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goitrogenic effect of low doses of fluoride (to be published).In a comparison of villages in an area of endemic goitre inwhich the iodine intake was constant but in which the waterfluoride varied (0-20-2 p.p.m.), we found a highly signifi-cant correlation between goitre incidence and water fluo-ride, despite the fact that the water-fluoride concentrationwas never greater than 0-4 p.p.m.

Perhaps in our enthusiasm for preventive dentistry wehave forgotten that the level of fluoride intake which iseffective in preventing caries is dangerously close to thelevel which produces harmful effects.

T. K. DAYP. POWELL-JACKSON.

East Wing,Guy’s Hospital,London S.E.1.

CYRIL BARON.

The Spinney,More Lane,

Esher, Surrey.

SIR,-Your editorial rightly emphasises the need to

consider means other than water fluoridation to preventdental caries. The addition of one part per million fluorideto school milk, with the consent of the children’s parents,avoids any objection to compulsory fluoridation of thegeneral drinking-water, and is a simple, cheap, and safemeasure. The work of Ziegler in Switzerland, Imamurain Japan and Russoff and others in the U.S.A.3 makes itclear that this measure, as checked by follow-up of thechildren over many years, prevents 50% or more of dentaldecay in the permanent teeth, as against the 20% cited forfluoride toothpaste, the topical effect of which must belimited. Certainly the recent withdrawal of some schoolmilk will not make fluoridation any easier, except perhapsfor those local authorities who have overcome the legaldifficulties and continue to supply it.

CYCLOPHOSPHAMIDE AND ORGAN

TRANSPLANTATION

ALFREDO LANARI.

Instituto de Investigaciones Médicas,Donato Alvarez 3000,

Buenos Aires, Argentina.

SIR,—Dr. Starzl and his co-workers (July 10, p. 70)draw attention to the immunosuppressive action of cyclo-phosphamide. They report favourable results in 12

transplant patients who received the drug in combinationwith prednisone and A.L.G., and in 6 patients who receivedit as a substitute when azathioprine hepatotoxicity wassuspected. In the kidney-transplant programme of theInstituto de Investigaciones Medicas de la Facultad deMedicina de Buenos Aires, cyclophosphamide was used atthe end of 1967 in combination with azathioprine andcorticoids in accordance with the results obtained byBurnet et al. in mice with glomerulonephritis. Sincethat time, 19 patients have been treated, 11 of whom areat present alive. In 17 patients cyclophosphamide wasused from the beginning of transplantation, and in 2 itwas added at different periods in immunosuppressivetherapy. Interestingly, in one patient who developedjaundice, presumably secondary to azathioprine, onlycyclophosphamide and corticoids were used during a two-year period with good tolerance and preservation of renalfunction. The dosage employed was varied accordingto leucocyte levels, since leucopenia frequently appearedeven with low doses. Except for this complication andreversible partial alopecia, no other signs of toxicity ofcyclophosphamide were found. Our experience in trans-plant patients agrees entirely with the conclusion of Dr.Starzl and his co-workers; we recommend cyclophos-phamide as a first-line drug in the treatment of acute

1. Ziegler, E. Bull. Schweiz. Akad. Med. Wiss. 1962, 18.2. Imamura, Y. J. Oral Dis. Acad., Tokyo, 1959, 26, no. 1.3. Russoff, L. L., Konikoff, B. S., Frye, J. B., Johnston, J. E., Frye,

W. W. Am. J. clin. Nutr. 1962, 11, 94.4. Russell, P. J., Hicks, J. D., Burnet, F. M. Lancet, 1966, i, 1279.

rejection as well as in maintenance immunosuppressionin organ-transplant patients.

ENHANCED IMMUNE RESPONSE TOLEUKÆMIA

SIR,-Leukxmia blast cells have been shown to stimulateD.N.A. synthesis in vitro in autologous lymphocytesThis recognition by the host of an apparent antigen specificfor the leukxmia cell implies some level of immunitytowards the disease. Considerable evidence has also beenaccumulated suggesting that many other human tumoursevoke an immune response to

" tumour-specific " anti-gens.4,5 ,’ Drugs used to treat patients with neoplasticdiseases suppress normal immune reactivity. A cyclicpattern of lymphocyte reactivity in vitro during courses ofchemotherapy has lately been reported.7,s Patients whorespond favourably to chemotherapy with tumour regressionnot only recover their cellular response after treatment,but " rebound " to levels higher than pretreatment levels,

CYCLIC RESPONSE IN MIXED-LEUCOCYTE CULTURES

* First day of chemotherapy. t Last day of chemotherapy.

We have examined the in-vitro response of lymphocytesfrom patients with acute leukaemia to phytohsmaggtutinin(P.H.A.), allogeneic lymphocytes, and autologous leukxmiablast cells during a 4-week cycle of chemotherapy, All

patients studied thus far have been treated with the four-drug combination of prednisone, oncovin, methotrexate,and purinethol (P.o.M.P.) 9 for 5 days every month.

Peripheral-blood lymphocytes were cultured for 3-7-dayperiods and the degree of stimulation was measured by3H-thymidine incorporation. The results are expressedas the ratio of d.p.m. in the stimulated cultures to controlnon-stimulated cultures. Control cultures for the allo-

geneic and blast-cell cultures consisted of mitomycin-treated autologous leucocytes. A ratio greater than 2represents a significant response in our laboratory.Our results are similar to those previously reported.’,’

There is a period of 10-17 days following chemotherapywhen peripheral-blood lymphocytes have a higher thanbaseline (prechemotherapy) response to non-specific andspecific stimuli. More significant is the hyperreactivity toautologous blast cells, as shown in the table. This patientwith acute leukaemia has the ideal control, a normal identicaltwin, whose lymphocyte reactivity was examined at thesame time-intervals. While the patient clearly demon-strated a

" rebound " in response to P.H.A., allogeneiccells, and her own blast cells, the normal twin’s reactivityremained constant, without a positive response to the blast

1. Fridman, W. H., Kourilsky, F. M. Nature, 1969, 224, 277.2. Viza, D. C., Bernard-Degaui, O., Bernard, C., Harris, R. Lancet,

1969, ii, 493.3. Leventhal, B. G., Halterman, R. H., Herberman, R. B. Proc. Am.

Ass. Cancer Res. 1971, 12, 51.4. Hellström, I., Hellström, K. E., Bill, A. H., Pierce, G. E., Yang,

J. P. S. Int. J. Cancer, 1970, 6, 172.5. Morton, D. L., Holmes, E. G., Eilber, F. R., Wood, W. C. Am.

intern. Med. 1971, 74, 587.6. Hersh, E. M., Oppenheim, J. J. Cancer Res. 1967, 27, 98.7. Cheema, A. R., Hersh, E. M. Meeting of American Society of

Clinical Oncology, Chicago, April 7, 1971.8. Harris, J. E., Thomas, H. M. Proceedings of Sixth Leukocyte Cul-

ture Conference (in the press).9. Henderson, E. S. Seminars Hemat. 1969, 6, 271.

705

cells. This observation suggests that chemotherapy and theimmune apparatus of the host may be acting synergistically.More investigation is required to determine the true

specificity of this rebound phenomenon.

ROGER H. HALTERMANBRIGID G. LEVENTHAL.

Leukemia Service,Medicine Branch, N.C.I.,

Bethesda, Maryland 20014, U.S.A.

CIRRHOSIS AND LYMPHOPROLIFERATIVEDISORDERS

R. HEIMANN.

Department of Pathology,Institut Jules Bordet,

Centre des Tumeurs del’Université Libre de Bruxelles,

Brussels, Belgium.

SIR,-I have read Dr. Paton’s comments (July 31, p.259) about my letter (July 10, p. 101) with the greatestinterest and am somewhat surprised by his dogmaticstatement that I am wrong in supposing that an associationbetween cirrhosis and lymphomata has not been previouslyreported. I don’t believe that my letter and the paper byWetherley-Mein and Cottom 1 cited by Dr. Paton impliedthe same thing. I suggested a possible relationship be-tween cirrhosis and lymphoproliferative disorders. These

workers, on the other hand, described portal fibrosis invarious types of acute leukaemia. They felt that " age, typeof ieuksmia, and duration of disease cannot be correlatedwith any of the changes observed in the portal tract ".They even added that " in the few patients in whom thetype of leukaemia could be recognised, there was nothingto suggest that any particular line of cell differentiationwas associated with excessive collagen formation ".As a humble morbid anatomist, I am fully aware that the

line is sometimes difficult to draw between portal fibrosisand cirrhosis, but it must be admitted that lymphopro-liferative disorders and acute leukxmias are not exactlysynonymous. Nevertheless, Dr. Paton is right when hedeplores the lack of information concerning the treatmentgiven to the patients mentioned in my letter. I hasten toadd that if these patients had received methotrexate therapy(which can produce cirrhosis, as everybody knows) I wouldnot have considered writing the letter in the first place.None of our 8 patients-all adults-were given metho-trexate ; 4 did not receive any cytostatic treatment, 2 weregiven chemotherapy for about a month before death

(purinethol, cyclophosphamide, vincristine in 1 case,

purinethol in the other), and the last 2 patients receivedlong-term chemotherapy (one received chlorambucil duringfive years, the other chlorambucil, purinethol, and T.E.M.for nine years). Therefore, chemotherapy cannot be blamedfor cirrhosis in at least 6 of the 8 cases. As to the drugstaken by the 2 patients who received long-term cytostatictreatment, we all know that they produce liver damage, butto my knowledge it is not proven that they cause cirrhosis.Taking into account the low incidence of cirrhosis that I

found in necropsies at our institute (20/814 or 2-45%),I am inclined to believe that the various forms of chemo-therapy given to the cancer patients, all adults, are notvery cirrhogenic. In the paper of Amromin et al.2 on liverdamage after chemotherapy for leuksemia and lymphoma,also cited by Dr. Paton, there is one very interesting point:these workers found 4 cases of cirrhosis or severe fibrosisamong 139 patients who came to necropsy, and they wereall in patients with chronic lymphocytic leukaemia or

lymphosarcoma-none had received methotrexate. Thisreinforces my impression that lymphoproliferative dis-orders and cirrhosis are related, independently of anytreatment.

1. Wetherley-Mein, G., Cottom, D. G. Br. J. Hœmat. 1956, 2, 345.2. Amromin, G. D., Deliman, R. M., Shanbrom, E. Gastroenterology,

1962, 42, 401.

ROENTGENOLOGICAL EVALUATION OFACHILLES-TENDON XANTHOMATOSIS

SIR,-We are trying to devise a rapid, simple, andreliable radiological method of assessing the extent ofxanthomatous infiltration of Achilles tendon. Tendonxanthomas are frequently present in hyperlipidasmicpatients, and may be the only clinical manifestation of

hyperlipidsmia. They can usually be found over theextensor tendons of the fingers and toes as well as theAchilles tendons. Their presence may orientate the

diagnosis towards a specific type of hyperlipoproteinxrnia-i.e., they are more likely to be found in types II and IIIof Fredrickson’s classification.l Progression or regressionin their size will give an idea of the efficacy of treatment.It is thus important, for screening and follow-up of hyper-lipoproteinaemia, to be able to measure their size withsome accuracy. Clinical evaluation alone is rather unsatis-

factory as a reference index. Achilles tendon xanthomas,because of their frequent involvement and ease of access,provide an ideal site for such precise measurements.

We have used a modification of the "mammography"technique 2 to study these lesions.Four people were examined. Two patients, one male

and one female, were being treated for hyperlipidaemiaat the clinic of nutrition, metabolism and atherosclerosisof the Institut de Recherches Cliniques de Montreal.They had type-ll hyperlipidaemia, according to the criteriaof Fredrickson et al.1 Thev were paired with two normal

Fig. 1-Soft-tissue radiograph of ankle in patient with type-11hyperlipoproteinaemia.

The Achilles tendon is diffusely enlarged (25-0 mm. thick,measured 8 cm. above the lowest point of the tuber calcanei), andthe adipose tissue anterior to the tendon is reduced. The adiposetissue is heavily infiltrated by bands of connective tissue. Theanterior aspect of the tendon bulges forward. The originaldarker film clearly showed the calcareous deposits (Monckebergtype) in the posterior tibial artery. They are hardly seen on thislighter film reproduction. Similar changes were observed inthe right ankle.

1. Fredrickson, D. S., Levy, R. I., Lees, R. S. New Engl. J. Med.1967, 276, 34, 94, 148, 215, 273.

2. Gershon-Cohen, J., Forman M. Bull. N.Y. Acad. Med. 1964,40, 674.