- Email: [email protected]
Subcutaneous clodronate
THE LANCET 25
Cases of malaria in Kilifi, Kenya coast Mefloquine sales Malaria rate in UK residents
160
Mefloquine phx recommended
20
Cases of malaria in Kilifi
140 120
15 100 80 10 60 40
5
20 0 1989–
1990–
1991–
1992–
1993–
1994–
1995–
Malaria rate per 10 000 UK visits to Kenya
180
0 1996–
Quarter years Figure: Cases of malaria since 1989 in Kilifi, Kenya phx =prophylax is. Mefloquine sales are adjusted by a constant. Published with permission of KEMRI.
or enhance anti-mosquito measures. Further evidence on the change in incidence was seen in data on reported chemoprophylaxis use in MRL surveillance reports. The number of malaria cases who were not taking any prophylaxis remained static over the 5-year period suggesting continued transmission in non-protected travellers. On the other hand, numbers of reported cases using chloroquine and proguanil fell substantially from 1993 onwards with only a small rise in cases in travellers using mefloquine prophylaxis. The increased use of mefloquine was confirmed by the sales trend of the manufacturers (Roche UK Ltd, personal communication). We suggest that the three-fold reduction in imported malaria in the face of apparently stable malaria transmission on the Kenya coast, and no changes in tourist accommodation, may be the result of the widespread use of mefloquine by travellers. Mefloquine continues to be effective in preventing malaria in British tourists to Kenya. Part of this work was supported by KEMRI.
*R H Behrens, D J Bradley, R W Snow, K Marsh *Travel Clinic, Hospital for Tropical Diseases, London NW1 0PE, UK; Malaria Reference Laboratory, London School of Hygiene and Tropical Medicine; and KEMRI Clinical Research Centre Kilifi Unit, Kilifi, Kenya
1 2
3 4
Bradley DJ. Prophylaxis against malaria for travellers from the United Kingdom. BMJ 1993; 306: 1247–52. Pryce DI, Behrens RH, Bradley DJ. The changing pattern of imported malaria in British visitors to Kenya 1987–1990. J R Soc Med 1993; 86: 152–53. Kenya 95–96 factbook. Nairobi: Newspread International, 1995: 89. Snow RW, Schellenberg JR, Peshu N, et al. Periodicity and space-time clustering of severe childhood malaria on the coast of Kenya. Trans R Soc Trop Med Hyg 1993; 87: 386–90.
hyaluronidase 150 units subcutaneously, a subcutaneous infusion of pamidronate 15 mg in 1 L normal saline at 40 mL/h was attempted. Within 2 h he developed pain, erythema, and pruritus at the infusion site requiring discontinuation of pamidronate. A 57-year-old man with large-cell anaplastic lung cancer and hypercalcaemia had a subcutaneous infusion of clodronate 1500 mg in 1 L normal saline given over 24 h, preceded by an injection of 300 units of subcutaneous hyaluronidase. The infusion was tolerated well with no local irritation. After serum calcium returned to normal, he was discharged home on day 6. A 48-year-old man with transitional-cell cancer and hypercalcaemia received 300 units of subcutaneous hyaluronidase and clodronate 1500 mg in 1 L of normal saline infused subcutaneously over 12 h. This was tolerated well. He became normocalcaemic and was discharged home on day 7. Clodronate was well tolerated and efficacious in these patients when administered subcutaneously. The local irritation experienced by the first patient is consistent for aminobisphosphonates such as pamidronate, alendronate, and ibandronate; the amino group conveys greater potency, but results in more local irritation and a higher incidence of side effects.4 The low oral bioavailability (<5%) of bisphosphonates limits their effectiveness given by mouth. Intramuscular injections are painful. The subcutaneous route may offer advantages in the care of patients with advanced cancer, allowing easy administration in the home or hospital. It may also have a part to play in the treatment of Paget’s disease and osteoporosis.5 *Paul Walker, Sharon Watanabe, Peter Lawlor, Eduardo Bruera Palliative Care Program, Grey Nuns Community Health Centre, Division Palliative Care Medicine, University of Alberta, Edmonton, T6L5X 8 AB, USA
Subcutaneous clodronate SIR—Bisphosphonates are the drugs of choice for treatment of malignant hypercalcaemia.1 Improvements in bone pain,2 and a decrease in the number of events associated with bone metastasis (including pathological fractures and the need for radiation therapy)3 have been observed. Intravenous administration is sometimes inconvenient. A 70-year-old man with squamous-cell cancer of the larynx and hypercalcaemia was fed via a gastrostomy. After
Vol 348 • August 3, 1996
1
2
3
Kovacs CS, MacDonald SM, Chik CL, Bruera E. Hypercalcemia of malignancy in the palliative care patient: a therapeutic strategy. J Pain Symptom Manage 1995; 10: 224–33. Ernst DS, MacDonald RN, Paterson AHG, Jensen J, Brasher P, Bruera E. A double-blind crossover trial of intravenous clodronate in metastatic bone pain. J Pain Symptom Manage 1992: 7: 4–11. Paterson AHG, Powles TJ, Kanis JA, McCloskey E, Hanson J, Ashley S. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993; 11: 59–65.
345
THE LANCET 4
5
Pecherstorfer M, Herrmann Z, Body JJ, et al. Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy. J Clin Oncol 1996; 14: 268–76. Plosker GL, Goa KL. Clodronate: a review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs 1994; 47: 945–82.
Graft-versus-myeloma effect SIR—As described by Verdonck and colleagues1 and also reported by Tricot and colleagues,2 there is an apparent antitumour effect of donor lymphocyte infusions when multiple myeloma recurs after allogeneic bone marrow transplantation. We report two additional cases. A 51-year-old woman was diagnosed as having multiple myeloma, IgG-κ stage IIIA, in June, 1987. She underwent bone marrow transplantation in November, 1987, with a graft from her HLA-identical sister, after cyclophosphamide and whole body irradiation. In the following years, plasma M protein gradually decreased from 34 g/L to 14 g/L by November, 1990, and her marrow became normal. In December, 1992, she had a pathological fracture and the M protein increased to 21 g/L. M protein was detected in urine, and pathological plasma cells (4%) reappeared in marrow. She received donor leucocyte infusions in March, 1993, achieving a partial remission, with fall in M protein to 14 g/L and normal marrow. However, M protein in urine did not decrease and, in October, 1994, M protein in plasma rose. In January, 1995, VAD therapy (vincristine, doxorubicin, and dexamethasone) was begun because of a rise in M protein to 28 g/L. The patient responded to chemotherapy and, after three courses, M protein was 15 g/L. In March, 1995, she received, for a second time, donor leucocyte infusions (total 3·1108/kg lymphocytes), This time, intravenous interleukin-2 (9106 IU continuously for 24 h followed by 0·9106 IU twice daily for 1 mo) was started after infusion of the first leucopheresis product. However, despite this treatment, M protein concentration slowly increased to 20 g/L in December, 1995. Our second patient, a 38-year-old man, presented in March, 1988, with an eyelid plasmocytoma, which was successfully removed. In April, 1989, the plasmocytoma relapsed in the right parotid gland and, after surgery with postoperative irradiation, he was regarded as in remission. In July, 1989, he had a spontaneous costal fracture and radiography showed multiple osteolytic lesions. Aspirate from bone marrow contained 50% plasma cells, and there was a trace of Bence-Jones proteinuria of κ-type. There was no M protein in plasma. After intermittent melphalan/prednisone courses for 1 year, on February 12, 1991, he underwent bone marrow transplantation, with his HLA-identical brother as donor, after conditioning with busulphan and cyclophosphamide. Repeated tests for bone marrow morphology and Bence-Jones proteinuria were normal, and skeletal surveys showed no osteolytic lesions until April, 1993, when he had a traumatic fracture that did not heal. To correct pseudoarthrosis, he underwent surgery in September, 1994, when a marrow transplant was taken from the iliac crest. Morphology showed a relapse, with infiltrating plasma cells and κ positivity in the iliac crest, and also in a specimen from a new lesion in the right acromion. After local irradiation he was given donor leucocyte infusions in June, 1995 (total 4·6108/kg lymphocytes), together with interleukin-2. However, new osteolytic lesions were detected in August, 1995, and treated with local irradiation. In September, 1995, the patient developed graft-versus-host disease (GVHD) of the liver and gut necessitating intervention with prednisone and cyclosporin. GVHD
346
responded to treatment and thereafter he has been in good condition, working full-time. Our case reports support the findings of a graft-versusmyeloma effect of lymphocyte infusions which appear to be a potent treatment for patients with recurrent multiple myeloma after marrow transplantation. These patients otherwise have a poor outlook. However, this procedure is not without risks, and may be complicated by GVHD and pancytopenia.3 *Johan Aschan, Berit Lönnqvist, Olle Ringdén, Gunilla Kumlien, Gösta Gahrton Departments of *Haematology, Clinical Immunology, Transplantation Surgery and Blood Bank, Karolinska Institute, Huddinge Hospital, S-141 86 Huddinge, Sweden
1 2
3
Verdonck L, Lokhorst H, Dekker A, Nieuwenhuis K, Petersen E. Graft-versus-myeloma effect in two cases. Lancet 1996; 347: 800–01. Tricot G, Vesole D, Jagannath S, Hilton J, Munshi N, Barlogie B. Graft-versus-myeloma effect: proof of principle. Blood 1996; 87: 1196–98. Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995; 86: 2041–50.
Torticollis in ancient Macedonians SIR—Acheson and Nitsas (April 20, p 1126)1 report that torticollis was common in statuettes of Macedonians. We would point out that our theory about ocular torticollis of Alexander the Great2 was based not only on the recent archaeological finds at Vergina, but also on a series of earlier discovered statues of the Emperor and the information provided by historical texts about the curious posture of his neck and head. It is well known that many statues of this era show inclination of the head, as the artistic style of this epoque demanded—among these the statues to which Acheson and Nitsas refer. But with respect to the ivory head of Alexander, Andronicus3 himself identifies this without any reservations, basing his opinion not only on the characteristics of the face, known from other representations of the Emperor, but also on historical sources (eg, the descriptions of three texts of Plutarch) that confirm the inclination of the neck of Alexander and the turning of his head. No one has doubted this identification. Hartle4 regards the ivory statuettes of Alexander and of his father, Philip, as realistic representations of them both. *J Lascaratos, A Damanakis Athens University, Hippocratous 164b, Athens 11471, Greece
1 2
3 4
Acheson JF, Nitsas N. Ocular torticollis in the Macedonians. Lancet 1996; 347: 1126. Lascaratos J, Damanakis A. Ocular torticollis: a new explanation for the abnormal head-posture of Alexander the Great. Lancet 1996; 347: 521–23. Andronicus M. Vergina: the royal tombs. Athens: Ekdotike Athenon, 1993: 124–29. Hartle RW. The search for Alexander’s portrait. In: Lindsay Adams W, Borza EN, eds. Philip II, Alexander the Great and the Macedonian Heritage. New York: University Press of America, 1982: 153–76.
DEPARTMENT OF ERROR 12 years on: co-proxamol revisited—In this letter by Haigh (June 29, p 1840) in the third from last line, “instead of” should have read “or”. Changing the natural history of HIV disease—In figure 3 of this article by Feinberg (July 27, p 239) the t¹ left-side top should have read ~1·6 days and the t¹ left-side bottom should have read ~6 hours. FDA urges approval of oral HIB vaccine—In this news item (July 30, p 185), 7·5 g PedVaxHIB Haemophilus influenzae type B vaccine was incorrectly described as an oral preparation. It is a pre-mixed liquid injectable formulation.
Vol 348 • August 3, 1996
Cases of malaria in Kilifi, Kenya coast Mefloquine sales Malaria rate in UK residents
160
Mefloquine phx recommended
20
Cases of malaria in Kilifi
140 120
15 100 80 10 60 40
5
20 0 1989–
1990–
1991–
1992–
1993–
1994–
1995–
Malaria rate per 10 000 UK visits to Kenya
180
0 1996–
Quarter years Figure: Cases of malaria since 1989 in Kilifi, Kenya phx =prophylax is. Mefloquine sales are adjusted by a constant. Published with permission of KEMRI.
or enhance anti-mosquito measures. Further evidence on the change in incidence was seen in data on reported chemoprophylaxis use in MRL surveillance reports. The number of malaria cases who were not taking any prophylaxis remained static over the 5-year period suggesting continued transmission in non-protected travellers. On the other hand, numbers of reported cases using chloroquine and proguanil fell substantially from 1993 onwards with only a small rise in cases in travellers using mefloquine prophylaxis. The increased use of mefloquine was confirmed by the sales trend of the manufacturers (Roche UK Ltd, personal communication). We suggest that the three-fold reduction in imported malaria in the face of apparently stable malaria transmission on the Kenya coast, and no changes in tourist accommodation, may be the result of the widespread use of mefloquine by travellers. Mefloquine continues to be effective in preventing malaria in British tourists to Kenya. Part of this work was supported by KEMRI.
*R H Behrens, D J Bradley, R W Snow, K Marsh *Travel Clinic, Hospital for Tropical Diseases, London NW1 0PE, UK; Malaria Reference Laboratory, London School of Hygiene and Tropical Medicine; and KEMRI Clinical Research Centre Kilifi Unit, Kilifi, Kenya
1 2
3 4
Bradley DJ. Prophylaxis against malaria for travellers from the United Kingdom. BMJ 1993; 306: 1247–52. Pryce DI, Behrens RH, Bradley DJ. The changing pattern of imported malaria in British visitors to Kenya 1987–1990. J R Soc Med 1993; 86: 152–53. Kenya 95–96 factbook. Nairobi: Newspread International, 1995: 89. Snow RW, Schellenberg JR, Peshu N, et al. Periodicity and space-time clustering of severe childhood malaria on the coast of Kenya. Trans R Soc Trop Med Hyg 1993; 87: 386–90.
hyaluronidase 150 units subcutaneously, a subcutaneous infusion of pamidronate 15 mg in 1 L normal saline at 40 mL/h was attempted. Within 2 h he developed pain, erythema, and pruritus at the infusion site requiring discontinuation of pamidronate. A 57-year-old man with large-cell anaplastic lung cancer and hypercalcaemia had a subcutaneous infusion of clodronate 1500 mg in 1 L normal saline given over 24 h, preceded by an injection of 300 units of subcutaneous hyaluronidase. The infusion was tolerated well with no local irritation. After serum calcium returned to normal, he was discharged home on day 6. A 48-year-old man with transitional-cell cancer and hypercalcaemia received 300 units of subcutaneous hyaluronidase and clodronate 1500 mg in 1 L of normal saline infused subcutaneously over 12 h. This was tolerated well. He became normocalcaemic and was discharged home on day 7. Clodronate was well tolerated and efficacious in these patients when administered subcutaneously. The local irritation experienced by the first patient is consistent for aminobisphosphonates such as pamidronate, alendronate, and ibandronate; the amino group conveys greater potency, but results in more local irritation and a higher incidence of side effects.4 The low oral bioavailability (<5%) of bisphosphonates limits their effectiveness given by mouth. Intramuscular injections are painful. The subcutaneous route may offer advantages in the care of patients with advanced cancer, allowing easy administration in the home or hospital. It may also have a part to play in the treatment of Paget’s disease and osteoporosis.5 *Paul Walker, Sharon Watanabe, Peter Lawlor, Eduardo Bruera Palliative Care Program, Grey Nuns Community Health Centre, Division Palliative Care Medicine, University of Alberta, Edmonton, T6L5X 8 AB, USA
Subcutaneous clodronate SIR—Bisphosphonates are the drugs of choice for treatment of malignant hypercalcaemia.1 Improvements in bone pain,2 and a decrease in the number of events associated with bone metastasis (including pathological fractures and the need for radiation therapy)3 have been observed. Intravenous administration is sometimes inconvenient. A 70-year-old man with squamous-cell cancer of the larynx and hypercalcaemia was fed via a gastrostomy. After
Vol 348 • August 3, 1996
1
2
3
Kovacs CS, MacDonald SM, Chik CL, Bruera E. Hypercalcemia of malignancy in the palliative care patient: a therapeutic strategy. J Pain Symptom Manage 1995; 10: 224–33. Ernst DS, MacDonald RN, Paterson AHG, Jensen J, Brasher P, Bruera E. A double-blind crossover trial of intravenous clodronate in metastatic bone pain. J Pain Symptom Manage 1992: 7: 4–11. Paterson AHG, Powles TJ, Kanis JA, McCloskey E, Hanson J, Ashley S. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993; 11: 59–65.
345
THE LANCET 4
5
Pecherstorfer M, Herrmann Z, Body JJ, et al. Randomized phase II trial comparing different doses of the bisphosphonate ibandronate in the treatment of hypercalcemia of malignancy. J Clin Oncol 1996; 14: 268–76. Plosker GL, Goa KL. Clodronate: a review of its pharmacological properties and therapeutic efficacy in resorptive bone disease. Drugs 1994; 47: 945–82.
Graft-versus-myeloma effect SIR—As described by Verdonck and colleagues1 and also reported by Tricot and colleagues,2 there is an apparent antitumour effect of donor lymphocyte infusions when multiple myeloma recurs after allogeneic bone marrow transplantation. We report two additional cases. A 51-year-old woman was diagnosed as having multiple myeloma, IgG-κ stage IIIA, in June, 1987. She underwent bone marrow transplantation in November, 1987, with a graft from her HLA-identical sister, after cyclophosphamide and whole body irradiation. In the following years, plasma M protein gradually decreased from 34 g/L to 14 g/L by November, 1990, and her marrow became normal. In December, 1992, she had a pathological fracture and the M protein increased to 21 g/L. M protein was detected in urine, and pathological plasma cells (4%) reappeared in marrow. She received donor leucocyte infusions in March, 1993, achieving a partial remission, with fall in M protein to 14 g/L and normal marrow. However, M protein in urine did not decrease and, in October, 1994, M protein in plasma rose. In January, 1995, VAD therapy (vincristine, doxorubicin, and dexamethasone) was begun because of a rise in M protein to 28 g/L. The patient responded to chemotherapy and, after three courses, M protein was 15 g/L. In March, 1995, she received, for a second time, donor leucocyte infusions (total 3·1108/kg lymphocytes), This time, intravenous interleukin-2 (9106 IU continuously for 24 h followed by 0·9106 IU twice daily for 1 mo) was started after infusion of the first leucopheresis product. However, despite this treatment, M protein concentration slowly increased to 20 g/L in December, 1995. Our second patient, a 38-year-old man, presented in March, 1988, with an eyelid plasmocytoma, which was successfully removed. In April, 1989, the plasmocytoma relapsed in the right parotid gland and, after surgery with postoperative irradiation, he was regarded as in remission. In July, 1989, he had a spontaneous costal fracture and radiography showed multiple osteolytic lesions. Aspirate from bone marrow contained 50% plasma cells, and there was a trace of Bence-Jones proteinuria of κ-type. There was no M protein in plasma. After intermittent melphalan/prednisone courses for 1 year, on February 12, 1991, he underwent bone marrow transplantation, with his HLA-identical brother as donor, after conditioning with busulphan and cyclophosphamide. Repeated tests for bone marrow morphology and Bence-Jones proteinuria were normal, and skeletal surveys showed no osteolytic lesions until April, 1993, when he had a traumatic fracture that did not heal. To correct pseudoarthrosis, he underwent surgery in September, 1994, when a marrow transplant was taken from the iliac crest. Morphology showed a relapse, with infiltrating plasma cells and κ positivity in the iliac crest, and also in a specimen from a new lesion in the right acromion. After local irradiation he was given donor leucocyte infusions in June, 1995 (total 4·6108/kg lymphocytes), together with interleukin-2. However, new osteolytic lesions were detected in August, 1995, and treated with local irradiation. In September, 1995, the patient developed graft-versus-host disease (GVHD) of the liver and gut necessitating intervention with prednisone and cyclosporin. GVHD
346
responded to treatment and thereafter he has been in good condition, working full-time. Our case reports support the findings of a graft-versusmyeloma effect of lymphocyte infusions which appear to be a potent treatment for patients with recurrent multiple myeloma after marrow transplantation. These patients otherwise have a poor outlook. However, this procedure is not without risks, and may be complicated by GVHD and pancytopenia.3 *Johan Aschan, Berit Lönnqvist, Olle Ringdén, Gunilla Kumlien, Gösta Gahrton Departments of *Haematology, Clinical Immunology, Transplantation Surgery and Blood Bank, Karolinska Institute, Huddinge Hospital, S-141 86 Huddinge, Sweden
1 2
3
Verdonck L, Lokhorst H, Dekker A, Nieuwenhuis K, Petersen E. Graft-versus-myeloma effect in two cases. Lancet 1996; 347: 800–01. Tricot G, Vesole D, Jagannath S, Hilton J, Munshi N, Barlogie B. Graft-versus-myeloma effect: proof of principle. Blood 1996; 87: 1196–98. Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia effect of donor lymphocyte transfusions in marrow grafted patients. Blood 1995; 86: 2041–50.
Torticollis in ancient Macedonians SIR—Acheson and Nitsas (April 20, p 1126)1 report that torticollis was common in statuettes of Macedonians. We would point out that our theory about ocular torticollis of Alexander the Great2 was based not only on the recent archaeological finds at Vergina, but also on a series of earlier discovered statues of the Emperor and the information provided by historical texts about the curious posture of his neck and head. It is well known that many statues of this era show inclination of the head, as the artistic style of this epoque demanded—among these the statues to which Acheson and Nitsas refer. But with respect to the ivory head of Alexander, Andronicus3 himself identifies this without any reservations, basing his opinion not only on the characteristics of the face, known from other representations of the Emperor, but also on historical sources (eg, the descriptions of three texts of Plutarch) that confirm the inclination of the neck of Alexander and the turning of his head. No one has doubted this identification. Hartle4 regards the ivory statuettes of Alexander and of his father, Philip, as realistic representations of them both. *J Lascaratos, A Damanakis Athens University, Hippocratous 164b, Athens 11471, Greece
1 2
3 4
Acheson JF, Nitsas N. Ocular torticollis in the Macedonians. Lancet 1996; 347: 1126. Lascaratos J, Damanakis A. Ocular torticollis: a new explanation for the abnormal head-posture of Alexander the Great. Lancet 1996; 347: 521–23. Andronicus M. Vergina: the royal tombs. Athens: Ekdotike Athenon, 1993: 124–29. Hartle RW. The search for Alexander’s portrait. In: Lindsay Adams W, Borza EN, eds. Philip II, Alexander the Great and the Macedonian Heritage. New York: University Press of America, 1982: 153–76.
DEPARTMENT OF ERROR 12 years on: co-proxamol revisited—In this letter by Haigh (June 29, p 1840) in the third from last line, “instead of” should have read “or”. Changing the natural history of HIV disease—In figure 3 of this article by Feinberg (July 27, p 239) the t¹ left-side top should have read ~1·6 days and the t¹ left-side bottom should have read ~6 hours. FDA urges approval of oral HIB vaccine—In this news item (July 30, p 185), 7·5 g PedVaxHIB Haemophilus influenzae type B vaccine was incorrectly described as an oral preparation. It is a pre-mixed liquid injectable formulation.
Vol 348 • August 3, 1996