Randomized clinical trial comparing removal followed by topical imiquimod versus removal followed by topical methylprednisolone in the treatment of keloids

Laser-assisted drug delivery in the treatment of keloids: A case of extensive refractory keloids successfully treated with fractional carbon dioxide laser followed by topical application and intralesional injection of steroid suspension

Extramammary Paget disease is an uncommon cutaneous neoplasm that presents as erythematous plaques most frequently located in the anogenital region. Management of patients with extramammary Paget disease involves evaluation of the individual for: (1) a disease-associated, unsuspected, visceral malignancy and (2) secondary adenocarcinoma in the underlying dermis or regional lymph nodes. Several modalities, each with variable effectiveness, are available to treat the cutaneous component of the disease: electrodesiccation and curettage, laser surgery, aminolevulinic acid photodynamic therapy, radiotherapy, topical chemotherapy, and wide surgical excision. However, surgical excision using the Mohs micrographic technique is currently the modality of choice for treating the cutaneous lesions of extramammary Paget disease. Recently, a topical imidazoquinoline immunomodulator that induces cytokine production and stimulates the innate and cellular immune responses--imiquimod cream-has been used for the management of primary or relapsing extramammary Paget disease. Complete healing, without recurrence, of extramammary Paget disease in patients whose cutaneous lesions were treated topically with imiquimod 5% cream was observed. We describe a man with suprapubic extramammary Paget disease whose condition was primary and limited to his skin. Biopsy-confirmed complete resolution of his disease was observed after the topical application of imiquimod 5% cream 3 times per week (on alternate days) for 16 weeks. After reviewing the published reports of other patients with extramammary Paget disease whose disease was successfully treated with imiquimod cream, we suggest that topical imiquimod 5% cream-at least 3 times per week (with 1-2 d of nontreatment in between) for a minimum of 8 to 16 weeks--be considered as an initial treatment for primary cutaneous extramammary Paget disease. Surgical excision or an alternative therapeutic modality is recommended for patients whose extramammary Paget disease persists or recurs after treatment with topical imiquimod.

Patients with metastatic skin disease in malignant melanoma can be difficult to treat effectively, often requiring repeated treatments with different modalities in an attempt to control their disease. Treatment of nonsurgically resectable melanoma deposits is unsatisfactory, as they are often multiple and recurring. Anecdotal evidence from individual use of imiquimod in superficial metastases and intralesional interleukin (IL)-2 in subcutaneous deposits suggests that the combination may be more effective in bulky subcutaneous disease. To investigate the combination of topical imiquimod and, for selected lesions, intralesional IL-2, to treat a small cohort of patients with accessible melanoma metastases resistant to other treatments. Thirteen patients were recruited: all had evidence of multiple cutaneous and/or subcutaneous metastases. Imiquimod was applied to the metastases on a daily basis for 4 weeks, before the introduction of intralesional IL-2. This was injected up to three times a week, into selected lesions, with 0.1 mL injected per lesion at a concentration of 3.6 MIU mL(-1), a total of 1 mL being given at each session. The treated lesions were assessed individually at intervals of 3 months. Thirteen patients were treated, with 10 being eligible for assessment. In total, 182 lesions were treated: 137 purely cutaneous lesions and 41 subcutaneous lesions. Overall, a clinical response was seen in 92 lesions (50.5%) with 74 (40.7%) of these being a complete response (CR) with 91% of the CRs being in the cutaneous lesions. New lesions did appear during the treatment course; however, patients with cutaneous disease experienced a marked slowing of the appearance of new cutaneous lesions. No cutaneous lesions that responded reappeared on cessation of treatment. The combination of imiquimod and IL-2 is effective in controlling this mixed cutaneous and subcutaneous disease, and is well tolerated. Imiquimod alone is often enough to elicit a response in purely cutaneous lesions. The addition of intralesional IL-2 increases the response rates in subcutaneous lesions, and in otherwise refractory cutaneous lesions.

Cytokine Induction in Hairless Mouse and Rat Skin After Topical Application of the Immune Response Modifiers Imiquimod and S-28463

The maturation state of dendritic cells is one of the factors that affect their capacity to induce antigen-specific cytotoxic T lymphocytes. Topical cutaneous application of imiquimod can induce the maturation and migration of cutaneous dendritic cells. To evaluate the synergistic effect of topical application of imiquimod plus intratumoral injection of syngeneic bone marrow-derived dendritic cells in the treatment of melanoma. For the B16F10 melanoma model, naive C57BL/6 mice were inoculated intradermally with 2x10(3) B16F10 melanoma cells in the right upper flank. Four groups (untreated control, dendritic cells alone, imiquimod alone and imiquimod plus dendritic cells) were included in the animal study, with five mice in each group. Tumour size was measured every 2 weeks, and histochemical and immunohistochemical staining carried out. ELISpot and PKH assays were performed to assess immune activity. Combined treatment of topical application of imiquimod and intratumoral injection of dendritic cells led to significant tumour regression, in contrast to partial eradication of the tumours with imiquimod or dendritic cells alone. These findings suggest that combination therapy with topical application of imiquimod and intratumoral administration of dendritic cells is a potent strategy for the treatment of melanoma.

Concomitant vulval high-grade squamous intraepithelial lesion (HSIL) and cervical intraepithelial neoplasia (CIN) have rarely been associated in a young woman and should prompt investigation for high-risk Human Papillomavirus (HPV). Conservative treatment strategies for vulval HSIL typically range from skinning vulvectomy to topical applications of immunomodu-lator creams. Imiquimod 5% topical application has been associated with local side effects, including itching and burning. Systemic side effects are extremely rare. The authors report a unique case of generalized lymphadenopathy following topical application of imiquimod 5%. A 32-year-old, nulligravida woman of Asian ethnicity presented with subfertility. Incidentally, her general examination showed the presence of raised, multifocal, maculopapular le-sions (Bowenoid papulosis) with biopsy showing usual-type vulval high-grade squamous intraepi-thelial lesion (HSIL). After a brief application of topical imiquimod 5%, she developed sudden, tender generalized lymphadenopathy. Aspiration cytology showed caseation necrosis, and she was hence started on anti-tubercular therapy. Resolution of lymphadenopathy was observed at the one-month follow-up. This is the first reported case of acute, tender generalized lymphadenopathy with topical imiquimod in a patient with CIN and vulval HSIL. The underlying mechanism involves alteration of cell-mediated immunity, and the resultant likely functional maturation of epidermal Langerhans cells in vivo is hypothesized. This forms an alternative to surgery, as it is a convenient, self-administered modality that does not affect psychosexual health. Additionally, it has been implicated in HPV virus clearance, unlike surgery, and was hence recommended in this case. This report underscores this rare phenomenon that can pose a significant therapeutic challenge to clinicians, necessitating regular and long-term follow-up.

Hypertrophic (HTSs) and keloid scars are common dermatological complaints produced by disruption of the normal wound-healing process. Despite a wide array of therapeutic options available to treat these lesions, HTSs and keloids continue to pose a significant challenge to clinicians in everyday practice. The chemotherapeutic drug 5-fluorouracil (5-FU) is a well-known treatment option reserved for recalcitrant HTSs and keloid lesions. We present clinicians with a comprehensive review of the published data concerning the use of 5-FU in the treatment of HTSs and keloids. The current evidence suggests that 5-FU is a safe and practical alternative for the treatment of HTSs and keloids as it may substantially improve the appearance of proliferative scars and reduce the chance of recurrence. This therapeutic option is most effective in conjunction with adjuvant therapy such as corticosteroids. Additional randomized controlled clinical trials with large sample sizes should be conducted to corroborate the existing efficacy and safety data in patients with HTSs and keloids.Electronic supplementary materialThe online version of this article (doi:10.1007/s13555-016-0118-5) contains supplementary material, which is available to authorized users.

Objective:To evaluate the feasibility and efficacy of a pulsed dye laser (PDL) during a 5-week course of 5% topical imiquimod application in a patient with a nodular basal cell carcinoma (BCC) and to review the literature for data on PDL treatment of BCC.Methods:A 74-year-old patient with a 7-mm biopsy-proven BCC on his nose was treated with topical daily imiquimod for 2 weeks. Subsequently a laser session was performed with a flash lamp-pumped dye laser at 595 nm (Dermobeam 2000; Deka M.E.L.A., Florence, Italy) employing one pass with the following parameters: fluence 15 J/cmResults:Topical imiquimod was continued for a further 3 weeks after the PDL session with a minimal increase in irritation. The tumor cleared and there has been no recurrence for 12 months. The literature search revealed a total of 7 small studies that included 120 tumors, the majority treated with a 595-nm device (104/120). Overall 81/120 (67.5%) treated tumors have been assessed as complete responders. No differences were recorded in relapse rates in association with the localization of the tumor, the histology (superficial vs. non-superficial), the wavelength of the device employed (595 vs. 585 nm), or the application of dynamic cooling. From the treatment parameters, only the use of multiple vs. single PDL sessions affected the outcome favorably (Conclusion:The combination of PDL with imiquimod could be a promising approach for the treatment of BCC and should be further evaluated in future studies.

Lentigo maligna (LM) is an in situ melanoma which usually occurs in sun-damaged skin on the head and neck of elderly patients. Depending on the anatomical site and its size treatment of LM can be problematic and usually includes surgical excision or radiotherapy. Recent reports indicate that topical imiquimod may be an effective treatment. However, no data on the underlying immune response in the skin during treatment of LM with topical imiquimod are available so far. We report a 62-year-old caucasian woman with a histologically verified LM which was successfully treated with topical imiquimod 5% cream. Skin biopsy specimens were obtained before, during (at week 10) and 4 weeks after cessation of topical treatment with imiquimod 5% cream. Histological and immunohistochemical examination was performed in order to detect residual atypical melanocytes and to characterize the inflammatory infiltrate. A complete clinical and histological clearance of the skin lesion was achieved, with no recurrence up to 9 months after the end of treatment. During topical application of imiquimod 5% cream a depletion of epidermal and dermal CD1a+ dendritic cells was observed. The inflammatory infiltrate consisted of CD68+ macrophages and mainly of CD3+ T cells with a slight predominance of CD8+ T cells. An enhanced expression of granzyme B and TIA-1 was also noted particularly in the epidermis and near the dermoepidermal junction. In conclusion, our data indicate that imiquimod 5% cream induces a cytotoxic T-cell-mediated immune response in situ which may account for the complete destruction of the malignant melanocytes in LM. Further clinical trials and longer follow-up periods on the use of imiquimod for LM are warranted.

BACKGROUND> An unchecked proliferation of fibrous tissue after an injury to the skin is the basic mechanism for keloid formation. Recent studies have shown the inhibitory effect of interferons on dermal fibroblast growth and/or collagen production. Various therapeutic modalities have been used for the treatment of keloids, although only with limited success. There are only a few reports on the use of interferons in the treatment of keloids. To our knowledge no controlled clinical trials have examined the efficacy of intralesional interferon-alpha 2b on mature keloid lesions. In this study, recombinant human interferon-alpha 2b was examined for its ability to modify keloids clinically. Twenty-two patients with at least two mature keloids were studied twice weekly for 3 weeks. Patients were treated by injection of recombinant human interferon-alpha 2b, 0.5 million per cm2 of keloid, into one lesional site and diluent alone into another lesional site. Lesions were measured before and on days 8, 15, 22, and 29 after starting treatment. Only 13 of 22 patients could be evaluated at the end of the study; seven patients withdrew from the study because of severe local pain during injection. Three of the 13 patients showed insignificant reduction in the height of keloids after interferon treatment. No serious laboratory abnormalities were detected.

Topical Imiquimod Treatment Prevents UV-Light Induced Loss of Contact Hypersensitivity and Immune Tolerance

Topical imiquimod before intradermal trivalent influenza vaccine for protection against heterologous non-vaccine and antigenically drifted viruses: a single-centre, double-blind, randomised, controlled phase 2b/3 trial

Topical imiquimod is a potent adjuvant to a weakly-immunogenic protein prototype vaccine

To report a new, alternative treatment for nasal papillomata in human immunodeficiency virus positive patients with multiple recurrences after surgical removal. A human immunodeficiency virus positive patient presented with multiple, recurrent nasal papillomata which developed after repeated surgical removal procedures. In this patient, complete and persistent resolution of the lesions was achieved after topical treatment with imiquimod cream. Imiquimod is a class of non-nucleoside imidazoquinolinamines which promotes local cytokine release from antigen-presenting cells inducing a T-h1 dominant cell-mediated response against virus-infected cells. Topical imiquimod 5 per cent cream, applied for four to 16 weeks, may offer some benefit in the management of recurrent nasal papillomata in human immunodeficiency virus positive patients. Such treatment may be preferable to surgery or destructive therapeutic options when patients are unwilling or are poor surgical candidates, and also avoids potential surgical sequelae such as scar formation and stenosis.

Topical imiquimod cream (trade name: Aldara) is a Toll-like receptor (TLR) 7 agonist that is approved for the treatment of cutaneous tumors. Aldara is also used as a vaccine adjuvant in clinical trials in patients with glioma and other tumors. The main mechanism of action ascribed to Aldara has been the local activation of TLR7(+) cells near the application site. Here we report the unexpected finding that Aldara has therapeutic and immunomodulatory activity as a single agent in mice bearing intracranial tumors. Repeated administration of Aldara onto the skin significantly increased the survival of mice bearing intracranial GL261 glioma and EMT6 breast carcinoma. Aldara treatment was associated with a reduction in the number CD4(+)Foxp3(+) regulatory T cells in the blood and brain tumor site. Mice treated with Aldara exhibited a generalized lymphopenia in the blood amidst an increase in brain tumor infiltrating CD4(+) and CD8(+) T cells and dendritic cells. Brain-infiltrating CD8(+) T cells were tumor reactive as demonstrated by degranulation and interferon-γ secretion in a GL261-dependent manner. In addition, soluble imiquimod directly inhibited the proliferation of GL261 cells in a TLR7-independent manner. This is the first report demonstrating that topical application of imiquimod can enhance T-cell responses to intracranial tumors as a single agent. The results must be interpreted with caution considering anatomical and biological differences between mice and humans. Nevertheless, Aldara that is being used as a vaccine adjuvant in clinical trials may have direct antitumor effects that are independent of exogenous antigen. Further studies in humans are warranted.