Value of the Brompton mixture in palliative care To the editor: As one who has personally benefited from the administration of the Brompton mixture in the treatment of the pain of malignant disease, I read with much interest the article by Mount, Ajemian and Scott on use of the Brompton mixture for patients with cancer (Can Med Assoc J 115: 122, 1976). I have read various journals to the point of understanding and have thought much about this form of therapy and, because of its effectiveness in controlling constant back pain, leg discomfort and abdominal distress that I myself have suffered, I would like to contribute a brief account of the efficacy of the Brompton mixture. Therapy with the Brompton cocktail for pain relief in terminal carcinoma can be initiated in two ways: through sequential increments to the pain relief threshold or sequential decrements from an initial high dose. Sequential increments are preferable since high initial dosage can cause excessive sedation with risk of respiratory depression and accumulation of respiratory secretions leading to pneumonia. Regular 4-hourly dosage is more efficient since 24 hours can be divided into equal seg-
ments and sedative action continues for about 4 hours. Gradual experimentation leads to establishment of a dosage controlling pain without excessive sedation. Respiratory complications are again troublesome with too big a dosage, especially as the cough mechanism is less efficient in a patient with cancer than in a well person. Vomiting can be controlled by (a) separating intake of solids and fluids, (b) eating slowly, and (c) eating lesser amounts more frequently. Discomfort and pain can be controlled efficiently with the Brompton mixture and the patient remains awake to participate in reading, writing, performing simple chores within physical competence and being generally capable of a full and enjoyable life and it is nothing short of a miracle of comfort and ability to enjoy life day by day. Gradually a dosage is found that sedates yet gives relief with full consciousness and, to the degree of energy available, ability to participate in household activity. In this respect home care contributes significantly to success, particularly since efficient home nurse visiting is available. I can vouch for the remarkable effectiveness of the Brompton mixture. I urge that copies of the article by Mount and his associates be made
?. I I I 5 c:. K
cc.
available for nurses, doctors and relatives who undertake this especially valuable procedure for treatment of terminal cancer. W. J. ENDICOTr, MD 901 Helena St. Trail, BC
Training centres in physical medicine To the editor: As a family physician I appreciate that musculoskeletal disorders are the second most frequent reason a patient visits the family doctor. It is my firm belief that these disorders will increase in importance in the years to come. Young people have more leisure time, enabling them to participate in more sports, and people are now living longer - hence, the incidence of musculoskeletal disorders in older people is increasing. I frequently get requests from physicians in my area as to the whereabouts of training centres in physical medicine. There is keen interest in this subject because of the frequency with which we see musculoskeletal problems, but, unfortunately, this aspect of medicine is not emphasized in medical school. There are two places where physicians may acquire more training in diagnosis and treatment by medical
has the answer. Gyole For the prevention and treatment of
postoperative nausea and vomiting, consider Gravol Gravol is available in several parenteral forms: 50 mglml urn In 1 and 2 ml ampoules and 5 ml vials and 10 mglml lIv in 5 ml ampoules. (cilmenhydrinate). ravol (dimenhydrlnate) is also available in the following forms: mg tablets. 75 mg long-acting c sules. 100 mg adult suppo 15 mgIS ml iiquid In 75m1 plastIc contaIners. mg pediatric suppositories.
ravol*
4)R.T.M.
ada's most widely used sntlnsuseent.
..ppos.t.I.s sppoaltrnl.,
caps.Ms
11 1 CMA JOURNAL/FEBRUARY 19, 1977/VOL. 116 345
manipulation and steroid injection. The department of orthopedics, University of Rochester (New York) Medical Centre, regularly holds courses for physicians and physical therapists led by Dr. James Cyriax. a specialist in orthopedic medicine from England. One could also write to Dr. Charles M. Godfrey, president of the North American Academy of Manipulative Medicine, 484 Church St., Toronto, Ont. M4Y 2C7. R.G. HOLMES, MD 283 Aylmer St. Peterborough, Ont.
Pleomorphic carcinoma of the thyroid To the editor: The interesting report entitled "A functioning pleomorphic carcinoma of the thyroid" by Karnauchow and Wall (Can Med Assoc J 115: 41, 1976) documents the coexistence of tumour cells morphologically similar to those of both follicular carcinoma and sarcoma with some carcinoid-like elements. It also showed that at least some of the tumour cells retained the capacity to concentrate iodine, and there was clinical evidence of thyrotoxicosis. While Karnauchow and Wall suggested that the carcinoid elements were similar to what is sometimes observed in medullary carcinomas, they presented no evidence that the tumour cells were in any other way related to parafollicular or c-cells. Nevertheless they concluded that c-cells are a consequence of follicular metaplasia and not a distinctive histologic type. Their conclusion that the literature supports the view that human parafollicular cells are a consequence of metaplasia of follicular cells and are thus abnormal is based on an inadequate review and a misunderstanding of the literature. The references reviewed on normal human thyroid were either ultrastructural studies or were done when specific methods for detecting calcitonin-containing cells were not available. Recent studies of normal adult human thyroid glands using the immunoperoxidase method have shown that calcitonin-containing cells are not uniformly distributed in the thyroid, but when the thyroid is systematically sampled they are consistently found.1'2 Wolfe and associates3 have made similar observations on neonatal human thyroid glands. This nonuniform distribution explains why these cells have seldom been found in ultrastructural studies of the normal human thyroid. Thyroid tumours consisting of spindle-shaped cells are frequently classified as anaplastic carcinomas. These are not typically thought of as medullary carcinomas. However, Hazard, Hawk and
Crile4 observed that medullary carcinomas can have spindle-cell elements. While the presence of amyloid is helpful in the morphologic differentiation of these tumours, the most specific test is to stain for calcitonin by an immunologic method. This can be done on formalin-fixed, paraffin-embedded tissue. It is doubtful that the tumour of Karnauchow and Wall's patient included calcitonin-producing elements, but if it did their suggestion that c-cells might arise directly from follicular cells rather than from cells of neural crest origin should be considered. PAUL J. MCMILLAN, PH D Associate professor Department of anatomy Loma Linda University school of medicine Loma Linda, CA
References 1. WOLFE HJ, VOELKEL EF, TA5HJIAN AH jst: Distribution of calcitonin-containing cells in the normal adult human thyroid gland: a correlation of morphology with peptide content. I Clips Endocrinol Metab 38: 688, 1974 2. MCMILLAN PJ, Hooscnt WM. DaPTos U: Distribution of calcitonin-containing cells in the human thyroid. Am J Anat 140: 73, 1974 3. WOLFE HJ, DELELLIS RA, VOELKEL EF, et al: Distribution of calcitonin-containing cells in the normal neonatal human thyroid gland: a correlation of morphology with peptide content. I Clin Endocrinol Metab 41: 1076, 1975 4. HAZARD JB, HAWK WA, CRILE G .iR: Medullary (solid) carcinoma of the thyroid; a clinicopathologic entity. I Clin Endocrinol Metab 19: 152, 1959
To the editor: Dr. McMillan is right. We did not present evidence relating parafollicular cells to those forming carcinoid-like lesions. We reported a neoplasm in which carcinoid-like lesions do not as a rule arise and thought that it presented a good opportunity to rebut the orthodox view ascribing neural crest origin to the parafollicular cells. The report was not intended to be a discourse on the latter but to indicate that they are not necessary for formation of lesions resembling carcinoid. Thus if enterochromaffin-like cells can be formed from follicular epithelium, why not parafollicular cells? Dr. McMillan is wrong in claiming that our suggestion concerning the probable origin of parafollicular cells was based "on an inadequate review... of the literature". One of us is interested in the amine precursor uptake and decarboxylation (APUD)1 group of cells (embracing parafollicular, enterochromaffin, islands of Langerhans, etc.) and has read, during the past 5 to 6 years, a little further than the papers quoted in our report may indicate. As for "misunderstanding" the literature, we are not sure Dr. McMillan realizes the immensity and complexity of this subject. There is no doubt that parafollicular cells exist in some thyroid glands that is, of course, if we could be sure
346 CMA JOURNAL/FEBRUARY 19, 1977/VOL. 116
where and what is a typical parafollicular cell.2 Wolfe and colleagues,3 using the immunoperoxidase method, have demonstrated them not only in the parafollicular location but also within the thyroid follicles. Did these originate from the Schwann's cells (like the melanocytes of Masson)4 or from the follicular epithelium? Did they move in or out of the follicles? And move they must - otherwise we would not see them in both locations. There is no experimental evidence that the APUD cells of pancreatic islands are not of neural derivation5 and that the neural elements can be formed from epidermis.6 Even the supporters of their origin from the neural crest state that such contention still lacks the necessary proof.7 Indeed, if the orthodox approach is used, many oncologic phenomena encountered in practice could not be explained without undue intellectual acrobatics. The immunoperoxidase reaction is not better than the electron microscope. There is no doubt about the specificity of the f9rmer, but one has to remember that parkfollicular cells may be inactive or produce minute amounts of calcitonin mixed with prostaglandin2 and serotonin8 or even with melatonin9 or adrenocorticotropic hormone.1 We have sent Dr. McMillan paraffin blocks of this tumour and asked him to perform the immunoperoxidase reaction. Who knows? The tissue may contain calcitonin. Its absence, however, would not invalidate the contention that the parafollicular cells arose from follicular epithelium. P.N. KARNAUCHOW, MD C.B. WALL, MD North Bay Civic Hospital North Bay, Ont.
References 1. PEARSE AGE: The cytochemistry of the thyroid C cells and their relationship to calcitonin. Proc R Soc Lond [Biol] 164: 478, 1966 2. WILLIAMS ED, KARIM 5MM, SANDLER M: Prostaglandin secretion by medullary carcinoma of the thyroid. A possible cause of the associated diarrhoea. Lancet 1: 22, 1968 3. WOLFE Hi, MELVIN KEW, CERVI-SKINNER Si, et al: C-cell hyperplasia preceding medullary thyroid carcinoma. N Engi J Med 289: 437, 1973
4. MAsso.i P: My conception of cellular nevi. Cancer 4: 9, 1951 5. PICTET RL, et al: The neural crest and the origin of the insulin-producing and other gastrointestinal hormone-producing cells. Science 191: 191, 1976 6. WHAN HL, LIOHTBODY LE, TcNEN IT, et al: Induction of neural differentiation in cultures of amphibian undetermined presumptive epidermis by cyclic AMP derivatives. Science 188: 366, 1975 7. PEARSE AGE, POLAK iM: Neural crest origin of the endocrine polypeptide (APUD) cells of the gastrointestinal tract and pancreas. Gut 12: 783, 1971 8. KAPLAN EL, SIZEMORE GW, PESKIN GW, et al: Humoral similarities of carcinoid tumours and medullary carcinoma of the thy-
roid. Surgery 74: 21, 1973 9. RAIKHLIN NT, Kvamo. IM: Melatonin and enterochromaffin cells. Ada Histochem [Jena] 55: 19, 1976 10. Sziu 1, CsAPo Z, LAszLo FA, et al: Medullary cancer of the thyroid gland associated with hypercorticism. Cancer 24: 167, 1969
ments and sedative action continues for about 4 hours. Gradual experimentation leads to establishment of a dosage controlling pain without excessive sedation. Respiratory complications are again troublesome with too big a dosage, especially as the cough mechanism is less efficient in a patient with cancer than in a well person. Vomiting can be controlled by (a) separating intake of solids and fluids, (b) eating slowly, and (c) eating lesser amounts more frequently. Discomfort and pain can be controlled efficiently with the Brompton mixture and the patient remains awake to participate in reading, writing, performing simple chores within physical competence and being generally capable of a full and enjoyable life and it is nothing short of a miracle of comfort and ability to enjoy life day by day. Gradually a dosage is found that sedates yet gives relief with full consciousness and, to the degree of energy available, ability to participate in household activity. In this respect home care contributes significantly to success, particularly since efficient home nurse visiting is available. I can vouch for the remarkable effectiveness of the Brompton mixture. I urge that copies of the article by Mount and his associates be made
?. I I I 5 c:. K
cc.
available for nurses, doctors and relatives who undertake this especially valuable procedure for treatment of terminal cancer. W. J. ENDICOTr, MD 901 Helena St. Trail, BC
Training centres in physical medicine To the editor: As a family physician I appreciate that musculoskeletal disorders are the second most frequent reason a patient visits the family doctor. It is my firm belief that these disorders will increase in importance in the years to come. Young people have more leisure time, enabling them to participate in more sports, and people are now living longer - hence, the incidence of musculoskeletal disorders in older people is increasing. I frequently get requests from physicians in my area as to the whereabouts of training centres in physical medicine. There is keen interest in this subject because of the frequency with which we see musculoskeletal problems, but, unfortunately, this aspect of medicine is not emphasized in medical school. There are two places where physicians may acquire more training in diagnosis and treatment by medical
has the answer. Gyole For the prevention and treatment of
postoperative nausea and vomiting, consider Gravol Gravol is available in several parenteral forms: 50 mglml urn In 1 and 2 ml ampoules and 5 ml vials and 10 mglml lIv in 5 ml ampoules. (cilmenhydrinate). ravol (dimenhydrlnate) is also available in the following forms: mg tablets. 75 mg long-acting c sules. 100 mg adult suppo 15 mgIS ml iiquid In 75m1 plastIc contaIners. mg pediatric suppositories.
ravol*
4)R.T.M.
ada's most widely used sntlnsuseent.
..ppos.t.I.s sppoaltrnl.,
caps.Ms
11 1 CMA JOURNAL/FEBRUARY 19, 1977/VOL. 116 345
manipulation and steroid injection. The department of orthopedics, University of Rochester (New York) Medical Centre, regularly holds courses for physicians and physical therapists led by Dr. James Cyriax. a specialist in orthopedic medicine from England. One could also write to Dr. Charles M. Godfrey, president of the North American Academy of Manipulative Medicine, 484 Church St., Toronto, Ont. M4Y 2C7. R.G. HOLMES, MD 283 Aylmer St. Peterborough, Ont.
Pleomorphic carcinoma of the thyroid To the editor: The interesting report entitled "A functioning pleomorphic carcinoma of the thyroid" by Karnauchow and Wall (Can Med Assoc J 115: 41, 1976) documents the coexistence of tumour cells morphologically similar to those of both follicular carcinoma and sarcoma with some carcinoid-like elements. It also showed that at least some of the tumour cells retained the capacity to concentrate iodine, and there was clinical evidence of thyrotoxicosis. While Karnauchow and Wall suggested that the carcinoid elements were similar to what is sometimes observed in medullary carcinomas, they presented no evidence that the tumour cells were in any other way related to parafollicular or c-cells. Nevertheless they concluded that c-cells are a consequence of follicular metaplasia and not a distinctive histologic type. Their conclusion that the literature supports the view that human parafollicular cells are a consequence of metaplasia of follicular cells and are thus abnormal is based on an inadequate review and a misunderstanding of the literature. The references reviewed on normal human thyroid were either ultrastructural studies or were done when specific methods for detecting calcitonin-containing cells were not available. Recent studies of normal adult human thyroid glands using the immunoperoxidase method have shown that calcitonin-containing cells are not uniformly distributed in the thyroid, but when the thyroid is systematically sampled they are consistently found.1'2 Wolfe and associates3 have made similar observations on neonatal human thyroid glands. This nonuniform distribution explains why these cells have seldom been found in ultrastructural studies of the normal human thyroid. Thyroid tumours consisting of spindle-shaped cells are frequently classified as anaplastic carcinomas. These are not typically thought of as medullary carcinomas. However, Hazard, Hawk and
Crile4 observed that medullary carcinomas can have spindle-cell elements. While the presence of amyloid is helpful in the morphologic differentiation of these tumours, the most specific test is to stain for calcitonin by an immunologic method. This can be done on formalin-fixed, paraffin-embedded tissue. It is doubtful that the tumour of Karnauchow and Wall's patient included calcitonin-producing elements, but if it did their suggestion that c-cells might arise directly from follicular cells rather than from cells of neural crest origin should be considered. PAUL J. MCMILLAN, PH D Associate professor Department of anatomy Loma Linda University school of medicine Loma Linda, CA
References 1. WOLFE HJ, VOELKEL EF, TA5HJIAN AH jst: Distribution of calcitonin-containing cells in the normal adult human thyroid gland: a correlation of morphology with peptide content. I Clips Endocrinol Metab 38: 688, 1974 2. MCMILLAN PJ, Hooscnt WM. DaPTos U: Distribution of calcitonin-containing cells in the human thyroid. Am J Anat 140: 73, 1974 3. WOLFE HJ, DELELLIS RA, VOELKEL EF, et al: Distribution of calcitonin-containing cells in the normal neonatal human thyroid gland: a correlation of morphology with peptide content. I Clin Endocrinol Metab 41: 1076, 1975 4. HAZARD JB, HAWK WA, CRILE G .iR: Medullary (solid) carcinoma of the thyroid; a clinicopathologic entity. I Clin Endocrinol Metab 19: 152, 1959
To the editor: Dr. McMillan is right. We did not present evidence relating parafollicular cells to those forming carcinoid-like lesions. We reported a neoplasm in which carcinoid-like lesions do not as a rule arise and thought that it presented a good opportunity to rebut the orthodox view ascribing neural crest origin to the parafollicular cells. The report was not intended to be a discourse on the latter but to indicate that they are not necessary for formation of lesions resembling carcinoid. Thus if enterochromaffin-like cells can be formed from follicular epithelium, why not parafollicular cells? Dr. McMillan is wrong in claiming that our suggestion concerning the probable origin of parafollicular cells was based "on an inadequate review... of the literature". One of us is interested in the amine precursor uptake and decarboxylation (APUD)1 group of cells (embracing parafollicular, enterochromaffin, islands of Langerhans, etc.) and has read, during the past 5 to 6 years, a little further than the papers quoted in our report may indicate. As for "misunderstanding" the literature, we are not sure Dr. McMillan realizes the immensity and complexity of this subject. There is no doubt that parafollicular cells exist in some thyroid glands that is, of course, if we could be sure
346 CMA JOURNAL/FEBRUARY 19, 1977/VOL. 116
where and what is a typical parafollicular cell.2 Wolfe and colleagues,3 using the immunoperoxidase method, have demonstrated them not only in the parafollicular location but also within the thyroid follicles. Did these originate from the Schwann's cells (like the melanocytes of Masson)4 or from the follicular epithelium? Did they move in or out of the follicles? And move they must - otherwise we would not see them in both locations. There is no experimental evidence that the APUD cells of pancreatic islands are not of neural derivation5 and that the neural elements can be formed from epidermis.6 Even the supporters of their origin from the neural crest state that such contention still lacks the necessary proof.7 Indeed, if the orthodox approach is used, many oncologic phenomena encountered in practice could not be explained without undue intellectual acrobatics. The immunoperoxidase reaction is not better than the electron microscope. There is no doubt about the specificity of the f9rmer, but one has to remember that parkfollicular cells may be inactive or produce minute amounts of calcitonin mixed with prostaglandin2 and serotonin8 or even with melatonin9 or adrenocorticotropic hormone.1 We have sent Dr. McMillan paraffin blocks of this tumour and asked him to perform the immunoperoxidase reaction. Who knows? The tissue may contain calcitonin. Its absence, however, would not invalidate the contention that the parafollicular cells arose from follicular epithelium. P.N. KARNAUCHOW, MD C.B. WALL, MD North Bay Civic Hospital North Bay, Ont.
References 1. PEARSE AGE: The cytochemistry of the thyroid C cells and their relationship to calcitonin. Proc R Soc Lond [Biol] 164: 478, 1966 2. WILLIAMS ED, KARIM 5MM, SANDLER M: Prostaglandin secretion by medullary carcinoma of the thyroid. A possible cause of the associated diarrhoea. Lancet 1: 22, 1968 3. WOLFE Hi, MELVIN KEW, CERVI-SKINNER Si, et al: C-cell hyperplasia preceding medullary thyroid carcinoma. N Engi J Med 289: 437, 1973
4. MAsso.i P: My conception of cellular nevi. Cancer 4: 9, 1951 5. PICTET RL, et al: The neural crest and the origin of the insulin-producing and other gastrointestinal hormone-producing cells. Science 191: 191, 1976 6. WHAN HL, LIOHTBODY LE, TcNEN IT, et al: Induction of neural differentiation in cultures of amphibian undetermined presumptive epidermis by cyclic AMP derivatives. Science 188: 366, 1975 7. PEARSE AGE, POLAK iM: Neural crest origin of the endocrine polypeptide (APUD) cells of the gastrointestinal tract and pancreas. Gut 12: 783, 1971 8. KAPLAN EL, SIZEMORE GW, PESKIN GW, et al: Humoral similarities of carcinoid tumours and medullary carcinoma of the thy-
roid. Surgery 74: 21, 1973 9. RAIKHLIN NT, Kvamo. IM: Melatonin and enterochromaffin cells. Ada Histochem [Jena] 55: 19, 1976 10. Sziu 1, CsAPo Z, LAszLo FA, et al: Medullary cancer of the thyroid gland associated with hypercorticism. Cancer 24: 167, 1969
