BRIEF COMMUNICATIONS
Some newer approaches to the treatment of the mucosa of patients with superficial bladder cancer: 1. Continuous bladder irrigation with 5-fluorouracil J.G. CONNOLLY,* MD, FRCS (EDIN), FRCS[C]; CHERYL ANDERSON,t M Sc PHM; IvY JOHNSON,. B SC One of the most challenging prob- mours were more aggressive than lems in urology is the management the primary, and in 10% of the of the patient with superficial patients with recurrences lethal inbladder cancer (stage 0, A or Ti). vasive cancer developed. There are The tumours are often readily de- many other studies in the literature stroyed by simple means and, showing recurrences in about two provided they are well differentiated, thirds of patients with superficial there is little likelihood of dissemina- bladder cancer and progressive tion. However, the prognosis in such (more aggressive) disease in a signifa patient is dependent on the malig- icant proportion.2 Any effort dinant potential of the bladder mucosa rected at eliminating or reducing the remaining after the ablation of the rate of recurrence of bladder cancer presenting tumour. must take into consideration the The bladder is a reservoir, and widespread abnormalities that are the carcinogens responsible for the found in the bladder mucosa of painitiation of bladder cancer are tients with superficial bladder canprobably excreted in the urine. cer. The search for a suitable Because the entire bladder mucosa chemotherapeutic agent to bring is exposed to these carcinogens the about this change is ongoing, and mucosal abnormalities can be wide- one of the approaches being studied spread. However, they may not be by us is the topical use of 5-fluorgrossly visible. Many of the "re- ouracil (5-FU) in bladder irrigation. currences" (really new tumours ocKlein and colleagues3-5 first decurring at new sites) originate in monstrated that topical preparations these areas of epithelial dysplasia. of 5-FU could be used successfully The problem of recurrences in to treat certain premalignant and patients with superficial bladder malignant skin conditions. This apcancer is serious. In one series1 the proach represented a significant adrecurrence rate was 73%. Approxi- vance in the treatment of certain mately 20% of the recurrent tu- cutaneous malignant tumours. One of the observations repeatedly made in treating skin tumours with the From the department of surgery, topical application of 5-FU was University of Toronto and Women's that, as early as the fourth day after College Hospital, Toronto treatment was started, skin lesions *Associate professor, department of not previously visible were unsurgery, University of Toronto, and masked. Areas of seemingly normal research associate, Ontario Cancer skin, usually in a satellite arrangeTreatment and Research Foundation tAssistant director of pharmacy, ment around the tumour being Women's College Hospital, Toronto, treated, became inflamed and redand assistant professor, faculty of dened, but with continued applicapharmacy, University of Toronto tion of 5-FU they became grossly Research assistant, department of and histologically normal. One exsurgery, University of Toronto Reprint requests to: Dr. J.G. Connolly, planation offered for this phenomWomen's College Hospital, 76 Grenville enon has been that these areas, while St., Toronto, Ont. M55 1B2 grossly normal, have a higher rate
318 CMA JOURNAL/AUGUST 4, 1979/VOL 121
of cell turnover and therefore incorporate more 5-FU than normal skin. In some ways these lesions resemble the changes found in the mucosa of patients with superficial bladder cancer. It is most likely that recurrences in superficial bladder cancer originate from these areas of epithelial dysplasia. If one is to reduce the rate of recurrence in multiple superficial bladder cancer, then these areas of epithelial disease must be destroyed. Because of the data available from dermatologic practice6-8 it seemed unlikely that a single instillation of 5-FU into the urinary bladder would be effective in this respect. To confirm this impression we conducted the following study.
Methods and observations All of the patients treated in the study had multiple superficial bladder cancer. Some were considered candidates for total cystectomy because of a failure to respond to other forms of treatment, including radiotherapy. The minimal effective dose of 5FU required to block the synthesis of deoxyribonucleic acid is 1.3 .g/ ml.9 At the beginning of this study a solution containing 65 mg of 5FU in 1000 ml of saline was used as the irrigating fluid. The bladder of four patients was irrigated, with continuous outflow, in three consecutive 8-hour sessions. No local or systemic adverse effects were noted. A further four patients were then treated with the same concentration of 5-FU but the bladder was irrigated, with continuous outflow, for 96 hours. Again no adverse effects
were noted. The concentration of 5FU was then increased to 100 mg in 1000 ml of saline and the bladder of four patients was irrigated, with continuous outflow, for 96 hours, again without adverse effects. A control urine specimen was collected from each patient prior to the beginning of the bladder irrigations. During treatment all bladder washings were collected for each 24hour period. The volume was measured and a sample taken for ultraviolet spectrophotometric analysis in the 5-FU range, with the control urine as a blank. No new medications were administered while the irrigations were being done. We recovered from the bladder washings 5% and 10% of the total dose of 5-FU instilled. There was no evidence of bladder disturbance, either during or after irrigation. No effects on the hematopoietic system and no systemic effects were detected.
We have recently increased the concentration of 5-FU to 150 mg in 1000 ml of saline and have completed three 5-day irrigations in 10 patients, with no side effects being noted. Since we have no data on the optimum dose of 5-FU used in this manner we propose to do a trial with this concentration, using each patient as his or her own control, to see if we can influence the recurrence rate. This study was supported by grant 273 from the Ontario Cancer Treatment and Research Foundation. References 1. GREENE LF, HANASH KA, FARROW
GM: Benign papilloma or papillary carcinoma of the bladder. J Urol 110: 205, 1973 2. BARNES RW, DICK AL, HADLEY HL,
et al: Survival following transurethral resection of bladder carcinoma. Cancer Res 37: 2895, 1977 3. KLEIN E, STOLL HL, MILGROM H, et
al: Tumors of the skin. VI. Study on effects of local administration of 5fluorouracil in basal-cell carcinoma. J Invest Dermatol 47: 22, 1966 4. KLEIN E: Tumors of the skin. IX.
Local cystostatic therapy of cutaneous and mucosal premalignant and malignant lesions. NY State J Med 68: 886, 1968 5. KLEIN E, STOLL HL, MILLER E, et al: The effects of 5-fluorouracil (5-FU) ointment in the treatment of neoplastic dermatoses. Dermatologica 140: 21, 1970 6. WEIN AJ, BENSON GS: The treatment of urethral condyloma acuminatum with 5-fluorouracil cream. Urology 9: 413, 1977 7. LEwis RJ, BENDL BJ: Erythroplasia of Queyrat: report of a patient successfully treated with topical 5-fluorouracil. Can Med Assoc J 104: 148, 1971 8. DRETLER SP, KLEIN LA: The eradica-
tion
of
intraurethal
condylomata
acuminata with 5 per cent 5-fluorou-
racil cream. I Urol 113: 195, 1975 9. KESSEL D, HALL TC: Influence of ribose donors on the action of 5fluorouracil. Cancer Res 29: 1749,
1969
Powassan virus meningoencephalitis: a case report MICHAEL S. WILsoN,* MB, CH B, DCH, DRCOG; BRIAN A. WHERRETT,* MD, CM, FRCP[C]; M.S. MAHDY,t MPH, D Sc
Powassan virus is a tick-borne member of the flavivirus genus (group B arboviruses) of the Togaviridae family. It was first isolated by McLean and Donohue in 1958 from a 5-year-old boy from Powassan, Ont.' Forest rodents, such as groundhogs, chipmunks, squirrels, snowshoe hares and porcupines, were found to be the main reservoirs of the virus. Ixodes ticks in Canada and Ixodes and Dermacentor ticks in the United States were found to be the vectors of the 2 virus. In this paper we present a From *the department of pediatrics, Queen's University, Kingston, Ont. and tthe laboratory services branch, Ontario Ministry of Health, Toronto Reprint requests to: Dr. Brian A. Wherrett, Department of pediatrics, Queen's University, Kingston, Ont. K7L 3N6
case of Powassan virus meningoencephalitis and discuss the clinical picture in relation to that of other cases reported in the literature.
Case report Clinical course A 13-month-old girl was admitted to Kingston General Hospital Aug. 22, 1977 with a 4-day history of anorexia, lethargy, fever (temperature 38 to 390C) and a rash. She had been treated with penicillin. Three weeks before the illness started she had been bitten by a tick over the right eyebrow. The family cat was under treatment for tick infestation and had apparently carried the tick to the child. The cat was subsequently found to have Powassan virus antibodies. At the time of examination she had a temperature of 400C, was
320 CMA JOURNAL/AUGUST 4, 1979/VOL. 121
lethargic, and had slight neck stiffness and an erythematous morbilliform rash over the legs and arms. The hemoglobin value was 12.9 g/dl and the Leukocyte count was 17.7 x 10./l (55% were neutrophils, 32% lymphocytes, 11 % monocytes and 2% band forms). The cerebrospinal fluid was clear and colourless; the neutrophil and lymphocyte counts were 17.5 x 10./l and 3.6 x 10./l respectively, and the serum total protein and blood glucose concentrations were 30 and 83 mg/dl respectively. A diagnosis of partially treated pyogenic meningitis was made, and intravenous therapy with ampicillin, 400 mg/kg and chloramphenicol, 100 mg/kg daily was started. No organism was cultured from the cerebrospinal fluid or the urine. Staphylococcus aureus (coagulasenegative) was cultured from the
Some newer approaches to the treatment of the mucosa of patients with superficial bladder cancer: 1. Continuous bladder irrigation with 5-fluorouracil J.G. CONNOLLY,* MD, FRCS (EDIN), FRCS[C]; CHERYL ANDERSON,t M Sc PHM; IvY JOHNSON,. B SC One of the most challenging prob- mours were more aggressive than lems in urology is the management the primary, and in 10% of the of the patient with superficial patients with recurrences lethal inbladder cancer (stage 0, A or Ti). vasive cancer developed. There are The tumours are often readily de- many other studies in the literature stroyed by simple means and, showing recurrences in about two provided they are well differentiated, thirds of patients with superficial there is little likelihood of dissemina- bladder cancer and progressive tion. However, the prognosis in such (more aggressive) disease in a signifa patient is dependent on the malig- icant proportion.2 Any effort dinant potential of the bladder mucosa rected at eliminating or reducing the remaining after the ablation of the rate of recurrence of bladder cancer presenting tumour. must take into consideration the The bladder is a reservoir, and widespread abnormalities that are the carcinogens responsible for the found in the bladder mucosa of painitiation of bladder cancer are tients with superficial bladder canprobably excreted in the urine. cer. The search for a suitable Because the entire bladder mucosa chemotherapeutic agent to bring is exposed to these carcinogens the about this change is ongoing, and mucosal abnormalities can be wide- one of the approaches being studied spread. However, they may not be by us is the topical use of 5-fluorgrossly visible. Many of the "re- ouracil (5-FU) in bladder irrigation. currences" (really new tumours ocKlein and colleagues3-5 first decurring at new sites) originate in monstrated that topical preparations these areas of epithelial dysplasia. of 5-FU could be used successfully The problem of recurrences in to treat certain premalignant and patients with superficial bladder malignant skin conditions. This apcancer is serious. In one series1 the proach represented a significant adrecurrence rate was 73%. Approxi- vance in the treatment of certain mately 20% of the recurrent tu- cutaneous malignant tumours. One of the observations repeatedly made in treating skin tumours with the From the department of surgery, topical application of 5-FU was University of Toronto and Women's that, as early as the fourth day after College Hospital, Toronto treatment was started, skin lesions *Associate professor, department of not previously visible were unsurgery, University of Toronto, and masked. Areas of seemingly normal research associate, Ontario Cancer skin, usually in a satellite arrangeTreatment and Research Foundation tAssistant director of pharmacy, ment around the tumour being Women's College Hospital, Toronto, treated, became inflamed and redand assistant professor, faculty of dened, but with continued applicapharmacy, University of Toronto tion of 5-FU they became grossly Research assistant, department of and histologically normal. One exsurgery, University of Toronto Reprint requests to: Dr. J.G. Connolly, planation offered for this phenomWomen's College Hospital, 76 Grenville enon has been that these areas, while St., Toronto, Ont. M55 1B2 grossly normal, have a higher rate
318 CMA JOURNAL/AUGUST 4, 1979/VOL 121
of cell turnover and therefore incorporate more 5-FU than normal skin. In some ways these lesions resemble the changes found in the mucosa of patients with superficial bladder cancer. It is most likely that recurrences in superficial bladder cancer originate from these areas of epithelial dysplasia. If one is to reduce the rate of recurrence in multiple superficial bladder cancer, then these areas of epithelial disease must be destroyed. Because of the data available from dermatologic practice6-8 it seemed unlikely that a single instillation of 5-FU into the urinary bladder would be effective in this respect. To confirm this impression we conducted the following study.
Methods and observations All of the patients treated in the study had multiple superficial bladder cancer. Some were considered candidates for total cystectomy because of a failure to respond to other forms of treatment, including radiotherapy. The minimal effective dose of 5FU required to block the synthesis of deoxyribonucleic acid is 1.3 .g/ ml.9 At the beginning of this study a solution containing 65 mg of 5FU in 1000 ml of saline was used as the irrigating fluid. The bladder of four patients was irrigated, with continuous outflow, in three consecutive 8-hour sessions. No local or systemic adverse effects were noted. A further four patients were then treated with the same concentration of 5-FU but the bladder was irrigated, with continuous outflow, for 96 hours. Again no adverse effects
were noted. The concentration of 5FU was then increased to 100 mg in 1000 ml of saline and the bladder of four patients was irrigated, with continuous outflow, for 96 hours, again without adverse effects. A control urine specimen was collected from each patient prior to the beginning of the bladder irrigations. During treatment all bladder washings were collected for each 24hour period. The volume was measured and a sample taken for ultraviolet spectrophotometric analysis in the 5-FU range, with the control urine as a blank. No new medications were administered while the irrigations were being done. We recovered from the bladder washings 5% and 10% of the total dose of 5-FU instilled. There was no evidence of bladder disturbance, either during or after irrigation. No effects on the hematopoietic system and no systemic effects were detected.
We have recently increased the concentration of 5-FU to 150 mg in 1000 ml of saline and have completed three 5-day irrigations in 10 patients, with no side effects being noted. Since we have no data on the optimum dose of 5-FU used in this manner we propose to do a trial with this concentration, using each patient as his or her own control, to see if we can influence the recurrence rate. This study was supported by grant 273 from the Ontario Cancer Treatment and Research Foundation. References 1. GREENE LF, HANASH KA, FARROW
GM: Benign papilloma or papillary carcinoma of the bladder. J Urol 110: 205, 1973 2. BARNES RW, DICK AL, HADLEY HL,
et al: Survival following transurethral resection of bladder carcinoma. Cancer Res 37: 2895, 1977 3. KLEIN E, STOLL HL, MILGROM H, et
al: Tumors of the skin. VI. Study on effects of local administration of 5fluorouracil in basal-cell carcinoma. J Invest Dermatol 47: 22, 1966 4. KLEIN E: Tumors of the skin. IX.
Local cystostatic therapy of cutaneous and mucosal premalignant and malignant lesions. NY State J Med 68: 886, 1968 5. KLEIN E, STOLL HL, MILLER E, et al: The effects of 5-fluorouracil (5-FU) ointment in the treatment of neoplastic dermatoses. Dermatologica 140: 21, 1970 6. WEIN AJ, BENSON GS: The treatment of urethral condyloma acuminatum with 5-fluorouracil cream. Urology 9: 413, 1977 7. LEwis RJ, BENDL BJ: Erythroplasia of Queyrat: report of a patient successfully treated with topical 5-fluorouracil. Can Med Assoc J 104: 148, 1971 8. DRETLER SP, KLEIN LA: The eradica-
tion
of
intraurethal
condylomata
acuminata with 5 per cent 5-fluorou-
racil cream. I Urol 113: 195, 1975 9. KESSEL D, HALL TC: Influence of ribose donors on the action of 5fluorouracil. Cancer Res 29: 1749,
1969
Powassan virus meningoencephalitis: a case report MICHAEL S. WILsoN,* MB, CH B, DCH, DRCOG; BRIAN A. WHERRETT,* MD, CM, FRCP[C]; M.S. MAHDY,t MPH, D Sc
Powassan virus is a tick-borne member of the flavivirus genus (group B arboviruses) of the Togaviridae family. It was first isolated by McLean and Donohue in 1958 from a 5-year-old boy from Powassan, Ont.' Forest rodents, such as groundhogs, chipmunks, squirrels, snowshoe hares and porcupines, were found to be the main reservoirs of the virus. Ixodes ticks in Canada and Ixodes and Dermacentor ticks in the United States were found to be the vectors of the 2 virus. In this paper we present a From *the department of pediatrics, Queen's University, Kingston, Ont. and tthe laboratory services branch, Ontario Ministry of Health, Toronto Reprint requests to: Dr. Brian A. Wherrett, Department of pediatrics, Queen's University, Kingston, Ont. K7L 3N6
case of Powassan virus meningoencephalitis and discuss the clinical picture in relation to that of other cases reported in the literature.
Case report Clinical course A 13-month-old girl was admitted to Kingston General Hospital Aug. 22, 1977 with a 4-day history of anorexia, lethargy, fever (temperature 38 to 390C) and a rash. She had been treated with penicillin. Three weeks before the illness started she had been bitten by a tick over the right eyebrow. The family cat was under treatment for tick infestation and had apparently carried the tick to the child. The cat was subsequently found to have Powassan virus antibodies. At the time of examination she had a temperature of 400C, was
320 CMA JOURNAL/AUGUST 4, 1979/VOL. 121
lethargic, and had slight neck stiffness and an erythematous morbilliform rash over the legs and arms. The hemoglobin value was 12.9 g/dl and the Leukocyte count was 17.7 x 10./l (55% were neutrophils, 32% lymphocytes, 11 % monocytes and 2% band forms). The cerebrospinal fluid was clear and colourless; the neutrophil and lymphocyte counts were 17.5 x 10./l and 3.6 x 10./l respectively, and the serum total protein and blood glucose concentrations were 30 and 83 mg/dl respectively. A diagnosis of partially treated pyogenic meningitis was made, and intravenous therapy with ampicillin, 400 mg/kg and chloramphenicol, 100 mg/kg daily was started. No organism was cultured from the cerebrospinal fluid or the urine. Staphylococcus aureus (coagulasenegative) was cultured from the
