STEM CELLS IN CHRONIC GRANULOCYTIC LEUKÆMIA—OLD BETTER THAN NEW?

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424 more consternation. But that seems unlikely to deter health-service administrators and their clinical advisers. In these columns we have repeatedly2,3 called for more advice to doctors on what drugs to use, how to use them, on their potential dangers, and on necessary pre- cautions. There are rumours that preliminary discus- sions are taking place about the possibility of producing a redesigned British National Formulary. Could not its editorial committee follow the lead of the W.H.O., have the courage of their convictions, and advise us on the "best buys" in the British drug market? · CONSEQUENCES OF SMALL-BOWEL RESECTION INCREASING numbers of patients are undergoing resec- tion of the small intestine for treatment of regional enteritis (Crohn’s disease)-a condition which seems to be becoming more common. Since many of these pa- tients are young, information on the long-term meta- bolic consequences is much needed. Almost total excision of the small intestine may sometimes be necessary and with elemental diets4 and long-term parenteral nutrition at home,’ survival is possible with only a few centimetres of small intestine. Usually, however, the resection is less drastic and, in time, considerable anatomical and func- tional adaptation can be expected.6 There are great regional differences in small-bowel absorption because specific active transport is localised to particular areas; therefore both the site and the length of resection deter- mine the severity of the absorption defect. Other factors influencing the clinical outcome are the activity of resi- dual disease, the extent of any large-bowel resection,7 and integrity of the ileocaecal valve.8 Compston and Creamer9 have reviewed 43 patients who had lost between 15 and 194 cm of small intestine. 38 had Crohn’s disease and in 37 the resection was limited to the ileum. In general the patients were in good physical shape and only 5 were unable to work full time because of illness. Diarrhoea was seldom a problem and was well controlled in most patients by codeine phos- phate or diphenoxylate (’Lomotil’) together with restric- tion of dietary fat intake. There was no relation between stool frequency and the length . of small intestine resected. According to one theory, diarrhoea after limited ileal resection is due to the cathartic effect of in- creased amounts of bile acids reaching the colon, but Compston and Creamer found very little- benefit from the bile-salt-sequestrating agent cholestyramine. About half the patients were at or above their ideal weight, and this seemed to have been achieved by a considerable in- crease in calorie intake. Biochemical screening revealed few serious abnormalities but iron deficiency was com- 2. Lancet, 1976, ii, 351. 3. ibid. 1977, ii, 1215. 4. Russell, R. I. Gut, 1975, 16, 68. 5. Fleming, C. R., McGill, D. B., Berkner, S Gastroenterology, 1977, 73, 1077. 6. Dowling, R. H. in Modern Trends in Gastroenterology—4 (edited by W. I. Card and B. Creamer) p. 73. London, 1970. 7. Cummings, J. H. James, W. P. T., Wiggins, H. S. Lancet, 1973, i, 344. 8. Singleton, A. O., Redmond, D. C., McMurray, J. E. Ann. Surg. 1964, 159, 690. 9. Compston, J. E., Creamer, B. Q. Jl Med. 1977, 46, 485. mon and 1 patient had megaloblastic anaemia due to folate deficiency. Most patients had received regular in- jections of vitamin B12 after ileal resection. 2 patients had serious deficiency of the fat-soluble vitamins A or K. Vitamin-D deficiency was much more common. The same group’" examined bone biopsy specimens from 25 patients with small-intestinal resections and found osteo- malacia in 9 (36%); 4 had mild disease and in these serum calcium, phosphate, and alkaline phosphatase were normal. Clearly bone biopsy is the only certain method of diagnosing osteomalacia. Treatment with parenteral vitamin D was not always fully effective but early experience with oral 1-a-hydroxy-vitamin D is encouraging. It works faster, individual dosage require- ments are more easily established, and toxicity is more I quickly reversed.. Discovery of this high proportion of patients with osteomalacia after small-intestinal resection raises fears that similar troubles are in store for patients who have had jejunoileal bypass operations for obesity. Other ill- effects of ileal resectionl include an increased incidence of gallstones and renal oxalate stones, and some workers report increased gastric-acid secretion with peptic ulcer- ation. Nevertheless the prognosis after small-intestinal resection is better than might be expected-provided that complications are treated early. STEM CELLS IN CHRONIC GRANULOCYTIC LEUKÆMIA—OLD BETTER THAN NEW? If the Ph marker chromosome, first demonstrated by Nowell and Hungerford’ in dividing leucocytes from pa- tients with chronic granulocytic leukxmia (C.G.L.), really reflects a somatic mutation occurring in a single bone-marrow stem cell, whose progeny then expand to populate the marrow at the expense of normal myeloid elements, much can be deduced about the way in which normal haemopoiesis may work. The later finding that the Ph’ chromosome was present also in erythroid and megakaryocytic precursors in c.G.L. implied that this stem cell was pluripotent-that is, it could differentiate along granulocytic, erythroid, or megakaryocytic lines.2 Because monocytes share a common progenitor cell with granulocytes, monocytes in C.G.L. should also carry the Ph* chromosome, and this has proved .to be the case.3 Confirmation of the hypothesis that a pluripotent stem cell is involved in C.G.L. has come from another source. Fialkow and his colleagues studied patients with C.G.L. who were heterozygous for two isoenzymes of glucose-6- phosphate dehydrogenase (G-6-P.D.) Since transmission of the G-6-P.D. gene is sex-linked, females who inherit both isoenzymes will be "mosaics" with only one iso- enzyme expressed in any given cell because of random inactivation of the X-chromosome locus. Fialkow showed that all the granulocytes and red cells from indi- vidual women with C.G.L. had the same isoenzyme.4 He 10. Compston, J. E., Ayers, A. B., Horton, L. W. L., Tighe, J. R., Creamer, B. Lancet, 1978, i, 9. 11. Shaffer, E. A., Brown, R. A., Dutton, J. W. in Recent Advances of Gastroen- terology, vol. III (edited by I. A. D. Bouchier); p. 73. Edinburgh, 1976. 1. Nowell, P. C., Hungerford, D. A. Science, 1960, 132, 1497. 2. Rastrick, J. M., Fitzgerald, P. H., Gunz, F. W. Br. med. J. 1968, i, 96. 3. Golde, D. W., Burgaleta, C., Sparkes, R. S., et al. Blood, 1977, 49, 367. 4. Fialkow, P. J. New Engl. J. Med. 1974, 291, 26.

Transcript of STEM CELLS IN CHRONIC GRANULOCYTIC LEUKÆMIA—OLD BETTER THAN NEW?

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more consternation. But that seems unlikely to deterhealth-service administrators and their clinical advisers.

In these columns we have repeatedly2,3 called formore advice to doctors on what drugs to use, how to usethem, on their potential dangers, and on necessary pre-cautions. There are rumours that preliminary discus-sions are taking place about the possibility of producinga redesigned British National Formulary. Could not itseditorial committee follow the lead of the W.H.O., havethe courage of their convictions, and advise us on the"best buys" in the British drug market? ·

CONSEQUENCES OF SMALL-BOWEL RESECTION

INCREASING numbers of patients are undergoing resec-tion of the small intestine for treatment of regionalenteritis (Crohn’s disease)-a condition which seems tobe becoming more common. Since many of these pa-tients are young, information on the long-term meta-bolic consequences is much needed. Almost total excisionof the small intestine may sometimes be necessary andwith elemental diets4 and long-term parenteral nutritionat home,’ survival is possible with only a few centimetresof small intestine. Usually, however, the resection is lessdrastic and, in time, considerable anatomical and func-tional adaptation can be expected.6 There are greatregional differences in small-bowel absorption becausespecific active transport is localised to particular areas;therefore both the site and the length of resection deter-mine the severity of the absorption defect. Other factorsinfluencing the clinical outcome are the activity of resi-dual disease, the extent of any large-bowel resection,7and integrity of the ileocaecal valve.8Compston and Creamer9 have reviewed 43 patients

who had lost between 15 and 194 cm of small intestine.38 had Crohn’s disease and in 37 the resection waslimited to the ileum. In general the patients were in goodphysical shape and only 5 were unable to work full timebecause of illness. Diarrhoea was seldom a problem andwas well controlled in most patients by codeine phos-phate or diphenoxylate (’Lomotil’) together with restric-tion of dietary fat intake. There was no relation betweenstool frequency and the length . of small intestineresected. According to one theory, diarrhoea afterlimited ileal resection is due to the cathartic effect of in-creased amounts of bile acids reaching the colon, butCompston and Creamer found very little- benefit fromthe bile-salt-sequestrating agent cholestyramine. Abouthalf the patients were at or above their ideal weight, andthis seemed to have been achieved by a considerable in-crease in calorie intake. Biochemical screening revealedfew serious abnormalities but iron deficiency was com-

2. Lancet, 1976, ii, 351.3. ibid. 1977, ii, 1215.4. Russell, R. I. Gut, 1975, 16, 68.5. Fleming, C. R., McGill, D. B., Berkner, S Gastroenterology, 1977, 73, 1077.6. Dowling, R. H. in Modern Trends in Gastroenterology—4 (edited by W. I.

Card and B. Creamer) p. 73. London, 1970.7. Cummings, J. H. James, W. P. T., Wiggins, H. S. Lancet, 1973, i, 344.8. Singleton, A. O., Redmond, D. C., McMurray, J. E. Ann. Surg. 1964, 159,

690.9. Compston, J. E., Creamer, B. Q. Jl Med. 1977, 46, 485.

mon and 1 patient had megaloblastic anaemia due tofolate deficiency. Most patients had received regular in-jections of vitamin B12 after ileal resection. 2 patientshad serious deficiency of the fat-soluble vitamins A or K.Vitamin-D deficiency was much more common. Thesame group’" examined bone biopsy specimens from 25patients with small-intestinal resections and found osteo-malacia in 9 (36%); 4 had mild disease and in theseserum calcium, phosphate, and alkaline phosphatasewere normal. Clearly bone biopsy is the only certainmethod of diagnosing osteomalacia. Treatment with

parenteral vitamin D was not always fully effective butearly experience with oral 1-a-hydroxy-vitamin D is

encouraging. It works faster, individual dosage require-ments are more easily established, and toxicity is more Iquickly reversed..

Discovery of this high proportion of patients withosteomalacia after small-intestinal resection raises fearsthat similar troubles are in store for patients who havehad jejunoileal bypass operations for obesity. Other ill-effects of ileal resectionl include an increased incidenceof gallstones and renal oxalate stones, and some workersreport increased gastric-acid secretion with peptic ulcer-ation. Nevertheless the prognosis after small-intestinalresection is better than might be expected-providedthat complications are treated early.

STEM CELLS IN CHRONIC GRANULOCYTICLEUKÆMIA—OLD BETTER THAN NEW?

If the Ph marker chromosome, first demonstrated byNowell and Hungerford’ in dividing leucocytes from pa-tients with chronic granulocytic leukxmia (C.G.L.),really reflects a somatic mutation occurring in a singlebone-marrow stem cell, whose progeny then expand topopulate the marrow at the expense of normal myeloidelements, much can be deduced about the way in whichnormal haemopoiesis may work. The later finding thatthe Ph’ chromosome was present also in erythroid andmegakaryocytic precursors in c.G.L. implied that thisstem cell was pluripotent-that is, it could differentiatealong granulocytic, erythroid, or megakaryocytic lines.2Because monocytes share a common progenitor cell withgranulocytes, monocytes in C.G.L. should also carry thePh* chromosome, and this has proved .to be the case.3Confirmation of the hypothesis that a pluripotent stemcell is involved in C.G.L. has come from another source.Fialkow and his colleagues studied patients with C.G.L.who were heterozygous for two isoenzymes of glucose-6-phosphate dehydrogenase (G-6-P.D.) Since transmissionof the G-6-P.D. gene is sex-linked, females who inheritboth isoenzymes will be "mosaics" with only one iso-enzyme expressed in any given cell because of randominactivation of the X-chromosome locus. Fialkowshowed that all the granulocytes and red cells from indi-vidual women with C.G.L. had the same isoenzyme.4 He

10. Compston, J. E., Ayers, A. B., Horton, L. W. L., Tighe, J. R., Creamer, B.Lancet, 1978, i, 9.

11. Shaffer, E. A., Brown, R. A., Dutton, J. W. in Recent Advances of Gastroen-terology, vol. III (edited by I. A. D. Bouchier); p. 73. Edinburgh, 1976.

1. Nowell, P. C., Hungerford, D. A. Science, 1960, 132, 1497.2. Rastrick, J. M., Fitzgerald, P. H., Gunz, F. W. Br. med. J. 1968, i, 96.3. Golde, D. W., Burgaleta, C., Sparkes, R. S., et al. Blood, 1977, 49, 367.4. Fialkow, P. J. New Engl. J. Med. 1974, 291, 26.

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concluded that c.G.L. is indeed a monoclonal defect aris-

ing in a single stem cell. A single isoenzyme is pres-ent also in monocytes and macrophages cultured fromwomen with c.G.L.,s the results of the chromosome andisoenzyme studies tally well.

Since the Ph’ chromosome was not found in the bone-marrow cells of monozygotic twin sibs of patients withC.G.L. and was absent from patients’ lymphocytes andskin fibroblasts, it was regarded as an acquired defectaffecting marrow stem cells with commitment to myeloidbut not lymphoid differentiation. But this stem cell mayin fact be less restricted in its capacity for differentia-tion.6 About 20% of patients with C.G.L. who entertransformation have a blast cell with morphological,enzymic, and antigenic characteristics identical to thoseof the blast-cells of "common" acute lymphoblasticteuksemia (A.L.L.),7-<J which are themselves thought to beprimitive stem cells with the capacity for lymphoid dif-ferentiation. This implies that the afflicted stem cell inC.G.L. can, at least in some cases, give rise to lymphoidprogeny. A corresponding normal pluripotential stemcell would then give rise to progeny committed to eitherlymphoid or myeloid differentiation and the latter wouldthen produce red cells, granulocytes, monocytes, or plate-lets. Whether c.G.L. always involves this "early" stemcell or sometimes affects only the committed myeloidstem cell is unknown.’10

How can this knowledge help the patient with C.G.L.?Blast-cell transformation remains notoriously difficult totreat, but the use of cytotoxic drugs active against A.L.L.for patients with the lymphoid type of transformationmay yield worthwhile remissions.7.11,12 What for therest? An ingenious approach has been pioneered byBuckner and his colleagues in Seattle.13 Since stem cells,but not mature granulocytes, survive cryopreservation,they harvested bone-marrow from newly diagnosed pa-tients and stored it for periods ranging from 8 to 32months in liquid nitrogen. When the disease trans-

formed, the patients received cytotoxic drugs, total bodyirradiation, and transfusions of their own reconstitutedbone-marrow cells. The autograft was successful in fiveof the seven patients. Leukaemia recurred in only one pa-tient and most of the deaths seemed to be due to compli-cations of the irradiation. A surprising observation wasthe failure of the autograft to restore lymphoid function.A variation of this approach is reported on p. 437 by DrGoldman and his colleagues. They speculated that if

granulocyte precursors were increased in the blood of apatient with C.G.L. at diagnosis, pluripotential stem cellsmight be in circulation also. They therefore stored bloodcells, but not bone-marrow.from their patient and usedthem in conjunction with cytotoxic drugs when the pa-tient entered blast-cell transformation. This patient wasapparently restored to a chronic phase of his disease and

5. Fialkow, P. J., Jacobson, R. J., Papayannopoulou, T. Am. J. Med. 1977, 63,125.

6. Boggs, D. R. Blood, 1974, 44, 449.7. Janossy, G., Greaves, M. F., Revesz, T., et al. Br. J. H&oelig;mat. 1976, 34, 179.8. Peterson, L. C., Bloomfield, C. D., Brunning, R. D. Am. J. Med. 1976, 60,

209. 9. Janossy, G., Woodruff, R. K., Paxton, A., et al. Blood, (in the press).10 Janossy, G., Roberts, M., Greaves, M. F. Lancet, 1976, ii, 1058.11. Beard, M. E. J., Durrant, J., Catovsky, D. et al. Br. J. H&oelig;mat. 1976, 34,

169.12. Marmont, A. M., Damasio, E., E. Acta h&oelig;mat. 1973, 50, 1.13 Buckner, C D., Stewart, P., Clift, R. A., et al. Exp. Hemat. 1978, 6, 96.

was alive and well without further treatment six monthsafter the procedure. Though the Hammersmith groupcannot prove that transfused stem cells were responsiblefor repopulating the patient’s marrow, the result in thisone patient is encouraging. The approach offers at leasta ray of hope in a disease whose prognosis has hardlychanged in twenty years.

PATIENT PARTICIPATION

LIKE sin, but contrariwise, everyone is in favour ofpatient participation. This favour was given more

definite form at Oxford on Feb. 18 when a gathering ofpatients, doctors, and community workers attended theinaugural meeting of the National Association for Pa-tient Participation in General Practice. Sir GeorgeGodber, lately chief medical officer at the Department ofHealth and now chairman of the Health EducationCouncil, on being installed as president, said that theHealth Service must make the best of what it had got,and, in doing so, must build on its base in the com-munity. He thought that self-care and care in the com-munity were in the long term more important than insti-tutionalised medical care. He looked to patients’associations and committees to help the professionals,whom he likened to arthropods hiding their specialisedknowledge under a carapace; when the carapace wasmoulted, as it inevitably must be, it would be patientswho helped to protect the naked professional.The meeting was chaired by Dr Alistair Wilson, a

general practitioner in Aberdare, Glamorgan, in whosegroup practice a patients’ committee has flourished forfive years, and who with Dr Tim Paine of Bristol hasbeen the instigator of the Association. Dr Wilson listedthe places where patients’ committees have been formed,and many members of committees spoke during themeeting. They gave their own ideas about how to drawpatients into the running of health centres and grouppractices, and they described other activities such ashealth-education lectures, brains trusts, lunch-timesocial meetings, and other efforts to increase self-care inthe community (for example, collecting prescriptions forthe housebound, a baby-sitting service for young peoplewith few friends, and cooking meals for the elderly atthe weekends when the local-authority services were notworking).

In the discussion periods, the more important issuesbegan to be debated. How could anyone set up a pa-tients’ committee if the doctors were firmly opposed toit? Why were health education lectures almost invariablya failure? Could patients’ committees succeed in work-ing-class areas? The most active and successful of thecommittees seemed to be in those practices where thedoctors were most keen that they succeeded. It was leftto a community worker to ask the key question (and onewhich went unanswered); do patients’ associationsachieve any real transfer of decision-making power inthe National Health Service away from the professionalsand towards the people? If the answer is no, then thesecommittees are not participation, but paternalism.Clearly, however, the Association is a lusty infant,rapidly adding cells to a growing body, and getting anincreasingly powerful voice: we hope that it will soonfind out what it should be saying.