558
4. Yoffe
G, Blick M, Kantarijian H, Spitzer G, Gutterman JU, Talpaz M. Molecular analysis of interferon-induced suppression of Philadelphia chromosome in patients with chronic myeloid leukemia. Blood 1987; 69: 961-63. 5. Opalka B, Wandl UB, Becher R, et al. Minimal residual disease in patients with chronic myelogenous leukemia undergoing long-term treatment with recombinant interferon &agr;-2b alone or in combination with interferon-&ggr;. Blood 1991; 78: 2188-93. 6. Opalka B, Kloke O, Bartram CR, et al. Elimination by interferon-alpha of malignant clone in chronic myeloid leukaemia. Lancet 1989; i: 1334. 7. Kawasaki ES, Clark SS, Coyne MY, et al. Diagnosis of chronic myelogenous leukemia and acute leukemia by detection of leukemia-specific mRNA sequences amplified in vitro. Proc Natl Acad Sci USA 1988; 85: 5689-702.
Blindness associated with
high-dose
carboplatin SIR,-Neurotoxicity has been described with cisplatin, including otoxicity, peripheral neuropathy, Lhermitte’s sign, retinal toxicity, and transient cortical blindness, sometimes with seizure activity.1-33 At this hospital about 180 patients with various tumour types have been safely treated with carboplatin (800-1200 mg/m2). In the past 6 months we have seen sudden onset of clinical cortical blindness in 2 patients with advanced epithelial ovarian cancer and impaired renal function receiving carboplatin at a high dose calculated on the basis of Calvert and co-workers4 formula using renal function and area under the curve (AUC): dose (mg) AUC(25 + GFR [glomerular filtration rate]). A 60-year-old woman with stage III papillary serous cystadenocarcinoma of the ovary was referred after surgery with residual disease greater than 5 cm. She had a raised CA 125 (tumour marker) at 1280 IU. She had a 10-year history of hypertension treated by thiazides; her kidneys were of normal size and unobstructed on computed tomography (CT) and her GFR was 35 ml/min as measured with 51Cr-edetic acid. Her serum sodium was initially 128 mmol/1 but all other biochemical and liver function tests were normal. She received high-dose carboplatin as part of a phase III study with an AUC of 12 (total dose of 720 mg). The second course was given at the same dose 1 month later with a GFR of 38 ml/min. CT after two courses showed a partial response with a decreased concentration of serum CA 125. Before the third course of carboplatin, GFR was 45 ml/min and again a dose was given on the basis of the formula. On day 13 after this course the patient had severe headache. She had bilateral visual loss, which was complete for light and colours. Her vital signs were stable and she had no abnormal neurological signs. She was taking piperacillin, gentamicin, and flucloxacillin for a neutropenic pyrexia, and platelet transfusions were being given daily ( < 20 x 109). Brain CT was normal and her erythrocyte sedimentation rate (ESR) was 26 mm/h. Visual-evoked potentials suggested a bilateral toxic ambylopia. Over the next week she gradually improved and after 3 weeks was able to read large print. Chemotherapy was stopped and she died 3 months later of progressive epithelial ovarian cancer. A 61-year-old woman with a stage II adenocarcinoma of the ovary was referred after surgery with bulky residual disease. She had no history of hypertension or renal disease. GFR (by 51Cr-edetic acid) was 50 ml/min with normal serum urea and creatinine. She received carboplatin with an AUC of 12 (total dose 900 mg). Intestinal obstruction and renal impairment developed with raised urea (27 mmol/1) and creatinine (322 mmol/1). She was treated conservatively, and by day 10 urea (7 mmol/1) and creatinine (160 mmol/1) were approaching normal. On that morning she had severe headache and loss of vision. Visual loss was bilateral and complete for light and colours. Blood pressure was raised at 210/105 mm Hg but there were no abnormal neurological signs. She was taking only metronidazole and her platelets and neutrophils were normal. Brain CT showed some swelling of the occipital lobe with effacement of the sulci but without hydrocephalus, and ESR was 60 mm/h. She received high-dose steroids and antihypertensive treatment. Over the next week she returned to normal. Her tumour was responding to carboplatin and she therefore was continued on this treatment with an AUC of 6 without further visual difficulties. Visual disturbances (sore eyes, blurred vision, choroidoretinitis, optic neuritis, and ocular disturbances) in 10 patients taking carboplatin have been reported to the manufacturers (Bristol Myers); none of these had sudden blindness. The 2 cases in this report are characterised by either a past history of hypertension and =
impaired renal function (GFR acid < 60 ml/min) or acute deterioration with an already decreased renal output. 3 other patients have received carboplatin at high doses with initial GFR values of less than 60 ml/min and none complained of visual disturbances, although eye testing for minor losses were not done. Carboplatin has no reported nephrotoxicity at conventional doses, and at high doses the fall in GFR always recovers between coursesBecause carboplatin crosses the blood-brain barrier the blindness in our 2 patients is probably caused by central-nervoussystem toxicity in the presence of poor renal excretion. The mechanism of this toxicity remains unclear. We conclude that it is unwise to give high-dose carboplatin with a GFR of less than 50 ml/min. We do not know if intravenous hydration would decrease the risk of neurological toxicity. M. E. R. O’BRIEN K. TONGE P. BLAKE E. MOSKOVIC E. WILTSHAW
Department of Medicine, Royal Marsden Hospital, London SW3 6JJ, UK
Pippit CH, Muss HB, Homesley HD, et al, Cisplatin-associated cortical blindness. Gynecol Oncol 1981; 12: 253-55. 2. Cattaneo MT, Filipazzi V, Piazza E, et al. Transient blindness and seizure associated with cisplatin therapy. J Cancer Res Clin Oncol 1988; 114: 528-30. 3. Wilding G, Caruso R, Lawrence TS, et al. Retinal toxicity after high-dose cisplatin therapy J Clin Oncol 1985; 3: 1683-89. 4. Calvert AH, Newell AH, Gumbrell LA, et al. The clinical pharmacokinetics of carboplatin. prospective validation of a dosage formula for use in high-dose single agent and combination studies. Proc ASCO 1989; 8: A271. 5. Hardy JR, Tan S, Fryall I, et al. How nephrotoxic is carboplatin? Br J Cancer 1990; 61: 1.
644.
Uveitis after antineutrophil cytoplasmic antibody contamination of immunoglobulin replacement therapy SIR,-We report
an
unusual
case
of
a
boy with X-linked
agammaglobulinaemia (XLA) in whom retinal vasculitis and uveitis developed in association with a unique punctate fundal change. A 9-year-old boy, one of three living children, had one brother and three maternal uncles who died in infancy. The boy presented at age 4 months with a history of cough and poor feeding. He proved to have lobar pneumonia, septicaemia, and purulent conjunctivitis, with neutropenia and necrotic ulceration of both fauces. Serum immunoglobulins were: IgG 0-8 g/1 (normal for age, 2-41-6 13), IgA less than 0-11 g/l (0-10-0-46), and IgM 0-11 g/1 (026-060). Subsequent lymphocyte phenotyping showed normal properties of T-cell subpopulations, but undetectable B cells (CD20 positive to transformation < 1 %). responses Lymphocyte were normal. He was and phytohaemagglutinin pokeweed mitogen initially treated with fresh frozen plasma, followed by intramuscular human normal immunoglobulin from 1983 to 1988. Since then he has received intravenous immunoglobulin (’Sandoglobulin’) (initially 0-2 g/kg body-weight every 2 weeks, increasing to 0-4 g/kg body-weight every 2 weeks), which maintained trough IgG concentrations of 6-3-7-4 g/1 (normal range for age 8-0-18-0 g/l). Within 3 months of this dose increase he presented with decreased vision of 6/24, with a granulomatous uveitis in the left eye and a quiet right eye with acuity 6/6. The uveitis responded to topical steroids and he was lost to follow-up. 1 year later, nongranulomatous bilateral anterior uveitis in white symptom-free eyes, acuities 6/6, was diagnosed. Over the next 3 months chronic relapsing panuveitis developed (acuity 6/24 right and 6/9 left). This condition was associated with bilateral discrete outer retinal, pale yellow, regular lesions (between 200 and 400 pm) scattered throughout the fundi of both eyes, and a larger grey, placoid-like lesion was identified below the right disc, which was swollen (figure, upper). Fluorescein angiography (figure, lower) revealed leakage and staining of the arterioles, venules, and right disc. Punctate hyperfluorescent lesions of 200-400 um were noted in early/mid phases in both fundi. These lesions were evenly distributed and extended to the equator, corresponding to the distribution of the creamy punctate lesions seen clinically. There was no evidence of renal or other systemic disease and a Kveim test was negative. Neither HLA-A29 nor B27 were expressed.
4. Yoffe
G, Blick M, Kantarijian H, Spitzer G, Gutterman JU, Talpaz M. Molecular analysis of interferon-induced suppression of Philadelphia chromosome in patients with chronic myeloid leukemia. Blood 1987; 69: 961-63. 5. Opalka B, Wandl UB, Becher R, et al. Minimal residual disease in patients with chronic myelogenous leukemia undergoing long-term treatment with recombinant interferon &agr;-2b alone or in combination with interferon-&ggr;. Blood 1991; 78: 2188-93. 6. Opalka B, Kloke O, Bartram CR, et al. Elimination by interferon-alpha of malignant clone in chronic myeloid leukaemia. Lancet 1989; i: 1334. 7. Kawasaki ES, Clark SS, Coyne MY, et al. Diagnosis of chronic myelogenous leukemia and acute leukemia by detection of leukemia-specific mRNA sequences amplified in vitro. Proc Natl Acad Sci USA 1988; 85: 5689-702.
Blindness associated with
high-dose
carboplatin SIR,-Neurotoxicity has been described with cisplatin, including otoxicity, peripheral neuropathy, Lhermitte’s sign, retinal toxicity, and transient cortical blindness, sometimes with seizure activity.1-33 At this hospital about 180 patients with various tumour types have been safely treated with carboplatin (800-1200 mg/m2). In the past 6 months we have seen sudden onset of clinical cortical blindness in 2 patients with advanced epithelial ovarian cancer and impaired renal function receiving carboplatin at a high dose calculated on the basis of Calvert and co-workers4 formula using renal function and area under the curve (AUC): dose (mg) AUC(25 + GFR [glomerular filtration rate]). A 60-year-old woman with stage III papillary serous cystadenocarcinoma of the ovary was referred after surgery with residual disease greater than 5 cm. She had a raised CA 125 (tumour marker) at 1280 IU. She had a 10-year history of hypertension treated by thiazides; her kidneys were of normal size and unobstructed on computed tomography (CT) and her GFR was 35 ml/min as measured with 51Cr-edetic acid. Her serum sodium was initially 128 mmol/1 but all other biochemical and liver function tests were normal. She received high-dose carboplatin as part of a phase III study with an AUC of 12 (total dose of 720 mg). The second course was given at the same dose 1 month later with a GFR of 38 ml/min. CT after two courses showed a partial response with a decreased concentration of serum CA 125. Before the third course of carboplatin, GFR was 45 ml/min and again a dose was given on the basis of the formula. On day 13 after this course the patient had severe headache. She had bilateral visual loss, which was complete for light and colours. Her vital signs were stable and she had no abnormal neurological signs. She was taking piperacillin, gentamicin, and flucloxacillin for a neutropenic pyrexia, and platelet transfusions were being given daily ( < 20 x 109). Brain CT was normal and her erythrocyte sedimentation rate (ESR) was 26 mm/h. Visual-evoked potentials suggested a bilateral toxic ambylopia. Over the next week she gradually improved and after 3 weeks was able to read large print. Chemotherapy was stopped and she died 3 months later of progressive epithelial ovarian cancer. A 61-year-old woman with a stage II adenocarcinoma of the ovary was referred after surgery with bulky residual disease. She had no history of hypertension or renal disease. GFR (by 51Cr-edetic acid) was 50 ml/min with normal serum urea and creatinine. She received carboplatin with an AUC of 12 (total dose 900 mg). Intestinal obstruction and renal impairment developed with raised urea (27 mmol/1) and creatinine (322 mmol/1). She was treated conservatively, and by day 10 urea (7 mmol/1) and creatinine (160 mmol/1) were approaching normal. On that morning she had severe headache and loss of vision. Visual loss was bilateral and complete for light and colours. Blood pressure was raised at 210/105 mm Hg but there were no abnormal neurological signs. She was taking only metronidazole and her platelets and neutrophils were normal. Brain CT showed some swelling of the occipital lobe with effacement of the sulci but without hydrocephalus, and ESR was 60 mm/h. She received high-dose steroids and antihypertensive treatment. Over the next week she returned to normal. Her tumour was responding to carboplatin and she therefore was continued on this treatment with an AUC of 6 without further visual difficulties. Visual disturbances (sore eyes, blurred vision, choroidoretinitis, optic neuritis, and ocular disturbances) in 10 patients taking carboplatin have been reported to the manufacturers (Bristol Myers); none of these had sudden blindness. The 2 cases in this report are characterised by either a past history of hypertension and =
impaired renal function (GFR acid < 60 ml/min) or acute deterioration with an already decreased renal output. 3 other patients have received carboplatin at high doses with initial GFR values of less than 60 ml/min and none complained of visual disturbances, although eye testing for minor losses were not done. Carboplatin has no reported nephrotoxicity at conventional doses, and at high doses the fall in GFR always recovers between coursesBecause carboplatin crosses the blood-brain barrier the blindness in our 2 patients is probably caused by central-nervoussystem toxicity in the presence of poor renal excretion. The mechanism of this toxicity remains unclear. We conclude that it is unwise to give high-dose carboplatin with a GFR of less than 50 ml/min. We do not know if intravenous hydration would decrease the risk of neurological toxicity. M. E. R. O’BRIEN K. TONGE P. BLAKE E. MOSKOVIC E. WILTSHAW
Department of Medicine, Royal Marsden Hospital, London SW3 6JJ, UK
Pippit CH, Muss HB, Homesley HD, et al, Cisplatin-associated cortical blindness. Gynecol Oncol 1981; 12: 253-55. 2. Cattaneo MT, Filipazzi V, Piazza E, et al. Transient blindness and seizure associated with cisplatin therapy. J Cancer Res Clin Oncol 1988; 114: 528-30. 3. Wilding G, Caruso R, Lawrence TS, et al. Retinal toxicity after high-dose cisplatin therapy J Clin Oncol 1985; 3: 1683-89. 4. Calvert AH, Newell AH, Gumbrell LA, et al. The clinical pharmacokinetics of carboplatin. prospective validation of a dosage formula for use in high-dose single agent and combination studies. Proc ASCO 1989; 8: A271. 5. Hardy JR, Tan S, Fryall I, et al. How nephrotoxic is carboplatin? Br J Cancer 1990; 61: 1.
644.
Uveitis after antineutrophil cytoplasmic antibody contamination of immunoglobulin replacement therapy SIR,-We report
an
unusual
case
of
a
boy with X-linked
agammaglobulinaemia (XLA) in whom retinal vasculitis and uveitis developed in association with a unique punctate fundal change. A 9-year-old boy, one of three living children, had one brother and three maternal uncles who died in infancy. The boy presented at age 4 months with a history of cough and poor feeding. He proved to have lobar pneumonia, septicaemia, and purulent conjunctivitis, with neutropenia and necrotic ulceration of both fauces. Serum immunoglobulins were: IgG 0-8 g/1 (normal for age, 2-41-6 13), IgA less than 0-11 g/l (0-10-0-46), and IgM 0-11 g/1 (026-060). Subsequent lymphocyte phenotyping showed normal properties of T-cell subpopulations, but undetectable B cells (CD20 positive to transformation < 1 %). responses Lymphocyte were normal. He was and phytohaemagglutinin pokeweed mitogen initially treated with fresh frozen plasma, followed by intramuscular human normal immunoglobulin from 1983 to 1988. Since then he has received intravenous immunoglobulin (’Sandoglobulin’) (initially 0-2 g/kg body-weight every 2 weeks, increasing to 0-4 g/kg body-weight every 2 weeks), which maintained trough IgG concentrations of 6-3-7-4 g/1 (normal range for age 8-0-18-0 g/l). Within 3 months of this dose increase he presented with decreased vision of 6/24, with a granulomatous uveitis in the left eye and a quiet right eye with acuity 6/6. The uveitis responded to topical steroids and he was lost to follow-up. 1 year later, nongranulomatous bilateral anterior uveitis in white symptom-free eyes, acuities 6/6, was diagnosed. Over the next 3 months chronic relapsing panuveitis developed (acuity 6/24 right and 6/9 left). This condition was associated with bilateral discrete outer retinal, pale yellow, regular lesions (between 200 and 400 pm) scattered throughout the fundi of both eyes, and a larger grey, placoid-like lesion was identified below the right disc, which was swollen (figure, upper). Fluorescein angiography (figure, lower) revealed leakage and staining of the arterioles, venules, and right disc. Punctate hyperfluorescent lesions of 200-400 um were noted in early/mid phases in both fundi. These lesions were evenly distributed and extended to the equator, corresponding to the distribution of the creamy punctate lesions seen clinically. There was no evidence of renal or other systemic disease and a Kveim test was negative. Neither HLA-A29 nor B27 were expressed.
