- Email: [email protected]
Experience with topical timolol maleate for the treatment of ulcerated infantile hemangiomas (IH)
LETTERS RESEARCH Experience with topical timolol maleate for the treatment of ulcerated infantile hemangiomas (IH) To the Editor: Ulceration is the most common complication of infantile hemangiomas (IH).1 Oral beta-blocker therapy has been reported to be of benefit.1 Whether topical timolol maleate gelforming solution is appropriate treatment for ulcerated cutaneous IH remains controversial.2,3 We performed a retrospective case analysis evaluating adverse events from the use of timolol gelforming solution in treating ulcerated IH. After approval from the internal review board of the Children’s Hospital of Philadelphia, 30 children were identified from January 2009 to August 2014 with a diagnosis of ulcerated IH treated with timolol. Exclusion criteria included concomitant use of oral corticosteroids. Demographic information is listed in Table I. Table II illustrates that most patients were treated with 1 drop of timolol maleate 0.5% gel-forming solution twice daily. Most ulcers occurred in skin folds including the diaper area (30%), consistent with the existing literature.1 Ulcers ranged in documented size from ‘‘focal’’ to 3 cm. Timolol was applied for 5 to 345 days, with a median and mean Table I. Patient demographics Characteristics
Gender Female Male Race Caucasian Other Gestational age Preterm Termy No. of hemangiomas 1 2 $3 Associated conditions None Spinal intrathecal hemangioma
Percent (N = 30)*
73.3 (22) 26.7 (8) 92.3 (24) 7.7 (2) 29.2 (7) 70.8 (17) 56.7 (17) 30.0 (9) 13.3 (4) 96.7 (29) 3.3 (1)
*Absolute numbers not totaling 30 indicate that information was not available for all study participants. Percentages are then recorded as a fraction of patients for whom that information was available. y Defined as 37 and 0/7 weeks of age.
J AM ACAD DERMATOL
LETTERS application time of 44 and 77 days, respectively. When patients transitioned to oral propranolol were excluded, these values were 67 and 93 days, respectively. Only 3 patients were instructed to avoid application of timolol to the ulcer itself (Table II). Timolol was discontinued after ulcer resolution (21), transition to propranolol (6), or surgical excision of IH (1). Two patients remained on timolol for IH treatment after ulcer resolution at the end of the study period. Three patients were treated simultaneously with oral propranolol and timolol. One of these patients had an adverse response to therapy. This was sleep disturbance, which resolved with a decrease in dose and frequency of propranolol administration. Another patient reported a single episode of cold extremities that responded rapidly to rewarming. Of the patients for whom vital signs were assessed after initiating timolol, all values were within normal range for age (Table II). Our study is limited by its retrospective design and inability to confirm the timing of ulceration and resolution with timolol therapy, and whether families applied timolol as instructed (Table II). No ulcerated perioral hemangiomas were treated in our cohort and we caution against use of timolol in this area, despite reports of tolerability.4 Our data suggest that timolol may be a well-tolerated alternative to oral propranolol in treating IH ulceration up to approximately 3 cm in size. However, we recommend a comprehensive history and physical examination and close clinical follow-up to monitor for potential adverse events of beta-blockade. Caregivers should be counseled that complete healing of ulcerated IH may take at least 2 to 3 months. Prospective, randomized controlled trials are warranted to evaluate the safety and relative efficacy of topical timolol for ulcerated IH. Markus D. Boos, MD, PhD, and Leslie CasteloSoccio, MD, PhD Section of Dermatology, Department of Pediatrics, Children’s Hospital of Philadelphia, and Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia Funding sources: None. Conflicts of interest: None declared. MARCH 2016 567
Age at Patient ulceration, mo no.
Location
IH size, mm
Length Ulcer size, of ulcerated mm IH therapy, d
1
1.5
Gluteal cleft
NR
15
222
2
4
Axilla
NR
15
42
3
13
Abdomen
60
4
17
4
11
Buttock
30
6
18
5
9
Mons, near clitoris
10
2
203
6
6
Abdomen
30
13
120
7
3
Occiput
20-30
2
33
8
3
Vertex scalp
30
NR
16
9
3
Parietal scalp
11 3 15
4
99
10
4
Neck fold
NR
10
85
11
18
55 3 35
4
29
Neck Forehead
40
5
15
13
2
Buttock
20
NR
36
14
3
Labia
40
5
345
15
2
Posterior auricular scalp
NR
NR
20
16
7
Parietal scalp
40 3 45 10
183
17
3
Inguinal fold
NR
6
99
18
1
Upper lip
NR
NR
10
Initial glucose (mg/dL)*
Adverse events
0.5% 1 drop bid 0.5% 1 drop bid 0.5% 2 drops bid 0.5% 1 drop bid 0.5% 1 drop bid 0.5% 1 drop bid 0.25% 1/2 drop bid 0.5% 1 drop bid 0.5% 1 drop bid 0.5% 1 drop bid 0.5% 1-2 drops bid 0.5% 1 drop bid 0.5% 2 drops bid 0.5% 1 drop daily 0.5% 1 drop bid 0.5% 2 drops bid 0.5% 1 drop bid 0.5% 1 drop bid
NS
No
143/82y 137
NR
None
NS
No
NR
NR
NR
None
NS
No
NR
NR
NR
None
NS
No
NR
NR
NR
None
To affected area
No
121/83
123
NR
None
To affected area
No
98/43
133
NR
None
To IH
No
115/60
131
NR
None
NS
No
89/65
154
118
None
To affected area
No
NR
NR
NR
None
NS
No
79/32z 135
NR
None
To ulcer
No
NR
NR
NR
None
NS
No
90/63
150
85
None
To affected area
No
106/85
154
117
None
To affected area Yes (1.5 mg/kg/d) 108/57
133
NR
None
To affected area
No
NR
NR
NR
None
To IH
No
86/55
131
NR
None
To IH
No
101/61
137
NR
None
To cutaneous lip only
No
71/49
160
98
None
MARCH 2016
1.25
Initial BP Initial (mm Hg)* HR*
Site applied
J AM ACAD DERMATOL
12
Concomitant propranolol use (dose)
Timolol dosing
568 Letters
Table II. Characteristics of ulcerated infantile hemangiomas treated with topical timolol
21 22 23 24 25 26 27 28 29 30
3 4 2 6 2 0.25 5 5 6 4 3
Labia Buttock Index finger Neck fold Inguinal fold Nasal tip Gluteal cleft Crown of scalp Neck fold Upper aspect of back Lower aspect of back Left elbow/antecubital fossa
NR 30 3 14 30-40 NR 20 NR NR NR NR 50 3 50
Focal 5 5 NR 8 NR NR NR NR 5
40 3 30 10 60
30
49 82 51 37 44 5 20 44 155 99 128 18
0.25% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop
To IH
No
100/60
95
NR
None
To IH
No
NR
NR
NR
Cool extremities
NS
No
NR
NR
NR
None
To affected area
No
NR
NR
NR
None
To IH
No
NR
NR
NR
None
To IH
No
92/58
136
98
None
To IH
No
96/50
123
NR
None
To IH, avoiding No NR ulcer To ulcer Yes (1.5 mg/kg/d) 105/52
NR
NR
None
139
NR
None
NS
NR
NR
None
114
NR
114
NR
bid bid bid bid
J AM ACAD DERMATOL
20
61
VOLUME 74, NUMBER 3
19
bid daily bid bid daily No
NR
tid To ulcer
Yes (1.5 mg/kg/d) 109/56
bid bid
To IH, avoiding ulcer
No
105/59
Sleep disturbance Diarrheax
bid, Twice daily; BP, blood pressure; HR, heart rate; IH, infantile hemangioma; NR, not recorded; NS, not specified ( patient instructions did not provide specifics regarding the method of application); tid, three times daily. *Vital signs as listed represent the first values obtained after initiation of timolol therapy. y Next 2 BP measurements were 129/66 and 103/65 at same dose. z Patient was clinically asymptomatic at time of this measurement; next BP measurement was 95/42 at same dose. x Single episode after course of cephalexin, resolved while continuing timolol therapy.
Letters 569
J AM ACAD DERMATOL
570 Letters
MARCH 2016
Correspondence to: Leslie Castelo-Soccio, MD, PhD, Children’s Hospital of Philadelphia, 3550 Market St, Second Floor, Philadelphia, PA 19104 E-mail: [email protected] REFERENCES 1. P€ uttgen KB. Diagnosis and management of infantile hemangiomas. Pediatr Clin North Am. 2014;61:383-402. 2. McMahon P, Oza V, Frieden IJ. Topical timolol for infantile hemangiomas: putting a note of caution in ‘‘cautiously optimistic.’’. Pediatr Dermatol. 2012;29:127-130. 3. Berk D, Lehman P, Franz TJ, et al. On topical timolol gel-forming solution for infantile hemangiomas. Pediatr Dermatol. 2013;30: 160-161. 4. Beal BT, Chu MB, Siegfried EC. Ulcerated infantile hemangioma: novel treatment with topical brimonidine-timolol. Pediatr Dermatol. 2014;31:754-756. http://dx.doi.org/10.1016/j.jaad.2015.10.021
Lack of TERT promoter mutations in melanomas with extensive regression To the Editor: The recently discovered TERT promoter mutations have been shown to play an important role in melanoma pathogenesis.1 These mutations imply an increased gene expression, with the restoration of telomerase activity and the stabilization of telomeres length.2 Interestingly, some authors have described absence of telomerase activity and shortening of telomeres in regressing swine melanoma cell lines.3 Therefore, although most studies have focused on immunologic response to explain spontaneous regression, telomere dysfunction has been proposed as an additional mechanism.4 We sought to determine whether melanomas with and without regression harbor different prevalences of TERT promoter mutations. A case-control study was designed in a series of 110 primary melanoma samples diagnosed between January 2012 and December 2014. Ethical approval from the Institutional Review Board and informed consent from all patients were obtained. Clinical characteristics and histologic parameters were collected. Regression was classified as absent (47%; 52/110), partial with less than 50% of the specimen involved (41%; 45/110), or extensive with more than 50% involvement (12%; 13/110). Genomic DNA was extracted from formalin-fixed and paraffin-embedded sections using the GeneRead DNA FFPE Kit (Qiagen), according to manufacturer’s protocol. Mutational status of TERT promoter region was determined by polymerase chain reaction and Sanger sequencing as has been previously described.5 The relationship between mutational status and clinicopathologic features was evaluated
Fig 1. Association of TERT promoter mutation status and clinicopathologic features. TERT promoter mutations are associated with sex, location, histological subtype, Breslow thickness, ulceration, regression, and mitosis. P values were derived from 2-test and considered statistically significant if \.05.
Fig 2. Distribution of TERT promoter mutations according to regression. TERT promoter mutations were significantly associated with melanomas without regression. None of the melanomas with extensive regression harbored recurrent mutations.
using 2 and logistic regression analysis. P values \.05 were considered statistically significant. TERT promoter mutations were detected in 30% (33/110) of melanoma samples. The somatic changes 146C[T and 124C[T were detected in 45% (15/33) and 27% (9/33) of the samples, respectively. Mutations
Gender Female Male Race Caucasian Other Gestational age Preterm Termy No. of hemangiomas 1 2 $3 Associated conditions None Spinal intrathecal hemangioma
Percent (N = 30)*
73.3 (22) 26.7 (8) 92.3 (24) 7.7 (2) 29.2 (7) 70.8 (17) 56.7 (17) 30.0 (9) 13.3 (4) 96.7 (29) 3.3 (1)
*Absolute numbers not totaling 30 indicate that information was not available for all study participants. Percentages are then recorded as a fraction of patients for whom that information was available. y Defined as 37 and 0/7 weeks of age.
J AM ACAD DERMATOL
LETTERS application time of 44 and 77 days, respectively. When patients transitioned to oral propranolol were excluded, these values were 67 and 93 days, respectively. Only 3 patients were instructed to avoid application of timolol to the ulcer itself (Table II). Timolol was discontinued after ulcer resolution (21), transition to propranolol (6), or surgical excision of IH (1). Two patients remained on timolol for IH treatment after ulcer resolution at the end of the study period. Three patients were treated simultaneously with oral propranolol and timolol. One of these patients had an adverse response to therapy. This was sleep disturbance, which resolved with a decrease in dose and frequency of propranolol administration. Another patient reported a single episode of cold extremities that responded rapidly to rewarming. Of the patients for whom vital signs were assessed after initiating timolol, all values were within normal range for age (Table II). Our study is limited by its retrospective design and inability to confirm the timing of ulceration and resolution with timolol therapy, and whether families applied timolol as instructed (Table II). No ulcerated perioral hemangiomas were treated in our cohort and we caution against use of timolol in this area, despite reports of tolerability.4 Our data suggest that timolol may be a well-tolerated alternative to oral propranolol in treating IH ulceration up to approximately 3 cm in size. However, we recommend a comprehensive history and physical examination and close clinical follow-up to monitor for potential adverse events of beta-blockade. Caregivers should be counseled that complete healing of ulcerated IH may take at least 2 to 3 months. Prospective, randomized controlled trials are warranted to evaluate the safety and relative efficacy of topical timolol for ulcerated IH. Markus D. Boos, MD, PhD, and Leslie CasteloSoccio, MD, PhD Section of Dermatology, Department of Pediatrics, Children’s Hospital of Philadelphia, and Department of Dermatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia Funding sources: None. Conflicts of interest: None declared. MARCH 2016 567
Age at Patient ulceration, mo no.
Location
IH size, mm
Length Ulcer size, of ulcerated mm IH therapy, d
1
1.5
Gluteal cleft
NR
15
222
2
4
Axilla
NR
15
42
3
13
Abdomen
60
4
17
4
11
Buttock
30
6
18
5
9
Mons, near clitoris
10
2
203
6
6
Abdomen
30
13
120
7
3
Occiput
20-30
2
33
8
3
Vertex scalp
30
NR
16
9
3
Parietal scalp
11 3 15
4
99
10
4
Neck fold
NR
10
85
11
18
55 3 35
4
29
Neck Forehead
40
5
15
13
2
Buttock
20
NR
36
14
3
Labia
40
5
345
15
2
Posterior auricular scalp
NR
NR
20
16
7
Parietal scalp
40 3 45 10
183
17
3
Inguinal fold
NR
6
99
18
1
Upper lip
NR
NR
10
Initial glucose (mg/dL)*
Adverse events
0.5% 1 drop bid 0.5% 1 drop bid 0.5% 2 drops bid 0.5% 1 drop bid 0.5% 1 drop bid 0.5% 1 drop bid 0.25% 1/2 drop bid 0.5% 1 drop bid 0.5% 1 drop bid 0.5% 1 drop bid 0.5% 1-2 drops bid 0.5% 1 drop bid 0.5% 2 drops bid 0.5% 1 drop daily 0.5% 1 drop bid 0.5% 2 drops bid 0.5% 1 drop bid 0.5% 1 drop bid
NS
No
143/82y 137
NR
None
NS
No
NR
NR
NR
None
NS
No
NR
NR
NR
None
NS
No
NR
NR
NR
None
To affected area
No
121/83
123
NR
None
To affected area
No
98/43
133
NR
None
To IH
No
115/60
131
NR
None
NS
No
89/65
154
118
None
To affected area
No
NR
NR
NR
None
NS
No
79/32z 135
NR
None
To ulcer
No
NR
NR
NR
None
NS
No
90/63
150
85
None
To affected area
No
106/85
154
117
None
To affected area Yes (1.5 mg/kg/d) 108/57
133
NR
None
To affected area
No
NR
NR
NR
None
To IH
No
86/55
131
NR
None
To IH
No
101/61
137
NR
None
To cutaneous lip only
No
71/49
160
98
None
MARCH 2016
1.25
Initial BP Initial (mm Hg)* HR*
Site applied
J AM ACAD DERMATOL
12
Concomitant propranolol use (dose)
Timolol dosing
568 Letters
Table II. Characteristics of ulcerated infantile hemangiomas treated with topical timolol
21 22 23 24 25 26 27 28 29 30
3 4 2 6 2 0.25 5 5 6 4 3
Labia Buttock Index finger Neck fold Inguinal fold Nasal tip Gluteal cleft Crown of scalp Neck fold Upper aspect of back Lower aspect of back Left elbow/antecubital fossa
NR 30 3 14 30-40 NR 20 NR NR NR NR 50 3 50
Focal 5 5 NR 8 NR NR NR NR 5
40 3 30 10 60
30
49 82 51 37 44 5 20 44 155 99 128 18
0.25% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop 0.5% 1 drop
To IH
No
100/60
95
NR
None
To IH
No
NR
NR
NR
Cool extremities
NS
No
NR
NR
NR
None
To affected area
No
NR
NR
NR
None
To IH
No
NR
NR
NR
None
To IH
No
92/58
136
98
None
To IH
No
96/50
123
NR
None
To IH, avoiding No NR ulcer To ulcer Yes (1.5 mg/kg/d) 105/52
NR
NR
None
139
NR
None
NS
NR
NR
None
114
NR
114
NR
bid bid bid bid
J AM ACAD DERMATOL
20
61
VOLUME 74, NUMBER 3
19
bid daily bid bid daily No
NR
tid To ulcer
Yes (1.5 mg/kg/d) 109/56
bid bid
To IH, avoiding ulcer
No
105/59
Sleep disturbance Diarrheax
bid, Twice daily; BP, blood pressure; HR, heart rate; IH, infantile hemangioma; NR, not recorded; NS, not specified ( patient instructions did not provide specifics regarding the method of application); tid, three times daily. *Vital signs as listed represent the first values obtained after initiation of timolol therapy. y Next 2 BP measurements were 129/66 and 103/65 at same dose. z Patient was clinically asymptomatic at time of this measurement; next BP measurement was 95/42 at same dose. x Single episode after course of cephalexin, resolved while continuing timolol therapy.
Letters 569
J AM ACAD DERMATOL
570 Letters
MARCH 2016
Correspondence to: Leslie Castelo-Soccio, MD, PhD, Children’s Hospital of Philadelphia, 3550 Market St, Second Floor, Philadelphia, PA 19104 E-mail: [email protected] REFERENCES 1. P€ uttgen KB. Diagnosis and management of infantile hemangiomas. Pediatr Clin North Am. 2014;61:383-402. 2. McMahon P, Oza V, Frieden IJ. Topical timolol for infantile hemangiomas: putting a note of caution in ‘‘cautiously optimistic.’’. Pediatr Dermatol. 2012;29:127-130. 3. Berk D, Lehman P, Franz TJ, et al. On topical timolol gel-forming solution for infantile hemangiomas. Pediatr Dermatol. 2013;30: 160-161. 4. Beal BT, Chu MB, Siegfried EC. Ulcerated infantile hemangioma: novel treatment with topical brimonidine-timolol. Pediatr Dermatol. 2014;31:754-756. http://dx.doi.org/10.1016/j.jaad.2015.10.021
Lack of TERT promoter mutations in melanomas with extensive regression To the Editor: The recently discovered TERT promoter mutations have been shown to play an important role in melanoma pathogenesis.1 These mutations imply an increased gene expression, with the restoration of telomerase activity and the stabilization of telomeres length.2 Interestingly, some authors have described absence of telomerase activity and shortening of telomeres in regressing swine melanoma cell lines.3 Therefore, although most studies have focused on immunologic response to explain spontaneous regression, telomere dysfunction has been proposed as an additional mechanism.4 We sought to determine whether melanomas with and without regression harbor different prevalences of TERT promoter mutations. A case-control study was designed in a series of 110 primary melanoma samples diagnosed between January 2012 and December 2014. Ethical approval from the Institutional Review Board and informed consent from all patients were obtained. Clinical characteristics and histologic parameters were collected. Regression was classified as absent (47%; 52/110), partial with less than 50% of the specimen involved (41%; 45/110), or extensive with more than 50% involvement (12%; 13/110). Genomic DNA was extracted from formalin-fixed and paraffin-embedded sections using the GeneRead DNA FFPE Kit (Qiagen), according to manufacturer’s protocol. Mutational status of TERT promoter region was determined by polymerase chain reaction and Sanger sequencing as has been previously described.5 The relationship between mutational status and clinicopathologic features was evaluated
Fig 1. Association of TERT promoter mutation status and clinicopathologic features. TERT promoter mutations are associated with sex, location, histological subtype, Breslow thickness, ulceration, regression, and mitosis. P values were derived from 2-test and considered statistically significant if \.05.
Fig 2. Distribution of TERT promoter mutations according to regression. TERT promoter mutations were significantly associated with melanomas without regression. None of the melanomas with extensive regression harbored recurrent mutations.
using 2 and logistic regression analysis. P values \.05 were considered statistically significant. TERT promoter mutations were detected in 30% (33/110) of melanoma samples. The somatic changes 146C[T and 124C[T were detected in 45% (15/33) and 27% (9/33) of the samples, respectively. Mutations