20.) Detection of CD8+ T cell responses to human papillomavirus type 16 antigens in women using imiquimod as a treatment for high-grade vulval intraepithelial neoplasia.

21.) Bowenoid papulosis of the vulva-immunotherapeutical approach with topical imiquimod.

22.) Imiquimod is highly effective for extensive, hyperproliferative condyloma in children.

 

 

1.)  Use of Imiquimod Cream 5% in the Treatment of Localized Morphea.

J Cutan Med Surg. 2004 May 3 [Epub ahead of print]

Man J, Dytoc MT.

Division of Dermatology, University of Alberta, T6G 2G3, Edmonton, Alberta, Canada.

Fibrosis is characterized by the increased deposition of collagen and other matrix components by fibroblasts. This process occurs as a reaction to inflammation and is mediated by numerous cytokines including transforming growth factor beta (TGF-beta). Localized cutaneous scleroderma or morphea is characterized by fibrosis. Current treatment for morphea includes topical, intralesional, or systemic corticosteroids, vitamin D analog (calcitriol and calcipotriol), photochemotherapy, laser therapy, antimalarials, phenytoin, D-penicillamine, and colchicine, all with varying degrees of success. In this case report, imiquimod cream 5% (Aldara(R)), which induces interferon and in turn inhibits TGF-beta, was employed to treat morphea.

2.) Efficacy of imiquimod 5% cream for basal cell carcinoma in transplant patients.

Clin Exp Dermatol. 2004 May;29(3):237-9. Related Articles, Links

Vidal D, Alomar A.

Department of Dermatology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.

Summary Imiquimod 5% cream has proven to be effective in superficial and nodular basal cell carcinomas in nonimmunosuppressed patients and treating squamous cell carcinomas in situ in transplant patients. The objective of this open-label study was to determine the efficacy of imiquimod 5% cream in treating basal cell carcinoma in transplant patients. At our unit, four renal transplant patients and one cardiac transplant patient were diagnosed with 10 basal cell carcinomas in 2001. Four tumours were superficial, three nodular and three infiltrative. Five basal cell carcinomas received imiquimod 5% cream at night four times weekly for 6 weeks, without occlusion, and the other five tumours were treated on 5 nights per week for 5 weeks. Biopsies taken 6 weeks after the end of treatment showed no tumour in seven of 10 of the cases. Notably, all four superficial basal cell carcinomas, two of the three of nodular lesions and one of the three of infiltrative cases had completely cleared.

 

3.) Using imiquimod for genital warts in female patients.

J Womens Health (Larchmt). 2004 Apr;13(3):265-71.

Cox JT, Petry KU, Rylander E, Roy M.

Student Health Service, University of California, Santa Barbara, California 93106, USA. [email protected]

Genital warts (GW) are the manifestation of infection with specific types of human papillomavirus (HPV), one of the most common sexually transmitted viral infections in the world. Genital warts can be either raised (exophytic) or flat. Exophytic genital warts are most commonly secondary to inoculation of the basal epithelium with nononcogenic HPV types 6 and 11, whereas flat warts are usually secondary to potentially oncogenic HPV types 16 and 31. Genital warts can occasionally cause irritation and discomfort, particularly during intercourse, although most cases are asymptomatic. It is the psychosocial effects of infection, such as a sense of shame, depression, and anxiety, that represent the more significant toll for most patients with GW. Current therapies for GW are mainly ablative and do not directly enhance the immune response to HPV. Therefore, recurrence is a problem for many patients. Imiquimod 5% cream is a patient-applied therapy that directly enhances the immune response to HPV and is safe and effective for the treatment of GW. A reduction in viral load is observed following treatment. Low recurrence rates compared to other treatment modalities may be due to the stimulation of the cell-mediated immune response by imiquimod.

 

4.)  Medical and surgical therapies for keloids.

Dermatol Ther. 2004;17(2):212-8.

Kelly AP.

Division of Dermatology, King/Drew Medical Center, Los Angeles, CA.

Keloids are benign, but sometimes painful and/or pruritic, proliferative growths of dermal collagen, usually resulting from excessive tissue response to trauma. Although benign, the social and psychological impact on affected individuals must be considered. Keloids often arise secondary to ear piercing and operative procedures. No single treatment modality is always successful. The more common ones are discussed. Some of the medical therapies include corticosteroids, interferon, 5-fluorouracil, and imiquimod. Primary excision and cryosurgery are among the major surgical options. Radiation therapies and other physical modalities are also discussed.

 

5.) In vivo and in situ modulation of the expression of genes involved in metastasis and angiogenesis in a patient treated with topical imiquimod for melanoma skin metastases.

Br J Dermatol. 2004 Apr;150(4):761-7.

Hesling C, D'Incan M, Mansard S, Franck F, Corbin-Duval A, Chevenet C, Dechelotte P, Madelmont JC, Veyre A, Souteyrand P, Bignon YJ.

Laboratory of Molecular Oncology/UMR 484, Centre Jean Perrin, Clermont-Ferrand, France.

8There is a growing body of evidence to support the efficacy of topical imiquimod in the treatment of primary skin carcinomas. Conflicting data exist concerning the use of imiquimod for the treatment of skin melanoma metastases. To date, only the impact of imiquimod on cytokines involved in immunological processes has been studied extensively. We report a woman successfully treated with imiquimod (once daily for 8 weeks) for skin melanoma metastases in whom we investigated the expression of molecules involved in metastasis and angiogenesis. Before and after treatment, a skin lesion was biopsied and the expression of the following molecules was investigated using real-time reverse transcription-polymerase chain reaction: matrix metalloproteinase (MMP)-1, 2 and 9 and their inhibitors KiSS-1 and tissue inhibitor of metalloproteinase (TIMP)-1, vascular endothelial growth factor (VEGF), fibroblast growth factor-2, and angiogenesis inhibitors (thrombospondin-1 and 2). Interferon (IFN)-alpha was also investigated as an in vivo marker of imiquimod activity. IFN-alpha was upregulated by the treatment. Under imiquimod, the following molecules were upregulated: TIMP-1, KiSS-1 and MMP-1. MMP-2 expression was not modified. MMP-9 expression was dramatically decreased. The expression of angiogenesis inhibitors was slightly increased but VEGF expression remained at a basal level. These results suggest that imiquimod could downregulate metastasis invasion and angiogenesis. However, these data were obtained at a transcriptional level and from a single case, and further investigations should include migration assays and additional cases in order to confirm that imiquimod may be safely used for treatment of melanoma metastases.

9.)  Pharmacokinetics and safety of imiquimod 5% cream in the treatment of actinic keratoses of the face, scalp, or hands and arms.
 

 Arch Dermatol Res. 2004 Apr 9 [Epub ahead of print]

Harrison LI, Skinner SL, Marbury TC, Owens ML, Kurup S, McKane S, Greene RJ.

Department of Pharmacokinetics and Drug Metabolism, 3 M Pharmaceuticals, 3 M Center 270-3S-05, MN 55144, St. Paul, USA.

The safety and efficacy of imiquimod 5% cream is being evaluated for the treatment of dysplastic lesions of the epidermis (actinic keratoses, AK). The objective of this clinical study was to describe the pharmacokinetics and safety of topical imiquimod during multiple dosing of AK subjects. A total of 58 adult subjects with 5 to 20 AK lesions at the treatment site applied imiquimod cream three times per week for up to 16 weeks as follows: 12 males and 11 females applied 12.5 mg imiquimod to the face; 11 males applied 25 mg to the entire balding area of the scalp; and 12 males and 12 females applied 75 mg to both hands and forearms. Pharmacokinetics and safety were assessed after the first and last doses, as well as biweekly. Imiquimod and its metabolites were measured in the serum and urine using sensitive liquid chromatography/mass spectrometry methods. Less than 0.6% of the applied doses was recovered in the urine of all subjects. Serum imiquimod levels were low, reflecting minimal dermal absorption, and increased with dose, although not proportionally. Peak levels at the end of dosing were 0.1, 0.2, and 1.6 ng/ml for the face, scalp, and hands/arms groups, respectively. A two- to fourfold accumulation was seen at the end of dosing. Local application site reactions were the most common adverse event, reported by approximately 50% of the subjects in each treatment group. The small number of systemic adverse events, including 'flu-like symptoms, were mostly mild and did not show a dose response. Thus, minimal systemic absorption and good safety margins for topical imiquimod were seen in AK subjects with doses as high as 75 mg three times per week for 16 weeks.

10.) Combination topical treatment of molluscum contagiosum with cantharidin and imiquimod 5% in children: A case series of 16 patients.
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11.)  Imiquimod as a possible treatment for keratoacanthoma.

J Drugs Dermatol. 2004 Jan-Feb;3(1):71-4.

Bhatia N.

UCSD School of Medicine, San Diego, CA, USA. [email protected]

Imiquimod is an immune-response modifier that has the potential to be useful in many dermatological indications (Table 1). To date, the approved use is for condyloma acuminata; approval for use in treating basal cell carcinoma (BCC) has been filed with the FDA and is expected to be approved in the coming months. In the interim, the expansion of the horizons for this immunomodulator depends on the application of the science and immunology behind the drug to the appropriate disease states. Recent investigations have presented explanations on the possible mechanisms behind the anti-tumor activity of imiquimod, more specifically for its use in treating superficial BCC. There are studies currently underway as well as anecdotal data published for its possible use in treating squamous cell carcinoma (SCC), although this is not as widely accepted for off-label use as BCC among many dermatologists. However, many patients who may not be surgical candidates that present with tumors other than BCC have been successfully treated with imiquimod. This is a case of an elderly patient who could not undergo surgery that presented with a large keratoacanthoma and was clear of her tumor after five months using imiquimod 5% cream on a daily basis.

12.)  Imiquimod for the treatment of Bowen's disease and invasive squamous cell carcinoma.

J Drugs Dermatol. 2003 Dec;2(6):669-73.

Nouri K, O'Connell C, Rivas MP.

Department of Dermatology and Otolaryngology, University of Miami School of Medicine, USA. [email protected]

Topical imiquimod is an immune response modifier FDA approved for the treatment of anogenital warts. Recent studies have reported its effectiveness in the treatment of some types of basal cell carcinomas. There have also been some case reports and case series reporting success treating of squamous cell carcinoma in situ with imiquimod. We report two patients with squamous cell carcinoma in situ and one with invasive squamous cell carcinoma treated with 5% imiquimod cream. Lesions were located on shin, posterior shoulder, and nasal tip. 5% imiquimod cream was applied at night for six weeks. Side effects included erythema and crusting in one patient. Biopsies taken four weeks after treatment revealed no residual squamous cell carcinoma in situ or squamous cell carcinoma. Topical 5% imiquimod cream is becoming established as a promising treatment for squamous cell carcinoma in situ. It also seems to be an alternative treatment for some cases of squamous cell carcinoma.

13.)  An open label evaluation of the efficacy of imiquimod 5% cream in the treatment of recalcitrant subungual and periungual cutaneous warts.

J Dermatolog Treat. 2003 Dec;14(4):233-6.

Micali G, Dall'Oglio F, Nasca MR.

Dermatology Clinic, University of Catania, Piazza S. Agata La Vetere 6, 95124 Catania, Italy. [email protected]

BACKGROUND: Periungual and subungual warts are very difficult to eradicate with current therapies. Most are destructive in nature (liquid nitrogen, cantharidin, vascular lesion laser) and inflammation, pain and pigment dyschromia are common side effects. Furthermore, failure to respond or appearance of new lesions often leads to even more destructive treatments (CO(2) laser, excisional surgery) and can lead to more pain and scarring. METHODS: In an open trial, the efficacy, safety, and tolerability of topical imiquimod 5% cream was assessed in 15 patients with resistant and recurrent periungual and subungual warts over a 16 week period. RESULTS: Twelve patients (80%) completed therapy, showing complete resolution after a mean time of three weeks (range 1-6 weeks), with the remaining three patients (20%) being classified as non-responders. Local side effects (erythema, pruritus, burning and pain) were generally mild and well-tolerated. No relapses occurred during a 6-month follow-up. CONCLUSION: Topical imiquimod is an interesting novel treatment for multiple periungual and subungual warts. Tolerability is excellent when compared to other commonly used modalities and there are few side effects. This trial suggests a high clinical response rate. This treatment is applicable to patients who have failed conventional therapies before embarking on potentially scarring approaches such as excisional surgery.

14.)  [Standard and experimental therapy of cutaneous T-cell lymphoma]

Hautarzt. 2003 Dec;54(12):1177-84.

[Article in German]

Beyeler M, Dummer R.

Dermatologische Klinik Universitatsspital Zurich, Zurich.

Cutaneous T-cell lymphoma represent a heterogeneous group of diseases characterized by skin invasion of monoclonal T-lymphocytes. These cutaneous T-cell lymphomas are divided into 3 groups based on clinical, histological and immunohistological characteristics: Indolent with a survival time of over 10 years, aggressive with a survival time less than 10 years and provisional (EORTC classification). Standard treatments such as PUVA, total skin electron beam, methotrexate, polychemotherapy regimens, retinoids and photopheresis have been used for years. Bexarotene is a newly registered drug. To achieve better response rates, several new drugs are being evaluated in clinical trails, including imiquimod, denileukon-diftitox, liposomal doxorubicin, adeno-interferon-gamma and various combination approaches.

J Invest Dermatol. 2003 Nov;121(5):1205-9.

Sidbury R, Neuschler N, Neuschler E, Sun P, Wang XQ, Miller R, Tomai M, Puscasiu E, Gugneja S, Paller AS.

Department of Pediatrics, Children's Memorial Hospital, Northwestern University Medical School, Chicago, Illinois 60614, USA.

Vascular tumors occur in approximately 10% of all infants and may be associated with significant morbidity. Available therapies for vascular tumors, such as systemic corticosteroids, vincristine, and interferon-alpha, may cause toxicity, limiting their use to complicated cases. Using a mouse hemangioendothelioma model, we investigated the efficacy and mechanism of action of imiquimod, a topically applied inducer of cytokines. Application of imiquimod cream, whether initiated at the time of cell inoculation or when tumors became visible, significantly decreased tumor growth and increased animal survival in comparison with control mice. Imiquimod-treated tumors showed decreased tumor cell proliferation, increased tumor apoptosis, and increased expression of tissue inhibitor of matrix metalloproteinase-1 with decreased activity of matrix metalloproteinase-9. The demonstration that local application of imiquimod inhibits vascular tumor enlargement in the mouse vascular tumor model suggests a novel, less toxic means of treating infantile hemangioendotheliomas and perhaps other cutaneous vascular tumors.

16.)  Therapeutic response of a brother and sister with xeroderma pigmentosum to imiquimod.

Dermatol Surg. 2002 Jun;28(6):518-23.

Weisberg NK, Varghese M.

Department of Dermatology, Weill Cornell Medical School, New York, New York 10021, USA.

BACKGROUND: Xeroderma pigmentosum (XP) is an autosomal recessive disease marked by solar sensitivity, photophobia, early onset of freckling, and solar-induced cutaneous neoplastic changes. These patients can often develop hundreds of cutaneous tumors, making surgical therapy difficult. Imiquimod 5% cream has been shown to have activity in treating various cutaneous malignancies. OBJECTIVE: To examine the effectiveness and tolerability of imiquimod 5% cream in treating facial basal cell carcinomas (BCCs) in a brother and sister with XP. These patients were developing skin cancers faster than could be managed surgically and had failed 6 months of chemoprophylaxis with isotretinoin. METHODS: Imiquimod 5% cream was applied to the faces of these two patients as frequently as tolerated, with the goal of gaining control over the many clinically evident BCCs present on the faces of these siblings. We also examined whether we could reduce the rate of new neoplasm development. RESULTS: The brother in our study tolerated imiquimod 5% cream twice a day every day with minimal inflammatory response. He had clinical resolution of many of the BCCs present within the treatment area as well as shrinking of many of the remaining lesions. He has continued to produce new tumors at a substantially reduced rate relative to his pretreatment baseline. The sister in our study exhibited a severe inflammatory response to imiquimod 5% cream, with facial swelling and erosion of the treated area with application as infrequent as three times a week. In spite of the vastly different inflammatory response, her cutaneous tumors responded favorably to therapy as well. CONCLUSION: Imiquimod 5% cream was effective in treating facial BCCs in these siblings with XP. As well, we have noted a significant reduction in the development of new tumors within the imiquimod-treated area. The inflammatory response to this medicine was at opposite extremes among these two siblings. However, this did not appear to alter the therapeutic benefit of this therapy.

17.)  Imiquimod, a topical immune response modifier, in the treatment of cutaneous metastases of malignant melanoma.

Dermatology. 2002;205(2):135-8.

Bong AB, Bonnekoh B, Franke I, Schon MP, Ulrich J, Gollnick H.

Department of Dermatology and Venereology, Otto von Guericke University, Magdeburg, Germany.

BACKGROUND: Imiquimod 5% cream (Aldara, a novel topical immune response modifier, has been approved for the topical treatment of anogenital HPV-induced warts. In addition, several studies have demonstrated antitumoral activity in solar keratoses, superficial basal cell carcinomas and Bowen's disease. AIM: Given the convincing therapeutic results of imiquimod when used for treating selected types of epithelial skin cancer, we became interested to study imiquimod as an adjuvant for treating cutaneous metastases of malignant melanoma. METHODS: Three patients with multiple, i.e. more than 15, cutaneous in-transit metastases of malignant melanoma in unilateral localization on the leg were treated topically with imiquimod 5% cream. RESULTS: Twice daily application under occlusive conditions for a period of 21-28 weeks resulted in >90% regression of cutaneous metastases in 2 patients. The third patient showed marked response only when topical imiquimod was intermittently supplemented by intralesional interleukin (IL)-2 for 2 weeks. Unwanted side effects were mild in all patients. CONCLUSION: Overall, imiquimod as a single agent or in combination with intralesional IL-2 may be a promising immunomodulatory compound for the adjuvant topical treatment of patients with multiple cutaneous metastases of malignant melanoma.

Dermatol Surg. 2000 Jun;26(6):577-8; discussion 578-9.

Kagy MK, Amonette R.

University of Tennessee-Memphis, Memphis, Tennessee, USA.

BACKGROUND: Imiquimod 5% cream has been used effectively to treat superficial basal cell carcinomas (BCCs). OBJECTIVE: The purpose of this study is to examine the effectiveness, tolerability, and desirability of imiquimod 5% cream in treating superficial non-facial basal cell carcinomas in a patient with basal cell nevus syndrome. METHODS: Three biopsy-proven nonfacial BCCs were treated for 18 weeks with once daily application of 5% imiquimod cream. The lesions were then removed to search histologically for residual tumor. RESULTS: The two adequately treated tumors revealed no residual BCC upon removal. Our patient reported that he tolerated the treatment but he would not desire this treatment again based on the length of treatment time and the degree of local inflammation at the treatment sites. CONCLUSION: Imiquimod 5% cream appears to be effective in eradicating superficial nonfacial BCCs. The degree of local inflammatory response may affect the patients' tolerability of treatment and therefore patient compliance.

Curr Opin Infect Dis. 2003 Apr;16(2):85-9.

Garland SM.

Department of Microbiology and Infectious Diseases, The Royal Women's Hospital, Carlton, Victoria, Australia. [email protected]

PURPOSE OF REVIEW: Imiquimod is the first member of a new class of immune response modifiers; it was first approved in 1997 for the topical treatment of external genital and perianal warts. It is an imidazoquinoline, a novel synthetic compound which is an immune response stimulator, enhancing both the innate and acquired immune pathways (particularly T helper cell type 1-mediated immune responses) resulting in antiviral, antitumour and immunoregulatory activities. The mechanism of action of imiquimod involves cytokine induction in the skin, which then triggers the host's immune system to recognize the presence of a viral infection or tumour, ultimately to eradicate the associated lesion. RECENT FINDINGS: Imiquimod, a patient-applied topical 5% cream is clinically efficacious and safe in the management of condylomata acuminata and other warty manifestations of human papillomavirus infections. Although not licensed for use against other viral skin infections, preliminary data suggest imiquimod's success against molluscum contagiosum, caused by a poxvirus. Initial studies with imiquimod for the management of HPV-related intraepithelial dysplasias (bowenoid papulosis/vulvar intraepithelial neoplasia) as well as for ultraviolet-induced skin lesions such as actinic keratoses, Bowen's disease, and basal cell carcinomas show great promise in immunocompetent and immunosuppressed patients. SUMMARY: In the future, imiquimod and newer generations of imidazoquinolines (resiquimod) require further investigation for potential clinical utility in treating other cutaneous and mucosal viral infections, dysplasias and neoplasia, as well as potential vaccine adjuvants.

20.)  Detection of CD8+ T cell responses to human papillomavirus type 16 antigens in women using imiquimod as a treatment for high-grade vulval intraepithelial neoplasia.

Gynecol Oncol. 2004 Jan;92(1):167-74.

Todd RW, Steele JC, Etherington I, Luesley DM.

Department of Gynaecologic Oncology, Birmingham Women's NHS Trust, Birmingham B15 2TG, UK. [email protected]

OBJECTIVES: To investigate CD8+ T cell reactivity to human papillomavirus (HPV) 16 antigens in patients with high-grade vulval intraepithelial neoplasia (VIN) before, during and after treatment with 5% imiquimod cream. METHODS: CD8-enriched responder cell populations were obtained from 10 patients with high-grade VIN using imiquimod cream as a treatment. Overlapping synthetic peptides covering the entire primary sequences of the HPV16 E6, E7 and E4 proteins were used to screen for CD8+ T cell responses using an ELISPOT assay of interferon (IFN)-gamma release. RESULTS: Reactivity to the proteins was detected in all patients on at least one occasion. With the exception of one patient, CD8+ T cell reactivity generally increased at some stage during treatment. The magnitude and specificities of responses changed over the treatment period. This was particularly noticeable in response to peptides derived from the E4 protein. CD8+ T cell reactivity to HPV16 E7 appeared to be dominant amongst women with high-grade VIN. The magnitude and specificity of response had no correlation with clinical response to imiquimod. CONCLUSIONS: HPV16 specific CD8+ T cell activity was detected in patients with high-grade VIN. Imiquimod use appeared to increase the magnitude of the response and broaden the specificity of response in some patients. Despite the presence of these CD8+ T cells, the disease state persisted; therefore, a role for HPV-specific cytotoxic T cells (CTLs) in VIN resolution remains unproven.

21.)  Bowenoid papulosis of the vulva-immunotherapeutical approach with topical imiquimod.

Arch Gynecol Obstet. 2003 Oct;268(4):333-6. Epub 2003 Jan 23.

Richter ON, Petrow W, Wardelmann E, Dorn C, Kupka M, Ulrich U.

Department of Obstetrics and Gynecology, University of Bonn School of Medicine, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany. [email protected]

INTRODUCTION. Bowenoid papulosis is a characteristic lesion of the ano-genital region and represents a form of squamous cell carcinoma in situ, very often associated to the oncogenic high-risk human papilloma virus (HPV) types 16, 18, 31 and 33. Therapies applied so far, in general, show high rates of relapse, and patients complain of pruritus and pain. Imiquimod cream is a topical immune response modifier with indirect antiviral and antitumor effects through the stimulation of local cytokine production and cell-mediated immune response. CASE REPORT. In the present paper we report on the topical application of imiquimod cream in a woman with a high-risk HPV-associated vulvar intraepithelial neoplasia grade III (VIN III) of the vulva. DISCUSSION. In addition a review of the literature is given.

22.)  Imiquimod is highly effective for extensive, hyperproliferative condyloma in children.

Pediatr Dermatol. 2003 Sep-Oct;20(5):440-2.

Majewski S, Pniewski T, Malejczyk M, Jablonska S.

Department of Dermatology and Venereology, Warsaw School of Medicine, Warsaw, Poland.

We describe a dramatic response to imiquimod of long-lasting, highly proliferative extensive perianal condylomas involving the anal canal in a 19-month-old girl. Her mother was free of condyloma and allegedly had no human papillomavirus (HPV) infection during pregnancy. There was no evidence of sexual abuse. Application of 5% imiquimod cream to the child every other day for 3 weeks resulted in almost complete resolution of the warts, with total clearance within another 2 weeks. The inflammatory reaction was moderate. Since there is still discussion of whether imiquimod may be prescribed for small children, this case of very extensive condyloma provides evidence that the compound is safe and highly effective.

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DATA-MEDICOS/DERMAGIC-EXPRESS /MAY JOURNAL 2.004/ DR. JOSE LAPENTA R. 
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