been seriously underestimated." Also, he wrote, the Australian data were basically in line with those from previous studies of British immigrants to New Zealand and the United States. He first compared smoking habits of British immigrants and native-born Australians and found Australians had smoked somewhat fewer cigarettes per capita until World War II, but had caught up with and passed the British in the 1950's. As to smoking habits, Dr. Dean •"Lung cancer in Australia." The Medical Journal of .lustralia, June 30, 1962. said, "Insofar as British immigrants have adopted the smoking habits of the country to which they have mi- grated - and the evidence from South Africa suggests this is the usual prac- tice - British immigrants will have become heavier smokers than the men and women they have left behind them." Yet, during the years 1950 to 1958, British-born men migrating to Aus- tralia had a lung cancer mortality rate about 40oJo lower than the rate for men of the same age in England and Wales, and the corresponding figure for women was about 35oJo lower. In his Australian study, Dr. Dean found that, ". .. during the years from 1950 to 1958 (excluding 1952), male British immigrants had a lung cancer mortality rate that was 67oJo higher than that of Australian-born men, but 39% lower than that of men in Eng- land and Wales." "During the same period," Dr. Dean says, "female British immi- grants had a lung cancer rate 33oJo higher than Australian-born women, but 34% lower than women in Eng- land and Wales." X-Ray Survey Follow-up Suggests ... Unidentified Factors In Lung Cancer A follow-up of a mass x-ray cam- paign conducted in 1953 in Allegheny County, Pa., has disclosed a signifi- cantly greater risk of dying of lung cancer among those who did not par- ticipate in the campaign than in those who did, three Pittsburgh physicians report.' The discrepancy does not appear to be attributable to biases in the data, foreign birth, tuberculosis, or ci a- rette smoking, according to Drs. C.~. McClure, B. K. Milmore and A. G. Gilliam. The finding, they say, "sup- ports the idea that some factors as- sociated with high risk of lung cancer have not yet been identified." From March 1953 to December 1958, a total of 1,946 residents of the county at the time of the 1953 survey •"Relative risk from lung cancer in Aile- gheny County, Pa. (1953-1958 )." Iournal o f Chronic Diseases, November 1962, were certified as having died of pri- mary lung cancer. Of these, 892 were identified as survey participants, and the remaining 1,054 as non-partici- pants. Smoking Influence Doubted Compared to the national rates of lung cancer deaths for each of the years involved, the authors say. there was an over-all deficiency of 71.8 deaths (-7.4 percent) among the survey participants, and an over-all excess of 344.5 deaths (+48.5 per- cent) among the non-participants. "In the absence of smoking histor- ies from the non-participants," the authors observe, "one cannot say whether this factor could account for their excess lung cancer but it would appear unlikely that the smoking ques- tion had much influence on whether people were x-rayed or not." Records Show 20 °Jo Lung Cancer Error (Continued f ront page 1) recorded as due to some other cause of death. If one wishes only to know the num- ber of lung cancer cases, the actual does not vary "greatly" from the cases recorded but, they add, "if one wishes to correlate some variable such as cig- arette smoking with lung cancer, the individual death records must be con- sidered. Here, the error is far greater." The death records and histories totalled 13,307. Of these, the investi- gators found, 269 gave primary lung cancer as the cause of death. However, thev note, 49 of these patients never had cancer of the lung, and one more was thought to be cured at the time of death, an error of 18.2 percent. In addition, cancer of the lung, un- specified as to whether primary or secondary, was said to have been the cause of 695 deaths. In this group, it was found that 126 never had primary lung cancer, a discrepancy of 18.1 percent. Other Errors Also Found If the two groups are totalled, the scientists point out, the combination- "constitutes a 20.4 percent overstate- ment of primary cancer" of the lung. Errors of varying size were also found for other recorded sites of can- cer death in their study. "It is rather surprising," the inves- tigators say, "that so many physicians report a cancer death according to the site of the metastasis rather than by the primary site. ... Errors of diag- nosis have always occurred and will continue unless universal accept- ance of autopsies takes place. Several papers have been published on the accuracy of diagnosis and there has been speculation whether trends such as are found in lung cancer are as pronounced as they appear to be. Changes in the accuracy of diagnosis could well alter the statistics." The scientists conclude: "It is be- lieved that the data from the Massa- chusetts clinics are probably more ac- curate than for the state as a whole since the clinics specialize in malig- nancy and have life-time follow-up of all cases. A cross-section of all Massachusetts cancer deaths may well show greater error than the sample from the clinics. It is believed that they would never show less, and such ratios as have been compiled may be accepted as indicating minimum errors." 3 TIMN 0115609 T.200092

Question Chronic Disease Statistics (Continued f rom page 1) from quite different causes - at times cancer, at other times circulatory dis- ease." They demonstrate that a similar bias could be introduced into a study of iheir own, in which selection of age groups and mortality ratios among industrial workers produces an apparent job health risk which actu- ally may not exist. "It is interesting to note," they add, "that this hazard could be claimed to affect death from lung cancer or from circulatory causes depending on one's reliance on mortality ratios or on dif- ferences in death probabilities. The congruence between the projected findings of this imaginary study to tho,e of the lung cancer and smoking str,iies is noteworthy; especially if one keeps in mind that most popula- tions of smokers so investigated were concentrated in the older age groups." They call for re-evaluation of pres- ent statistical methods in the field of chronic disease epidemiology before conclusions about the causes of such diseases are reached. "While comparisons between smok- ers and non-smokers are always con- troversial," they say, "there too are populations who may differ in many other ways besides addiction to a single habit and accordingly may vary widely in mortality and morbidity patterns during their life spans. The extent of these differences and their force on mortality in middle and older ages have not been truly explored." Their own study involved a group of 4,573 white workers in a heavy in- dustry, residing in seven states, from 1940 to 1957. For the entire group (ages 25 to 85), they point out, deaths from lung cancer, other cancer and coronary diseases occurred about as frequently as in the U.S. population as a whole. If, however, the workers being stud- ied are limited to those aged 65 and up, the death rates for cancer and coronary diseases appear to increase markedly. An investigator who adopts this age limitation "apparently dis- covers an industrial hazard where in actuality none may exist." When the comparisons are limited to those under the age of 65, there is found a "favorable balance of sur- vival" into older age groups that "can- not be appreciated fully if large segments of their life spans are omit- ted." The result of this survival at younger ages makes more of the group eligible for "degenerative and neoplas- tic disease" after the age of 65. "Conclusions drawn from epidemi- ological studies," the authors state, "depend in the last analysis on the methods selected to compute the risk of reaction and death from specific causes. In most investigations of chronic diseases the data cover only limited segments of the life span and are restricted to a relative small num- ber of diseases from which members of the cohort may die.... The prior unknown mortality experience in con- trasted populations or differing con- current mortality from diseases other than the one under study may lead to apparent differences in age-specific rates when in fact the 'net' risks are essentially identical." Find Smoking-Arteriosclerosis Link 'Tenuous' (Continued f rom page 1) of those whose smoking habits were unknown or unclassified. The number of men in each category ranged from 70 (pipe and cigar smokers) up to 288 (moderate smokers). The researchers said that incidence figures in the categories did not "vary significantly," adding that "This find- ing is in direct contradiction to clinical findings and suggests that myocardial infarcts may be more productive of severe symptoms, and thus more eas- ily recognized, in heavy smokers than in non-smokers." The doctors also graded aortic spec- imens, making allowance for the sub- jects' chronological ages. 'Fhex found that the degree of aortic sclerosis was directly proportional to age in 60% of their subjects, regardless of smok- ing habits. In the other 40oJo, however, they found that premature sclerotic changes were more than twice as com- mon among heavy and moderate smok- ers than in non-smokers and users of pipes and cigars. The researchers concluded, "Me incidence of myocardial infarction is only very slightly higher in heavy smokers of cigarettes than in non- smokers, and there is no consistent rise in the incidence of such lesions with degree of cigarette smoking. The incidence of other types of lesions re- lated to arteriosclerosis is not affected by smoking habits." Surgeons Find Lung Cancer Arising in Old TB Scars In the patient with tuberculosis, the diagnostician must be alert to the pos- sibility of co-existing cancer of the lung, three Mississippi surgeons ad- vise.' This warning emerges from a study of 34 patients found to have both diseases. This experience, the surgeons say, supports the theory that lung scar- ring may be one cause of primary lung cancer. Of their patients, 31 had both le- sions in the same lung. Delay in diag- nosis of the neoplasms averaged 13 months, they found, and most often was attributable to the attending phy- sician. TB Came First in 19 The patients were seen at the Mis- sissippi State Sanatorium between 1951 and 1960. Nineteen developed pulmonary tuberculosis at least three years before the onset of malignancy, which usually arose in the old tuber- culosis lesions. In the remaining 15 patients, tuberculosis and lung cancer apparently arose simultaneously, the surgeons state. "our experience and review of the literature," they report, "while not conclusive, supports the concept that persistent epithelial regenerative ef- forts in areas of scarring from tuber- culosis or other chronic pulmonary disease mat be an etiologic factor in carcinoma. The authors are Drs. Jesse L. Wof- ford, Watts R. Webb and Hans-Karl Strauss. •"Tubereulods ecarrin6 and primary laas cancer." Archives of Sur daT. December 1962. Research Grants The Scientific Advisory Board to the Tobacco Industry Re- search Committee awarded 52 additional research grants to in- dependent scientists in 1962, the chairman of the T.LR.C., Tim- othy V. Hartnett, announced re- cently. Mr. Hartnett also noted in a statement that T.I.R.C. had ap- propriated $800,000 in new funda to bring to $6,250,000 the total made available to finance grants made by the Board. 4 TIMN 0115610 T200093