599 CHEMOTHERAPY OF NON-PULMONARY TUBERCULOUS CONDITIONS By PETER H. BUXTON, M.R.C.P. - From the Middlesex Hospital, London Many drugs have been tested for their effect in vitro on the growth of the tubercle bacillus; some of these have been tested in experimental tubercu- losis in animals and some have been given clinical trials (Feldman, 1946). By far the most effective yet to have had extensive clinical trials is strepto- mycin. Apart from the toxic effects of this drug on the vestibular and auditory apparatus, its value was limited by the rapid development of drug re- sistence by the tubercle bacillus. At first attempts were made to combat this by giving intermittent treatment; they were not successful. In 1949 the Medical Research Council were able to show, as a result of clinical trials then proceeding with para- amino salicylic acid. (PAS) and streptomycin in pulmonary tuberculosis, that if PAS was given concurrently with streptomycin therapy there was a considerable reduction in the incidence of streptomycin resistant strains of tubercle bacilli produced; this has since been confirmed by many other workers. It is now general practice to give PAS by mouth in all cases of tuberculous infection that are treated by streptomycin systemically. The dosage of PAS usually recommended is 20 g. per day for adults, given in divided doses four times a day, but it is wise to start with a smaller dosage, such as I2 g. per day, which should be increased gradually. Side effects of the drug are anorexia, nausea and vomiting, which tend to occur at the start of treatment. Different forms of the drug have been produced in an attempt to counteract these side effects; our experience has been that the granule form is that best tolerated and that if the dose is increased slowly, digestive disturoances usually subside as treatment is continued. The place of other antibiotics and antibacterial substance$ introduced for the treatment of tuberculosis has recently been summarized by Scadding (i95i). Treatment of Tuberculous Lymphadenitis General measures such as bed rest and sanatorial treatment are still necessary in the active stage of the disease. Chemotherapy alone with intramuscular strepto- mycin and oral PAS is the treatment of choice for extensive involvement of glands in the exudative phase. Surgical removal is the best treatment for caseating glands or for localized groups of infected glands. When chemotherapy alone is used, streptomycin should be given intramuscularly in the dosage of I g. per day for adults and io mg. per lb. body weight per day for children; this dose is usually divided into two injections given night and morn- ing. PAS should be given orally concurrently with streptomycin treatment. Treatment is continued till there is no further evidence of activity as &-judged by the temperature, sedimentation rate, re- duction in size and tenderness of glands and gain of weight. lf after I2 weeks' treatment there is still evidence of activity, it is better to discontinue all drugs and observe the patient for two weeks, as occasionally persistent pyrexia may be due to streptomycin or PAS. If, however, the patient's condition continues to deteriorate during this rest period, a further course of streptomycin and PAS should be given. In the treatment of widespread tuberculous adenitis the use of streptomycin and PAS in conjunction with general measures has shortened considerably the course of the, disease. In some cases the temperature response and im- provement in the patient's general condition have been dramatic. When chemotherapy is given -as. a cover for surgery in the presence of active disease, treatment with intramuscular streptomycin and oral PAS in the dosage mentioned above should be started at least 24 hours before operation and continued for at least a week after operation, and o.5 g. of Protected by copyright. on March 10, 2020 by guest. http://pmj.bmj.com/ Postgrad Med J: first published as 10.1136/pgmj.27.314.599 on 1 December 1951. Downloaded from
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599
CHEMOTHERAPY OF NON-PULMONARYTUBERCULOUS CONDITIONS
By PETER H. BUXTON, M.R.C.P.- From the Middlesex Hospital, London
Many drugs have been tested for their effect invitro on the growth of the tubercle bacillus; someof these have been tested in experimental tubercu-losis in animals and some have been given clinicaltrials (Feldman, 1946). By far the most effectiveyet to have had extensive clinical trials is strepto-mycin. Apart from the toxic effects of this drugon the vestibular and auditory apparatus, its valuewas limited by the rapid development of drug re-sistence by the tubercle bacillus. At first attemptswere made to combat this by giving intermittenttreatment; they were not successful. In 1949 theMedical Research Council were able to show, as aresult of clinical trials then proceeding with para-amino salicylic acid. (PAS) and streptomycin inpulmonary tuberculosis, that if PAS was givenconcurrently with streptomycin therapy there wasa considerable reduction in the incidence ofstreptomycin resistant strains of tubercle bacilliproduced; this has since been confirmed by manyother workers. It is now general practice to givePAS by mouth in all cases of tuberculous infectionthat are treated by streptomycin systemically.The dosage of PAS usually recommended is
20 g. per day for adults, given in divided dosesfour times a day, but it is wise to start with asmaller dosage, such as I2 g. per day, which shouldbe increased gradually. Side effects of the drugare anorexia, nausea and vomiting, which tend tooccur at the start of treatment. Different forms ofthe drug have been produced in an attempt tocounteract these side effects; our experience hasbeen that the granule form is that best toleratedand that if the dose is increased slowly, digestivedisturoances usually subside as treatment iscontinued.The place of other antibiotics and antibacterial
substance$ introduced for the treatment oftuberculosis has recently been summarized byScadding (i95i).
Treatment of Tuberculous LymphadenitisGeneral measures such as bed rest and sanatorial
treatment are still necessary in the active stage ofthe disease.
Chemotherapy alone with intramuscular strepto-mycin and oral PAS is the treatment of choice forextensive involvement of glands in the exudativephase. Surgical removal is the best treatment forcaseating glands or for localized groups of infectedglands.When chemotherapy alone is used, streptomycin
should be given intramuscularly in the dosage ofI g. per day for adults and io mg. per lb. bodyweight per day for children; this dose is usuallydivided into two injections given night and morn-ing. PAS should be given orally concurrently withstreptomycin treatment. Treatment is continuedtill there is no further evidence of activity as
&-judged by the temperature, sedimentation rate, re-duction in size and tenderness of glands and gainof weight. lf after I2 weeks' treatment there isstill evidence of activity, it is better to discontinueall drugs and observe the patient for two weeks,as occasionally persistent pyrexia may be due tostreptomycin or PAS. If, however, the patient'scondition continues to deteriorate during this restperiod, a further course of streptomycin and PASshould be given. In the treatment of widespreadtuberculous adenitis the use of streptomycin andPAS in conjunction with general measures hasshortened considerably the course of the, disease.In some cases the temperature response and im-provement in the patient's general condition havebeen dramatic.When chemotherapy is given -as. a cover for
surgery in the presence of active disease, treatmentwith intramuscular streptomycin and oral PAS inthe dosage mentioned above should be started atleast 24 hours before operation and continued forat least a week after operation, and o.5 g. of
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streptomycin either dry or in solution should beapplied locally at the time of operation. Usingthis technique a very high percentage of operationwounds heal by first intention, leaving minimaldisfigurement.
In cases of cold abscess treatment is by aspira-tion and replacement with streptomycin solution,0.5 g. m i ml. distilled water. Surgical removal ofthe infective focus may be, required later, and it iswiser, if this is planned, to reserve systemicstreptomycin treatment till then.
Treatment of Bone and Joint TuberculosisThere is no large series of cases yet published
in this country- showing-the -long-term results ofstreptomycin treatment in bone and joint tubercu-losis. Since the advent of streptomycin no majorchange has taken place in the principles of treat-ment laid down by Girdlestone (1940) and Mercer(1950). Importance is stiU attached to generalmeasures such as bed rest, sunlight and fresh air.Immobilization of the affected part and reductionof the deformity are the main aims of treatment;in adults excision of the infected joint orarthrodesis are often necessary. Treatment withstreptomycin and PAS has not produced startlingimprovement in the actual bony disease, but it hasbeen impressive in reducing cachexia and allowingtuberculous sinuses to heal.
In joint tuberculosis, Streeten (I.949) claimedrapid improvement and relief of pain with cureand useful mobility in the synovial type of disease,by preliminary alkalinization of the joint spacewith sodium hydroxide and borax buffer solution;streptomycin 0.2 to 0.5 g. was then injected dailyinto the joint cavity. Unfortunately the follow-upperiod in his cases was too short to give a finalassessment of the method.At present most workers use the classical
methods of treatment outlined above with, inaddition, intramuscular streptomycin i g. per dayand oral PAS 20 g. per day. Should tuberculoussinuses arise, local streptomycin is given as well.Cold abscesses should be treated conservatively ifpossible; aspiration and replacement with strepto-mycin solution may be used but incision should bereserved for cases where the skin is discolouredand about to break, or the abscess is spreading, orwhere there is pressure on vital parts or secondaryinfection. In all cases of secondary infection theinfecting organism should be isolated and theappropriate antibiotic given after in vitro sen-sitivity tests.As in cases; of tuberculous adenitis there is no
dramatic cure of the underlying disease withstreptomycin therapy, but tuberculous sinuses canbe expected to close and cachexia is relieved.
Tuberculous SinusesTuberculous sinuses may be treated with
streptomycin given locally (Ahem, 1950), or thevdrvgpay. be given systemically with oral PAS(Davis, I949). The adherents of local treatmentalone argue that their results as regards closure ofthe sinuses are as good as when systemic treat-ment also is given, but that their method has theadvantage of saving the patient much discomfortfrom repeated intramuscular injections. They alsostate that though the drug is only given locally,therapeutic blood levels are obtained and the con-centration of the drug at the site of the infection isgreater than that obtained by intramuscular treat-ment alone. There is, however, always a greaterchance of producing drug sensitivity when anyantibiotic drug is administered in large doseslocally, and there is also the danger that the drugmay not penetrate through dense granulationtissue and necrotic d6bris in sufficiently high con-centrations to exert a bacteriostatic effect on deep-seated viable tubercle bacilli. If a deep focus ofinfection is suspected, it is better to treat this eitherby systemic streptomycin and PAS, or by surgery,the sinus itself being treated by local applicationsof streptomycin.
Results of streptomycin treatment in closure ofsinuses are excellent, but there is always a dangerof breakdown unless the underlying infection can-be removed or controlled.
Treatment of Tuberculous PeritonitisOnly three cases of tuberculous peritonitis
treated with streptomycin have been reported inthis country, and in all the results were mostsuccessful (Grant et al., 1951; Salmon, 1951).Scarcity of puDlished reports is probably due tothe fact that individual centres have only hadoccasional cases to treat. At the MiddlesexHospital we have treated three cases. One, aftera severe emotional shock, developed tuberculousmeningitis and died, buLt the other two are ap-parently cured, though the period of follow-up isonly six months.Treatment in our cases and the other three re-
ported cases was by streptomycin, i g. per dayintramuscularly, with PAS by mouth. The totaldose of streptomycin was 8o to ioo g. Salmonstresses the importance of good nursing andattention to diet. The dramatic response totreatment in his case is shown by the fact that 21years after the onset of her illness, the patientcompleted a normal pregnancy and delivered her-self of a normal full-term child.
Treatment of Tuberculous MeninglitixStreptomycin is the most potent drug yet dis-
covered for the treatment oftuberculous meningitis.
6o December 1951
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BUXTON: Chemotherapy of Non-Pulmonary Tuberculous Conditions
Since it was introduced the average survival ratehas been approximately i in 4, though individualcentres have reported survival rates of 50 per cent.The most reassuring feature is the high percentageof survivors classified as clinically well after twoto three years' observation (Ministry of Health,1950).Most workers are agreed that the most important
single factor affecting prognosis is the severity ofthe disease at the start of treatment. The earlydiagnostic features have been well described byRubie and Mohun (I949).Pathology:A brief account of the pathology of the disease
is given as it has an important bearing on thetreatment and complications. At post-mortem incases of tuberculous meningitis the two character-istic findings are a widespread arteritis, and agelatinous exudate most marked over the base ofthe brain. The arteritis leads to thrombosis andcerebral softening, and often accounts for thesudden onset of focal signs. The exudate, whichin time is converted into fibrin, accounts for theblocks that arise in the cerebrospinal fluid path-ways.The sites of these blocks, shown in Fig. i, are
remarkably constant and are probably due partlyto the varying rates of flow at different points, andpartly to the supine position in bed and immobilityof the patient so typical of the disease. Thecommonest sites of obstruction are the cisternachiasmatica and the transverse fissure, blockageat these sites producing a communicating hydro-cephalus. The collection of exudate at thecisterna chiasmatica may also account for thepituitary or hypothalamic disorders not in-frequently encountered during treatment. Exudateand adhesions in the region of the transversefissure may cause obstruction to the venous returnfrom the choroid plexuses by blocking the greatvein of Galen, so leading to an enormous increasein intraventricular pressure.Apart from the dangers of obstruction, this
exudate also prevents the access of streptomycin toviable tubercle bacilli.
TreatmentGeneral measures are of the utmost importance
in determining the successful outcome of treat-ment. Bed rest in the active stage of the disease,good nursing, a nutritious diet and meticulous careover intrathecal therapy are essential.
Intramuscular stre.ptomycin. Most workers arenow agreed that streptomycin should be givenintramuscularly twice daily for the first six monthsof treatment at least. A total dose of 2 g. per day
Schematic diagram of cerebrospinal fluid pathwaysshowing routes for intrathecal therapy; L. lumbar;C. cistemal; V. ventricular. Sites where exudatecollects: a. cisterna chiasmatica; b. transversefissure; d. basal cisterns.
is given for adults and 20 mg. per lb. body weightper day for children. A dose of i g. per day hasbeen suggested in order to reduce the incidence ofdamage to the eighth nerve, but one of our casesfailed to respond to the smaller dose and asvestibular damage following treatment of thisdisease with streptomycin is almost inevitable, itseems unjustifiable in such a lethal infection notto use the larger dose. On intramuscular strepto-mycin, 2 g. per day, levels of 4 to i6 microg. arefound in the spinal fluid, depending on the activityof the meningitis. ln the early days of strepto-mycin therapy some workers considered thatintrathecal treatment was unnecessary as bacterio-static levels of streptomycin were found in thespinal fluid on intramuscular therapy alone.However, a report from the Medical ResearchCouncil in I948 showed that cases given intra-muscular treatment alone did not respond so wellas those in whic the drug was also given intm-thecally.
Intrathecal treatment. In cases uncomplicatedby blockage of the cerebrospinal fluid pathways,intrathecal treatment should be given by the
lumbar route. The usual dosage is ioo mg. dailyfor adults and 50 mg. daily for children.The technique of intrathecal injection is of
great importance as most cases require a minimumof ioo lumbar punctures and repeated bloodypunctures predispose to block. A reliable non-touch technique should be used. Our routinefor the intrathecal administration of streptomycinwas to draw into a io ml. all glass syringe i ml.of a solution containing ioo mg. per ml. ofstreptomycin dissolved in pyrogen-free distilledwater; with the lumbar puncture needle in situ,the syringe was then attached and cerebrospinalfluid was slowly withdrawn to the io ml. mark.The streptomycin solution, thus further dilutedwith cerebrospinal fluid, was then slowly re-injected, withdrawal and reinjection occupyingtwo minutes each-; if withdrawal and reinjectionare done too rapidly severe headache, if notactual cerebral damage, may occur.
Indications for the ventricular route. As statedabove, the common sites of block produce acommunicating hydrocephalus, and in such casesthe lumbar route may be used for intrathecaltreatment. if, however, spinal block or basalcistern block arise, frontal burr-holes must bemade and intrathecal therapy continued by theintraventricular route.The diagnosis of spinal or basal cistern block is
difficult clinically, thotigh it usually occurs in themore severe cases and is associated with severeheadache and vomiting; papilloedema may ormay not occur. The cerebrospinal fluid findingsare, however, the best guide. A rising proteinfigure, particularly if this is over 6oo mg. per100 ml., and increasing difficulty in withdrawal ofthe lumbar fluid associated with no rise in pressureof the fluid on compression of the jugular veins,are indications of spinal block. Absolute block isindicated by either a dry tap or the removal of afew drops of xanthochromic fluid of high proteincont,ent. Once such a block is suspected burr-holes should be made and the degree of obstructionassessed by taking simultaneous lumbar andventricular fluid pressures while the patient istilted.The dose of streptomycin recommended for
intraventricular therapy is 50 mg. per day foradults and 25 mg. per day for children, alternateventricles being used on successive days. If theintraventricular pressure is found to be raised,this should be reduced to normal by withdrawal ofcerebrospinal fluid before the introduction ofstreptomycin. Ventricular treatment should becontinued till there is resolution of spinal block.When this occurs treatment is continued by thelumbar route.
Cisternal puncture is seldom of value in the
diagnosis of block and is not practicable in an iUlpatient for daily intrathecal treatment.
Direct instillation of streptomycin into the siteswhere maximum exudate is known to arise-thechiasmal region and interpeduncular space-hasbeen attempted. Such treatment requires ex-tensive neurosurgery, and is now considered tohave little place in the management of the disease,as by the time indications for this treatment arise,dense adhesions and widespread arteritis arealready present.
Duration of intrathecal therapy. As individualprognosis is difficult and occasionally cases withgross neurological signs make a good functionalrecovery, treatment should not be withheld till thestage of decerebrate rigidity is reached (Smith andVollum, 1950). The risks of saving a life withresidual mental defect are usually over-emphasized,except perhaps in the case of young infants(Illingworth and Lorber, I95I).
It is generally agreed that daily intrathecaltreatment should be given for at least the first sixweeks. After this initial period opinions differ asto the intensity of treatment necessary. Whatevergeneral scheme is adopted this must be modifiedin the light of clinical and laboratory findings. Itmust be stressed that persistent headache, pyrexia,development of focal signs and continued loss ofweight, are most likely to be due to activity of thedisease rather than to over-zealous treatment.When the clinical signs mentioned are assessed,consideration must be given to tuberculous lesionsoutside the central nervous system as well aswithin it. The most reliable guides to progress inthe spinal fluid are the cell count and the sugarcontent. A raised lymphocyte count usuallyindicates activity of the disease; though strepto-mycin itself may cause a rise in cells, these areusually predominantly polymorphonuclears. Afalling sugar figure in the fluid is very suggestiveof activity of the disease. Intrathecal therapyshould be continued while there is still clinicalevidence of activity of the disease in the centralnervous system, or if the spinal fluid contentsremain grossly abnormal. As improvement takesplace clinically and in the laboratory findings,intrathecal injections may be reduced in fre-quency, but they should not be stopped entirelytill there is no clinical evidence of activity, till thesugar and chloride contents of the spinal fluid haverisen to within io per cent. of normal, and till thecells are less than 20 per cmm. When this stage isreached intrathecal therapy is stopped, but intra-muscular therapy is continued for at least amonth. Weekly lumbar punctures should be donewhen intrathecal treatment is stopped to confirmthat improvement is maintained. At the weeklyexaminations of the spinal fluid the streptomycin
December i95i BUXTON: Chemotherapy of Non-Pulmonary Tuberculous Conditions 603
content of the fluid is estimated. Levels of morethan 2 microg. per ml. on intramuscular treatmentalone indicate breakdown of the blood-brainbarrier, strongly suggesting activity of themeningitic process. The protein content of thespinal fluid is of little value in estimating activityof the disease as it may take months to return tonormal after the patient has otherwise recoveredcompletely. If improvement is maintained whenintrathecal therapy has been stopped for a month,intramuscular treatment may be discontinued.After a further period of observation in hospital,adults should be sent to convalescence, andchildren, if practicable, to a convalescent school.After streptomycin treatment is stopped, monthlyclinical and lumbar puncture exantinations shouldbe carried out to check progress, and if this ismaintained the intervals between examinations canbe progressively lengthened.Damage to the vestibular apparatus occurs in
nearly all cases, and is no indication for withhold-ing treatment. Survivors under the age of 50years are left with little residual disability owing tothe development of other compensating mechan-isms. One of our survivors, a child with absentlabyrinthine response to ice water, successfullylearnt to skate.
Deafness is not considered to be an indicationfor stopping treatment. Once it has occurred, itis doubtful whether recovery will take place evenif streptomycin treatment is stopped immediately.
Additional drug treatmentPara-amino salicylic acid should be given orally
to all cases concurrently with streptomycintherapy.
Sulphetrone has been popular on the Continentas an adjuvant to streptomycin treatment. In thiscountry results after giving the drug by mouth havebeen unconvincing, and it is considered that severetoxic effects occur too frequently to justify itsroutine use orally. It has been used intrathecally,but again with inconclusive results tCathie andMacFarlane, 1950).
Streptokinase is an enzyme obtained fromStreptococcus pyogenes which will lyse fibrinousexudate in vitro. It has been used intrathecally inan attempt to prevent adhesions and block (Cathie,1949). Lorber, assessing the value of the drug witha control series of cases, has recently shown thatits efficacy is very doubtful. As it may itself pro-duce meningeal irritation the use of the enzymeis probably no longer justifiable.
Intrathecal tuberculin. Smith and Vollum (1950)have suggested that one of the factors in tubercu-lous meningitis restricting the survival rate, andperhaps explaining the occurrence and disappear-
ance of block, is the host response to tuberculo-protein. They showed that if minute amounts ofpurified protein derivative (PPD) were injectedinto the subarachnoid fluid of patients withtuberculous meningitis, a very brisk meningealreaction occurred, When this had subsided theyfound, surprisingly, clinical improvement in casespreviously considered hopeless. They also foundlater evidence of resolution of exudate previouslypresent.
It may be that the use of intrathecal PPD willmark an advance in the treatment of tuberculousmeningitis, though results in a recent paper byFletcher (195I) were not so promisina. It wasstressed by Smith and Vollum that intrathecalPPD treatment was potentially extremely dan-gerous, and it would seem wise till further in-formation is available to reserve it for severe casesdeteriorating despite intensive streptomycintherapy.
Summary and ConclusionsPresent trends in the treatment of some non-
pulmonary tuberculous conditions are discussed.The main principle of treatment is to bring anadequate concentration of streptomycin to the siteof the infection. This is usually best attained bythe blood stream. The drug should therefore beadministered intramuscularly except in superficialinfections where local treatment alone may suffice.In cases of tuberculous meningitis it is necessaryto attain a high concentration of streptomycin inthe cerebrospinal fluid so that the drug maydiffuse through exudate to reach the underlyinginfection in bacteriostatic concentrations, thusintrathecal treatment is necessary in these cases aswell as intramuscular. The management of intra-thecal block is discussed.The routine addition of PAS to streptomycin
treatment has reduced the incidence of strepto-mycin resistant tubercle nacilli found in treatedcases. This is important not oily for the patientundergoing treatment but also for contacts whomay be infected by him.
Treatment with streptomycin and PAS offershope of cure in cases of tuberculous meningitis,a previously fatal disease, and has improved theprognosis and shortened the course of othertuberculous infections. It is stressed, however,that general measures and good management arestill of the utmost importance in attaining success-ful results.
BIBLIOGRAPHYAHERN, R. T. (I950), Lancet, i, 443.CATHIE, I. A. B. (1949), Lancet, i, 441.CATHIE, I. A. B., and MAcFARLANE, J. C. W. (I950), Ibid.,
ii, 784.DAVIS, R. H. (I949), Ihd., ii, 982.
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FELDMAN, W. H. (I946), 'Harben Lecture,' J. Rey. Inst. Pub.Health i Hygiene, 9, 267, 297, 343.
FLETCHER, A. P. (es'I), Lancet, H, 290.GIRDLESTONE, G. R. (1940) 'Tuberculosis of Bone and Joint,'
Oxford Univ. Press, Oxford.GRANT, R. A., GRUNBERG, A., and LINDSAY BLAIR, J.
(I95I), Brit. med. Y., i, 740.ILLINGWORTH, R. S., and LORBER, J. (xIS9), Lancet, ii, 5ix.LORBER, J. (Is9I), Ibid., i, 1334.MEDICAL RESEARCH COUNCIL (I948).
MERCER, W. (I950), 'Orthopaedic Surgery,' Arnold, London.MINISTRY OF HEALTH STREPTOMYCIN TRIALS (I950),
'Meningitis and Miliary Tuberculosis,' H.M. StationeryOffice, London.
RUBIE, J., and MOHUN, A. F. (I949), Brit. med. J., i, 338.SALMON, H. W. (i95i), Lancet, ii, I53.SCADDING, J. G. (I95I), Postgrad. med. .7., 27, 549.SMITH, H. V., and VOLLUM, R. L. (I950), Lancet, i, 275.STREETEN, D. H. P. (I949), South African med. 7., 23, 777, 8So.
The Comfort Crookshank Award for Cancer Research
The Comfort Crookshank Award for CancerResearch was awarded at the Middlesex Hospital,on October 8, to Dr. J. J. Pittner. After receivingthe award he delivered a lecture entitled ' TheGeBiesis of Mammary Cancer in Mice.' Hedescribed experiments which had been performedwith strains of mice which had been maintainedfor more than zo generatio'ns by brother-to-sistermating. Some of these strains were infected withthe ' milk agent' which is responsible for somemammary carcinomata in those truce hereditarilysusceptible to its influence. Suspensions' of theagent, when diluted within limits, produced ahighet incidence of cancer than when undiluted.With repeated doses a smaller incidence of cancerwas obtained than with single doses in other miceand their progeny. These last two facts suggestthat an active immunity could be developed againstthe milk agent. Tumour material which had beenfrozen and dried produced tumours at the site ofinoculation in those mice which would supportgrowth of transplants of fresh tumour material-more tumours were produced by intraperitonealthan by subcutaneous' injections. Evidenceshowed that male mice had infected females withthe milk agent.
Dr. Bittner showed pictures of sections of wholemammary glands in which there were hyperplasticnodules said by some to be precancerous and tobe associated with those breasts susceptible to themilk agent. He stated that some were of the
opinion that the degree to which breasts producedhyperplastic nodules i-n response to artificiallyadministered oestrogens was directly proportionalto their susceptibility to the milk agent. Thisobservation, together with further evidence ad-duced from experiments on various strains of micein which ovariectomy and transplantation ofovaries and aarenals were carried out, led to thehypothesis that the milk agent was responsible foraltering the hormone balance of mice infectedwith it. Finally, in support of this hypothesisthere was the striking fact that those mice infectedby the milk agent excreted a smaller amount of17-ketosteroids than those free of agent. Dr.Bittner said it was possible that alteration of thehormone balance was directly responsible for theproduction of mammary cancer in mice, and thatthe role of the milk agent might merely be that ofupsetting the hormones.
In mice there occur mammary adenocarcino-mata, both spontaneous and chemically induced,which are not associated with the milk agent; thus,arguing by analogy, it is possible that there areseveral kinds of human breast cancer one of whichmay be transmitted by a milk agent. If this is so,it must be borne in mind that-human females couldbe infected from the male or by such things asblood transfusion. However, Dr. Bittner calcu-lated that it would be at least 8o years before itcould be determined whether a milk agent playedany part in human breast cancer.
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