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Acute ifosfamide-induced proximal tubular toxic reaction
Volume 118 Number 2
Editorial correspondence
this regard, we agree with the authors when they note that "we must create a new paradigm to encourage, support, nurture, and sustain women in academic positions." Finally, the authors fail to acknowledge that pediatrics has traditionally been considered weaker in matters such as academic excellence, research productivity, and competitiveness in obtaining research grants than fields such as internal medicine. These perceptions of the quality of academic pediatrics, whether real or only imagined, arose during the many decades when pediatrics was a male-dominated specialty and should not be attributed to the increase in the number of women academicians. It certainly is time to start talking about helping women to achieve success in academic pediatrics, but more constructive suggestions than "potluck dinners" are needed. Instead of bemoaning a crisis in academic pediatrics because the proportion of women has increased, we should all work together as academic pediatricians to represent pediatrics as a field with rigorous thinkers who can and will develop the academic careers of our trainees, male and female.
Members of the Faculty* Department of Pediatrics Tufts University School of Medicine Staff Members * Floating Hospital for Infants and Children New England Medical Center Boston, MA 02111 *Mary G. Ampola, MD, Kathleen Braden, MD, Betsy Busch, MD, Carol Curtin, LICSW, Basil Darras, MD, William H. Dietz, MD, PhD, Henry S. Dorkin, MD, Ellen Elias, MD, John M. Fiascone, MD, David R. Fulton, MD, Robert Geggel, MD, Karen HarveyWilkes, MD, Richard J. Grand, MD, Joel Herskowitz, MD, Mira Irons, MD, Lynne K. Karlson, MD, Edward M. Kaye, MD, George T. Klauber, MD, Colin Marchant, MD, Gerald R. Marx, MD, Sallyanne McColgan, PhD, Linda McKibben, MD, MPH, Munir Mobassaleh, MD, Kristan Outwater, MD, Kevin P. Petit, MD, Randi Pleskow, MD, Cathy Rosenfield, MD, Jane G. Schaller, MD, Molly Schwenn, MD, Ilona Szer, MD, John F. Thompson, MD, Timos Valaes, MD, Menno Verhave, MD, Nancy E. Vinton, MD, William F. H. Yee, MD
325
women in these positions in 1990. There is therefore no evidence as yet for a return toward a 50:50 distribution, and we doubt that there will ever be an equal ratio of women to men in many areas of medicine, much less in academic disciplines. The numbers of women in pediatric PL-1 positions may, however, be approaching a plateau, while the number of men in PL-1 positions continues to decline. Some universities have already made significant attempts to address some of the issues that have been raised. Yale has established an office for women in medicine, and its director has published an article that addresses many of the points that we considered) The Tufts faculty raise the issue that "pediatrics has traditionally been considered weaker in matters such as academic excellence." We agree that this perception has been associated with male dominance in academic pediatrics, a fact that persists. We did not attribute weakness to increasing numbers of women in academic pediatrics. In fact, an increase in the number of female investigators in academic pediatrics is exactly what needs to take place in the future! We are also taken to task for one of the suggestions that we made about remedying the problem. It would perhaps be more worthwhile if the Tufts faculty would offer real alternatives and their own constructive suggestions for helping women achieve success in academic pediatrics. We believe, and surmise that the faculty at Tufts Would agree, that academic pediatrics must do a better job of training sufficient numbers of our leaders, both male and female, for the future. We also believe that it is naive to think that the changes in policies, procedures, traditions, and prejudices necessary to achieve real progress will come either quickly or easily. Men will not dominate pediatrics in the next century; we had best plan for this now and implement from strength.
Herbert T. Abelson, MD Department of Pediatrics University of Washington School of Medicine Children's Hospital and Medical Center Seattle, WA 98195 Raleigh Anne Bowden. AID Department of Pediatrics University of Washington School of Medicine Fred Hutchinson Cancer Research Center Seattle, WA 98104
Reply To the Editor." Our article addressed the facts that more women are entering pediatrics, that these women have fewer role models for academic careers than do their male counterparts, that women are presently underrepresented as principal investigators from major granting sources, and that a concerted effort must be made to change this situation by developing support systems to encourage more women to pursue investigative careers. If we are unable to do so, pediatric science will suffer. It seems clear that the Tufts faculty missed the point and added their hypothesis, not ours. We noted that "extended extrapolation" of the data given in our Figure was "questionable," but additional information from the National Residency Matching Program for 1989 and 1990 suggests a continuing trend, with a total of 524 men and 797 women in level 1 pediatric residency (PL-1) positionsin 1989 and 507 men and 832
REFERENCE
1. Waxman M. Women in medicine and the medical scmnces: problems, progress, and prospects. Conn Med 1988;52:717-20.
Acute ifosfamide-induced proximal tubular toxic reaction To the Editor." Ifosfamide-induced glomerular and tubular toxic reaction has recently been reported by Burk et al. (J PEDIATR 1990;I 17:331-5)
326
Editorial correspondence
The Journal of Pediatrics February 1991
to occur in children with Witms tumor exposed to 39 to 99 gm/m 2 of the drug. They suggested that such complications may depend on the cumulative dose of ifosfamide. We report the case of a child who had severe Fanconi syndrome after her first exposure to that drug (9 gm/m2). The child has been treated for metastatic mesenchymoma of the liver at the Brussels Children's Hospital. She received her first course of chemotherapy according to the International Society of Pediatric Oneology (SIOP) soft tissue sarcoma stage IV protocol; this included vincristine, epirubicin, and carboplatin. Serum chemistry values were normal. Aminoaciduria as measured by high-performance liquid "chromatography was within normal limits. The second cycle of chemotherapy started 5 weeks later and included vincristine, actinomycin D, and ifosfamide. This last drug was given for 3 consecutive days at 3 gm/m 2 per day with mesna, (3.6 gin/ m 2 per day, and hyperhydration (3 L/m2). Two days after the end of the ifosfamide administration, there was a drop in the serum potassium (1.9 mEq/L), phosphorus (1.9 mEq/L), and bicarbonate (14 mEq/L) concentrations with transient signs of renal insufficiency. The renal phosphorus threshold was decreased. Despite metabolic acidosis, urinary pH ranged from 6.5 to 7.5. Glycosuria without albuminuria was found. The child was given daily oral supplements of potassium, phosphorus, and bicarbonate. A third cycle of chemotherapy, including vineristine, etoposide (VP-16213), and ifosfamide, was given three months after the first; ifosfamide was again given for 3 consecutive days with mesna protection, but the dosage was reduced to 1.5 g m / m 2 per day because of prolonged neutropenia after the second cycle of chemotherapy. Five days after the end of the treatment, there was again a drop in the serum electrolyte concentrations (potassium, 2.5 mEq/L; bicarbonate, 17 mEq/L; phosphorus, 1.6 mEq/L). The renal phosphorus threshold was still decreased. Excessive urinary loss of potassium (141 mEq/L for 24 hours) and glucose was found, in addition
to a gross excess of aminoacids, especially glutamine, glycine, serine, taurine, cysteine, and proline. An increase in the urinary /32-microglobulin concentration was another indicator of proximal tubulopathy. The vasopressin test result was normal. Renal biopsy subsequently revealed areas of focal proximal tubular sclerosis compatible with a toxic tubulopathy. The patient is currently in complete remission, 6 months after the completion of chemotherapy. She has no sign of glomerular or tubular dysfunction. Our patient differs from those reported by Burk et al. by the fact that the Fanconi syndrome developed shortly after the first exposure to the drug. In addition, the limited amount of ifosfamide given (13.5 gm/m 2) might be a reason that the glomerular filtration rate did not decrease and tubular functions recovered completely. Our experience, together with that of other investigators, 1 indicates that in some patients an ifosfamide-induced renal toxic reaction is not dose related. However, it is possible that the severity and persistence of glomerular and tubular dysfunctions are dependent on the cumulative dose of the drug. These disorders can lead to severe morbidity and even deathZ; physicians should be aware of the potential toxic effects associated with ifosfamide therapy and should search for them as soon as a child is exposed to the drug. Christine Devalek, MD Khalid lsmaili, MD Alice Ferster, MD Eric Sariban, MD, PhD Hbpital Universitaire des Enfants Brussels 1020, Belgium REFERENCES
1. Skinner R, Pearson ADJ, Price L, Coulthard MG, Craft AW. Nephrotoxieity of ifosfamide in children. Lancet 1989; 1:159. 2. Husband D J, Watkin SW. Fatal hypokalaemia associated with ifosfamide-mesna chemotherapy. Lancet 1988; 1: l 116.
CORRECTIONS In the article " L a t e - o n s e t O r n i t h i n e T r a n s c a r b a m y l a s e Deficiency in M a l e Patients, by Finkelstein et al., which a p p e a r e d in the D e c e m b e r 1990 issue of THE JOURNAL on page 901, column 1, at the end of p a r a g r a p h 3, the phrase printed as " a n d t h a t male-to-male transmission of this disorder is possible" should read as follows: " a n d t h a t male-to-female transmission of this disorder is possible." In the article " U s e of Topically Applied Nitroglycerin in the T r e a t m e n t of P u r p u r a F u l m i n a n s , " by I r a z u z t a a n d M e M a n u s , which appeared in the D e c e m b e r 1990 issue of THE JOURNAL on page 994, at the b o t t o m of column 1, the sentence printed " A m e t h e m o g l o b i n level o b t a i n e d on the third day was 3 % " should read as follows: " A m e t h e m o g l o b i n level o b t a i n e d on the third day was 0.3 % ."
Editorial correspondence
this regard, we agree with the authors when they note that "we must create a new paradigm to encourage, support, nurture, and sustain women in academic positions." Finally, the authors fail to acknowledge that pediatrics has traditionally been considered weaker in matters such as academic excellence, research productivity, and competitiveness in obtaining research grants than fields such as internal medicine. These perceptions of the quality of academic pediatrics, whether real or only imagined, arose during the many decades when pediatrics was a male-dominated specialty and should not be attributed to the increase in the number of women academicians. It certainly is time to start talking about helping women to achieve success in academic pediatrics, but more constructive suggestions than "potluck dinners" are needed. Instead of bemoaning a crisis in academic pediatrics because the proportion of women has increased, we should all work together as academic pediatricians to represent pediatrics as a field with rigorous thinkers who can and will develop the academic careers of our trainees, male and female.
Members of the Faculty* Department of Pediatrics Tufts University School of Medicine Staff Members * Floating Hospital for Infants and Children New England Medical Center Boston, MA 02111 *Mary G. Ampola, MD, Kathleen Braden, MD, Betsy Busch, MD, Carol Curtin, LICSW, Basil Darras, MD, William H. Dietz, MD, PhD, Henry S. Dorkin, MD, Ellen Elias, MD, John M. Fiascone, MD, David R. Fulton, MD, Robert Geggel, MD, Karen HarveyWilkes, MD, Richard J. Grand, MD, Joel Herskowitz, MD, Mira Irons, MD, Lynne K. Karlson, MD, Edward M. Kaye, MD, George T. Klauber, MD, Colin Marchant, MD, Gerald R. Marx, MD, Sallyanne McColgan, PhD, Linda McKibben, MD, MPH, Munir Mobassaleh, MD, Kristan Outwater, MD, Kevin P. Petit, MD, Randi Pleskow, MD, Cathy Rosenfield, MD, Jane G. Schaller, MD, Molly Schwenn, MD, Ilona Szer, MD, John F. Thompson, MD, Timos Valaes, MD, Menno Verhave, MD, Nancy E. Vinton, MD, William F. H. Yee, MD
325
women in these positions in 1990. There is therefore no evidence as yet for a return toward a 50:50 distribution, and we doubt that there will ever be an equal ratio of women to men in many areas of medicine, much less in academic disciplines. The numbers of women in pediatric PL-1 positions may, however, be approaching a plateau, while the number of men in PL-1 positions continues to decline. Some universities have already made significant attempts to address some of the issues that have been raised. Yale has established an office for women in medicine, and its director has published an article that addresses many of the points that we considered) The Tufts faculty raise the issue that "pediatrics has traditionally been considered weaker in matters such as academic excellence." We agree that this perception has been associated with male dominance in academic pediatrics, a fact that persists. We did not attribute weakness to increasing numbers of women in academic pediatrics. In fact, an increase in the number of female investigators in academic pediatrics is exactly what needs to take place in the future! We are also taken to task for one of the suggestions that we made about remedying the problem. It would perhaps be more worthwhile if the Tufts faculty would offer real alternatives and their own constructive suggestions for helping women achieve success in academic pediatrics. We believe, and surmise that the faculty at Tufts Would agree, that academic pediatrics must do a better job of training sufficient numbers of our leaders, both male and female, for the future. We also believe that it is naive to think that the changes in policies, procedures, traditions, and prejudices necessary to achieve real progress will come either quickly or easily. Men will not dominate pediatrics in the next century; we had best plan for this now and implement from strength.
Herbert T. Abelson, MD Department of Pediatrics University of Washington School of Medicine Children's Hospital and Medical Center Seattle, WA 98195 Raleigh Anne Bowden. AID Department of Pediatrics University of Washington School of Medicine Fred Hutchinson Cancer Research Center Seattle, WA 98104
Reply To the Editor." Our article addressed the facts that more women are entering pediatrics, that these women have fewer role models for academic careers than do their male counterparts, that women are presently underrepresented as principal investigators from major granting sources, and that a concerted effort must be made to change this situation by developing support systems to encourage more women to pursue investigative careers. If we are unable to do so, pediatric science will suffer. It seems clear that the Tufts faculty missed the point and added their hypothesis, not ours. We noted that "extended extrapolation" of the data given in our Figure was "questionable," but additional information from the National Residency Matching Program for 1989 and 1990 suggests a continuing trend, with a total of 524 men and 797 women in level 1 pediatric residency (PL-1) positionsin 1989 and 507 men and 832
REFERENCE
1. Waxman M. Women in medicine and the medical scmnces: problems, progress, and prospects. Conn Med 1988;52:717-20.
Acute ifosfamide-induced proximal tubular toxic reaction To the Editor." Ifosfamide-induced glomerular and tubular toxic reaction has recently been reported by Burk et al. (J PEDIATR 1990;I 17:331-5)
326
Editorial correspondence
The Journal of Pediatrics February 1991
to occur in children with Witms tumor exposed to 39 to 99 gm/m 2 of the drug. They suggested that such complications may depend on the cumulative dose of ifosfamide. We report the case of a child who had severe Fanconi syndrome after her first exposure to that drug (9 gm/m2). The child has been treated for metastatic mesenchymoma of the liver at the Brussels Children's Hospital. She received her first course of chemotherapy according to the International Society of Pediatric Oneology (SIOP) soft tissue sarcoma stage IV protocol; this included vincristine, epirubicin, and carboplatin. Serum chemistry values were normal. Aminoaciduria as measured by high-performance liquid "chromatography was within normal limits. The second cycle of chemotherapy started 5 weeks later and included vincristine, actinomycin D, and ifosfamide. This last drug was given for 3 consecutive days at 3 gm/m 2 per day with mesna, (3.6 gin/ m 2 per day, and hyperhydration (3 L/m2). Two days after the end of the ifosfamide administration, there was a drop in the serum potassium (1.9 mEq/L), phosphorus (1.9 mEq/L), and bicarbonate (14 mEq/L) concentrations with transient signs of renal insufficiency. The renal phosphorus threshold was decreased. Despite metabolic acidosis, urinary pH ranged from 6.5 to 7.5. Glycosuria without albuminuria was found. The child was given daily oral supplements of potassium, phosphorus, and bicarbonate. A third cycle of chemotherapy, including vineristine, etoposide (VP-16213), and ifosfamide, was given three months after the first; ifosfamide was again given for 3 consecutive days with mesna protection, but the dosage was reduced to 1.5 g m / m 2 per day because of prolonged neutropenia after the second cycle of chemotherapy. Five days after the end of the treatment, there was again a drop in the serum electrolyte concentrations (potassium, 2.5 mEq/L; bicarbonate, 17 mEq/L; phosphorus, 1.6 mEq/L). The renal phosphorus threshold was still decreased. Excessive urinary loss of potassium (141 mEq/L for 24 hours) and glucose was found, in addition
to a gross excess of aminoacids, especially glutamine, glycine, serine, taurine, cysteine, and proline. An increase in the urinary /32-microglobulin concentration was another indicator of proximal tubulopathy. The vasopressin test result was normal. Renal biopsy subsequently revealed areas of focal proximal tubular sclerosis compatible with a toxic tubulopathy. The patient is currently in complete remission, 6 months after the completion of chemotherapy. She has no sign of glomerular or tubular dysfunction. Our patient differs from those reported by Burk et al. by the fact that the Fanconi syndrome developed shortly after the first exposure to the drug. In addition, the limited amount of ifosfamide given (13.5 gm/m 2) might be a reason that the glomerular filtration rate did not decrease and tubular functions recovered completely. Our experience, together with that of other investigators, 1 indicates that in some patients an ifosfamide-induced renal toxic reaction is not dose related. However, it is possible that the severity and persistence of glomerular and tubular dysfunctions are dependent on the cumulative dose of the drug. These disorders can lead to severe morbidity and even deathZ; physicians should be aware of the potential toxic effects associated with ifosfamide therapy and should search for them as soon as a child is exposed to the drug. Christine Devalek, MD Khalid lsmaili, MD Alice Ferster, MD Eric Sariban, MD, PhD Hbpital Universitaire des Enfants Brussels 1020, Belgium REFERENCES
1. Skinner R, Pearson ADJ, Price L, Coulthard MG, Craft AW. Nephrotoxieity of ifosfamide in children. Lancet 1989; 1:159. 2. Husband D J, Watkin SW. Fatal hypokalaemia associated with ifosfamide-mesna chemotherapy. Lancet 1988; 1: l 116.
CORRECTIONS In the article " L a t e - o n s e t O r n i t h i n e T r a n s c a r b a m y l a s e Deficiency in M a l e Patients, by Finkelstein et al., which a p p e a r e d in the D e c e m b e r 1990 issue of THE JOURNAL on page 901, column 1, at the end of p a r a g r a p h 3, the phrase printed as " a n d t h a t male-to-male transmission of this disorder is possible" should read as follows: " a n d t h a t male-to-female transmission of this disorder is possible." In the article " U s e of Topically Applied Nitroglycerin in the T r e a t m e n t of P u r p u r a F u l m i n a n s , " by I r a z u z t a a n d M e M a n u s , which appeared in the D e c e m b e r 1990 issue of THE JOURNAL on page 994, at the b o t t o m of column 1, the sentence printed " A m e t h e m o g l o b i n level o b t a i n e d on the third day was 3 % " should read as follows: " A m e t h e m o g l o b i n level o b t a i n e d on the third day was 0.3 % ."