correspondence
ry.3,4 We injected PRP a median of 3 days (inter- Johannes L. Tol, M.D., Ph.D. quartile range, 2 to 4) after injury. In a Cox Aspetar Qatar Orthopedic and Sports Medicine Hospital regression analysis, adjustment for the time be- Doha, Qatar Since publication of their letter, the authors report no further tween injury and injection did not materially potential conflict of interest. change the treatment effect. We injected three 1-ml depots at each proce- 1. Huard J, Li Y, Fu FH. Muscle injuries and repair: current trends in research. J Bone Joint Surg Am 2002;84-A:822-32. dure. According to a recent study by Magalon et 2. Hamilton BH, Best TM. Platelet-enriched plasma and muscle al.,5 this total of 3 ml corresponds to a PDGF strain injuries: challenges imposed by the burden of proof. Clin dosage of 40,000 pg (which is slightly less than J Sport Med 2011;21:31-6. 3. Wright-Carpenter T, Klein P, Schäferhoff P, Appell HJ, Mir the dosage reported by Anitua et al.). IGF-1 was LM, Wehling P. Treatment of muscle injuries by local adminisnot analyzed in their study. Magalon et al. de- tration of autologous conditioned serum: a pilot study on sportsscribe dosages of other growth factors and show men with muscle strains. Int J Sports Med 2004;25:588-93. 4. Bernuzzi G, Petraglia F, Pedrini MF, et al. Use of platelet-rich the content of different PRP preparation systems.5 plasma in the care of sports injuries: our experience with ultraGustaaf Reurink, M.D. Jan A.N. Verhaar, M.D., Ph.D. Erasmus Medical Center Rotterdam, the Netherlands
sound-guided injection. Blood Transfus 2014;12:Suppl 1:s229-s234. 5. Magalon J, Bausset O, Serratrice N, et al. Characterization and comparison of 5 platelet-rich plasma preparations in a single-donor model. Arthroscopy 2014;30:629-38. DOI: 10.1056/NEJMc1409204
Pyogenic Granuloma as a Cutaneous Adverse Effect of Vemurafenib To the Editor: Vemurafenib has altered the prognosis of patients with metastatic melanoma with BRAF V600 mutations.1 However, this agent is associated with a wide spectrum of cutaneous toxic effects, including squamous-cell carcinoma, primary melanoma, keratoacanthoma, and rashes.2 We have identified pyogenic granuloma as a further cutaneous event associated with vemurafenib. A 69-year-old man who had presented 2 years previously with a superficial spreading melanoma with a Breslow thickness of 1 mm was found to have bilateral axillary lymphadenopathy; a biopsy revealed melanoma with a BRAF V600E mutation. Staging investigations showed metastatic disease, with a 23-mm lesion in the right thalamic region, a 40-by-22-mm mass in the right axillary node, enlarged left axillary lymph nodes, and peritoneal deposits. Treatment was initiated with vemurafenib at a standard dose of 960 mg twice daily. Within 6 days, a widespread rash developed, which necessitated an interruption in treatment for 1 week and reinitiation at 75% of the initial dose (720 mg twice daily). At 12 weeks, a keratoacanthoma over the left clavicle and a rapidly enlarging vascular lesion on the left alar rim of the nose developed (Fig. 1A).
Both lesions were excised, with the latter requiring grafting. Histologic analysis of the nasal lesion confirmed pyogenic granuloma (Fig. 1B). Vemurafenib was continued, but 4 weeks after excision, six further pyogenic granulomas erupted close to the nasal skin graft (Fig. 1C). Four of these lesions were curetted, and two were left in situ. At this point, 24 weeks of vemurafenib had been administered, with a complete tumor response on imaging. In view of the rapid recurrence of lesions, vemurafenib was withheld for 2 weeks, during which no further lesions erupted, and the two residual pyogenic granulomas remained static in size. On reinstitution of treatment at 50% of the full dose (480 mg twice daily), these two lesions grew very slowly (Fig. 1D). The pattern of occurrence of pyogenic granulomas on and off treatment and the dose dependency suggest a mechanism driven by vemurafenib. Paradoxical activation of the MAPK pathway has been postulated as causing the development of squamous-cell carcinomas and keratoacanthomas in patients treated with this drug.3 This factor, coupled with the observation that pyogenic granulomas strongly overexpress MAP kinases,4 leads us to hypothesize that the molecular mechanisms driving dermatologic tox-
n engl j med 371;13 nejm.org september 25, 2014
The New England Journal of Medicine Downloaded from nejm.org on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
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B
D
C
Figure 1. Eruptions of Pyogenic Granulomas in a Patient with Metastatic Melanoma Treated with Vemurafenib. Twelve weeks after the initiation of vemurafenib, a rapidly enlarging vascular lesion appeared on the left alar rim of the patient’s nose. Panel A shows the appearance at 16 weeks, before curettage and grafting. A section obtained from the lesion showed a lobulated vascular proliferation composed of small vessels that included endothelial cells with surrounding pericytes within the dermis, features of pyogenic granuloma pericytes (Panel B, hematoxylin and eosin staining). Treatment with vemurafenib continued, and 4 weeks after surgery, six new lesions grew rapidly, as shown at 24 weeks (Panel C). Four of these six lesions were removed, and vemurafenib was interrupted for 2 weeks, during which the remaining two lesions did not grow in size and no new pyogenic granulomas appeared. On reinstitution of treatment at 50% of the original dose, the two remaining pyogenic granulomas grew very slowly in size, as shown at 29 weeks (Panel D). (Panels A, B, and D are reproduced with permission from Addenbrooke’s Hospital, and Panel C with permission from West Suffolk Hospital NHS Foundation Trust.)
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n engl j med 371;13
nejm.org
september 25, 2014
The New England Journal of Medicine Downloaded from nejm.org on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
notices
ic effects associated with vemurafenib are also responsible for the development of pyogenic granulomas. If this is the case, treatment with dual BRAF and MEK inhibition might prevent eruption of these lesions, in keeping with trial data showing that combined inhibition results in a significantly lower incidence of dermatologic events.5 Stephen John Sammut, M.D. Addenbrooke’s Hospital Cambridge, United Kingdom
Nevianna Tomson, M.B., Ch.B. West Suffolk Hospital Bury St. Edmunds, United Kingdom
letters. (For authors of Journal articles who are responding to letters, we will only publish new relevant relationships that have developed since publication of the article.) • Include your full mailing address, telephone number, fax number, and e-mail address with your letter. • All letters must be submitted at authors.NEJM.org. Letters that do not adhere to these instructions will not be considered. We will notify you when we have made a decision about possible publication. Letters regarding a recent Journal article may be shared with the authors of that article. We are unable to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and any other form or medium.
Pippa Corrie, Ph.D. Addenbrooke’s Hospital Cambridge, United Kingdom [email protected]
corrections
Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. 1. Chapman PB, Hauschild A, Robert C, et al. Improved sur-
vival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16. 2. Anforth R, Fernandez-Peñas P, Long GV. Cutaneous toxicities of RAF inhibitors. Lancet Oncol 2013;14(1):e11-e18. 3. Gibney GT, Messina JL, Fedorenko IV, Sondak VK, Smalley KSM. Paradoxical oncogenesis — the long-term effects of BRAF inhibition in melanoma. Nat Rev Clin Oncol 2013;10:390-9. 4. Arbiser JL, Weiss SW, Arbiser ZK, et al. Differential expression of active mitogen-activated protein kinase in cutaneous endothelial neoplasms: implications for biologic behavior and response to therapy. J Am Acad Dermatol 2001;44:193-7. 5. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367:1694-703. DOI: 10.1056/NEJMc1407683 Correspondence Copyright © 2014 Massachusetts Medical Society.
Urinary Sodium and Potassium Excretion, Mortality, and Cardiovascular Events (August 14, 2014;371:612-23). Reference 30 (page 623) should have read, “D’Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998;17: 2265-81,” rather than “Austin PC. Propensity-score matching in the cardiovascular surgery literature from 2004 to 2006: a systematic review and suggestions for improvement. J Thorac Cardiovasc Surg 2007;134:1128-35.” The article is correct at NEJM.org. The Child or Adolescent with Elevated Blood Pressure (June 12, 2014;370:2316-25). There were three errors in Table 4 (page 2322). In the Amiloride row, the first entry under Common Adverse Events should have been “Hyperkalemia,” rather than “Hypokalemia.” In the Hydralazine row, the entry in the Initial Dose column should have begun, “0.75 mg/kg/day . . . ,” rather than “0.75 mg/kg/dose . . . .” In the Minoxidil row, the entry in the Initial Dose column should have ended, “5 mg/day,” rather than “5 mg/kg/day.” The article is correct at NEJM.org.
instructions for letters to the editor
Letters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material that has been submitted or published elsewhere. Please note the following:
notices
• Letters not related to a Journal article must not exceed 400 words.
Notices submitted for publication should contain a mailing address and telephone number of a contact person or department. We regret that we are unable to publish all notices received. Notices also appear on the Journal’s website (NEJM.org/medical-conference). The listings can be viewed in their entirety or filtered by specialty, location, or month.
• A letter can have no more than five references and one figure or table.
Peripheral Venous Interventions & Ultrasound 2014
• Letters in reference to a Journal article must not exceed 175 words (excluding references) and must be received within 3 weeks after publication of the article.
• A letter can be signed by no more than three authors. • Financial associations or other possible conflicts of interest must be disclosed. Disclosures will be published with the
The course will be offered in Lake Buena Vista, FL, Oct. 9–11. Contact Educational Symposia, 5620 W Sligh Ave., Tampa, FL 33634; or call (800) 338-5901 or (813) 806-1000; or see http:// www.edusymp.com.
n engl j med 371;13 nejm.org september 25, 2014
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ry.3,4 We injected PRP a median of 3 days (inter- Johannes L. Tol, M.D., Ph.D. quartile range, 2 to 4) after injury. In a Cox Aspetar Qatar Orthopedic and Sports Medicine Hospital regression analysis, adjustment for the time be- Doha, Qatar Since publication of their letter, the authors report no further tween injury and injection did not materially potential conflict of interest. change the treatment effect. We injected three 1-ml depots at each proce- 1. Huard J, Li Y, Fu FH. Muscle injuries and repair: current trends in research. J Bone Joint Surg Am 2002;84-A:822-32. dure. According to a recent study by Magalon et 2. Hamilton BH, Best TM. Platelet-enriched plasma and muscle al.,5 this total of 3 ml corresponds to a PDGF strain injuries: challenges imposed by the burden of proof. Clin dosage of 40,000 pg (which is slightly less than J Sport Med 2011;21:31-6. 3. Wright-Carpenter T, Klein P, Schäferhoff P, Appell HJ, Mir the dosage reported by Anitua et al.). IGF-1 was LM, Wehling P. Treatment of muscle injuries by local adminisnot analyzed in their study. Magalon et al. de- tration of autologous conditioned serum: a pilot study on sportsscribe dosages of other growth factors and show men with muscle strains. Int J Sports Med 2004;25:588-93. 4. Bernuzzi G, Petraglia F, Pedrini MF, et al. Use of platelet-rich the content of different PRP preparation systems.5 plasma in the care of sports injuries: our experience with ultraGustaaf Reurink, M.D. Jan A.N. Verhaar, M.D., Ph.D. Erasmus Medical Center Rotterdam, the Netherlands
sound-guided injection. Blood Transfus 2014;12:Suppl 1:s229-s234. 5. Magalon J, Bausset O, Serratrice N, et al. Characterization and comparison of 5 platelet-rich plasma preparations in a single-donor model. Arthroscopy 2014;30:629-38. DOI: 10.1056/NEJMc1409204
Pyogenic Granuloma as a Cutaneous Adverse Effect of Vemurafenib To the Editor: Vemurafenib has altered the prognosis of patients with metastatic melanoma with BRAF V600 mutations.1 However, this agent is associated with a wide spectrum of cutaneous toxic effects, including squamous-cell carcinoma, primary melanoma, keratoacanthoma, and rashes.2 We have identified pyogenic granuloma as a further cutaneous event associated with vemurafenib. A 69-year-old man who had presented 2 years previously with a superficial spreading melanoma with a Breslow thickness of 1 mm was found to have bilateral axillary lymphadenopathy; a biopsy revealed melanoma with a BRAF V600E mutation. Staging investigations showed metastatic disease, with a 23-mm lesion in the right thalamic region, a 40-by-22-mm mass in the right axillary node, enlarged left axillary lymph nodes, and peritoneal deposits. Treatment was initiated with vemurafenib at a standard dose of 960 mg twice daily. Within 6 days, a widespread rash developed, which necessitated an interruption in treatment for 1 week and reinitiation at 75% of the initial dose (720 mg twice daily). At 12 weeks, a keratoacanthoma over the left clavicle and a rapidly enlarging vascular lesion on the left alar rim of the nose developed (Fig. 1A).
Both lesions were excised, with the latter requiring grafting. Histologic analysis of the nasal lesion confirmed pyogenic granuloma (Fig. 1B). Vemurafenib was continued, but 4 weeks after excision, six further pyogenic granulomas erupted close to the nasal skin graft (Fig. 1C). Four of these lesions were curetted, and two were left in situ. At this point, 24 weeks of vemurafenib had been administered, with a complete tumor response on imaging. In view of the rapid recurrence of lesions, vemurafenib was withheld for 2 weeks, during which no further lesions erupted, and the two residual pyogenic granulomas remained static in size. On reinstitution of treatment at 50% of the full dose (480 mg twice daily), these two lesions grew very slowly (Fig. 1D). The pattern of occurrence of pyogenic granulomas on and off treatment and the dose dependency suggest a mechanism driven by vemurafenib. Paradoxical activation of the MAPK pathway has been postulated as causing the development of squamous-cell carcinomas and keratoacanthomas in patients treated with this drug.3 This factor, coupled with the observation that pyogenic granulomas strongly overexpress MAP kinases,4 leads us to hypothesize that the molecular mechanisms driving dermatologic tox-
n engl j med 371;13 nejm.org september 25, 2014
The New England Journal of Medicine Downloaded from nejm.org on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1265
The
A
n e w e ng l a n d j o u r na l
of
m e dic i n e
B
D
C
Figure 1. Eruptions of Pyogenic Granulomas in a Patient with Metastatic Melanoma Treated with Vemurafenib. Twelve weeks after the initiation of vemurafenib, a rapidly enlarging vascular lesion appeared on the left alar rim of the patient’s nose. Panel A shows the appearance at 16 weeks, before curettage and grafting. A section obtained from the lesion showed a lobulated vascular proliferation composed of small vessels that included endothelial cells with surrounding pericytes within the dermis, features of pyogenic granuloma pericytes (Panel B, hematoxylin and eosin staining). Treatment with vemurafenib continued, and 4 weeks after surgery, six new lesions grew rapidly, as shown at 24 weeks (Panel C). Four of these six lesions were removed, and vemurafenib was interrupted for 2 weeks, during which the remaining two lesions did not grow in size and no new pyogenic granulomas appeared. On reinstitution of treatment at 50% of the original dose, the two remaining pyogenic granulomas grew very slowly in size, as shown at 29 weeks (Panel D). (Panels A, B, and D are reproduced with permission from Addenbrooke’s Hospital, and Panel C with permission from West Suffolk Hospital NHS Foundation Trust.)
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n engl j med 371;13
nejm.org
september 25, 2014
The New England Journal of Medicine Downloaded from nejm.org on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
notices
ic effects associated with vemurafenib are also responsible for the development of pyogenic granulomas. If this is the case, treatment with dual BRAF and MEK inhibition might prevent eruption of these lesions, in keeping with trial data showing that combined inhibition results in a significantly lower incidence of dermatologic events.5 Stephen John Sammut, M.D. Addenbrooke’s Hospital Cambridge, United Kingdom
Nevianna Tomson, M.B., Ch.B. West Suffolk Hospital Bury St. Edmunds, United Kingdom
letters. (For authors of Journal articles who are responding to letters, we will only publish new relevant relationships that have developed since publication of the article.) • Include your full mailing address, telephone number, fax number, and e-mail address with your letter. • All letters must be submitted at authors.NEJM.org. Letters that do not adhere to these instructions will not be considered. We will notify you when we have made a decision about possible publication. Letters regarding a recent Journal article may be shared with the authors of that article. We are unable to provide prepublication proofs. Submission of a letter constitutes permission for the Massachusetts Medical Society, its licensees, and its assignees to use it in the Journal’s various print and electronic publications and in collections, revisions, and any other form or medium.
Pippa Corrie, Ph.D. Addenbrooke’s Hospital Cambridge, United Kingdom [email protected]
corrections
Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org. 1. Chapman PB, Hauschild A, Robert C, et al. Improved sur-
vival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16. 2. Anforth R, Fernandez-Peñas P, Long GV. Cutaneous toxicities of RAF inhibitors. Lancet Oncol 2013;14(1):e11-e18. 3. Gibney GT, Messina JL, Fedorenko IV, Sondak VK, Smalley KSM. Paradoxical oncogenesis — the long-term effects of BRAF inhibition in melanoma. Nat Rev Clin Oncol 2013;10:390-9. 4. Arbiser JL, Weiss SW, Arbiser ZK, et al. Differential expression of active mitogen-activated protein kinase in cutaneous endothelial neoplasms: implications for biologic behavior and response to therapy. J Am Acad Dermatol 2001;44:193-7. 5. Flaherty KT, Infante JR, Daud A, et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367:1694-703. DOI: 10.1056/NEJMc1407683 Correspondence Copyright © 2014 Massachusetts Medical Society.
Urinary Sodium and Potassium Excretion, Mortality, and Cardiovascular Events (August 14, 2014;371:612-23). Reference 30 (page 623) should have read, “D’Agostino RB Jr. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med 1998;17: 2265-81,” rather than “Austin PC. Propensity-score matching in the cardiovascular surgery literature from 2004 to 2006: a systematic review and suggestions for improvement. J Thorac Cardiovasc Surg 2007;134:1128-35.” The article is correct at NEJM.org. The Child or Adolescent with Elevated Blood Pressure (June 12, 2014;370:2316-25). There were three errors in Table 4 (page 2322). In the Amiloride row, the first entry under Common Adverse Events should have been “Hyperkalemia,” rather than “Hypokalemia.” In the Hydralazine row, the entry in the Initial Dose column should have begun, “0.75 mg/kg/day . . . ,” rather than “0.75 mg/kg/dose . . . .” In the Minoxidil row, the entry in the Initial Dose column should have ended, “5 mg/day,” rather than “5 mg/kg/day.” The article is correct at NEJM.org.
instructions for letters to the editor
Letters to the Editor are considered for publication, subject to editing and abridgment, provided they do not contain material that has been submitted or published elsewhere. Please note the following:
notices
• Letters not related to a Journal article must not exceed 400 words.
Notices submitted for publication should contain a mailing address and telephone number of a contact person or department. We regret that we are unable to publish all notices received. Notices also appear on the Journal’s website (NEJM.org/medical-conference). The listings can be viewed in their entirety or filtered by specialty, location, or month.
• A letter can have no more than five references and one figure or table.
Peripheral Venous Interventions & Ultrasound 2014
• Letters in reference to a Journal article must not exceed 175 words (excluding references) and must be received within 3 weeks after publication of the article.
• A letter can be signed by no more than three authors. • Financial associations or other possible conflicts of interest must be disclosed. Disclosures will be published with the
The course will be offered in Lake Buena Vista, FL, Oct. 9–11. Contact Educational Symposia, 5620 W Sligh Ave., Tampa, FL 33634; or call (800) 338-5901 or (813) 806-1000; or see http:// www.edusymp.com.
n engl j med 371;13 nejm.org september 25, 2014
The New England Journal of Medicine Downloaded from nejm.org on August 10, 2015. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
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