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Higher or lower doses of botulinum toxin for the treatment of chronic anal fissure?
April 2003
CORRESPONDENCE
patients? The Evidence-Based Medicine Working Group. JAMA 1994;271:703–707. 5. Vanner SJ, Depew WT, Paterson WG, et al. Predictive value of the Rome criteria for diagnosing the irritable bowel syndrome. Am J Gastroenterol 1999;94:2912–2917. doi:10.1053/gast.2003.50197
Higher or Lower Doses of Botulinum Toxin for the Treatment of Chronic Anal Fissure? Dear Sir: In their study, Minguez et al.1 have presented the longest-term follow-up so far of patients in whom chronic anal fissure (CAF) healed after botulinum toxin (BT-A) treatment. A relapse of chronic anal fissure was observed in 41.5% of patients in a follow-up period of 42 months. Surprisingly, a relatively small number of patients showed posterior fissure recurrence, only 29.3% (12 of 41 patients). On the other hand, in the group of patients with an anterior located fissure, the recurrence was 83% (10 of 12 patients). Therefore, not only the dose of BT-A but also the location of the injection should be reconsidered to achieve a significant decrease in maximum resting anal pressure. It is widely known that doses of BT-A higher2,3 than those applied by Minguez et al.1 are more efficient in the healing process of chronic anal fissure. Will the more efficient doses of BT-A (50 U of Botox) reduce the recurrence of chronic anal fissure? What is more, higher doses of BT-A seem to be rather safe in CAF treatment.3,4 When used for other purposes than CAF treatment, a higher dose of BT-A could cause significant problems, as the risk of BT-A penetrating both the adjacent tissues and those further from the injection point increases.4,5 It is difficult to ascertain which patients should be administered a higher dose of BT-A.4 The higher, and more effective, doses can stimulate production of antibodies and increase the risk of resistance to toxin in cases of reinjection.5 I am strongly convinced, that in cases of reinjection higher doses than those administered by Minguez et al.1 should be applied. In such cases, Minguez et al.1 used relatively small doses, identical to those administered at the beginning of treatment (10, 15, 21 U of Botox). However, there is evidence to suggest that application of higher doses of BT-A can favorably alter the outcome of the treatment in cases of fissures resistant to small doses of BT-A.2 The optimal dose of BT-A is not known yet,1,2,4 although it has been 10 years since Jost et al.6 described the method of treating CAF with BT-A. However, the toxin was administered into the external anal sphincter, not into the internal anal sphincter as Minguez et al.1 reported. What is more, up till last year, there had not been many publications reporting cases of doses higher than 20 U of BT-A (calculated in Botox).4 Presumably, this was due to the fact that the first application of BT-A into the anal wall caused fecal incontinence in 2 of 7 patients.7 The work of Minguez et al.,1 although, raises the question of whether to administer a high dose of BT-A straight away to treat CAF (Brisinda et al.3) or whether to apply a small dose first, and then, after a period of 1 to 3 months, consider reinjection of BT-A.1 There is no evidence to indicate which of the above-mentioned solutions is optimal. One vial of Botox consists of 100 U of BT-A, which can be used to prepare injections for several patients. One should only consider the time of administration of the drug after it has been prepared, as the time may differ depending on the type of BT-A preparation used. As
1165
the BT-A preparations are very expensive, very often one vial is used by different specialists for different purposes in our clinic. Therefore, smaller doses of BT-A would imply a more efficient use of the preparation. I hope that this way of using 1 vial of Botox and the relatively high efficacy of the treatment with small doses of BT-A (82% of fissure healing as reported by Jost8) is a chance to popularize BT-A treatment. It is also the answer to those who, in their articles9 or during panel discussions at conferences, ask about the costs of BT-A treatment and wonder if it is worth paying for them. Therefore, the work of Minguez et al.1 showing positive results of chronic anal fissure treatment with small doses of BT-A is important not only from clinical but also from economical point of view. MARIUSZ H. MADALINSKI II Department of Internal Medicine Saint Wojciech Adalbertus Hospital Gdansk, Poland 1. Minguez M, Herreros B, Espi A, Garcia–Granero E, Sanchiz V, Mora F, Lledo S, Benages A. Long-term follow-up (42 months) of chronic anal fissure after healing with botulinum toxin. Gastroenterology 2002;123:112–117. 2. Madalin´ ski M, Slawek J, Zbytek B, et al. Topical nitrates and the higher doses of botulinum toxin for chronic anal fissure. Hepatogastroenterology 2001;48:977–979. 3. Brisinda G, Maria G, Sganga G, et al. Effectiveness of higher doses of botulinum toxin to induce healing in patients with chronic anal fissures. Surgery 2002;131:179 –184. 4. Madalinski M, Slawek J, Duzynski W, et al. Side effects of botulinum toxin injection for benign anal disorders. Eur J Gastroenterol Hepatol 2002;14:853– 856. 5. Munchau A, Bhatia KP. Uses of botulinum toxin injection in medicine today. BMJ 2000;320:161–165. 6. Jost WH, Schimrigk K. Use of botulinum toxin in anal fissure. Dis Colon Rectum 1993;36:974. 7. Hallan RI, Williams NS, Melling J, et al. Treatment of anismus in intractable constipation with botulinum A toxin. Lancet 1988;24: 714 –717. 8. Jost WH. One hundred cases of anal fissure treated with botulinum toxin. Dis Colon Rectum 1997;40:1029 –1032. 9. Madoff RD. Pharmacologic therapy for anal fissure. N Engl J Med 1998;338:257–259. doi:10.1053/gast.2003.50198
Gender Difference for Promoter Methylation Pattern of hMLH1 and p16 in Sporadic MSI Colorectal Cancer Dear Sir: In their recent article on CpG island methylation in sporadic colorectal cancer, Hawkins et al.1 report that 34 of 43 (79%) MSI cancers showed methylation at more than 2 of 5 methylator phenotype-related loci, one of which was gene p16. Conversely, only 34 of 76 cancers (45%) with widespread CpG island methylation were MSI. In interpreting these results, the authors prompt the hypothesis that noninherited MSI cancers arise from a larger group of tumors with already established CpG island methylation which would lead to methylation and inactivation of the hMLH1 promoter. We investigated promoter methylation of p16 and of hMLH1 in 24 MSI colorectal cancers identified among 280 consecutive colorectal cancers, and in corresponding histologically normal colonic mucosa. Eight patients with MSI cancer (33%), one of whom with 2 synchro-
CORRESPONDENCE
patients? The Evidence-Based Medicine Working Group. JAMA 1994;271:703–707. 5. Vanner SJ, Depew WT, Paterson WG, et al. Predictive value of the Rome criteria for diagnosing the irritable bowel syndrome. Am J Gastroenterol 1999;94:2912–2917. doi:10.1053/gast.2003.50197
Higher or Lower Doses of Botulinum Toxin for the Treatment of Chronic Anal Fissure? Dear Sir: In their study, Minguez et al.1 have presented the longest-term follow-up so far of patients in whom chronic anal fissure (CAF) healed after botulinum toxin (BT-A) treatment. A relapse of chronic anal fissure was observed in 41.5% of patients in a follow-up period of 42 months. Surprisingly, a relatively small number of patients showed posterior fissure recurrence, only 29.3% (12 of 41 patients). On the other hand, in the group of patients with an anterior located fissure, the recurrence was 83% (10 of 12 patients). Therefore, not only the dose of BT-A but also the location of the injection should be reconsidered to achieve a significant decrease in maximum resting anal pressure. It is widely known that doses of BT-A higher2,3 than those applied by Minguez et al.1 are more efficient in the healing process of chronic anal fissure. Will the more efficient doses of BT-A (50 U of Botox) reduce the recurrence of chronic anal fissure? What is more, higher doses of BT-A seem to be rather safe in CAF treatment.3,4 When used for other purposes than CAF treatment, a higher dose of BT-A could cause significant problems, as the risk of BT-A penetrating both the adjacent tissues and those further from the injection point increases.4,5 It is difficult to ascertain which patients should be administered a higher dose of BT-A.4 The higher, and more effective, doses can stimulate production of antibodies and increase the risk of resistance to toxin in cases of reinjection.5 I am strongly convinced, that in cases of reinjection higher doses than those administered by Minguez et al.1 should be applied. In such cases, Minguez et al.1 used relatively small doses, identical to those administered at the beginning of treatment (10, 15, 21 U of Botox). However, there is evidence to suggest that application of higher doses of BT-A can favorably alter the outcome of the treatment in cases of fissures resistant to small doses of BT-A.2 The optimal dose of BT-A is not known yet,1,2,4 although it has been 10 years since Jost et al.6 described the method of treating CAF with BT-A. However, the toxin was administered into the external anal sphincter, not into the internal anal sphincter as Minguez et al.1 reported. What is more, up till last year, there had not been many publications reporting cases of doses higher than 20 U of BT-A (calculated in Botox).4 Presumably, this was due to the fact that the first application of BT-A into the anal wall caused fecal incontinence in 2 of 7 patients.7 The work of Minguez et al.,1 although, raises the question of whether to administer a high dose of BT-A straight away to treat CAF (Brisinda et al.3) or whether to apply a small dose first, and then, after a period of 1 to 3 months, consider reinjection of BT-A.1 There is no evidence to indicate which of the above-mentioned solutions is optimal. One vial of Botox consists of 100 U of BT-A, which can be used to prepare injections for several patients. One should only consider the time of administration of the drug after it has been prepared, as the time may differ depending on the type of BT-A preparation used. As
1165
the BT-A preparations are very expensive, very often one vial is used by different specialists for different purposes in our clinic. Therefore, smaller doses of BT-A would imply a more efficient use of the preparation. I hope that this way of using 1 vial of Botox and the relatively high efficacy of the treatment with small doses of BT-A (82% of fissure healing as reported by Jost8) is a chance to popularize BT-A treatment. It is also the answer to those who, in their articles9 or during panel discussions at conferences, ask about the costs of BT-A treatment and wonder if it is worth paying for them. Therefore, the work of Minguez et al.1 showing positive results of chronic anal fissure treatment with small doses of BT-A is important not only from clinical but also from economical point of view. MARIUSZ H. MADALINSKI II Department of Internal Medicine Saint Wojciech Adalbertus Hospital Gdansk, Poland 1. Minguez M, Herreros B, Espi A, Garcia–Granero E, Sanchiz V, Mora F, Lledo S, Benages A. Long-term follow-up (42 months) of chronic anal fissure after healing with botulinum toxin. Gastroenterology 2002;123:112–117. 2. Madalin´ ski M, Slawek J, Zbytek B, et al. Topical nitrates and the higher doses of botulinum toxin for chronic anal fissure. Hepatogastroenterology 2001;48:977–979. 3. Brisinda G, Maria G, Sganga G, et al. Effectiveness of higher doses of botulinum toxin to induce healing in patients with chronic anal fissures. Surgery 2002;131:179 –184. 4. Madalinski M, Slawek J, Duzynski W, et al. Side effects of botulinum toxin injection for benign anal disorders. Eur J Gastroenterol Hepatol 2002;14:853– 856. 5. Munchau A, Bhatia KP. Uses of botulinum toxin injection in medicine today. BMJ 2000;320:161–165. 6. Jost WH, Schimrigk K. Use of botulinum toxin in anal fissure. Dis Colon Rectum 1993;36:974. 7. Hallan RI, Williams NS, Melling J, et al. Treatment of anismus in intractable constipation with botulinum A toxin. Lancet 1988;24: 714 –717. 8. Jost WH. One hundred cases of anal fissure treated with botulinum toxin. Dis Colon Rectum 1997;40:1029 –1032. 9. Madoff RD. Pharmacologic therapy for anal fissure. N Engl J Med 1998;338:257–259. doi:10.1053/gast.2003.50198
Gender Difference for Promoter Methylation Pattern of hMLH1 and p16 in Sporadic MSI Colorectal Cancer Dear Sir: In their recent article on CpG island methylation in sporadic colorectal cancer, Hawkins et al.1 report that 34 of 43 (79%) MSI cancers showed methylation at more than 2 of 5 methylator phenotype-related loci, one of which was gene p16. Conversely, only 34 of 76 cancers (45%) with widespread CpG island methylation were MSI. In interpreting these results, the authors prompt the hypothesis that noninherited MSI cancers arise from a larger group of tumors with already established CpG island methylation which would lead to methylation and inactivation of the hMLH1 promoter. We investigated promoter methylation of p16 and of hMLH1 in 24 MSI colorectal cancers identified among 280 consecutive colorectal cancers, and in corresponding histologically normal colonic mucosa. Eight patients with MSI cancer (33%), one of whom with 2 synchro-