Seventy-Three Patients Had No Adverse Reaction Four and Six Weeks Respectively and Were Character

Canad. M. A. J. Sept. 2, 1961, vol. 85 WARWICK AND OTHERS: VINBLASTINE SULFATE 579

CLINICAL EXPERIENCE WITH eral rule this dose was repeated in seven to ten days VINBLASTINE SULFATE* if the white cell count had not fallen below or had returned to 3000 per c.mm. or more. Where no

0. H. WARWICK, M.D., R. E. ALISON, M.D., response was observed, treatment was discontinued. and J. M. XI. DARTE, M.D., Toronto To 14 of the patients showing objective improvement, maintenance therapy with 0.2 mg. per kg. FoLLowING the observations by Cutts, Beer and was given in a single injection at two- to four-week Noble' that extracts of the plant Vinca rosea Linn intervals if the white cell count was above 3000 caused leukopenia and marrow depression when per c.mm. injected into rats, a new alkaloid, vincaleukoblastine With this latter dosage schedule few serious (vinblasitine sulfate), was isolated." This substance toxic effects occurred, although most patients de- also caused marked hematopoietic depression3 and veloped a leukopenia of 3000 cells per c.mm. or less. was shown to affect experimental tumours.4-6 The In 19 patients the white cell count fell below 1000 growth-inhibiting effect of this agent in human per c.mm.; eight of these had leukemia. Except for malignancy has since been described.7-21 With the those patients whose marrow was extensively in- initial dosages used, the main adverse reactions volved by disease, the white cell level generally occurred at the sites of injection, on the blood, and returned to normal within 10 days to two weeks. on the nervous system. Severe granulocytopenia was Seventy-three patients had no adverse reaction noted in almost all patients, although thrombocyto- other than leukopenia. Local irritation, pain, penia was seldom observed. Remissions were re- thrombophlebitis, nausea or fever were noted in ported in acute leukemia, choriocarcinoma, Hodg- 20 cases, although the symptoms were usually mild kin's disease and occasionally in solid tumours. and transient. Two patients developed temporary This is a review of our experience with 120 pa- partial alopecia and two showed hyperuricemia and tients with malignant disease who were treated hyperuricuria. The development of a E. coli septi- with vinblastine sulfate between May 1959 and cemia in one patient with acute leukemia might May 1961, and includes the 46 patients previously have been related to the treatment with vinblastine reported by us.)' 12 Two points arise from this study sulfa,te. The agent might also have been a factor which we consider of particular interest. As used in in the development of confusion in one patient the treatment of the last 100 patients, vinblastine and convulsions in another. sulfate has caused few serious side effects and has The effects of vinblastine sulfate in 116 patients produced useful remissions in Hodgkin's disease. with malignant disease are summarized in Table I. Of the 120 patients treated, 31 had Hodgkin's The four patients with Hodgkin's disease who re- disease, 15 had lymphomas, 20 had leukemia, nine ceived radiation in conjunction with vinblastine had testicular tumours, four had choriocarcinoma sulfate are not included. Beneficial objective effects and 41 had miscellaneous solid tumours. In the occurred in 32 patients and no response was noted selection of cases several principles have been in 84. followed. In each patient histological proof of diag- Among the patients with epithelial tumours, one nosis was available and it was possible to assess with metastases to the skin from carcinoma of the objectively any effect of treatment on the disease stomach showed disappearance or diminution in process. The patients chosen had previously re- the size of these masses during a two-month period ceived established forms of therapy to which they on maintenance therapy. Another patient with were no longer responding favourably; exceptions carcinoma of the breast showed marked improve- to this were four patients with Hodgkin's disease ment in skin metastases with healing of ulceration, who received combined vinblastine and radiation, but the remission was maintained for only six and four patients whose disease was too generalized weeks. for radiation therapy and for whom vinblastine The patients with Hodgkin's disease will be con- sulfate was felt to offer as much hope of relief as sidered separately from those with other tumours any of the alkylating agents. of hematopoietic tissue. Of the patients with leuk- The dosage schedule of 0.15 mg. per kg. of vin- emia, only those with leukosarcoma and acute stem- blastine sulfate intravenously on three or four cell leukemia improved. A 7-year-old girl with successive days used in our first cases9 was leukosarcoma showed decrease in blast cells in the discontinued because of the relatively high in- marrow and reduction in the size of her enlarged cidence of adverse reactions. Since then the pa- liver, spleen and nodes for six weeks after the first tients have received 0.2 mg. per kg. in 10 divided course of treatment. A second course produced no doses of 0.02 mg. per kg. given at hourly or half- response. Two of the nine patients with acute stem- hourly intervals into the tubing of an intravenous cell leukemia had partial remissions which lasted infusion of 5%c glucose in normal saline. As a gen- four and six weeks respectively and were characterized by reduction of blast cells and shrinkage of the *Fronm the Ontario Cancer Institute and the Princess Margaret Hospital, Toronto, and the Department of Medicine, spleen, liver and lymph nodes. Two patients had University of Toronto. This project was supported by grants from the Ontario Cancer Treatment and Research Foundation. a complete remission for six and eight weeks. The We wish to thank Eli Lilly and Company for making available the supplies of Velbe (vinblastine sulfate). blast cells disappeared from the peripheral blood Canad. M. A. J. 580 WARWICK AND OTHERS: VINBLASTINE SULFATE Sept. 2, 1961, vol. 85

TABLE I.-SUMMARY OF EFFECTS OF VINBLASTINE SULFATE old woman with giant follicle lymphoma showed IN MALIGNANT DISEASE symptomatic improvement with reduction in the (Following the Etiologic Classification of the Standard Nomen- size of enlarged lymph nodes and loss of associated clature of Diseases and Operations) pain for three months. One 20-year-old man with Beneficial malignant lymphoma is of particular interest be- No objective Dura- Disease No. effect effect tion cause vinblastine sulfate given in 10 divided doses at one-half hour intervals produced a reduction Tumours of epitheliurm 80-81 in size of the mass and diminution in pain whereas Granulosa cell of ovary.... 0 Cholangioma 1 1 0 a single intravenous injection of the same dose

Stomach ...... 0 1 previously had not been effective. 1 Breast ...... 4 3 of nerve tissue, 0 None the tumours of vascular Thyroid ...... Bladder. 2 2 0 tissue, smooth muscle or connective tissue re- 0 Skin ...... sponded to treatment. 0 Bronchus ...... 2 2 Of the 17 patients with tumours of embryonal Esophagus ...... 0 0 Vulva ...... 1I 1 and mixed tissue the administration of vinblastine 0 Cervix ...... sulfate produced some response in three. A 21-year- Melanocarcinoma...... 40 4 0 woman with 16 lb. in Hypernephroma ...... 4 4 old choriocarcinoma gained Anaplastic carcinoma 1 1 0 weight, lung metastases disappeared and a tempo- Tumours of hematopoietic tissue 82-83 rary fall in urinary chorionic gonadotrophins oc- Acute lymphatic leukemia. 1 1 0 Acute granulocytic curred. This remission lasted six months and she leukemia...... 7 7 0 subsequently died of tumour emboli which lodged Chronic granulocytic leukemia...... 2 ..2 0 in the pulmonary arterioles. A 26-year-old man with Leukosarcoma 1 0 1 seminoma had an abdominal mass which dis- Acute stem cell leukemia.. 9 5 4 appeared for two months following treatment with Lymphosarcoma...... 9 7 2 Reticulum cell sarcoma 2 1 1 vinblas'tine sulfate. Hodgkin's disease ...... 27 11 16 It became apparent early in our study of this seemed Plasma cell myeloma ...... 3 2 1 agent that patients with Hodgkin's disease Giant follicle lymphoma ... 3 2 1 to respond more consistently and more favourably Lymphoma not specified ... 1 0 1 than did those with any of the other diseases Tumours of nerve tissue-84 Neuroepithelioma (neuro- treated. Thirty-one patients with advanced Hodg- blastoma of retina) ...... 2 2 0 kin's disease have been treated. Four of these are Glioblastoma multiforme. 1 1 0 Tumours of vascular tissue 85 not included in our assessment because the drug Hemangiosarcoma 0 was given in combination with radiation therapy. Tumours of smooth muscle 86 Of the remaining 27, no response was observed in Leiomyosarcoma ...... 0 Tumours of connective tissuie 87 11 and a favourable response in 16. Four of the Ewing's sarcoma.. 2 2 0 remissions were of short duration, lasting two to Osteogenic sarcoma 2 2 0 Tumours of embryonal and mixed tissue-8'18 six weeks. However, 12 of the 27 patients showed Choriocarcinoma 4 3 1 a marked improvement for periods ranging from 4 Seminoma ...... 3 two to 11 months. When a response was obtained Teratoma of testis 2 1 Nephroblastoma in patients with Hodgkin's disease, it was often (Wilms' tumour) 2 2 0 dramatic. The patient felt better within 24 to 48 Embryonal carcinoma of hours, and was aware of an improvement in ap- testis ...... 3 3 0 1 1 0 petite and sense of well-being. The reduction in Thymoma ...... Mixed tumour of salivary size of lymph nodes, liver and spleen took place gland...... 1 1 0 as rapidly as the symptomatic improvement in some cases; in others it occurred more slowly. Weight and marrow, and the liver, spleen and lymph nodes gain and improvement in anemia accompanied this returned to normal size. response. The following case histories illustrate Patients with lymphosarcoma have shown only these various points. short remissions. A rapidly progressive reticulum cell sarcoma in one 24-year-old man remained CASE 1 stationary for three months following administra- L.M., a 45-year-old man, was found to have Hodg- tion of vinblastine sulfate. Another patient with kin's disease by biopsy in November 1959. Radiation- multiple myeloma of seven years' duration had therapy did not halt the progress of the disease and developed severe anemia, bone pain, loss of he was admitted in March 1960 with malaise, sweating, appetite and energy. With vinblastine sulfate and severe chest pain and weight loss of 30 lb. On examina- small doses of radiation given to localized areas, tion he was cachectic and had fever, enlarged nodes in he gained 21 lb., the hemoglobin was maintained the left supraclavicular and left axillary areas and a at three g. above the admission level of 5.4 g. % mass in the outer aspect of the left upper arm. Ab- dominal tenderness precluded an adequate examina- and he returned to part-time work. The improve- tion. His hemoglobin, white blood count al(ndbonie ment had been maintained for three months when marrow were normal. His chest radiograph showed he developed an infection and died. One 50-year- right hilar adenopathy and a poorly defined lesioni in Canad. M. A. J. 581 Sept. 2, 1961, vol. 85 WARWICK ANTD OTHERS: VINBLASTINE SULFATE the right middle lobe. Three days after he received for six months and returned to full-time work. At the 11 mg. of vinblastine sulfate, the pain and abdominal end of January 1960, he noted general malaise, fever, tenderness had disappeared and the left deltoid mass cough, loss of appetite and night sweats, and lymph- was smaller. An abdominal mass and enlarged liver adenopathy and hepatomegaly were again found. Vin- could then be felt. After a second injection of vinblastine sulfate, 12 mg., given on January 20 and 27, blastine sulfate one week later, he developed a produced generalized improvement in well-being, and voracious appetite and by this time only a few small the nodes shrank to half their size. A third injection nodes could be felt anid the abdominal mass was was given to repeat the previous pattern of drug ad- diminishing. He gained 20 lb. over the next few ministration and the nodes disappeared. Remission this months. He showed continued improvement on time lasted only three months and he has recently main-teniance therapy for eight and one-half moonths. received further vinblastine sulfate. In November 1960, recurrent lymph node masses did not respond to vinblastine sulfate but became smaller CASE 4 with radiation. In January 1961, he developed acute empyema of the gallbladder and obstructive jaundice G.R., a 39-year-old man, developed Hodgkin's dis- due to Hodgkin's disease. Following operation a ease in the fall of 1957. A characteristic fever, fatigue, temporary remission was obtained with nitrogen sweating and lymphadenopathy were controlled initially mustard [methyl-bis (2-chloroethyl) amine] which by wide-field radiation. In April 1959, recurrent symp- lasted for four weeks. He died on March 15, 1961, with toms and signs subsided for six months following nitro- extensive Hodgkin's disease, obstructive jaundice, gen mustard therapy, but only a six-week remission pulmonary congestion and atelectasis. was obtained with a second course of nitrogen mustard. He was admitted in June 1960 with fever, fatigue and enlarged, tender inguinal nodes which produced pain CASE 2 on walking. He also had epigastric pain and a history S.L., a 35-year-old man, had Hodgkin's disease which of duodenal ulcer. On examination he had low-grade was diagnosed after inguinal node biopsy in 1951, fever and moderately enlarged nodes in both inguinal and over the next nine years he received therapy with regions. His hemoglobin was 9.7 g. %. He received vin- radiation and nitrogen mustard. In March 1960, he was blastine sulfate on June 7 and June 16. The fever and admitted to hospital with fever, malaise, sore throat, pain subsided and the groin nodes became smaller. He chest pain and vomiting, and was cachectic with high showed gradual improvement, and maintenance ther- fever, a mass in the left upper abdomen, obstructive apy was discontinued in November 1960. He has re- jaundice and edema. No beneficial effect was produced mained well and by May 1961 had gained 9 lb., his by cyclophosphamide [N, N-bis-(B-chlorethyl)-N', hemoglobin had risen to 11 g. % and he had no evidence O-Propylene phosphoric acid ester diamide mono- of active Hodgkin's disease. hydrate] and prednisone. He continued to deteriorate, and enlargement of the spleen and abdominal lymph CASE 5 nodes were noted. His hemoglobin was 7.8 g. %. Two days after the administration of 12.5 mg. of vin- Hodgkin's disease was diagnosed in W.P., a 64- blastine sulfate in April 1960, vomiting stopped and year-old man, by biopsy in May 1960, and radiation his temperature subsided, and two weeks later he was therapy to the axillae and left groin produced a good free of jaundice and edema. The abdominal mass was result. In July 1960, he required an abdominal para- no longer palpable and only the tip of the spleen centesis and his spleen was enlarged 5 cm. below the could be felt. When he was seen in June 1960, there left costal margin. He was admitted in September were no abnormal physical findings. His hemoglobin 1960, complaining of progressive weakness, shortness had risen to 11 g. % and he had gained 25 lb. Re- of breath and swelling of the ankles. On examination mission continued on vinblastine sulfate for eight he was acutely ill with pallor, gross ascites and edema months at which time an abdominal mass recurred, of his legs. Following paracentesis the liver was felt with ureteral obstruction. There was a temporary re- below the umbilicus, the spleen tip was palpable and sponse to radiation therapy but none to alkylating he had a large mass in the left lower quadrant. The agents. He died in April 1961. hemoglobin was 6.1 g. % but the serum proteins were normal. After paracenteses on two further occasions, vinblastine sulfate, 12 mg., was given intravenously on CASE 3 September 16 and September 23. He also received In 1952, P.McK., a 28-year-old man, was found to 3000 c.c. of whole blood. There was an immediate im- have Hodgkin's disease which was controlled by radia- provement in his appetite and general sense of well- tion until 1959 when he received prednisone and chlor- being. Following one further paracentesis in October, ambucil [p ( di-2-chloroethyl) amino phenyl butyric ascites and edema did not recur, and the liver, spleen acid] without any effect. He was admitted to hospital and abdominal mass could no longer be felt. He has in June 1960, severely ill with shortness of breath, continued on maintenance therapy every three to four wheezing, cough, nausea, vomiting and abdominal pain. weeks. In June 1961 he was well, his hemoglobin was On examination there were bilateral rhonchi, fullness in 12.1 g. % and he had gained 25 lb. The remarkable re- the upper abdomen and hepatomegaly to 6 cm. below mission obtained in this patient has continued for nine the right costal margin. The hemogram and chest months (Fig. 1). radiograph were normal. After he received 12 mg. of vinblastine sulfate on June 16 and June 22, his appetite CASE 6 became voracious, his cough improved and his abdominal pain disappeared. No abdominal masses could V.Mc., a 43-year-old man, was admitted to hospital be felt. Following one further injection of vinblastine in January 1960, complaining of anorexia, malaise and sulfate two weeks later, he had a complete remission fatigue. On examination he had pallor with enlarged Canad. M. A. J. 582 WARWICK AND OTHERS: VINBLASTINE SULFATE Sept. 2, 1961, vol. 85

Vinblastifne [ p p p p p p p Sulfate 12mg 12mg 12mg 10mg lOmg 10mg 10mg 10mg I0mgp- l0mg ,1N 2As 2J 2kS K 2AS Iu . e I .10-11. N / 1., \1 Paracentesis III Transfusion X 6 130 , 12-0 110 . 10-0, Hb

80 7-0

160 - 155- Weight . lbs 150- . 145 - \. 1401 . -~* . 135 I- -20 T 20 40 60 80 100 120 140 160 180 200 220 240 260 280 0 DAYS F ig. 1.-(Case 5) Hodgkin's disease illustrating response to treatment witlh vinblastine sulfate. cervical and hilar nodes and spleinomegaly to 10 cm. long as eight months, has produced relatively few below the left costal margin. Biopsy showed Hodgkin's serious toxic effects. Leukopenia, which was tempo- disease, and he received nitrogen mustard with im- rary, occturred in nearly all patients, but thirombo- provement for three months. In April 1960, he noted cytopenia was not observed. There was no definite vague upper abdominal distress with weakness, fatigue evidence of a correlation between the degree of and occasional night sweats. Over the next five months in he received wide-field radiation with some improve- leukopenia and the beneficial effect. Remissions ment. However, by January 1961 his hemoglobin had Hodgkin's disease halve been observed in the dropped to 8.7 g. % and in March he was again ad- absence of leukopenia following therapy. mitted with fatigue, lethargy, general malaise, decrease Five of the 51 patients with solid tumours have in appetite and productive cough. Examination- showed shown temporary improvement. In this series the reduced expansion of the right chest with dullness at agent was not continued when the patient failed the right lung base and a few enlarged nodes anid to respond to the initial course of treatment. splenomegaly to 1 cm. below the left costal margin. Radiographs of the chest showed bilateral multiple Results in leukemia and malignant lymphomas round densities up to 9 mm. in diameter. At the end other than Hodgkin's disease have been disappoint- of March, following the administration of 20 mg. of ing, with only temporary control of the disease re- vinblastine sulfate intravenously, he noticed steady sulting in 10 of 35 patients. Four of the nine pa- increase in well-being, loss of shortness of breath and tients with acute stem cell leukemia responded; improvement in appetite. When last examined at the two had partial remission lasting four and six weeks end of May 1961, he had no lymphadenopathy, hepato- and two had complete remissions for seven and megaly an-d splenomegaly. His hemoglobin was 11.3 g. eight weeks. One patient with leukosarcoma had % and the chest radiograph showed marked reduction in a partial remission of six weeks' duration. Five of 'the number and size of the lung lesions. He was work- the 15 patients with other malignant lymphomas ing full time. responded for periods of two and one-half to three months. DISCUSSION In our opinion the agent seems to have been most Vinblastine sulfate has now been used in 120 effective in the treatment of patients with Hodgkin's patients with malignant disease over a two-year disease. Twelve of 27 patients in the advanced period. The dosage of 0.2 mg. per kg. body weight stages of this disease, previously treated with intravenously, repeated in one week and in some radiation and chemotherapy, have had marked cases given at a two- to four-week intervals for as subjective and objective improvement lasting for Canad. M. A. J. WARWICK AND OTHERS: VINBLASTINE SULFATE 583 Sept. 2, 1961, vol. 85 two to 11 months. It is our impression that patients SUMMARY receiving intermittent therapy at two- to four-week One hundred and twenty patients with malignant intervals had longer remissions than those to whom disease have been treated with vinblastine sulfate. maintenance therapy was not given. Four addi- A total dose of 0.2 mg. per kg. given intravenously tional patients with disseminated Hodgkin's disease in 10 divided doses over a five- to ten-hour period received vinblastine sulfate in combination with repeated in one week, and at two- to four-week inter- radiation, either as the initial therapy or early in vals for as long as eight months, has produced few the course of their disease. Three of these have serious toxic effects. shown recurrent lymphadenopathy and systemic Useful temporary remissions have occurred in a few symptoms shortly after completion of treatment. patients with solid tumours, acute stem cell leukemnila, Fourteen of the patients received nitrogen lymphosarcoma and reticulum cell sarcoma. mustard and vinblastine sulfate in the management Twelve of 27 patients with advanced Hodgkin's dis- of Hodgkin's disease. Of the 12 who received nitro- ease have shown useful remissions lasting from two to one 11 months. gen mustard first, 11 had remissions lasting for Vinblastine sulfate seems to be as useful as nitrogen week to 32 weeks with a mean duration of mustard in Hodgkin's disease and may be effective eleven weeks. Six of these patients responded to when the patient is resistant to alkylating -agents. subsequent vinblastine sulfate administration for It is our opinion that localized Hodgkin's disease periods lasting from eight weeks to 47 weeks with should be treated with radiation therapy. Alkylating a mean duration of 20 weeks. The two patients agents and vinblastine sulfate should be reserved for who first received vinblastine sulfate had remissions advanced cases. for 35 to 37 weeks with no improvement following nitrogen mustard. This limited experience suggests REFERENCES that vinblastine sulfate may be as useful as nitro- 1. CuT'TS J. H., BEER, C. T. AND NOBLE, R. L.: Rev. Canad. Biol., 16: 476, 1957 (abstract). gen mustard in the treatment of Hodgkin's disease. 2. NOBLE, R. L., BEER, C. T. AND CUTTS, J. H.: Antn. New York Acad. Sc., 76: 882, 1958. Indeed, it would seem that when a remission is 3. CUTTS, J. H.: Proc. Am. A. Cancer Res., 2: 289, 1958 (abstract). obtained following vinblastine sulfate it will be of 4. CUTTS, J. H., BEER, C. T. AND NOBLE, R. L.: Cancer Res., than remission 20: 1023, 1960. longer duration on the average 5. JOHNSON, I. S., WRIGHT, H. F. AND SVOBODA, G. H.: J. obtained with nitrogen mustard. Lab. & Clin. Med., 54: 830, 1959 (abstract). 6. NOBLE, R. L., BEER, C. T. AND CUTTS, J. H.: Biochenm. There has been a long and continuing experi- Pharmacol., 1: 347, 1959. 7. HODES, M. K., ROHN, R. J. AND BOND, W.: J. Lab. & Clin. ence in the management of Hodgkin's disease in Med., 54: 826, 1959 (abstract). 8. HERTZ, R., LIPSETT, M. B. AND MoY, R. H.: Cantcer Res., this centre,13 and it is our firm conviction that 20: 1050, 1960. 9. WARWICK, 0. H., DARTE, J. M. M. AND BROWN, T. C.: alkylating agents and vinblastine sulfate should be Ibid., 20: 1032, 1960. 10. HODES, M. E., ROHN, R. J. AND BOND, W.: Canad. Cancer withheld until events show that radiation therapy Coaf., 4: 389, 1961. effective. The use of chemotherapeutic 11. HERTZ, R.: Ibid., 4: 383, 1961. is no longer 12. WARWICK, 0. H., DARTE, J. M. M. AND OLIN, J. S.: Ibid.,. agents for localized Hodgkin's disease in our 4: 373, 1961. 13. PETERS, M. V. AND MIDDLEMISS, K. C. H.: Amt. J. Roent- opinion constitutes improper treatment. genol., 79: 114, 1958.

PAGES OUT OF THE PAST: FROM THE JOURNAL OF FIFTY YEARS AGO THE ONTARIO MEDICAL COUNCIL and the homoeopaths one, it would be ample to do the work satisfactorily and well. The expected has happened and the Ontario Medical Another modification must be made, too, in the interest Council has yielded to the persistent demands for radical of the student. Now that the costly examinations are done changes in its methods and examinations. away with, the excessive fee should be greatly modified. Possibly it has not shown enough enthusiasm in the matter It is to be hoped that during the recess the re-organiza- of reorganization, but as this is under the consideration of tion committee will not, like the House of Lords, ba-lk at a committee it is too soon to criticize. the idea of reforming itself, but will rise to the occasion What is really important, though, is the tacit admission with the same promptness which characterized it when it that the universities are not only competent to carry on cut off the representative of two non-active universities. the work of medical education, but are to be trusted. Perhaps the incentive will not be quite as strong, but the Possibly the council was wise in retaining the power to necessity is certainly as great. examine candidates for a licence at the end of the fifth The council is to be congratulated on having as energetic year in medicine, surgery, and midwifery, and its action and progressive a man as Dr. Edward Ryan as its president; in appointing three university men as well as three from but an ardent university the profession at large as examiners was most commendable. he is not 'only a council enthusiast, In this way there will be a strong check on any university man as well. showing a tendency to fall from grace, and the standard To summarize the sweeping changes in a few words: the of medical education is likely to advance rather than university and council examinations have become identical; retrograde. council examinations are abolished with the exception of We are still of the opinion that the Medical Council is a test in medicine, surgery, and midwifery at the end of far too great in numbers, and if the five universities were five years of a successful university course.-Editorial, given one representative each, the general profession five, Cantad. M. A. J., 1: 883, 19 1.