Liver transplantation Liver transplantation in humans has developed logically from fundamental research.14 The first successful experimental transplantations in dogs were done more than 20 years ago by Goodrich and colleagues,5 and there is now a 13-year experience with liver transplantation in humans. Early work involved the use of auxiliary grafts,2'5 but implantation of a large organ like the liver into the peritoneal cavity led to problems of ventilation and major difficulties in establishing an adequate blood supply for the transplanted organ. Implantation after removal of the recipient's natural liver is complicated by problems in establishing good vascular supply; other complications include peritonitis secondary to anastomotic leaks, septic infarction of the gallbladder and plugging of the common bile duct. The most frequent systemic complications include renal failure, in adequate ventilation, lung infection and cerebrovascular accident. The first liver homograft replacement in a human was performed by Starzl6 in 1963. In a recent paper7 his group reported their combined experience with 93 cases of homograft liver replacement. The patients included those from Starzl's centre in Denver and those from another centre in London, England. The results are impressive: 27 of the 93 recipients survived for at least 1 year after transplantation and many were able to 'return to a full and useful life. One child with Wilson's disease lived for 6 years after transplantation and during this period there was no tendency to accumulate copper. Complicated preservation devices were not used and major incompatibilities, though usually present, did not seem to influence the outcome. There were no unequivocal hyperacute rejections even though three transplantations were performed in the presence of a major blood group incompatibility and three in the presence of cytotoxic antibodies. However, several technical problems arose.
There are many ways to restore continuity of the biliary tract:1'2 none is perfect. At first, bile-duct reconstruction over a T-tube (choledochocholedochostomy) was done for patients without atresia; it was associated with a high incidence of biliary fistula. Cholecystoduodenostomy (after ligation of the common duct) became, for a number of years, the method of choice; in November 1973 Starzl's group further revised the operative technique and began using cholecystojejunostomy with a Roux-en-Y-loop.7 In this way they hoped to remove the homograft from the mainstream of the gastrointestinal tract and allow drainage through a defunctionalized jejunal limb; choledochojejunostomy was used for those with obstruction of the cystic duct. Immunosuppressive therapy in the initial group of 5 patients was with azathioprine and prednisone; in the next 88 patients triple-drug immunosuppression plus equine antilymphocyte globulin was used. Azathioprine was replaced by cyclophosphamide in patients suspected of having azathioprine hepatotoxicity. Of the 93 patients composing the series reported by Starzl 56 were under 18 years of age; these were considered the "young group" and of these patients approximately 75% had biliary atresia. In only 1 of the 36 youngsters with extrahepatic biliary atresia was a malignant hepatic condition found at the time of transplantation. Four children beyond infancy with intrahepatic biliary atresia were included; two had incidental liver carcinomas. Of the other 16 recipients from the young group 9 had a form of chronic aggressive hepatitis, 3 had hepatomas that could not be excised by conventional partial hepatectomy and 2 had Wilson's disease. Nine of the 16 lived for at least 1 year after transplantation. The adult group comprised patients with a primary malignant hepatic tumour, chronic aggressive hepatitis or alcoholic cirrhosis. Of the 37 adults 7 lived for 1 year postoperatively. Two
patients in the group with small intrahepatic-duct-cell carcinomas were alive after 1 year; one was alive at the time of writing with multiple recurrences of the tumour in the transplanted liver. Three patients received livers that were irreparably damaged by ischemia during the operative procedure; the grafts of three more were no longer viable when the common duct was inadvertently tied off and an attempt to correct one of these resulted in bowel fistulas and lethal peritonitis. Cerebrovascular accident accounted for postoperative complications and eventual death in six patients, in each of whom the surgical procedure had been long and difficult. Irreparable hepatic ischemia and lethal cerebrovascular accident could both be related to long, complicated procedures. All the liver grafts examined at autopsy were free of rejection signs and two were completely normal. Results with this form of treatment are improving; acute and chronic rejection are not major problems and immunologic typing is therefore not critical to the procedure. Good results and a useful life can be anticipated in children with metabolic problems such as Wilson's disease, while liver cancer patients at the moment can expect only 1 to 2 years of useful life before the transplant itself becomes infiltrated with tumour. In Canada at least two patients operated on at NotreDame Hospital in Montreal have survived over 1 year after liver transplantation (L.D. MacLean: personal communication, 1976). The report by Abouna and colleagues in this issue of the Journal (page 615) is of great interest; this Canadian patient survived for more than 9 months after liver transplantation. This is an especially encouraging result in that the patient had widespread liver cancer at the time of operation and had had numerous previous abdominal operations, including a colectorny for ulcerative colitis. EARL M. COOPERMAN
CMA JOURNAL/OCTOBER 9, 1976/VOL. 115 595
References 1. DUEST AL: The present status of liver transplantation. Isr J Med Sci 9: 98, 1973 2. BEAUDoIN JG, MACLEAN LD: La transplantation h6terotopique du foie. Un Med Can 103: 2110, 1974 3. CanE IC, HAYASHI T, BERNARDEZ DB: Liver transplantation following extracorporeal hypothermia. Can I Surg 11: 452, 1968 4. LANGER B, KAMBOURI5 AA, MACKAY iD, et
al: Homotranspiantation of the canine liver. Can J Suarg 15: 79, 1972 5. GOODRICH EO, WELCH HF, NELSON JA, Ct al: Homotranspiantation of the canine liver. Surgery 39: 244, 1956 6. STARZL TE, MAitcHioRo TL, VON KAULA KN. et al: Homotranspiantation of the liver in humans. Siug Gynecol Obstet 117: 659, 1963 7. STARZL TE, PORTER KA, PUTNAM CW, Ct al:
Orthotopic liver transplantation in 93 patients. Surg G'necol Obstet 142: 487, 1976
Endometrial cancer: the present status of diagnosis The incidence of invasive cancer of the cervix has decreased over the past 30 years. The ability to diagnose and treat preinvasive cervical disease and to screen large segments of the population has made this possible. Why have we not been able to reduce the rate of endometrial cancer similarly? The frequency of endometrial cancer appears to be increasing, though analysis of statistics from national surveys in the United States1 and data from Statistics Canada indicates that the absolute rate of endometrial carcinoma has not increased. For cervical cancer, however, there has been a substantial increase, and in women over 50 years of age the endometrium is the most common site for invasive cancer of the female genital organs. For this reason there is renewed interest in endometrial cancer. Endometrial cancer is considered a disease of perimenopausal and postmenopausal women - 75% of cases occur between 50 and 70 years and 16% after age 70. However, in recent studies Gusberg2 and Kistner and associates3 reported that 4% of cases occurved before age 40, 20% between 40 and 50 and 75% after age 50. Improvement in survival rates depends on early diagnosis and treatment. The efficiency of the Papanicolaou smear (85 to 95% accuracy) in determining the presence of carcinoma of the cervix and its precursors has enabled the physician to make an early diagnosis of this disease. By contrast the cervicovaginal smear has an accuracy of only 50 to 70% in detecting endometrial cancer and a cytologic method for the diagnosis of endometrial cancer comparable to the Papanicolaou smear has not yet been developed. What we require is a simple diagnostic tool for use in patients who are at risk for endometrial cancer but who are asymptomatic. Such patients include women between 40 and 70 years of age who have one or more of the following: obesity, diabetes, hypertension, anovulatory menstrual
cycles, nulliparity, and a family history of cancer, especially genital cancer. Debate continues on the role of estrogens in the development of endometrial cancer. It does appear that prolonged stimulation of the endometrium by endogenous or exogenous estrogen results in the development of endometrial hyperplasia. This is thought to be reversible. Atypical adenomatous hyperplasia is considered to be a precursor of endometrial cancer; the progression rate is reportedly between 5 and 12% ,. but the precise factors causing conversion of premalignant to malignant epithehum are unknown. Investigations indicate that cells and glands that subsequently become malignant demonstrate abnormal DNA distribution and aneuploidy.5 Endometrial cancer and its precursors exfoliate cells into the uterine cavity and, for the past 33 years, investigators have been trying to devise simple methods of obtaining cytologic specimens. The procedure must be adaptable to the office or to clinic practice as a screening procedure to identify the individual with asymptomatic endometrial cancer. It must be inexpensive and reliable. It must be simple and not time-consuming. Most important, it must be safe and cause minimal pain and morbidity to the patient. Various techniques for obtaining intrauterine samples of endometrial cells are available and are more accurate than the cervicovaginal smear. For a number of reasons none has been widely accepted by clinicians: sometimes it is difficult to insert a sampler into the uterus of a patient in the high-risk postmenopausal group - in 2 to 10% of such patients cervical stenosis is so great that an anesthetic is necessary; obtaining intrauterine samples involves increased costs and time. If we are to improve the survival rates for this common gynecologic malignant lesion much of our effort must be directed towards establishing a method of obtaining cell samples from within the
596 CMA JOURNAL/OCTOBER 9, 1976/VOL. 115
Locasalen (flumethasone pivalate/salicylic acid)
topical corticosteroid / squamolytic Indications LOCASALEN is intended for the treatment of subacute to hyperchronic inflammatory and/or dysplastic skin diseases, as well as hyperkeratotic conditions in particular. The indications for LOCASALEN thus include chronic constitutional eczema or neurodermatitis; chronic exogenous eczema irrespective of origin, (e.g.: skin disorders due to attrition, occupational eczema); chronic eczema of microbial or mycotic origin; tylotic eczema; hyperkeratosis as encountered in ichthyosts or chronic dyshidrosis; pustulosis of the palms and soles; lichen planus; chronic cutaneous lupus erythematosus; psoriasis.
Contraindications Tuberculosis of the skin, syphilitic skin affections, viral and acute fungal infections of the skin. Systemic tungal infections. This preparation is not for ophthalmic use. LOCASALEN is contraindicated in individuals with a history of hypersensitivity to its components.
Adverse Reactions The local tolerability of LOCASALEN proved to be very good. Cases in which local irritation made it advisable to discontinue the medication accounted for less than 2% of the total number of patients treated. Adverse reactions consist mainly of local reddening of the skin, desquamation, pruntis and smarting. LOCASALEN contains no preservatives, odour correcting agents, emulsifiers, stabilizers or antibiotic supplements which have been recognized as potential sensitizers. Hypersensitivity to salicylic acid can occur; however, the incidence in the population as a whole is approximately 0.2%. Systemic side effects attributable to the transcutaneous absorption of salicylic acid or flumethasone pivalate have not been reported. Absorption of salicylic acid does occur; however, investigations have shown that irrespective of the smount of LOCASALEN employed, and even applied under occlusive dressings, plasma concentrations of salicylic acid did not exceed ordinary therapeutic levets as a result of transcutaneous absorption. Investigations have shown that under extreme conditions-where 40 to 60 grams of ointment were applied daly to 80-90% of the body surface under occlusive dressings-plasma cortisol and urinsry steroids have been observed to decrease below normal levels. This decrease proved transitory and was not accompanied by any clinical symptoms.
Precautions If sensitivity or idiosyncratic reactions occur, LOCA.LEN should be discontinued and appropriate measures taken. The safety of the use of topical corticosteroids in pregnant temales has not been established. Therefore they should not be used extensively on pregnant patients in large amounts or for prolonged periods of time. Patients should be advised to inform subsequent physicians of the prior use of corticosterolds. In the presence of an infection, the use of an appropriate antifungal or antibacterial agent should be instituted, If a favourable response does not occur promptly, LOCASALEN should be discontinued untf the infection has been adequately controlled.
Warnings
LOCASALEN is not indicated in acute weeping or subacute exudative stages. As transcutaneous absorption of the safcylic acid component may give rise to systemic effects, LOCASALEN should not be applied to extensive areas of the skin in small children or pregnant woman. Likewise corticosteroids are known to be absorbed percutaneousiy, therefore in patients requiring applications of LOCASALEN to extensive areas or for prolonged periods, adrensl function should be carefully monitored. All contact of the drug with the eyes, mouth, mucous membranes should be avoided.
Dosage and Administration
As a rule LOCASALEN should be applied once or twice dafy when dressings are not used and once daily when employed under occlusive dressing. It is not usually necessary to cover the treated area. The thickness of the layer should vary depending on the nature and severity of the skin disorder, since in this way, it is possible to regulate moisture retention. In cases in which transitory exudative must be anticipated, LOCASALEN should be applied in a very thin layer, thereby allowing larger quantities of molsture lo be released through the film of ointment. LOCASALEN can also exert an occlusive effect but only it applied in a thick layer. It penetrates well into the skin and when rubbed in thoroughly, leaves on the skin a transparent, olly film that can be removed with soap and water or a skin cleanser. Excess film can be removed reletively wet with paper tissue, scarcely leaving any perceptible sheen.
Supplied
Flumethasone Pivalate 0.02% and salicylic acid 3.0% ointment in tubasof 15gm and 50gm.
Reference: 1. Jenny, D., Schuppli, R.: Progress in the Treatment of Eczema, Praxix 59: 589, 1970.
CIBA DORVAL. QUEBEC H95 1 Bi
C-6035
There are many ways to restore continuity of the biliary tract:1'2 none is perfect. At first, bile-duct reconstruction over a T-tube (choledochocholedochostomy) was done for patients without atresia; it was associated with a high incidence of biliary fistula. Cholecystoduodenostomy (after ligation of the common duct) became, for a number of years, the method of choice; in November 1973 Starzl's group further revised the operative technique and began using cholecystojejunostomy with a Roux-en-Y-loop.7 In this way they hoped to remove the homograft from the mainstream of the gastrointestinal tract and allow drainage through a defunctionalized jejunal limb; choledochojejunostomy was used for those with obstruction of the cystic duct. Immunosuppressive therapy in the initial group of 5 patients was with azathioprine and prednisone; in the next 88 patients triple-drug immunosuppression plus equine antilymphocyte globulin was used. Azathioprine was replaced by cyclophosphamide in patients suspected of having azathioprine hepatotoxicity. Of the 93 patients composing the series reported by Starzl 56 were under 18 years of age; these were considered the "young group" and of these patients approximately 75% had biliary atresia. In only 1 of the 36 youngsters with extrahepatic biliary atresia was a malignant hepatic condition found at the time of transplantation. Four children beyond infancy with intrahepatic biliary atresia were included; two had incidental liver carcinomas. Of the other 16 recipients from the young group 9 had a form of chronic aggressive hepatitis, 3 had hepatomas that could not be excised by conventional partial hepatectomy and 2 had Wilson's disease. Nine of the 16 lived for at least 1 year after transplantation. The adult group comprised patients with a primary malignant hepatic tumour, chronic aggressive hepatitis or alcoholic cirrhosis. Of the 37 adults 7 lived for 1 year postoperatively. Two
patients in the group with small intrahepatic-duct-cell carcinomas were alive after 1 year; one was alive at the time of writing with multiple recurrences of the tumour in the transplanted liver. Three patients received livers that were irreparably damaged by ischemia during the operative procedure; the grafts of three more were no longer viable when the common duct was inadvertently tied off and an attempt to correct one of these resulted in bowel fistulas and lethal peritonitis. Cerebrovascular accident accounted for postoperative complications and eventual death in six patients, in each of whom the surgical procedure had been long and difficult. Irreparable hepatic ischemia and lethal cerebrovascular accident could both be related to long, complicated procedures. All the liver grafts examined at autopsy were free of rejection signs and two were completely normal. Results with this form of treatment are improving; acute and chronic rejection are not major problems and immunologic typing is therefore not critical to the procedure. Good results and a useful life can be anticipated in children with metabolic problems such as Wilson's disease, while liver cancer patients at the moment can expect only 1 to 2 years of useful life before the transplant itself becomes infiltrated with tumour. In Canada at least two patients operated on at NotreDame Hospital in Montreal have survived over 1 year after liver transplantation (L.D. MacLean: personal communication, 1976). The report by Abouna and colleagues in this issue of the Journal (page 615) is of great interest; this Canadian patient survived for more than 9 months after liver transplantation. This is an especially encouraging result in that the patient had widespread liver cancer at the time of operation and had had numerous previous abdominal operations, including a colectorny for ulcerative colitis. EARL M. COOPERMAN
CMA JOURNAL/OCTOBER 9, 1976/VOL. 115 595
References 1. DUEST AL: The present status of liver transplantation. Isr J Med Sci 9: 98, 1973 2. BEAUDoIN JG, MACLEAN LD: La transplantation h6terotopique du foie. Un Med Can 103: 2110, 1974 3. CanE IC, HAYASHI T, BERNARDEZ DB: Liver transplantation following extracorporeal hypothermia. Can I Surg 11: 452, 1968 4. LANGER B, KAMBOURI5 AA, MACKAY iD, et
al: Homotranspiantation of the canine liver. Can J Suarg 15: 79, 1972 5. GOODRICH EO, WELCH HF, NELSON JA, Ct al: Homotranspiantation of the canine liver. Surgery 39: 244, 1956 6. STARZL TE, MAitcHioRo TL, VON KAULA KN. et al: Homotranspiantation of the liver in humans. Siug Gynecol Obstet 117: 659, 1963 7. STARZL TE, PORTER KA, PUTNAM CW, Ct al:
Orthotopic liver transplantation in 93 patients. Surg G'necol Obstet 142: 487, 1976
Endometrial cancer: the present status of diagnosis The incidence of invasive cancer of the cervix has decreased over the past 30 years. The ability to diagnose and treat preinvasive cervical disease and to screen large segments of the population has made this possible. Why have we not been able to reduce the rate of endometrial cancer similarly? The frequency of endometrial cancer appears to be increasing, though analysis of statistics from national surveys in the United States1 and data from Statistics Canada indicates that the absolute rate of endometrial carcinoma has not increased. For cervical cancer, however, there has been a substantial increase, and in women over 50 years of age the endometrium is the most common site for invasive cancer of the female genital organs. For this reason there is renewed interest in endometrial cancer. Endometrial cancer is considered a disease of perimenopausal and postmenopausal women - 75% of cases occur between 50 and 70 years and 16% after age 70. However, in recent studies Gusberg2 and Kistner and associates3 reported that 4% of cases occurved before age 40, 20% between 40 and 50 and 75% after age 50. Improvement in survival rates depends on early diagnosis and treatment. The efficiency of the Papanicolaou smear (85 to 95% accuracy) in determining the presence of carcinoma of the cervix and its precursors has enabled the physician to make an early diagnosis of this disease. By contrast the cervicovaginal smear has an accuracy of only 50 to 70% in detecting endometrial cancer and a cytologic method for the diagnosis of endometrial cancer comparable to the Papanicolaou smear has not yet been developed. What we require is a simple diagnostic tool for use in patients who are at risk for endometrial cancer but who are asymptomatic. Such patients include women between 40 and 70 years of age who have one or more of the following: obesity, diabetes, hypertension, anovulatory menstrual
cycles, nulliparity, and a family history of cancer, especially genital cancer. Debate continues on the role of estrogens in the development of endometrial cancer. It does appear that prolonged stimulation of the endometrium by endogenous or exogenous estrogen results in the development of endometrial hyperplasia. This is thought to be reversible. Atypical adenomatous hyperplasia is considered to be a precursor of endometrial cancer; the progression rate is reportedly between 5 and 12% ,. but the precise factors causing conversion of premalignant to malignant epithehum are unknown. Investigations indicate that cells and glands that subsequently become malignant demonstrate abnormal DNA distribution and aneuploidy.5 Endometrial cancer and its precursors exfoliate cells into the uterine cavity and, for the past 33 years, investigators have been trying to devise simple methods of obtaining cytologic specimens. The procedure must be adaptable to the office or to clinic practice as a screening procedure to identify the individual with asymptomatic endometrial cancer. It must be inexpensive and reliable. It must be simple and not time-consuming. Most important, it must be safe and cause minimal pain and morbidity to the patient. Various techniques for obtaining intrauterine samples of endometrial cells are available and are more accurate than the cervicovaginal smear. For a number of reasons none has been widely accepted by clinicians: sometimes it is difficult to insert a sampler into the uterus of a patient in the high-risk postmenopausal group - in 2 to 10% of such patients cervical stenosis is so great that an anesthetic is necessary; obtaining intrauterine samples involves increased costs and time. If we are to improve the survival rates for this common gynecologic malignant lesion much of our effort must be directed towards establishing a method of obtaining cell samples from within the
596 CMA JOURNAL/OCTOBER 9, 1976/VOL. 115
Locasalen (flumethasone pivalate/salicylic acid)
topical corticosteroid / squamolytic Indications LOCASALEN is intended for the treatment of subacute to hyperchronic inflammatory and/or dysplastic skin diseases, as well as hyperkeratotic conditions in particular. The indications for LOCASALEN thus include chronic constitutional eczema or neurodermatitis; chronic exogenous eczema irrespective of origin, (e.g.: skin disorders due to attrition, occupational eczema); chronic eczema of microbial or mycotic origin; tylotic eczema; hyperkeratosis as encountered in ichthyosts or chronic dyshidrosis; pustulosis of the palms and soles; lichen planus; chronic cutaneous lupus erythematosus; psoriasis.
Contraindications Tuberculosis of the skin, syphilitic skin affections, viral and acute fungal infections of the skin. Systemic tungal infections. This preparation is not for ophthalmic use. LOCASALEN is contraindicated in individuals with a history of hypersensitivity to its components.
Adverse Reactions The local tolerability of LOCASALEN proved to be very good. Cases in which local irritation made it advisable to discontinue the medication accounted for less than 2% of the total number of patients treated. Adverse reactions consist mainly of local reddening of the skin, desquamation, pruntis and smarting. LOCASALEN contains no preservatives, odour correcting agents, emulsifiers, stabilizers or antibiotic supplements which have been recognized as potential sensitizers. Hypersensitivity to salicylic acid can occur; however, the incidence in the population as a whole is approximately 0.2%. Systemic side effects attributable to the transcutaneous absorption of salicylic acid or flumethasone pivalate have not been reported. Absorption of salicylic acid does occur; however, investigations have shown that irrespective of the smount of LOCASALEN employed, and even applied under occlusive dressings, plasma concentrations of salicylic acid did not exceed ordinary therapeutic levets as a result of transcutaneous absorption. Investigations have shown that under extreme conditions-where 40 to 60 grams of ointment were applied daly to 80-90% of the body surface under occlusive dressings-plasma cortisol and urinsry steroids have been observed to decrease below normal levels. This decrease proved transitory and was not accompanied by any clinical symptoms.
Precautions If sensitivity or idiosyncratic reactions occur, LOCA.LEN should be discontinued and appropriate measures taken. The safety of the use of topical corticosteroids in pregnant temales has not been established. Therefore they should not be used extensively on pregnant patients in large amounts or for prolonged periods of time. Patients should be advised to inform subsequent physicians of the prior use of corticosterolds. In the presence of an infection, the use of an appropriate antifungal or antibacterial agent should be instituted, If a favourable response does not occur promptly, LOCASALEN should be discontinued untf the infection has been adequately controlled.
Warnings
LOCASALEN is not indicated in acute weeping or subacute exudative stages. As transcutaneous absorption of the safcylic acid component may give rise to systemic effects, LOCASALEN should not be applied to extensive areas of the skin in small children or pregnant woman. Likewise corticosteroids are known to be absorbed percutaneousiy, therefore in patients requiring applications of LOCASALEN to extensive areas or for prolonged periods, adrensl function should be carefully monitored. All contact of the drug with the eyes, mouth, mucous membranes should be avoided.
Dosage and Administration
As a rule LOCASALEN should be applied once or twice dafy when dressings are not used and once daily when employed under occlusive dressing. It is not usually necessary to cover the treated area. The thickness of the layer should vary depending on the nature and severity of the skin disorder, since in this way, it is possible to regulate moisture retention. In cases in which transitory exudative must be anticipated, LOCASALEN should be applied in a very thin layer, thereby allowing larger quantities of molsture lo be released through the film of ointment. LOCASALEN can also exert an occlusive effect but only it applied in a thick layer. It penetrates well into the skin and when rubbed in thoroughly, leaves on the skin a transparent, olly film that can be removed with soap and water or a skin cleanser. Excess film can be removed reletively wet with paper tissue, scarcely leaving any perceptible sheen.
Supplied
Flumethasone Pivalate 0.02% and salicylic acid 3.0% ointment in tubasof 15gm and 50gm.
Reference: 1. Jenny, D., Schuppli, R.: Progress in the Treatment of Eczema, Praxix 59: 589, 1970.
CIBA DORVAL. QUEBEC H95 1 Bi
C-6035
