Imiquimod

? Imiquimod, available as a 5% cream, is a new topical treatment for adults with superficial basal cell carcinoma (BCC). The exact mechanism of action of imiquimod in superficial BCC is unknown. Imiquimod may act as a toll-like receptor-7 agonist, and is thought to exert its anti-tumor effect via modification of the immune response and stimulation of apoptosis in BCC cells. ? Topical imiquimod 5% cream effectively increased clinical and histologic clearance of single superficial BCC lesions compared with vehicle in patients enrolled in two large, well designed trials. Patients applied imiquimod five or seven times per week or vehicle for 6 weeks, and the composite clearance rates at 12 weeks post-treatment for the corresponding treatment groups were 75%, 73%, and 2%, respectively. ? In a trial investigating the long-term efficacy of imiquimod 5% cream following application five times per week for 6 weeks, a clinical clearance rate of 90% was reported at the initial 12-week post-treatment examination. The estimated rate of clinical clearance at the 1-year follow-up visit was 84%. ? Application site and local skin reactions were the most common adverse events reported by imiquimod recipients. The severity of erythema, erosion, and scabbing/crusting correlated positively with the composite and histologic response rates.     

Imiquimod: in superficial basal cell carcinoma

Imiquimod, available as a 5% cream, is a new topical treatment for adults with superficial basal cell carcinoma (BCC). The exact mechanism of action of imiquimod in superficial BCC is unknown. Imiquimod may act as a toll-like receptor-7 agonist, and is thought to exert its anti-tumor effect via modification of the immune response and stimulation of apoptosis in BCC cells. Topical imiquimod 5% cream effectively increased clinical and histologic clearance of single superficial BCC lesions compared with vehicle in patients enrolled in two large, well designed trials. Patients applied imiquimod five or seven times per week or vehicle for 6 weeks, and the composite clearance rates at 12 weeks post-treatment for the corresponding treatment groups were 75%, 73%, and 2%, respectively. In a trial investigating the long-term efficacy of imiquimod 5% cream following application five times per week for 6 weeks, a clinical clearance rate of 90% was reported at the initial 12-week post-treatment examination. The estimated rate of clinical clearance at the 1-year follow-up visit was 84%. Application site and local skin reactions were the most common adverse events reported by imiquimod recipients. The severity of erythema, erosion, and scabbing/crusting correlated positively with the composite and histologic response rates.     

Immunomodulation by imiquimod in patients with high-risk primary melanoma

Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist approved for the topical treatment of actinic keratoses, superficial basal cell carcinoma, and genital warts. Imiquimod leads to an 80-100% cure rate of lentigo maligna; however, studies of invasive melanoma are lacking. We conducted a pilot study to characterize the local, regional, and systemic immune responses induced by imiquimod in patients with high-risk melanoma. After treatment of the primary melanoma biopsy site with placebo or imiquimod cream, we measured immune responses in the treated skin, sentinel lymph nodes (SLNs), and peripheral blood. Treatment of primary melanomas with 5% imiquimod cream was associated with an increase in both CD4+ and CD8+ T cells in the skin, and CD4+ T cells in the SLN. Most of the CD8+ T cells in the skin were CD25 negative. We could not detect any increases in CD8+ T cells specifically recognizing HLA-A(*)0201-restricted melanoma epitopes in the peripheral blood. The findings from this small pilot study demonstrate that topical imiquimod treatment results in enhanced local and regional T-cell numbers in both the skin and SLN. Further research into TLR7 immunomodulating pathways as a basis for effective immunotherapy against melanoma in conjunction with surgery is warranted.     

浅表婴儿血管瘤分布特点与疗效的关系探讨

 目的:探讨浅表婴儿皮肤血管瘤（IH）皮损特点与疗效的关系。方法：纳入77例未经任何治疗的浅表IH患儿,按照初诊时皮损分布特点分为散在分布组（A组）41例和融合分布组（B组）36例。两组均使用激光联合外敷马来酸噻吗洛尔滴眼液治疗,每次激光治疗后1周开始外敷药水,瘤体基本消退时停止治疗。取入选病例皮损周边正常皮肤作为对照组。分别于治疗前、治疗后4、8、12、16、20周,检测血红素 (EI) 值。治疗后每4周评价疗效、记录激光次数及不良反应。结果：①治疗4周后,A组有效率为21.95%,B组有效率为5.56%,差异有统计学意义（X²=4.21,P＜0.05）。治疗时间越长,两组有效率差异越明显。②A组平均激光治疗（1.54±0.81）次,B组平均激光治疗（2.89±1.21）次,两组比较差异有统计学意义（t=5.67,P＜0.01）。③治疗前B组 EI值（811.91±198.86）明显高于A组（676.14±158.14）及对照组（314.58±27.00）,三组比较差异有统计学意义（F=91.95,P＜0.01）。治疗16周后,A组 EI值已明显下降,与对照组比较差异无统计学意义（P＞0.05）;B组EI值仍明显高于A组及对照组,三组比较差异有统计学意义（F=50.42,P＜0.01）。结论：散在分布的浅表IH比融合分布的浅表IH激光治疗次数少,疗程短,有效率高。     

Imiquimod-induced regression of actinic keratosis is associated with infiltration by T lymphocytes and dendritic cells: a randomized controlled trial

BACKGROUND: Imiquimod 5% cream is a topically applied immune response modifier that has been shown to give effective treatment of actinic keratosis (AK). The therapeutic effects of imiquimod are likely to involve the provocation of a cutaneous immune response against abnormal cells, an assumption based on a strong correlation between complete clearance rates and the severity of the local skin reactions (erythema, oedema, erosion/ulceration, weeping/exudation and scabbing/crusting); however, no clinical studies have conclusively proved this mechanism. OBJECTIVES: To determine the nature of cellular infiltrates induced by the application of imiquimod to AK lesions and to study cells involved in the cutaneous immune response. METHODS: Eighteen patients participated in this phase I, randomized, double-blind, parallel group, vehicle-controlled study. Enrolled patients were randomized in a 2 : 1 ratio to receive imiquimod cream or vehicle cream and applied study cream to five lesions on the scalp, forearm or upper trunk once daily, three days per week for up to 16 weeks. Each patient had punch biopsies of two distinct AK lesions: a lesion was biopsied before treatment to obtain baseline biomarker levels, and a different lesion was biopsied after 2 weeks of treatment. Biopsy specimens were examined using routine and immunohistochemical staining. RESULTS: The imiquimod group showed statistically significant increases from baseline to week 2 in tissue biomarker levels for CD3, CD4, CD8, CD11c, CD86/CD11c, CD68, HLA-DR and TUNEL. No significant differences were seen for the vehicle group. Complete clearance of all treated AK lesions was achieved in five of 11 (45%) imiquimod patients and in none of six vehicle patients. CONCLUSIONS: Imiquimod stimulates a cutaneous immune response characterized by increases in activated dendritic cells and CD4+ and CD8+ T cells.     

Imiquimod for actinic keratosis: systematic review and meta-analysis

Benefit and harm associated with treating actinic keratosis (AK) with the immune response modifier imiquimod was assessed using published randomized-controlled trials. Five randomized double-blind trials lasted 12-16 weeks and treated 1,293 patients. Complete clearance occurred in 50% of patients treated with imiquimod, compared to 5% treated with vehicle, and the number needed to treat (NNT) for one patient to have their keratosis completely cleared after 12-16 weeks was 2.2 (95% confidence interval 2.0-2.5). For partial (>/=75%) clearance the NNT was 1.8 (1.7-2.0). The proportion of patients with any adverse event, any local adverse event, or any treatment-related adverse event was substantially higher with imiquimod than with vehicle, and numbers needed to harm for one additional adverse event with imiquimod over 12-16 weeks ranged from 3.2 to 5.9. Particular local adverse events with imiquimod included erythema (27%), scabbing or crusting (21%), flaking (9%), erosion (6%), edema (4%), and weeping (3%). Imiquimod 5% cream was effective in the treatment of AK, preventing potential development of squamous cell carcinoma. Future investigation might be aimed at elucidating optimal dosing to minimize adverse events without detriment to efficacy, and evaluating long-term recurrence.     

Timolol maleate 0.5% or 0.1% gel-forming solution for infantile hemangiomas: a retrospective, multicenter, cohort study

Therapeutic options for superficial infantile hemangiomas (IH) are limited. Recently, timolol maleate gel, a topical nonselective beta-blocker, has been reported as a potentially effective treatment for superficial IH. This study is an extension of a previously published pilot study designed to further investigate the efficacy and safety and to identify predictors of good response of topical 0.5% or 0.1% timolol maleate gel-forming solution. This was a retrospective cohort study including patients enrolled from five centers. Patients were included if they were treated with timolol maleate 0.1% or 0.5% gel-forming solution and had photographic documentation of the IH and at least one follow-up visit. Patients with concomitant active treatment using other IH treatments were excluded. The primary endpoint was change in the appearance of IH as evaluated using a visual analog scale (VAS). Data from 73 subjects were available for final analysis. Timolol maleate gel-forming solution 0.5% was used in 85% (62/73) of patients, the remainder being treated with 0.1%. The median age at treatment initiation was 4.27 months (interquartile range [IQR] 2.63-7.21 mos), and patients were treated for a mean of 3.4 ± 2.7 months. All patients except one improved, with a mean improvement of 45 ± 29.5%. Predictors of better response were superficial type of hemangioma (p = 0.01), 0.5% timolol concentration (p = 0.01), and duration of use longer than 3 months (p = 0.04). Sleeping disturbance was noted in one patient. This study further demonstrates the efficacy and tolerability of topical timolol maleate and gradual improvement with longer treatment in patients with superficial IH.     

PIGMENTED BASAL CELL CARCINOMA SUCCESSFULLY TREATED WITH 5% IMIQUIMOD CREAM

Basal cell carcinoma (BCC) is the most common malignant skin tumor, amongst which the nodular, nodulo ulcerative and superficial types comprise nearly 80% of all BCCs. Topical Imiquimod, an immune response modifier has been found to be effective in superficial and nodular types of BCC with histological clearance rates of up to 100%. We report our experience of treatment a large pigmented BCC on the face with topical Imiquimod 5% cream.     

Successful treatment of anogenital Bowen's disease with the immunomodulator imiquimod,and monitoring of therapy by DNA image cytometry

Imiquimod (Aldara, 3M) is an immune response modifier used for the treatment of anogenital warts. We report a 55-year-old non-immunocompromised woman with extensive, human papillomavirus (HPV) 16-positive anogenital Bowen's disease. After 5 months of local treatment with imiquimod, the lesions completely regressed clinically and histologically, and HPV 16 DNA was no longer detectable. Moreover, DNA image cytometry revealed DNA aneuploidy (an indicator of prospective malignancy) in pretreatment samples but not in post-treatment samples. Therefore, imiquimod might be a treatment option for Bowen's disease, particularly in patients where other treatment modalities such as surgery are contraindicated.     

Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from two phase III, randomized, vehicle-controlled studies

BACKGROUND: Imiquimod is an immune response modifier that is a Toll-like receptor 7 agonist that induces interferon and other cytokines through the innate immune system and stimulates cell-mediated immunity through T cells. Imiquimod has been shown to be efficacious as a topical treatment for basal cell carcinoma (BCC). OBJECTIVE: We sought to evaluate the efficacy and safety of imiquimod 5% cream compared with vehicle for treating superficial BCC (sBCC). METHODS: Two identical studies were conducted. Subjects with one sBCC were dosed with imiquimod or vehicle cream once daily 5 or 7x/week for 6 weeks in these 2 randomized, double-blind, vehicle-controlled Phase III studies. The lesion site was clinically examined 12 weeks posttreatment and then excised for histological evaluation. RESULTS: Data from both studies were pooled. Composite clearance rates (combined clinical and histological assessments) for the 5 and 7x/week imiquimod groups were 75% and 73%, respectively. Histological clearance rates for the 5 and 7x/week imiquimod groups were 82% and 79%, respectively. Increasing severity of erythema, erosion, and scabbing/crusting was associated with higher clearance rates. CONCLUSION: Imiquimod appears to be safe and effective for the treatment of sBCC when compared with vehicle cream. The difference in clearance rates between the two imiquimod dosing groups was not significant. The 5x/week regimen is recommended.     

Open-label study to assess the safety and efficacy of imiquimod 5% cream applied once daily three times per week in cycles for treatment of actinic keratoses on the head

BACKGROUND: Local skin reactions are common during imiquimod treatment of actinic keratosis (AK). Cyclical application of imiquimod may improve tolerability while maintaining efficacy. OBJECTIVE: To assess the tolerability of imiquimod and clearance rate of AK lesions after imiquimod application. METHODS: Imiquimod 5% cream was administered three times per week for 4 weeks followed by 4 weeks of rest (cycle 1) to AK lesions on the head. If AK lesions remained visible at the end of cycle 1, a second treatment cycle was instituted. RESULTS: Fifty percent (30 of 60) of patients experienced complete clearance of AK lesions, and 75% (30 of 40) of patients experienced partial clearance of AK lesions after imiquimod treatment at the end of cycle 2. Moreover, 77% of patients who achieved complete clearance had no visible AK lesions 12 weeks post-treatment. Imiquimod was well tolerated. CONCLUSION: Imiquimod cycle therapy may be a safe and effective treatment option for AK lesions.     

Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: results from a randomized vehicle-controlled phase III study in Europe

BACKGROUND: Imiquimod is an immune response modifier that acts through toll-like receptor 7 to induce cytokine production and a subsequent innate and adaptive cell-mediated immune response. Clinical studies have demonstrated clinical and histological clearance of superficial basal cell carcinoma (sBCC) after treatment with imiquimod 5% cream. OBJECTIVES: To evaluate the safety and clinical efficacy of imiquimod (Aldaratrade mark; 3M Pharmaceuticals, St Paul, MN, U.S.A.) 5% cream for the treatment of sBCC in a multicentre, randomized, parallel, vehicle-controlled, double-blind, phase III clinical study conducted at 26 centres in Europe. METHODS: Subjects who had at least one histologically confirmed sBCC tumour were randomized to apply imiquimod or vehicle cream to the target tumour once daily, seven times per week (7 x/week) for 6 weeks. The target tumour location was identified with an indelible ink mark before treatment initiation. The treated tumour site was clinically assessed for treatment response at 12 weeks post-treatment and was then excised for histological evaluation. Efficacy assessments included the composite response rates (proportion of subjects with clinical and histological clearance) and response rates solely based on histology (proportion of subjects with histological clearance). Safety assessments, which included adverse events and scoring of local skin reactions (LSRs), were carried out throughout the study. RESULTS: In total, 166 subjects were enrolled in this study. For the intent-to-treat dataset, there was a statistically significant difference between imiquimod and vehicle groups for both composite clearance rates (clinical and histological assessments) and histological clearance rates. Composite clearance was demonstrated in 77% and 6% of subjects treated with imiquimod and vehicle cream, respectively. Histological clearance was demonstrated in 80% and 6% of subjects treated with imiquimod and vehicle cream, respectively. The most frequently reported safety findings were investigator-assessed LSRs and spontaneous reports by subjects of application site reactions, which occurred more frequently in the imiquimod group than in the vehicle group. CONCLUSIONS: Imiquimod 5% cream administered 7 x/week for 6 weeks is a safe and effective treatment for sBCC when compared with vehicle cream.     

Infantile hemangiomas: risk factors for complications,recurrence and unaesthetic sequelae

BackgroundInfantile hemangiomas (IH) occur in approximately 4% to 10% of the pediatric population. The identification of clinical subtypes and conditions that indicate increased risk for complications is essential for therapeutic success.ObjectivesTo identify risk factors for complications, recurrence and unaesthetic sequelae.MethodsRetrospective cohort of patients with infantile hemangiomas undergoing follow-up at the Dermatology Service of Universidade Federal de Ciências da Saúde de Porto Alegre, between 2006 and 2018.Results190 patients were included; 24% had some type of complication, ulceration being the most frequent, and 86% required treatment. On correlation, ulceration was statistically related to mixed IH (p = 0.004), segmental IH (p < 0.01) and location in the gluteal region (p = 0.001). The mean time of treatment with propranolol was 12.7 months. Patients with PHACES syndrome and segmental infantile hemangioma required longer treatment (p < 0.001 and p = 0.0407, respectively), as well as those who started treatment after five months of life (p < 0.0001). Recurrence occurred in 16.6% of the treated patients, all-female; 94% were located on the head and neck (mainly on the upper eyelid, cyrano, S3 segment, and with parotid involvement); 61% and 38.8% were of the mixed and deep subtypes, respectively. Approximately 1/3 of the patients had some unaesthetic sequelae.Study limitationsAs this is a retrospective study, data and photos of some patients were lost.ConclusionsMixed and segmental hemangiomas are risk factors for ulceration and sequelae. Recurrence occurs more often in females and segmental hemangiomas. Segmental infantile hemangioma and PHACES syndrome require a longer time of treatment. Specific protocols are required for infantile hemangiomas with a high risk of recurrence.     

Widespread skin-limited adult Langerhans cell histiocytosis: long-term follow-up with good response to interferon alpha

Langerhans cell histiocytosis (LCH) most frequently involves bone, but also involves the skin in 40% of cases; in 10% of patients it is limited to the skin. Cutaneous findings of skin-limited LCH are scaly papules, vesicles, nodules, tumours with erosion, ulceration, or crusting and/or purpura. We report a case of widespread adult-onset LCH confined to skin in which topical carmustine, photochemotherapy, systemic steroids, and 2-chlorodeoxyadenosine were only partially effective. However, longer remission was achieved by the use of subcutaneous interferon-alpha2b.     

Imiquimod 5% cream for the treatment of superficial basal cell carcinoma: a double-blind,randomized, vehicle-controlled study

BACKGROUND: Imiquimod 5% cream may provide an effective nonsurgical treatment for superficial basal cell carcinoma (sBCC) based on results of previous studies. OBJECTIVE: The objective of this phase II dose-response study was to explore various dosing regimens using imiquimod 5% cream for sBCC to find the most effective frequency of dosing with tolerable side effects. METHODS: Patients (n = 128) were dosed twice daily, once daily, 5 times a week, or 3 times a week in this 12-week, randomized, double-blind, vehicle-controlled study. At 6 weeks after treatment, the entire tumor area was clinically evaluated, excised, and examined exhaustively for histologic evidence of residual sBCC. RESULTS: Complete response rates were 100% (10/10), 87.1% (27/31), 80.8% (21/26), and 51.7% (15/29) for patients in the twice daily, once daily, 5 times a week, and 3 times a week imiquimod groups, respectively, and 18.8% (6/32) in the vehicle group. CONCLUSION: Imiquimod 5% cream was effective in the treatment of sBCC. Daily or 5 times a week dosing for 12 weeks demonstrated high efficacy results with acceptable safety profiles.     

Self-administered topical 5% imiquimod for the treatment of common warts and molluscum contagiosum

BACKGROUND: Despite numerous therapeutic options the treatment of common warts and molluscum contagiosum remains unsatisfactory for both patients and physicians. Imiquimod, a novel topical immune response modifier, has been successfully used for the treatment of external anogenital warts. OBJECTIVES: We aimed to evaluate the safety, tolerance and efficacy of imiquimod for the treatment of common cutaneous warts and mollusca that were resistant to previous therapeutic interventions. METHODS: Imiquimod 5% cream was self-applied by the patients to the warts or mollusca once daily for 5 days per week and left in place overnight. Assessment for response and the occurrence of side-effects was performed every 4 weeks until clinical cure or up to a maximum of 16 weeks. RESULTS: Twenty-eight of 50 (56%) patients with warts achieved a total clearance (n = 15; 30%) or a > 50% reduction in wart size (n = 13; 26%) after a mean treatment period of 9.2 weeks. Twelve of 15 (80%) patients with mollusca achieved a total clearance (n = 8; 53%) or a > 50% reduction in molluscum size (n = 4; 27%). There was no difference in response with regard to gender, human immunodeficiency virus serostatus or atopic predisposition. CONCLUSIONS: Patient-applied 5% imiquimod cream holds promise as an effective treatment of common warts and mollusca in a difficult-to-treat patient population.     

咪喹莫特联合激光治疗尖锐湿疣的疗效及复发情况与局部LC数量变化的相关性

目的:探讨咪喹莫特联合激光治疗尖锐湿疣的疗效及复发情况与局部表皮郎格罕斯细胞(LC)数量变化的相关性。方法:随机选取广州市黄埔区红十字会医院皮肤科2010年5月至2015年5月收治的尖锐湿疣患者200例,依据治疗方法将这些患者分为咪喹莫特联合激光治疗组(联合治疗组,n=100)和咪喹莫特治疗组(单独治疗组,n=100)两组,对两组患者的总疣体数、临床疗效、复发情况及局部LC数量、并发症发生情况进行统计分析。结果:联合治疗组患者的总疣体数均显著少于单独治疗组(P0.05),总有效率94.0%(94/100)显著高于单独治疗组的76.0%(76/100)(P0.05),复发率10.0%(10/100)显著低于单独治疗组的27.0%(27/100)(P0.05),并发症发生率18.0%(18/100)显著低于单独治疗组的45.0%(45/100)(P0.05),两组中治疗有效患者的局部LC数量均显著多于复发患者(P0.05)。结论:咪喹莫特联合激光治疗尖锐湿疣的疗效显著,复发率较低,与局部LC数量呈负相关关系。     

Segmental Hemangioma of Infancy Complicated by Life-Threatening Arterial Bleed

Abstract:   Infantile hemangiomas (IHs) are the most common benign vascular tumors of childhood. IH of "segmental" morphology, are clusters of hemangiomas with a configuration involving a broad anatomic territory of skin. They are the least common of all types and generally larger than regular hemangiomas, morphologically characterized as plaque-like lesions. Head and neck segmental hemangiomas have a higher risk of causing life-threatening complications and of having associated structural anomalies, i.e., PHACES syndrome (Posterior fossa malformations, hemangiomas, arterial anomalies, coartation of the aorta and other cardiac defects, eye abnormalities and sternal clefting or supra abdominal raphe). We present a patient with a segmental IH over the right anterior neck complicated by ulceration and life threatening arterial bleeding. Although segmental hemangiomas of head and neck have high incidence of ulceration, fortunately life threatening bleeding events are rare with only 7 previously recorded cases. We recommend that large, neck IH be followed closely for evidence of ulceration and that MRI/MRA be performed to adequately assess their vascular supply. Direct extension of the ulceration into arterial vessels is a possibility and can lead to severe bleeding. Life-threatening bleeding is an unusual complication of IH and may represents a surgical emergency. In such cases we recommend a multidisciplinary approach to their treatment.