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| Year : 2015 | Volume
: 47
| Issue : 4 | Page : 354-359 |
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Imiquimod - Its role in the treatment of cutaneous malignancies
Aditya Kumar Bubna
Assistant Professor, Department of Dermatology, Sri Ramachandra University, Porur, Chennai, Tamil Nadu, India
| Date of Submission | 08-Oct-2014 |
| Date of Decision | 26-Mar-2015 |
| Date of Acceptance | 20-Jun-2015 |
| Date of Web Publication | 21-Jul-2015 |
Correspondence Address:
Dr. Aditya Kumar Bubna
Assistant Professor, Department of Dermatology, Sri Ramachandra University, Porur, Chennai, Tamil Nadu
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0253-7613.161249
Imiquimod is a synthetic imidazoquinolone amine, which has potent immune response modifier activity, when topically used. This characteristic property of imiquimod has led to its use in a number of applications in dermatology, particularly in cutaneous malignancies, where it has been found to be effective and safe. Currently, additional mechanisms for its activity in actinic keratosis, basal cell carcinoma, and invasive squamous cell carcinoma have been elucidated. Its usage for cutaneous metastasis in breast cancer has been a further addition to its therapeutic armamentarium recently.
Keywords: Cutaneous malignancies, imidazoquinolone, imiquimod
How to cite this article:
Bubna AK. Imiquimod - Its role in the treatment of cutaneous malignancies. Indian J Pharmacol 2015;47:354-9 |
| » Introduction | |  |
Imiquimod is a synthetic compound which belongs to a new class of drugs referred to as imidazoquinolones. It acts as an immune response modifier in the body and has shown to have potent anti-viral and anti-tumor activity. [1] While screening drugs for anti-herpes virus activity, imiquimod's role as an immune response modifier was discovered. In 1999, the Food and Drug Administration (FDA) approved imiquimod for the treatment of external genital and perianal warts and in 2004, it was approved for treating actinic keratosis (AK) and superficial basal cell carcinoma (BCC). Recently, imiquimod has been found to be useful in a variety of dermatologic conditions. This article will review the clinical applications of 5% imiquimod cream in cutaneous premalignant and malignant conditions.
| » Mechanism of Action as Related to Cutaneous Malignancies | | |
Imiquimod acts on the innate and the adaptive immune responses both directly and indirectly. Direct action is by binding to toll-like receptors (TLR) seven and eight of macrophages, monocytes, and dendritic cells [2] and by induction of apoptosis. Indirect action occurs by imiquimod inducing the release of immune modulatory cytokines. Imiquimod's effectiveness is also attributed by its action on Langerhans cells thereby stimulating its ability to present antigens [1] and enhancing its migration to the draining lymph nodes where antigens are presented to T cells, thus activating the body's adaptive immune response.
Direct Actions
Recent studies have thrown light on the possible direct effects of imiquimod on cutaneous malignancies. Induction of apoptosis in tumor cell lines has been postulated as the prime mechanism here. Imiquimod activates the workhorses of apoptosis, namely the caspase family of proteases. [2] There are two pathways that induce apoptosis, the extrinsic and the intrinsic pathway. It has been demonstrated that imiquimod brings about apoptosis by working on the intrinsic pathway which converge at the mitochondria. On activation of the intrinsic apoptotic pathway, pro-apoptotic molecules such as apoptosis-inducing factor, smac, HtrA2, cytochrome C, and endonuclease G are released. [3] These molecules then stimulate caspase-9 in a multimeric complex called the apoptosome or bring about the destruction of malignant cells in an independent manner. The independent manner by which imiquimod brings about apoptosis of tumor cell lines is by up-regulating pro-apoptotic proteins of the Bcl-2 family of proteins namely Bax and Bak, and the BH3-only proteins such as Bim, Bid, Bmf, Noxa, and Puma. Hence, we see that there is an increased expression of pro-apoptotic proteins and a down-regulation of anti-apoptotic proteins. [3]
Indirect Actions
Indirect actions of imiquimod occur by inducing the release of various cytokines. These cytokines stimulate a cell-mediated immune response, and this may be of value in the drug's anti-tumor activity. [4] The main cytokines induced include IL-12, tumor necrosis factor-alpha (TNF-alpha), and interferon (INF)-gamma. These in turn increase the levels of cytotoxic T cells and natural killer cells in the local milieu by inducing 2'5'oligoadenylate synthetase and blocking angiogenesis. [2] Further increase in IL-12 down-regulates IL-10 and thus stimulates anti-tumor T cells. [4]
| » Pharmacokinetics | | |
Following the topical application of 5% imiquimod cream, there is minimal systemic absorption. Less than 0.9% of the drug is excreted by the urinary and the gastrointestinal system. [5]
| » Uses of Imiquimod in Cutaneous Premalignant and Malignant Conditions | | |
Actinic Keratosis
Actinic keratosis are premalignant skin lesions seen mainly in fair-skinned individuals with a risk of transformation to invasive squamous cell carcinoma (SCC), and, therefore, this needs to be adequately dealt with. Imiquimod as a 5% cream was first approved by the FDA as a therapeutic agent for AK in 2004 and has shown exceedingly promising results for the same. Recently, imiquimod cream in a 3.75% strength has also become available with similar efficacy as the 5% cream and fewer cutaneous adverse effects. Apart from this advantage, an added advantage witnessed with the 3.75% preparation of imiquimod was the shorter duration of treatment and a wider surface area of application (i.e., 200 cm 2 as compared to 25 cm 2 for the 5% preparation of imiquimod). [6]
Newer mechanisms of imiquimod action postulated for actinic keratosis
- Apart from the usual immunomodulatory role of imiquimod explained earlier, in AK, imiquimod additionally stimulated expression of E-selectin on tumor blood vessels, thereby promoting CD8+ cytotoxic T cells to occupy the tumor site, subsequently bringing about tumor regression clinically and histologically [7]
- Following imiquimod usage, there is the development of T cell memory that further diminishes the risk of AK development. [8]
Treatment regimens using imiquimod for actinic keratosis [Table 1]
Newer and potent imiquimod analog
A sister drug of imiquimod, resiquimod whose potency has been found to be 10-100 times greater than imiquimod. A European phase II study demonstrated a 40-74.2% lesion clearance postapplication of resiquimod on AK lesions thrice weekly for a period of 4 weeks. [7]
Superficial Basal Cell Carcinoma
BCC is a common cutaneous neoplasm that very rarely metastasizes. However, if neglected, it can have a locally aggressive course with the destruction of the underlying tissues.
Newer mechanism of imiquimod action postulated for basal cell carcinoma
Apart from the mechanism of action mentioned above, in cases of BCC, imiquimod has an additional mechanism in antagonizing tumorigenesis. Imiquimod blocks the activation of the Hedgehog (HH)/glioma-associated oncogene (GLI) signaling pathway. [12] It has been suggested that an aberrant activation of this pathway plays an important role in the pathogenesis of BCC. Imiquimod acts in a direct, nonclassical manner, independent of its agonistic activity on the TLR-MyD88 complex in antagonizing the activity of the HH/GLI signaling pathway. [13] Imiquimod binds to the adenosine receptors and activates protein kinase A, which in turn phosphorylates GLI, heralding down-regulation of GLI 1 mRNA and protein levels in BCC cells. Because of this, there is a negative effect on the HH/GLI signaling pathway thereby thwarting its oncogenic potential. [14]
The first study using 5% imiquimod cream for treating superficial BCC was published in 1999. In the study, 35 patients were randomized to several dosing regimens of imiquimod, 5% cream, at one end of the spectrum and a vehicle cream at the other end. Treatment was given for a period of 16 weeks. In case of localized reactions to the cream, patients were given a drug-free period of 7 days. Patients who were given a twice daily, once daily, and thrice a week dosing of the drug showed 100% clearance based on histology. Sixty percentage of patients who were dosed twice weekly with imiquimod showed the complete clearance. Those patients who received imiquimod only once a week, 50% of them only showed complete remission. For the twice daily group treatment lasted for 10 weeks, 13 weeks for the once daily group and 14.5 weeks for the thrice weekly treatment group. [4]
Key points
- Imiquimod, 5% cream, has been found effective in treating small superficial BCCs (maximum size of 2 cm in diameter) as demonstrated by several controlled trials and one systematic review [15]
- Imiquimod has also been tried in a case series for the treatment of large superficial BCC of size >2 cm by Lacarrubba et al. [16] with promising results. However, more such studies are warranted for using imiquimod for the same
- Multiple BCCs seen in Gorlin syndrome and xeroderma pigmentosum have also demonstrated a favorable outcome following application of 5% imiquimod [17],[18]
- However, though imiquimod has been employed in BCC, it may be appropriate only for selected primary low-risk lesions as a therapeutic modality. Surgical methods like Mohs micrographic surgery still remain the gold standard with a superior treatment outcome. [19],[20]
Nodular Basal Cell Carcinoma
Imiquimod, 5% cream, can be used as an alternative in patients with small nodular BCCs who are poor candidates for surgery. Phase II clinical trials demonstrating the efficacy of imiquimod for nodular BCC have been seen in a 6-week trial in Australia and New Zealand and a 12-week trial in the United States. After 6 weeks of treatment, complete histologic clearance was seen in 71% of the cases in the 6 weeks once daily regimen and in 76% of the cases in the 12 weeks trial group. [2]
Sclerodermiform Basal Cell Carcinoma
In literature, a case report showing successful treatment of sclerodermiform BCC has been demonstrated. A thrice-weekly application of 5% imiquimod cream for 16 weeks showed complete clearance histologically with only scar tissue remnants. The patient was followed up for a period of 9 months post therapy, with observation of no recurrence. [2]
Squamous Cell Carcinoma in situ or Bowen's Disease
SCC in situ may involve the skin and mucosal surfaces. Of particular importance, is the involvement of the genital mucosa with Bowen's disease. These lesions generally are associated with human papilloma virus (HPV) infection, in particular, HPV type 16 which has the potential of diminishing the activity of tumor suppressor proteins p53 and Rb. [21]
Newer activity of imiquimod for genital Bowen's disease
It has been clearly demonstrated for SCC in situ of the vulva and the anal region, imiquimod apart from its anti-neoplastic effects, has shown to possess anti-viral activity against HPV and therefore, this action may potentiate imiquimod's effect for the above indication because elimination of HPV is a must to ensure the drugs therapeutic efficacy. [22]
Salient features of imiquimod for squamous cell carcinoma in situ [Table 2] | Table 2: Salient features of imiquimod for squamous cell carcinoma in situ
Click here to view |
Invasive Squamous Cell Carcinoma
Five percentage imiquimod cream has shown efficacy even in invasive SCC.
Additional new mechanism of action of imiquimod for the above indication
Imiquimod in SCC additionally acts by down-regulating an anti-apoptotic regulator A20, thereby stimulating the nuclear factor kappa-beta signaling pathway in keratinocytes, eventually leading to apoptosis and tumor regression. [26]
Two immune-suppressed patients with renal transplant and having invasive SCC, one over the temple and the other over the sternum, were administered imiquimod 3 times a week for 12 weeks and imiquimod 3 times a week for 5 weeks and twice weekly for 7 weeks, respectively. Both patients when followed up at 6 and 8 months, respectively, had no evidence of residual tumor. [2]
Lentigo Maligna
Lentigo maligna (LM) is an in situ melanoma. The progression of LM to invasive melanoma is slow, owing to the sluggish radial growth phase and is estimated to be 5%. [27] The first reported successful treatment of LM was for an elderly patient who had LM on the scalp and was reluctant for surgery. Treatment was given for 7 months with various drug regimens and drug-free periods owing to localized reactions. There was complete clinical and histologic remission with no recurrence post 9 months of follow-up. [2] Ly et al. [28] and Powell et al. [29] have done a clinicopathologic evaluation of LM regression post 5% imiquimod cream usage and have demonstrated complete clearance in 53-75% of the treated patients. However, the major drawback for most of these studies was a follow-up for a maximum of period of only 1-year, which may be highly inadequate given the extremely slow radial growth phase seen in LM.
Key points
- Long-term treatment with imiquimod is mandated for the above indication
- May be combined with destructive therapies like CO 2 laser
- Even postclearance of lesions histologically, it is mandated to continue imiquimod application for a year.
Metastatic Melanoma
Several recent published studies have shown imiquimod to have promise in the treatment of metastatic melanoma (MM). Imiquimod was first used in a female patient who had lesions on the breast which were too extensive for surgery or radiotherapy. Imiquimod was applied thrice weekly along with systemic dacarbazine. By 12 weeks, the lesions treated with imiquimod completely resolved. Histopathology at 18 weeks showed apoptotic melanocytes surrounded by a dense lymphocytic infiltrate. [2]
Recent postulates in imiquimod's role for metastatic melanoma
Recently, the role of imiquimod in inhibiting melanoma has been further elaborated. Once imiquimod activates TLR7, plasmacytoid dendritic cells are stimulated, and are recruited to the site of the tumor and also the sentinel lymph nodes. There, they express TNF-related apoptosis inducing ligand, granzyme B, lysozyme, INF alpha, and other angiogenic inhibitors. A vascular endothelial growth factor is considered to be the prominent angiogenic factor in melanoma that promotes tumor growth. When these substances are released following imiquimod application, there is a block in tumor vascularization, which is an integral step necessary for the growth and invasiveness of the tumor, thereby halting tumor growth. [30],[31]
Key points
- Long-term treatment with imiquimod is required for this condition
- May be combined with other with other therapies such as radiotherapy and CO 2 laser
- Though imiquimod may eradicate the cutaneous metastasis of MM, lymphatic spread of the tumor cannot be prevented by imiquimod.
Mycosis Fungoides
Imiquimod has been of help especially in the management of early mycosis fungoides (MF). The role in MF may be due to IFN alpha, a cytokine induced by imiquimod. [32]
Key points
- For MF, imiquimod is an alternative treatment for localized plaques, that do not respond to conventional treatment modalities
- Duration of treatment extends from 4 months to 2 years
- Can be combined with systemic INFs in recalcitrant cases. [32]
Keratoacanthoma
Keratoacanthoma has been successfully treated with imiquimod applied daily for 4-12 weeks. Clinical regression was evident after 4-6 weeks. No recurrence was seen in the 4-6 months follow-up period. [2]
Extramammary Paget's Disease
Extramammary Paget's disease (EMPD) is a clinical condition simulating Paget's disease of the breast histologically and is clinically characterized by moist eczematous and erythematous plaques. Imiquimod acts by its immunomodulatory effect by stimulating synthesis of pro-inflammatory cytokines and inducing apoptosis of malignant cells. Successful treatment of EMPD has been seen following topical imiquimod usage. In a retrospective study by Luyten et al., [33] it was shown that imiquimod produced a high rate of clinical clearance when used as a first-time treatment modality, and also for recurrent cases. A response rate of >80% was observed following the usage of 5% imiquimod cream. Sanderson et al. [34] documented 29 cases of vulvar EMPD that demonstrated 50% of clinical resolution for primary cases of EMPD and in 73% of patients with recurrent disease. In some cases though, 5% imiquimod may not achieve complete clearance of lesions. However, even partial reduction in the lesion size is profitable for both the patient and the treating physician, because once lesions reduce in size a more conservative surgical approach can be carried out, helping in achieving a better cosmetic and functional outcome. [35]
Infantile Hemangioma
Imiquimod acts here by its anti-angiogenic properties. Hu et al. [36] have demonstrated the efficacy of 5% imiquimod in superficial infantile hemangioma.
Merkel Cell Carcinoma
Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor with an exorbitant malignant potential. Though MCC is a chemosensitive tumor, till date, no broadly accepted treatment protocol exists for the same. [37] Balducci et al. [38] have reported a case of MCC that showed complete remission posttopical application of 5% imiquimod combined with radiotherapy.
Kaposi's Sarcoma
Kaposi's sarcoma (KS) is a vascular neoplasm characterized by reddish-brown nodules and papules. Imiquimod acts by activating cytokines that have an antagonistic role in angiogenesis, pro-angiogenic factor down-regulation and induction of apoptosis in endothelial cells. [39] Goiriz et al. [40] reported a successful treatment outcome using 5% imiquimod cream in an 87-year-old man with widespread nodules of classical KS on both his lower limbs. Another patient with successful outcome following the usage of 5% imiquimod cream in a thrice weekly schedule for localized KS under occlusion for 8 h for a period of 3 months has been reported by Bernardini et al. [41]
Key point
In localized forms of KS imiquimod may have a role as monotherapy.
Cutaneous Metastasis Secondary to Carcinoma Breast
Breast cancer is a frequently diagnosed malignancy among women with an increased potential for cutaneous metastasis.
Role of imiquimod for this indication
The exact mechanism of imiquimod's role in breast cancer is unknown. However, it has been hypothesized that by binding to TLR7, imiquimod stimulates dendritic cells and macrophages releasing inflammatory cytokines which enable apoptosis of tumor cells. [42]
Adams et al. [43] and Dewan et al. [44] have elucidated the beneficial role of imiquimod in treating skin metastasis secondary to breast cancer. Henriques et al. [45] have further substantiated the beneficial role of imiquimod in metastatic breast cancer. Here, imiquimod applications were instituted 3 times a week following which there was an associated decrease in lesion thickness, intensity and pain score. In this report along with imiquimod, even chemotherapy was employed.
| » Adverse Effects | | |
The most frequent adverse effects include itching, burning pain, and soreness at the application site. Other localized reactions include erythema, erosions, flaking, stinging, crusting, and vesiculation. Less frequent side effects include vitiligo such as hypopigmentation, hyperkeratosis, rhinitis, upper respiratory tract infections, myalgia, and headache. Rarely fatigue, dyspepsia, alopecia, chills, diarrhea, fever, and angioedema have been reported. [5]
| » Conclusions | | |
Imiquimod, 5% cream, has shown to have promise in a variety of cutaneous oncological conditions. Unfortunately, however, the dermatologic work on imiquimod has mainly been in the form of case reports or small open trials. Very few double-blind cross-over trials have been done for the same. Hence, there is a need for larger multicentric studies which would be of more help for clinicians in successfully employing the immune response modifier activity of imiquimod for other off-label applications in dermatology.
Financial Support and Sponsorship
Nil.
Conflicts of Interest
There are no conflicts of interest.
| » References | | |
| 1. | Sauder DN. Immunomodulatory and pharmacologic properties of imiquimod. J Am Acad Dermatol 2000;43:S6-11.  |
| 2. | Navi D, Huntley A. Imiquimod 5 percent cream and the treatment of cutaneous malignancy. Dermatol Online J 2004;10:4. |
| 3. | Leverkus M. Imiquimod: Unexpected killer. J Invest Dermatol 2004;122:XV-XVI. |
| 4. | Beutner KR, Geisse JK, Helman D, Fox TL, Ginkel A, Owens ML. Therapeutic response of basal cell carcinoma to the immune response modifier imiquimod 5% cream. J Am Acad Dermatol 1999;41:1002-7. |
| 5. | Jobanputra KS, Rajpal AV, Nagpur NG. Imiquimod. Indian J Dermatol Venereol Leprol 2006;72:466-9. [ PUBMED]  |
| 6. | Gupta AK, Cooper EA, Abramovits W. Zyclara (imiquimod) cream, 3.75%. Skinmed 2010;8:227-9. |
| 7. | Dodds A, Chia A, Shumack S. Actinic keratosis: Rationale and management. Dermatol Ther (Heidelb) 2014;4:11-31. |
| 8. | Ulrich C, Bichel J, Euvrard S, Guidi B, Proby CM, van de Kerkhof PC, et al. Topical immunomodulation under systemic immunosuppression: Results of a multicentre, randomized, placebo-controlled safety and efficacy study of imiquimod 5% cream for the treatment of actinic keratoses in kidney, heart, and liver transplant patients. Br J Dermatol 2007;157 Suppl 2:25-31. |
| 9. | Salasche SJ, Levine N, Morrison L. Cycle therapy of actinic keratoses of the face and scalp with 5% topical imiquimod cream: An open-label trial. J Am Acad Dermatol 2002;47:571-7. |
| 10. | Goldenberg G, Linkner RV, Singer G, Frankel A. An investigator-initiated study to assess the safety and efficacy of imiquimod 3.75% cream when used after cryotherapy in the treatment of hypertrophic actinic keratoses on dorsal hands and forearms. J Clin Aesthet Dermatol 2013;6:36-43. |
| 11. | Shaffelburg M. Treatment of actinic keratoses with sequential use of photodynamic therapy; and imiquimod 5% cream. J Drugs Dermatol 2009;8:35-9. |
| 12. | Wolff F, Loipetzberger A, Gruber W, Esterbauer H, Aberger F, Frischauf AM. Imiquimod directly inhibits Hedgehog signalling by stimulating adenosine receptor/protein kinase A-mediated GLI phosphorylation. Oncogene 2013;32:5574-81. |
| 13. | Gruber W, Frischauf AM, Aberger F. An old friend with new skills: Imiquimod as novel inhibitor of Hedgehog signaling in basal cell carcinoma. Oncoscience 2014;1:567-73. |
| 14. | Mondal BC, Mukherjee T, Mandal L, Evans CJ, Sinenko SA, Martinez-Agosto JA, et al. Interaction between differentiating cell- and niche-derived signals in hematopoietic progenitor maintenance. Cell 2011;147:1589-600. |
| 15. | Roozeboom MH, Arits AH, Nelemans PJ, Kelleners-Smeets NW. Overall treatment success after treatment of primary superficial basal cell carcinoma: A systematic review and meta-analysis of randomized and nonrandomized trials. Br J Dermatol 2012;167:733-56. |
| 16. | Lacarrubba F, Potenza MC, Gurgone S, Micali G. Successful treatment and management of large superficial basal cell carcinomas with topical imiquimod 5% cream: A case series and review. J Dermatolog Treat 2011;22:353-8. |
| 17. | Yang JQ, Chen XY, Engle MY, Wang JY. Multiple facial basal cell carcinomas in xeroderma pigmentosum treated with topical imiquimod 5% cream. Dermatol Ther 2015. [Last accessed on 2015 Apr 25]. |
| 18. | Micali G, Lacarrubba F, Nasca MR, De Pasquale R. The use of imiquimod 5% cream for the treatment of basal cell carcinoma as observed in Gorlin's syndrome. Clin Exp Dermatol 2003;28 Suppl 1:19-23. |
| 19. | Clark CM, Furniss M, Mackay-Wiggan JM. Basal cell carcinoma: An evidence-based treatment update. Am J Clin Dermatol 2014;15:197-216. |
| 20. | Bath-Hextall F, Ozolins M, Armstrong SJ, Colver GB, Perkins W, Miller PS, et al. Surgical excision versus imiquimod 5% cream for nodular and superficial basal-cell carcinoma (SINS): A multicentre, non-inferiority, randomised controlled trial. Lancet Oncol 2014;15:96-105. |
| 21. | Tristram A, Hurt CN, Madden T, Powell N, Man S, Hibbitts S, et al. Activity, safety, and feasibility of cidofovir and imiquimod for treatment of vulval intraepithelial neoplasia (RT 3 VIN): A multicentre, open-label, randomised, phase 2 trial. Lancet Oncol 2014;15:1361-8. |
| 22. | Kim JM, Lee HJ, Kim SH, Kim HS, Ko HC, Kim BS, et al. Efficacy of 5% imiquimod cream on vulvar intraepithelial neoplasia in Korea: Pilot study. Ann Dermatol 2015;27:66-70. |
| 23. | Lacarrubba F, Nasca MR, Micali G. Advances in the use of topical imiquimod to treat dermatologic disorders. Ther Clin Risk Manag 2008;4:87-97. |
| 24. | Frega A, Sesti F, Sopracordevole F, Biamonti A, Scirpa P, Milazzo GN, et al. Imiquimod 5% cream versus cold knife excision for treatment of VIN 2/3: A five-year follow-up. Eur Rev Med Pharmacol Sci 2013;17:936-40. |
| 25. | Fox PA, Nathan M, Francis N, Singh N, Weir J, Dixon G, et al. A double-blind, randomized controlled trial of the use of imiquimod cream for the treatment of anal canal high-grade anal intraepithelial neoplasia in HIV-positive MSM on HAART, with long-term follow-up data including the use of open-label imiquimod. AIDS 2010;24:2331-5. |
| 26. | Sohn KC, Li ZJ, Choi DK, Zhang T, Lim JW, Chang IK, et al. Imiquimod induces apoptosis of squamous cell carcinoma (SCC) cells via regulation of A20. PLoS One 2014;9:e95337. |
| 27. | Erickson C, Miller SJ. Treatment options in melanoma in situ: Topical and radiation therapy, excision and Mohs surgery. Int J Dermatol 2010;49:482-91. |
| 28. | Ly L, Kelly JW, O'Keefe R, Sutton T, Dowling JP, Swain S, et al. Efficacy of imiquimod cream, 5%, for lentigo maligna after complete excision: A study of 43 patients. Arch Dermatol 2011;147:1191-5. |
| 29. | Powell AM, Robson AM, Russell-Jones R, Barlow RJ. Imiquimod and lentigo maligna: A search for prognostic features in a clinicopathological study with long-term follow-up. Br J Dermatol 2009;160:994-8. |
| 30. | Holcmann M, Drobits B, Sibilia M. How imiquimod licenses plasmacytoid dendritic cells to kill tumors. Oncoimmunology 2012;1:1661-3. |
| 31. | Aspord C, Tramcourt L, Leloup C, Molens JP, Leccia MT, Charles J, et al. Imiquimod inhibits melanoma development by promoting pDC cytotoxic functions and impeding tumor vascularization. J Invest Dermatol 2014;134:2551-61. |
| 32. | Fernandez-Guarino M. Emerging treatment options for early mycosis fungoides. Clin Cosmet Investig Dermatol 2013;6:61-9. |
| 33. | Luyten A, Sörgel P, Clad A, Gieseking F, Maass-Poppenhusen K, Lellé RJ, et al. Treatment of extramammary Paget disease of the vulva with imiquimod: A retrospective, multicenter study by the German Colposcopy Network. J Am Acad Dermatol 2014;70:644-50. |
| 34. | Sanderson P, Innamaa A, Palmer J, Tidy J. Imiquimod therapy for extramammary Paget's disease of the vulva: A viable non-surgical alternative. J Obstet Gynaecol 2013;33:479-83. |
| 35. | Toledo F, Silvestre JF, Cuesta L, Ballester I, Latorre N, Monteagudo A. Sequential use with imiquimod and surgery in extramammary Paget's disease. Dermatol Ther 2012;25:82-5. |
| 36. | Hu L, Huang HZ, Li X, Lin XX, Li W. Open-label nonrandomized left-right comparison of imiquimod 5% ointment and timolol maleate 0.5% eye drops in the treatment of proliferating superficial infantile hemangioma. Dermatology 2015;230:150-5. |
| 37. | Schrama D, Ugurel S, Becker JC. Merkel cell carcinoma: Recent insights and new treatment options. Curr Opin Oncol 2012;24:141-9. |
| 38. | Balducci M, De Bari B, Manfrida S, D'Agostino GR, Valentini V. Treatment of Merkel cell carcinoma with radiotherapy and imiquimod (Aldara): A case report. Tumori 2010;96:508-11. |
| 39. | Gündüz K, Günay U, Inanir I, Gençoglan G, Temiz P. Efficacy of 5% imiquimod cream in a patient with classic Kaposi sarcoma. J Dermatol Case Rep 2012;6:52-3. |
| 40. | Goiriz R, Ríos-Buceta L, De Arriba AG, Aragüés M, García-Diez A. Treatment of classic Kaposi's sarcoma with topical imiquimod. Dermatol Surg 2009;35:147-9. |
| 41. | Bernardini B, Faggion D, Calabró L, Oro E, Alaibac M. Imiquimod for the treatment of classical Kaposi's sarcoma. Acta Derm Venereol 2010;90:417-8. |
| 42. | Kohrt H. Breast cancer treatment with imiquimod: Applying an old lotion to a new disease. Clin Cancer Res 2012;18:6571-3. |
| 43. | Adams S, Kozhaya L, Martiniuk F, Meng TC, Chiriboga L, Liebes L, et al. Topical TLR7 agonist imiquimod can induce immune-mediated rejection of skin metastases in patients with breast cancer. Clin Cancer Res 2012;18:6748-57. |
| 44. | Dewan MZ, Vanpouille-Box C, Kawashima N, DiNapoli S, Babb JS, Formenti SC, et al. Synergy of topical toll-like receptor 7 agonist with radiation and low-dose cyclophosphamide in a mouse model of cutaneous breast cancer. Clin Cancer Res 2012;18:6668-78. |
| 45. | Henriques L, Palumbo M, Guay MP, Bahoric B, Basik M, Kavan P, et al. Imiquimod in the treatment of breast cancer skin metastasis. J Clin Oncol 2014;32:e22-5. |
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| M. V. Dmitrieva, M. A. Baryshnikov?, O. L. Orlova, V. S. Kosorukov | | Russian Journal of Biotherapy. 2022; 21(4): 10 | | [Pubmed] | [DOI] | | | 8 |
Treatment of basal cell carcinoma: An overview |
|
| Sheerja Bali, Eman Deif, Asha Rajeev | | Journal of Skin and Sexually Transmitted Diseases. 2022; 0: 1 | | [Pubmed] | [DOI] | | | 9 |
Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity |
|
| Tianhao Duan, Yang Du, Changsheng Xing, Helen Y. Wang, Rong-Fu Wang | | Frontiers in Immunology. 2022; 13 | | [Pubmed] | [DOI] | | | 10 |
Local skin reactions and the onset of influenza-like signs and symptoms induced by imiquimod |
|
| Neal Bhatia | | JAAD International. 2022; 7: 113 | | [Pubmed] | [DOI] | | | 11 |
Precise delivery of doxorubicin and imiquimod through pH-responsive tumor microenvironment-active targeting micelles for chemo- and immunotherapy |
|
| Yu-Han Wen, Po-I Hsieh, Hsin-Cheng Chiu, Chil-Wei Chiang, Chun-Liang Lo, Yi-Ting Chiang | | Materials Today Bio. 2022; : 100482 | | [Pubmed] | [DOI] | | | 12 |
Non-melanoma skin cancers: physio-pathology and role of lipid delivery systems in new chemotherapeutic treatments |
|
| Eliana B. Souto, Raquel da Ana, Vânia Vieira, Joana F. Fangueiro, João Dias-Ferreira, Amanda Cano, Aleksandra Zielinska, Amélia M. Silva, Rafal Staszewski, Jacek Karczewski | | Neoplasia. 2022; 30: 100810 | | [Pubmed] | [DOI] | | | 13 |
Cowpea Mosaic Virus Outperforms Other Members of the Secoviridae as In Situ Vaccine for Cancer Immunotherapy |
|
| Veronique Beiss, Chenkai Mao, Steven N. Fiering, Nicole F. Steinmetz | | Molecular Pharmaceutics. 2022; | | [Pubmed] | [DOI] | | | 14 |
Cutaneous metastasectomy: Is there a role in breast cancer? A systematic review and overview of current treatment modalities |
|
| Samantha Huang, Vishwas Parekh, James Waisman, Veronica Jones, Yuan Yuan, Nayana Vora, Richard Li, Jae Jung, Laura Kruper, Farah Abdulla, Yuman Fong, Wai-Yee Li | | Journal of Surgical Oncology. 2022; | | [Pubmed] | [DOI] | | | 15 |
Toll-like receptor-7 activation in CD8+ T cells modulates inflammatory mediators in patients with rheumatoid arthritis |
|
| Nitish Swain, Archana Tripathy, Prasanta Padhan, Sunil K. Raghav, Bhawna Gupta | | Rheumatology International. 2022; | | [Pubmed] | [DOI] | | | 16 |
Establishment of an efficacious treatment period for prophylactic treatment of auricular keloid recurrence postexcision using topical imiquimod: A demonstrative case series |
|
| Lina Chan, H.L. Greenberg | | JAAD Case Reports. 2022; | | [Pubmed] | [DOI] | | | 17 |
A Review of Existing Therapies for Actinic Keratosis: Current Status and Future Directions |
|
| Laura Del Regno, Silvia Catapano, Alessandro Di Stefani, Simone Cappilli, Ketty Peris | | American Journal of Clinical Dermatology. 2022; | | [Pubmed] | [DOI] | | | 18 |
Extramammary Paget’s disease: Updates in the workup and management |
|
| Reza Nabavizadeh, Khushali B. Vashi, Behnam Nabavizadeh, Vikram M. Narayan, Viraj A. Master | | Asian Journal of Urology. 2022; | | [Pubmed] | [DOI] | | | 19 |
Development of bioadhesive polysaccharide-based films for topical release of the immunomodulatory agent imiquimod on oral mucosa lesions |
|
| Lucas Garcia Camargo, Paula de Freitas Rosa Remiro, Gabriela Souza Rezende, Stephany Di Carla Santos, Michelle Franz-Montan, Ângela Maria Moraes | | European Polymer Journal. 2021; 151: 110422 | | [Pubmed] | [DOI] | | | 20 |
Ionizing radiation and toll like receptors: A systematic review article |
|
| Ali Mehdipour, Aliakbar Yousefi-Ahmadipour, Derek Kennedy, Mohammad Kazemi Arababadi | | Human Immunology. 2021; 82(6): 446 | | [Pubmed] | [DOI] | | | 21 |
Discovery of new TLR7 agonists by a combination of statistical learning-based QSAR, virtual screening, and molecular dynamics |
|
| Ardavan Abiri, Masoud Rezaei, Mohammad Hossein Zeighami, Younes Vaezpour, Leili Dehghan, Maedeh KhorramGhahfarokhi | | Informatics in Medicine Unlocked. 2021; 27: 100787 | | [Pubmed] | [DOI] | | | 22 |
Treatment of locally advanced cutaneous Merkel cell carcinoma with topical imiquimod |
|
| Komal Saini, Paul Chee | | JAAD Case Reports. 2021; 13: 121 | | [Pubmed] | [DOI] | | | 23 |
Prognostic Biomarker-Based Identification of Drugs for Managing the Treatment of Endometrial Cancer |
|
| Dilraj Kaur, Chakit Arora, Gajendra Pal Singh Raghava | | Molecular Diagnosis & Therapy. 2021; 25(5): 629 | | [Pubmed] | [DOI] | | | 24 |
Treatment approaches for treating hypertrophic scars and keloids |
|
| Chloe Gianatasio, Michael Abrouk, Jill S. Waibel | | Dermatological Reviews. 2021; 2(1): 11 | | [Pubmed] | [DOI] | | | 25 |
Harnessing the immune system against cancer: current immunotherapy approaches and therapeutic targets |
|
| Ayana R. Kumar, Aswathy R. Devan, Bhagyalakshmi Nair, Balachandran S. Vinod, Lekshmi R. Nath | | Molecular Biology Reports. 2021; 48(12): 8075 | | [Pubmed] | [DOI] | | | 26 |
Current Advances in Hypertrophic Scar and Keloid Management |
|
| Natasha Barone, Tyler Safran, Joshua Vorstenbosch, Peter G. Davison, Sabrina Cugno, Amanda M. Murphy | | Seminars in Plastic Surgery. 2021; 35(03): 145 | | [Pubmed] | [DOI] | | | 27 |
Improvement of Imiquimod Solubilization and Skin Retention via TPGS Micelles: Exploiting the Co-Solubilizing Effect of Oleic Acid |
|
| Martina Ghezzi, Silvia Pescina, Andrea Delledonne, Ilaria Ferraboschi, Cristina Sissa, Francesca Terenziani, Paula De Freitas Rosa Remiro, Patrizia Santi, Sara Nicoli | | Pharmaceutics. 2021; 13(9): 1476 | | [Pubmed] | [DOI] | | | 28 |
A case report of imiquimod topical therapy as treatment for cutaneous metastasis of breast cancer |
|
| Anthony L Nguyen, Esther G Chong, Joanne Lee, Saied Mirshahidi, Hamid Mirshahidi | | Rare Tumors. 2021; 13: 2036361320 | | [Pubmed] | [DOI] | | | 29 |
Current therapies for actinic keratosis |
|
| Caterina Dianzani, Claudio Conforti, Roberta Giuffrida, Paola Corneli, Nicola Meo, Eleonora Farinazzo, Anna Moret, Giovanni Magaton Rizzi, Iris Zalaudek | | International Journal of Dermatology. 2020; 59(6): 677 | | [Pubmed] | [DOI] | | | 30 |
The Next Generation of Pattern Recognition Receptor Agonists: Improving Response Rates in Cancer Immunotherapy |
|
| Daniel H. O’ Donovan, Yumeng Mao, Deanna A. Mele | | Current Medicinal Chemistry. 2020; 27(34): 5654 | | [Pubmed] | [DOI] | | | 31 |
Topical treatments for skin cancer |
|
| Jason K. Cullen, Jacinta L. Simmons, Peter G. Parsons, Glen M. Boyle | | Advanced Drug Delivery Reviews. 2020; 153: 54 | | [Pubmed] | [DOI] | | | 32 |
Recent advances in localized immunotherapy of skin cancers |
|
| Irene Russo, Alvise Sernicola, Mauro Alaibac | | Immunotherapy. 2019; 11(5): 443 | | [Pubmed] | [DOI] | | | 33 |
Black salve treatment of skin cancer: a review |
|
| Alvin Lim | | Journal of Dermatological Treatment. 2018; 29(4): 388 | | [Pubmed] | [DOI] | | | 34 |
TLR4-Based Immunotherapeutics in Cancer: A Review of the Achievements and Shortcomings |
|
| Maryam A. Shetab Boushehri, Alf Lamprecht | | Molecular Pharmaceutics. 2018; 15(11): 4777 | | [Pubmed] | [DOI] | | | 35 |
Resistance of Nonmelanoma Skin Cancer to Nonsurgical Treatments. Part I: Topical Treatments |
|
| T. Gracia-Cazaña, S. González, Y. Gilaberte | | Actas Dermo-Sifiliográficas (English Edition). 2016; 107(9): 730 | | [Pubmed] | [DOI] | |
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