260 have also learned of the serious danger and poor prognosis of autonomic failure. This extensive involvement of the peripheral autonomic nervous system may explain in part the dismal results of treatment in most cases of rabies. By calling attention to these findings I hope that more emphasis is put on the study of the peripheral autonomic system of patients with rabies in the hope of obtaining better results in treatment. Neuropathology Laboratory, Louisiana State University Medical Center, New Orleans, Louisiana 70112, U.S.A.

CARLOS A. GARCIA

BONE-MARROW CULTURE IN ACUTE MYELOID LEUKÆMIA

SIR,-In 1973 Crowther et al.1 reported encouraging results with the use of immunotherapy to prolong complete remission induced by cytotoxic drugs in patients with acute myeloid leukxmia (A.M.L.). Immunotherapy involved the weekly administration of allogeneic leuksemic blast cells and B.C.G. Some patients were given cytotoxic drugs in 5-day courses repeated every 4 weeks. Other immunotherapy regimens have since been developed, but prolongation of survival in A.M.L. patients treated by immunotherapy has not been proved.2-4 It has, however, been observed that a second remission is relatively easy to induce in patients who relapse after maintenance of the first remission with immunotherapy, and Freeman et a1.5 have suggested that the benefit of immunotherapy results not so much from an immunological effect as from a non-specific stimulatory effect of B.C.G. on bone-marrow function. Our experimental data gave no support to this hypothesis. We used an agar culture technique6 to count colony-forming units (c.F.u.c) in the marrow of patients with A.M.L. in remission. Remission was induced with repeated 5-day courses of cytarabine and daunorubicin. Patients who achieved remission were randomised so that some received weekly immunotherapy as in the original Barts studies’ and others did not: all were maintained with 5-day courses of cytarabine and 6-thioguanine alternating monthly with cytarabine and daunorubicin. Maintenance chemotherapy was stopped after 12 months but immunotherapy was continued indefinitely. Most patients (84%) were still being maintained with cytotoxic drugs but no patient had been treated with drugs in the 3 weeks preceding bone-marrow culture. Bone-marrow from thirty healthy volunteers and from fifteen patients who proved subsequently not to have haematological disease was used as controls. Colonies were defined as aggregates of cells containing 50 or more cells after culture for 10-12 days. The results are shown in the figure. Mean colony numbers were significantly higher in both groups of patients than in controls. Mean colony numbers in patients treated with and without immunotherapy were almost identical. There are problems associated with the interpretation of c.F.u.c numbers assayed by agar culture. Measurement of c.F.u.c numbers will only give a direct indication of the overall level of granulopoiesis if one assumes that the mean transittime through the c.F.u.c compartment in different conditions remains constant. Moreover, expressing c.F.u.c. numbers as a proportion of total nucleated marrow cells plated ignores possible variations in the relative distribution of mature and immature cells, such as might be seen in a marrow recovering from cytotoxic drug insult. With these qualifications there appears to be a modest expansion of the c.F.u.c compartment in patients with A.M.L. in remission maintained by monthly administration of cytotoxic drugs whether or not they receive im-

munotherapy. 1 Crowther, D., and others Br. med. J. 1973, i, 131 2. Powles, R. L., and others Br. J Cancer, 1973, 28, 365. 3. Gutterman, J U., and others Lancet, 1974, ii, 1405 4. Vogler, W R., Chan, Y. ibid. 1974, ii, 128. 5. Freeman, C B., and others Br. med J. 1973, iv, 571. 6. Robinson, W. A., Pike, B. L. in Hemopoietic Cellular Proliferation by F. Stohlman), p. 249. New York, 1970.

(edited

Bone-marrow culture in

patients with A.M.L.

in remission and in controls.

numbers are shown per 1 x 105 nucleated cells plated with mean values + 1 standard deviation: (1) non-immunotherapy patients, 48-0 + 26-4, (2) immunotherapy patients, 48-4 ± 27-2, and (3) controls, 37-1 ± 9-8. Differences between (1) and (3) and between (2) and (3) are significant (r=0-O15 and r=0-022, respectively, Student’s t

Colony

test).

,

We interpret our data as consistent with the hypothesis’-9 that the bone-marrow of patients with A.M.L. in remission is largely or almost completely repopulated by normal myeloid cells. There is no evidence from this study that immunotherapy specifically stimulates granulopoiesis. Department of Medicine, J. M. GOLDMAN Royal Postgraduate Medical School, N. A. BUSKARD Hammersmith Hospital, K. H. TH’NG London W12

LOCAL-REGIONAL RECURRENCE AFTER MASTECTOMY

SIR,-The data cited by Dr Karim (July 3, p. 36) on the incidence of local-regional metastasis in our breast-cancer series (48% in the controls, 28% in the adjuvant chemotherapy group) are wrong. He may have misinterpreted the results I presented at the DePCa Symposium held in New York in

April. The

accompanying

table shows the

true

comparative fre-

quency of treatment failure in different sites as analysed for the symposium. They are related to the findings observed 34

months after the

beginning

of the

c.M.F.

(cyclophosphamide,

methotrexate, fluorouracil) programme for operable breast with histologically involved axillary nodes. In the group with only local-regional recurrence the difference between controls and C.M.F. patients is statistically significant (P=0.05). Since in the control group 8 of 38 patients with distant relapse also showed recurrence at the level of the chest wall and/or supraclavicular fossa, the total difference in the incidence of local-regional relapse between the two treatment groups (21 of 179 patients or 11.7% vs. 5 of 207 or 2-4%) is even more significant (P=0.0005). Although for both groups the absolute

cancer

7. Harris, J., Freireich, E. J. Blood, 1970, 35, 61. 8. Greenberg, P. L., Nichols, W C., Schrier, S. L New 284, 1225 9. Bull, J. M., and others Blood, 1973, 42, 679.

Engl

J Med. 1971,

261 COMPARATIVE INCIDENCE OF RELAPSE IN DIFFERENT SITES (DATA AS OF APRIL 1, 1976)

*

Chest wall

and/or ipsilateral supraclavicular region.

recurrence-rate

is unknown because of the limited average fol-

low-up since radical mastectomy (controls 17.29 months, C.M.F. 17-24 months), the table shows that the local-regional control by C.M.F. treatment is very close to, if not better than, that usually reported after postoperative radiotherapy (3-7%), and far away from the percentages given by Dr Karim. May I appeal to research-workers, and to radiotherapists in particular, involved in the treatment of primary breast cancer to restrain their clinical emotions about the-preliminary data provided by controlled adjuvant studies’2 until long-term results are available. We all recognise that the treatment for operable breast cancer is in a state of flux. This, understandably, may raise both technical and psychological problems. However, only carefully planned randomised studies can provide useful guidelines about the future extent of surgery, the role of radiotherapy, and the value of different forms of medical treatment. As I have reiterated, both in publications,:24 and in talks, time is an essential ingredient for a critical evaluation of continuing studies. It is most unwise to jump to conclusions. The initial results of the melphalan’ and C.M.F.2 studies have provided sound evidence that the concept of treatment for primary breast cancer at high risk of early relapse must be changed. Unfortunately, changing the concept does not necessarily mean changing the end result. Whatever the conclusions of the combined local-systemic treatment are, they will, if they are convincing, be used in the redefinition of the usefulness of all available therapeutic tools. In the meantime, patients and physicians must be open to new findings and accept a period of therapeutic uncertainty. Istituto Nazionale Tumori,

Milan, Italy

GIANNI BONADONNA

BREAST FEEDING

SIR,-Dr Miles (July 17, p. 152) presented data which emphasised the reservations which were placed on breast-feeding rates such as those of Dr Smart and Dr Bamford (July 3, p. 42) which were limited to the first few days after delivery. Over the past two years I have collected data on methods of feeding in use at the time of the 6 week postnatal examination for all newly delivered patients in my practice. The group was relatively young and inexperienced (58% were under 25 and 62% were having their first baby) and was drawn from all social classes.

=8.28 p

Letter: Local-regional recurrence after mastectomy.

260 have also learned of the serious danger and poor prognosis of autonomic failure. This extensive involvement of the peripheral autonomic nervous sy...
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