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A NEW DEVELOPMENT IN RADIUMTHERAPY.

THE APPLICATION OF THE LATER DISINTEGRATION

PRODUCTS OF RADIUM TO THE TREATMENT

OF CERTAIN SKIN CONDITIONS.

BY JOHN P. McHUTCHISON, M.A., B.Sc.,PHYSICAL CHEMIST TO THE GLASGOW AND WEST OF SCOTLAND

RADIUM COMMITTEE ;

AND

W. HERBERT BROWN, M.D. GLASG.,DERMATOLOGIST TO THE VICTORIA INFIRMARY, GLASGOW.

As indicated in a communication to THE LANCET,1we have been able to extend the usefulness of radiumby employing it at a stage in its disintegration, atwhich hitherto it has not been applied to medicaltreatment. The particular radio-elements concernedhave not previously been used therapeutically, and adefinitely encouraging measure of success has attendedtheir use in certain skin conditions. The discoverywill be of special interest to radium institutes andother hospitals possessing radium, as it finds a

permanent use for otherwise valueless products, andso extends the range of radium treatment.

It is usual to speak of the therapeutic effects ofradium, but the actual element itself is of no value.Only when the radium breaks down do its specialpowers become apparent. The atoms of radium areconstantly changing into other atoms, and a series ofradio-elements is thereby brought into being. At eachstage of the disintegration energy is evolved, and it isthis energy which is employed in medical practice. I,The energy forms are three in number :- ’

’

1. Alpha Rays (a).-Fast moving atoms of helium.2. Beta Rays (/3).-Particles of negative electricity ejected

from the disintegrating atom, with high velocities.3. Gamma Rays (&ggr;).—Non-material pulses in the ether,

analogous to X rays, but of greater penetrative power.

All three kinds of rays possess definite powers ofaffecting the development and life of living cells, butthe alpha rays have so slight penetration that they

FIG. 1.

HALF-LIFE 1600 yrs. 3.8 days 3.0 mins. 26.8 mins. 19.5 mins.PERIOD

are of little or no therapeutic value, and as usuallyemployed, radium owes its therapeutic powers to thebeta and gamma rays. These are evolved during thethird and fourth stages of the disintegration as shownin Fig. 1.

Active Deposit of Rapid Change.The radio-elements shown constitute the active

deposit of rapid change and the longevity of thevarious elements is indicated by the time taken todecline to half. As generally used in medicine, theactual radio-elements employed are radium B andradium C, and the actual rays, the beta and gammarays of these elements. This is true whether an actualsalt of radium is employed, or whether the emanation,the first disintegration product, is used. If a radiumsalt is used, an equilibrium is established amongst thevarious products, and owing to the long life of radium,the strength of a radium plaque is, ordinarily speaking,constant. But if a tube of emanation is the source ofthe activity, the tube gradually loses its strength,according as the emanation declines, and with it theradium B and radium C. Shortly after all the

1THE LANCET, Feb. 9th, 1924; see also Nature, Feb. 23rd,1924.

emanation in the tube has disintegrated, there is noradium B or radium C left, and therefore the tube haslost its strength. In radium institutes and hospitalsemploying emanation such finished emanation tubeshave hitherto been of no medical use.But it is well known that while radium C is the

last member of the series to have powerful effects, the

FIG. 2.

HALF-LIFE 19.5 mins. 16 yrs. 11.1

4’9 days. 136 days (L ea d)

PERIOD

series does not end there. The subsequent elementsconstitute the active deposit of slow change and areshown in Fig. 2.

Active Deposit of Slow Change.It will be observed that radium D and radium E

emit both beta and gamma rays, but unlike thosefrom radium B and radium C, these are soft andpossess little penetrative power. Hence, althoughafter the decline of radium C in the emanation tubes,radium D and the subsequent elements grow up, theresidual activity has not until now been considered ofany value, and the finished emanation tubes thereforehave been counted waste.

It occurred to one of us, however, that although therays from radium D and radium E are feeble, yet ifthese radio-elements were concentrated from thefinished emanation tubes, their activity might find usein medical treatment where deep penetration was notnecessary, and owing to the long life of radium D,supply a fairly lasting source of radiation. In particularit was thought that such a strong preparation ofradium D and radium E in equilibrium might prove ofvalue in the treatment of some superficial skin diseases.This conjecture has proved on investigation to bejustified, and encouraging clinical results have beenobtained.

Clinical Investigation.Our choice of suitable cases for investigation was

naturally governed by the slight penetrative power ofradium D and E. From physical measurements itwas estimated that the effective penetration in tissuewould be about 3 mm., and therefore we selectedlocalised superficial conditions such as capillary nsevi,small cavernous neavi, and chronic patches of lupuserythematosus. Extensive superficial conditions likeeczema or psoriasis were ruled out as unsuitable fortreatment, since only a very limited area can con-veniently be treated by an applicator at a time.Lupus vulgaris, with deep-seated nodules, oftenbeyond 3 mm. in depth, and pearly rodent ulcerslikewise, were ruled out for investigation. Owing to thelimited penetration of radium D and E all the radiationis absorbed in the tissue being treated, whereas withordinary radium in skin conditions the rays go farbeyond the depth desired.

Method of Treatment.-At first it was thoughtadvisable to work along the lines of making applicatorsof fairly small intensity and giving long exposures-in keeping with recent technique in certain branchesof radium therapy. Therefore most of the clinicaltests were made with applicators of such strengthas to produce a mild erythematous reaction after14 days’ exposure. Latterly, stronger applicatorswere made which produced a reaction in seven oreight days ; but, as detailed in the account of thechemical work, applicators can easily be made of suchstrength as would limit the exposure to three days,or indeed less, the required reaction being producedin that time. This is an advantage in treating affectedareas of the face, and it is intended that most ofthe future work will be done with these strongerapplicators.

Applicators.—The applicators to contain the activeelements were usually of silver or nickel, and of

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different sizes and shapes to suit different situations.They were thin enough-generally 0-2 to 0-4 mm.-topermit of slight moulding and adjustment to the skinsurface. Most were of an oval shape, from 10 to12 sq. cm. in area, and had the active matter presentas sulphides along with lead (see " Preparation ofApplicators " below). In fixing the active powderto the applicator the powder was uniformly distributedover the metal, then moistened with chloroform, anda very thin coating given of a celluloid varnishmade up as follows : solution of celluloid in amylacetate, oz. ; acetone, oz. ; acetic acid, oz. ;acetic ether, oz. The active side of the applicatorwas covered with a layer of crepe-de-chine to

protect the active matter from contamination andfrom moisture. The applicator was then fixedover the affected area with zinc plaster, and thepatient instructed to keep it perfectly dry.

In every case the applicator was removed after adecided erythematous reaction was produced, and, ifnecessary, applied to the same area in about four tosix weeks time, after all trace of the previous reactionhad disappeared. Occasionally slight blistering wasproduced, necessitating dressing the part with boricointment. In one case a very marked crustedreaction was produced after 17 days’ application.From our experience blistering should be avoided.Good results are likely to be obtained if the applicatoris worn only long enough to produce a mild erythe-matous reaction.

Case Records and. Results.CASE ].—Miss M., aged 25. Port-wine naevus of the

left cheek and chin, colour rather bright red. Five applica-tions were given, but as this was one of the early casestreated the first two were tentative and were not of sufficientduration to produce the required reaction (Figs. 3 and 4).The actual facial appearance is even better than the,photo-graph indicates.

CASE 2.-D. T., girl, aged 7. Extensive and somewhatpatchy capillary naevus of right cheek, extending up toand over right eyebrow. The patchy portions were about thesize of a threepenny piece, bright red in colour with well-defined spider nsevi portions between. The skin on theareas treated became soft and white. Treatment in thiscase was done slowly and covered a period of two years,and the parents were very pleased with the result.

CASE 3.-Miss H., aged 16. A red capillary naevus ofport-wine type over left jaw and cheek. Four applicationswere made. The condition has responded and shows muchimprovement, but the result has not been so striking as inthe other cases owing to a mild degree of pigmentation i

resulting. One application in this case was overdone, Iproducing a definite crusted reaction, which may account for ’,the pigmentation. ’

CASE 4.-Baby L., aged 12 months. A circumscribednaevus of mixed type on abdomen ; it had previouslyulcerated in the centre, which accounts for a central scarpresent. The naevus was the size of a two-shilling piece,strawberry red in colour, and elevated above the skin byone-eighth of an inch. After two applications the naevushad completely flattened down and the colour faded to afaint bluish tinge. Slight pigmentation outside the areatreated has in this case also followed a somewhat overlongexposure, but this it is expected will gradually disappear.

CASE 5.-Baby R., aged 6 months. A small capillarynaevus on point of left shoulder, about size of a shilling,strawberry red colour, elevated above skin by one-sixteenthof an inch or more. With one application there wasimmediate improvement.CASE 6.-Miss G., aged 28. Lupus erythematosus. This

was an extensive chronic case involving a large area offorehead, nose, and part of one cheek. All precautions hadbeen previously taken to eliminate any source of focalinfection ; septic tonsils had been removed and decayedteeth extracted many months before, without any apparentchange. There was no evidence of tuberculosis. Treatmentwas confined to the patch on the forehead and to the cheek.Reaction to the treatment was marked, blistering beingnoticeable. The result is a very marked scarring over thecentral portions of the lesions, and this scarring has remainedfor over a year. Difficulty, however, was experienced inarresting the slow spread at the margin. The disease stillremains active in parts, but there is apparently a definitearrest with marked scar formation over most of the treated portions.

We consider the results very encouraging. Theparents of the infants all expressed themselves asgreatly pleased with the results produced, and theadult cases were so satisfied with the improvementthat they were most anxious to continue the treatmentto include all the affected areas, in spite of the incon-venience of wearing the applicators on the face.

Extraction of Radium D and Radium E.As the result of some ten years’ use of radium

emanation by the Glasgow infirmaries and hospitalsunder the auspices of the Glasgow and West of ScotlandRadium Committee, more than a kilogramme of finishedemanation tubes of various shapes and sizes had beencollected in the laboratory at Glasgow University.These tubes were the source of the radium D and Eused in the research. The radium D and radium E,it will be understood, formed a sub-metallic depositon the inside of the finished emanation tubes. Mostof this deposit is soluble in fairly strong hydrochloricor nitric acid, but, possibly owing to the recoil andbombardment which had taken place inside the tubesduring the disintegration, the active matter is slightlyembedded in the glass and its solution is not easilyeffected. The following table shows the solventpower of various acids under different conditions.

Solvent Action of Various Acids on Deposit of Rad-ium. Dand Radium E in Emanation Tubes.

Aqua regia (4 parts of cone. hydrochloric acid to1 part cone. nitric acid) is the best solvent to employ,and fairly prolonged boiling is necessary to effect themaximum solution. In none of the extractions wasit possible to extract more than 93 per cent. of theactivity, as judged by a beta ray electroscope.Experiments were made to determine if this residual6 or 7 per cent. activity could be removed, and it wasfound that this could be done by shaking the tubeswith dilute hydrofluoric acid, which, of course, woulddissolve some of the glass. This showed that someof the active matter is actually in the glass ; but thesmall quantity is not worth the effort required toobtain it.

In extracting, therefore, it is recommended to useaqua regia, and to keep this at boiling point for a dayor two on a sand bath. The tubes need only be broken,not powdered. Even on a sand bath very bad" bumping " will be experienced, and it was foundnecessary to employ a long upright condensing tubewith ground-tapered end fitting into the ground endof the flask, and to clamp both firmly.

Further Treatment.-The strong acid solution isremoved by decanting, and the tubes well washed withhot water, the washings being added to the extract.This is boiled down to quite small bulk, when an egtraquantity of concentrated nitric acid is added, afterwhich the solution is evaporated down on a waterbath practically to dryness. Depending on theparticular kind of applicator desired, as suggestedbelow, this evaporation would be continued to asnear dryness as is safely possible, with the subsequentaddition of boiling water to any required dilution, orthe slight acidity remaining would be neutralised withammonia before diluting. It will be found convenientto handle about 40 or 50 g. of tubes at a time. and

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this quantity may be expected to furnish sufficientactivity for four to eight applicators, according towhat strength of these is desired.

Preparation of Applicators.When the active matter is obtained in solution it is

necessary to fix it in some way for medical application,since the quantity is so small that it cannot be handledby itself. The most direct way is to associate it withsome substance and apply this activated material tothe diseased area ; but, owing to the screening effectof this substance, some of the strength of the radium Dand E is lost. Therefore to make the most powerfulapplicators, radium D and E must be obtained aloneand unassociated. This may be done by taking theacid extract to perfect dryness in a platinum basin

FIG. 3.

Port-wine najvus. Before treatment.

over a water bath, and most carefully dissolving off theinvisible film with hot water, which gives a neutralsolution containing nothing but radium D and E.The quantity of this solution required to give thedesired strength may be evaporated, portion byportion, in the actual applicator, and the depositedmatter protected by a thin film of collodion. By thismethod powerful applicators may be obtained, whichwill produce a reaction after only two or three days’exposure.Such applicators have the disadvantago of containing

no visible material, and much of the active matter isapt to be worn off without attracting notice. Forthese reasons it is suggested that the active matter ingeneral should be associated with a quantity of someordinary substance, so small as not to screen too muchof the radiation, and yet sufficiently perceptible topermit safe handling of the applicators.The methods that have been found successful

are: (1) precipitation and adsorption methods ; (2)electrolytic methods ; (3) replacement methods. InNos. (1) and (2) the active elements are associatedwith some finely divided material, and an activepowder thereby obtained, which can be fixed withcollodion on an applicator tray of suitable size andshape, and this applied to the area to be treated.No. (3) involves the use of a metal plate which therebybecomes the applicator.

1. Preeipitatiorz and Adsorption Methods.(a) If the original slightly acid solution is evaporated

portion by portion on a nickel tray, nickel nitrate is formedcontaining the active elements, and this can be changed to

the dry oxide by heating, or, if the acid solution is neutralisedwith ammonia and the solution evaporated on the applicator,a deposit of activated ammonium nitrate is obtained.

(b) Sulphides.—The first attempts made were to precipitatethe radio-elements along with lead sulphide by adding alead salt (e.g., lead nitrate) and precipitating with sulphur-etted hydrogen gas, and this method is recommended for thefirst trials of the new radiation. It takes advantage of thechemical similarity between lead and radium D ; radium E,which also forms an insoluble sulphide, is precipitated atthe same time. To the extract of, say, 30 g. of tubes, about0-5 g. of lead nitrate is added, and sulphuretted hydrogenpassed through. The quantity of lead nitrate added willbe regulated according to the intensity desired, and ifrequired the active powder can be diluted with ordinarylead sulphide. Iron sulphide and mercuric sulphideprecipitates may also be used to precipitate the radio-elements, but not copper sulphide. One disadvantage of

FIG. 4.

Same case as Fig. 3. After treatment.

using salts of the heavy metals is their marked screeningeffect, and two lighter nuclear substances are thereforesuggested.

(c) Ferric Hydroxide.-Very fine flms of ferric hydroxidecontaining the radio-elements can be prepared by adding asmall quantity of ferric chloride to the active solution,precipitating with caustic soda, and drying in oven.

(d) Calcium Carbonate.-Finely divided precipitated chalk,if shaken up for half an hour with the original acid solutionafter neutralising with ammonia and boiling off the excess,brings down about 80 per cent. of the activity by adsorption,and makes a clean-looking applicator. (Of course, a calciumsolution may be used and sodium carbonate solution added.)

This method has the very marked advantage thatif the active powder on the applicator becomesdamaged, it is sufficient to immerse it in dilute hydro-chloric acid, which puts the activated material intosolution again, from which it can be extracted by anyof the means suggested.

2. Electrolytic Methods.—In the above methods theactivated powder is spread on a tray and thus applied,but if the surface to be treated is uneven it is practicallyimpossible to ensure uniform distribution of the activepowder. Such uneven sites have arisen in cases oflupus erythematosus involving the nose, or naevus overan eyebrow or chin. In such cases it is most suitableto prepare applicators by electrolysis of the activesolution. This suggests itself very naturally too, asa good means of fixing the active matter withoutemploving any other material, and, of course, aneven deposit is easily obtained on any shape or sizeof applicator. Owing to the fact that radium E(similar in chemical properties to bismuth) in acid

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solution goes to the cathode, and radium D (similarto lead) in acid solution to the anode, it is not easyto extract both together. Therefore it is suggestedthat radium D should be plated out alone ; from thisradium E will grow, and in a month’s time equilibriumwill be established and a radium D and E depositobtained, of practically constant strength for severalyears.

Plating Out of Radium D.-To plate as dioxide in acidsolution requires the use of a platinum anode, and thereforeit should be plated out as the element in strong caustic sodasolution, using as cathode a nickel plate of required shape.To active solution add 10 c.cm. of 0-1 per cent. lead nitratesolution and make up to 150 c.cm. with strong caustic sodasolution. Electrolyse for 24 hours at 70° C., using nickelcathode with 2 volts and a very small current, so as toobtain an adherent deposit. This can be protected withcollodion or fine gauze if desired. The part of the electrodeon which no deposit is wanted may be protected with waxor varnish.

3. Replacement Methods.—It remains to mentionthe extraction by chemical replacement, and thismethod has the advantage that no material is presentto absorb any of the rays ; but as a rule replacementmethods are unsatisfactory, because while it is easyto deposit radium E on a metal plate by replacement,it is difficult to deposit radium D suitably ; and it isradium D, which by its long life is the storehouse ofthe activity; without its presence radium E quicklydeclines.

Metals such as zinc and magnesium, wmcn replaceradium D from which radium E grows, or radium D and Etogether are readily affected by skin excretions and aretherefore unsuitable as applicators. The only really suitablemetal for replacement is nickel. A nickel plate (of the requiredshape and with the unwanted part protected with wax orvarnish), when dipped in or boiled with a solution ofradium D and E replaces only radium E, but this practicallycompletely, and a very active plate is produced. But sinceno radium D is present the deposited activity due to radium Edecays to half of its original value in five days to one-quarterin 10 days, to one-eighth in 15 days, and so on. But if thecondition to be treated demands only a fairly short exposurethe method is quite practicable. Iron also replaces radium E,but, of course, if an iron plate is left in the solution it rusts,and in the rust formed are found not only radium E, butalso radium D by adsorption. This rust, of course, is aconstant source of radiation and may be employed as inprecipitation methods.

Strength of Applicators.The applicator most commonly used was an oval

tray, in. deep and 10 sq. cm. in area, and this causedthe erythematous reaction to appear after 14 days’exposure but it is obviously desirable to have someexpression of its strength more definite than thisreaction time. Unfortunately there is no convenientway of expressing the quantity of radium D andradium E present in the applicator, and in any case,if a carrier such as lead sulphide is used and the activefilm is protected with a collodion coating, there is ascreening effect and some of the radiation is absorbed.For these reasons it is considered best to specify thestrength of the finished applicator by reference to someeasily reproducible standard , such as the alpharadiation from a uranium oxide film, as measured byan electroscope. The electroscope used was a beta-rayinstrument made of brass, so mounted as to allow theapplicator to be placed underneath, and with a screenof 1/10 mm. aluminium inserted in the base of theelectroscope. The gold-leaf was 7 in. above the boardon which the applicator was placed, and the circularbase of the e’ectroscope 4 in. in diameter was 4. in.above the board. The uranium oxide tray was, ofcourse, placed inside the electroscope, when itsactivity was being determined.The activity of a 14-day applicator 10 sq. cm. in

area, when measured through the 7 in. =18 cm. ofair and 1/10 mm. aluminium, was almost five times theactivity of a circular uranium oxide film 4 cm. indiameter measured in the electroscope. If it isdesired to produce the reaction after only three days’exposure over the same area the activity requires tobe about 20 times that of the uranium standard.

The actual details of the electroscope measurements

It will be remembered, of course, that it is theintensity that determines the reaction ; a tray of5 sq. cm. area, producing a. leak, for example, of5 seconds, will produce the reaction in seven days, ascompared with a 5 seconds applicator over 10 sq. cm.It will also be understood that owing to the greatdifference in the penetrative quality of the raysemitted by radium D and E and uranium oxide, it isnot possible to express one in terms of the other. Butby using a standard film of uranium oxide for com-parison, as indicated above, it will be possible toprepare applicators of suitable strength, after whichthe particular electroscope measurements (e.g.,divisions of scale per minute per sq. cm.) may be usedas standards.

.

Summary.1. The radio-elements, radium D and radium E,

have been extracted from used radium emanationtubes, and in equilibrium together have been preparedfor medical use in the form of applicators of differentkinds.

2. Such applicators have been found to exert abeneficial action in the treatment of lupus erythema-tosus, and of various types of nævi. Conditions likeeczema and psoriasis will also respond, but it has notbeen found convenient to treat large affected areas bymeans of applicators.

3. The radiation from radium D and radium E hasthe unique property so far as radium treatment of skinconditions is concerned, that it is all absorbed by thepart being treated, since its effective penetration isonly about 3 mm. of tissue.

4. Radium D and E applicators retain their strengthand may be used for many years ; 16 years elapsebefore the activity declines to one-half of its originalvalue.

The authors desire to express their thanks to theGlasgow and West of Scotland Radium Committeefor granting the facilities required in the carrying outof the research. They will be pleased to assist withfurther information or fuller details on any point ifcommunications are addressed to Mr. McHutcbison,Radiometric Laboratory, Glasgow University.

ACUTE DILATATION OF THE STOMACHCOMPLICATING ARTIFICIAL

PNEUMOTHORAX.

BY L. R. SHORE, M.B. CAMB., M.R.C.P.,D.P.H. LOND.,

ASSISTANT PHYSICIAN, ROYAL CHEST HOSPITAL.

THis case is recorded on account of the unusualmode of death of a patient undergoing artificialpneumothorax treatment for pulmonary tuberculosis.The occurrence of acute dilatation of the stomachdoes not seem to have been previously recorded inthis connexion. ,

A woman, aged 32, was admitted to the Royal ChestHospital on May 15th, 1923, complaining of malaise andcough of 18 months’ duration. There had been loss offlesh since July, 1922. Sputum was scanty, containedtubercle bacilli; no haemoptysis. The past history was offair health ; " bronchitis " in May, 1922, and " inflammationof the stomach " at the age of 21. There was no familyhistory of tuberculosis.

Condition on Examination.-Very thin and pale ; slightbrown pigmentation of the face ; fingers slightly clubbed.Physical signs in chest: In front. Heart not displaced.