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Previous research has recently indicated that TLR7 is able to induce CD4 + T cell anergy, which is the opposite of the role it plays in innate immune cells. Therefore, TLR7 ligands may be used as a manner in which to induce CD4 + T cells "tolerance" in autoimmune diseases. T follicular helper (Tfh) cells were demonstrated to be a subset of CD4 + T cells that help B cells produce antibodies. The abnormal activity of Tfh cells, though, is their function as a primary pathogenic factor in systemic lupus erythematosus (SLE). However, the role of TLR7 in Tfh cells is not clear. Our study was aimed at determining the influence of TLR7 on Tfh cells in a murine model of SLE (MRL/lpr mice). We were surprised to find that the frequency of Tfh cells and germinal center (GC) B cells was significantly reduced after treatment with the TLR7 agonist imiquimod. Imiquimod also significantly reduced the expression of inducible costimulatory molecule (ICOS) and programmed death 1(PD-1) in Tfh cells and decreased IL-21 secretion. Moreover, imiquimod significantly reduced the mRNA expression of several transcription factors, including Bcl-6, c-Maf, Batf3, Nfatc2 and Stat3, and enhanced the expression of Prdm1 and Stat5b in CD4 + T cells. Imiquimod also ameliorated the progression of SLE in MRL/lpr mice by inhibiting anti-dsDNA antibodies and antinuclear antibody (ANA) secretion in the serum. Our findings indicated that TLR7 inhibited the development of Tfh cells both in vivo and ex vivo, which depended on many transcription factors aside from Bcl-6. Our results demonstrated that a TLR7 agonist has the potential to be used to inhibit Tfh cell responses during SLE., (Copyright © 2020. Published by Elsevier B.V.)

Therapeutic success of targeted therapy with BRAF inhibitors (BRAFi) for melanoma is limited by resistance development. Observations from preclinical mouse models and recent insights into the immunological effects caused by BRAFi give promise for future development of combination therapy for human melanoma. In our study, we used the transplantable D4M melanoma mouse model with the BRAF V600E mutation and concomitant PTEN loss in order to characterize alterations in tumor-infiltrating effector immune cells when tumors become resistant to BRAFi. We found that BRAFi-sensitive tumors displayed a pronounced inflammatory milieu characterized by high levels of cytokines and chemokines accompanied by an infiltration of T and NK cells. The tumor-infiltrating effector cells were activated and produced high levels of IFN-γ, TNF-α and granzyme B. When tumors became resistant and progressively grew, they reverted to a low immunogenic state similar to untreated tumors as reflected by low mRNA levels of proinflammatory cytokines and chemokines and fewer tumor-infiltrating T and NK cells. Moreover, these T and NK cells were functionally impaired in comparison to their counterparts in BRAFi-sensitive tumors. Their effector cell function could be restored by additional peritumoral treatment with the TLR7 agonist imiquimod, a clinically approved agent for nonmelanoma skin cancer. Indeed, resistance to BRAFi therapy was delayed and accompanied by high numbers of activated T and NK cells in tumors. Thus, combining BRAFi with an immune stimulating agent such as a TLR ligand could be a promising alternative approach for the treatment of melanoma., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Introduction: Standard of care for squamous cell carcinoma (SCC) is usually surgical, with either excision or Mohs micrographic surgery. However, surgery may not be ideal for elderly patients with numerous lesions, who are poor surgical candidates or who refuse surgery. Topical 5-fluorouracil (5-FU) and imiquimod have been studied off-label as monotherapies in the treatment of SCC in situ with promising results. However, long-term tumor-free survival rates are still less than with surgical management. Methods: We report a case of biopsy-proven invasive SCC in an 86-year-old Caucasian male with history of multiple actinic keratoses and no previous skin cancers. The patient declined surgical treatment due to concerns about cosmetic outcomes. A combination of topical 5% imiquimod cream, 2% 5-FU solution, and 0.1% tretinoin cream was used five nights per week under occlusion for a treatment goal of 30 total applications. The patient was evaluated in clinic every 2 weeks during which the site was treated with cryotherapy. The patient reported burning pain associated with treatment and only completed 24 of the 30 applications. Results: Follow-up biopsy 15 months after completing topical treatment revealed dermal scar with no evidence of residual carcinoma. Conclusion: Topical combination therapy with imiquimod, 5-FU, and tretinoin with intermittent, brief cryotherapy effectively treated a small, invasive SCC in this select patient who deferred surgery. Prospective randomized-controlled clinical trials to assess the role of combination topical treatment for invasive SCCs are warranted. J Drugs Dermatol. 2020;19(2)202-204. doi:10.36849/JDD.2020.2228

Rationale : The role of Monosodium Urate (MSU) crystals in gout pathophysiology is well described, as is the major impact of IL-1β in the inflammatory reaction that constitutes the hallmark of the disease. However, despite the discovery of the NLRP3 inflammasome and its role as a Pattern Recognition Receptor linking the detection of a danger signal (MSU) to IL-1β secretion in vitro , the precise mechanisms leading to joint inflammation in gout patients are still poorly understood. Methods : Acute urate crystal inflammation was obtained by subcutaneous injections of MSU crystals in mice. Symptoms were followed by scoring, cytokine quantification by ELISA and western blot, gene expression by RT-qPCR and RNAseq; Magnetic Resonance Imaging was also used to assess inflammation. Results : We provide an extensive clinical, biological and molecular characterization of an acute uratic inflammation mouse model which accurately mimics human gout. We report the efficacy of topical imiquimod treatment and its impact on Interferon-dependent down modulation of Il-1β gene expression in this experimental model. Conclusion : Our work reveals several key features of MSU-dependent inflammation and identifies novel therapeutic opportunities for gout patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Skin cancer is a broad term used to describe a number of different malignant indications of the skin. Skin cancers mostly comprise of the keratinocyte cancers [Basal Cell Carcinoma (BCC) and cutaneous Squamous Cell Carcinoma (SCC)], and melanoma. Surgical excision of these malignancies has been the preferred treatment of patients for decades. However, the decision to perform surgery can be affected by various considerations, including co-morbidities of the patient, the anatomical site of the lesion and potential intolerance for repeated excisions. Topical treatment of skin cancer may therefore be more appropriate in certain instances. Topical treatment potentially allows for higher drug levels at the tumor site, and may result in less overall toxicity than systemic agents. This review will specifically address the current agents used in topical treatment of skin cancers, and introduce emerging treatments from the natural product field that may also find utility in these indications., Competing Interests: Declaration of Competing Interest J.M.C. - Declaration of interest: recipient of fellowship co-sponsored by QBiotics Group. J.L.S. – Declaration of interest: none. P.G.P. - Declaration of interest: recipient of contract research funding from QBiotics Group; employee and has ownership interests in QBiotics Group. G.M.B. - Declaration of interest: recipient of fellowship co-sponsored by QBiotics Group; recipient of contract research funding from QBiotics Group., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Actinic keratosis (AK) is an early in situ epidermal cancer which can progress to invasive squamous cell carcinoma (SCC). Imiquimod 5% cream (IMIQ) and diclofenac 3% gel (DIC) are frequently used to treat AK; however, their long-term effects following repeated treatment cycles have never been compared., Objective: To compare IMIQ and DIC in the treatment of AK with respect to the risk of change to grade III AK or invasive SCC, after 3 years., Methods: Data were pooled from two randomized, active-controlled, open-label, multicentre, multinational, phase IV studies (Clinicaltrials.gov NCT00777127/NCT01453179), with two parallel groups. Studies were conducted between 2008 and 2015 and were almost identical in design. Patients eligible for inclusion were immunocompetent adults with 5-10 visible AK lesions on the face/scalp and grade I/II AK. The primary endpoint was inhibition of histological change to grade III AK or invasive SCC in the study treatment area, observed until month 36. Patients applied either IMIQ or DIC for a maximum of six treatment cycles., Results: In total, 479 patients (IMIQ 242; DIC 237) were included in the full analysis set. Histological change to grade III AK or invasive SCC was observed until month 36 in 13 (5.4%) patients treated with IMIQ, compared with 26 (11.0%) patients treated with DIC (absolute risk difference -5.6% [95% confidence interval -10.7%, -0.7%]). Time to histological change was greater in the IMIQ group than the DIC group (P = 0.0266). Frequency of progression to invasive SCC was lower with IMIQ than with DIC at all time points. Initial clearance rate was higher in the IMIQ group compared with the DIC group, while recurrence rate was lower. Both treatments were well tolerated., Conclusions: Over 3 years, IMIQ was superior to DIC in clearing AK lesions and preventing histological change to grade III AK or invasive SCC and recurrence., (© 2019 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Imiquimod 5% cream, an immune response modifier capable of inducing IFN-α, TNF-α, and interleukins 1, 6, and 8. It was approved for use in the management of genital and perianal warts and soon embraced as a method to diminish the recurrence of keloids postexcision. A previous meta-analysis included four studies. This meta-analysis is part of a larger systematic review project on the effect of moisturizers on scars. It was conducted following an a priori protocol and the guidance of the Joanna Briggs Institute. Databases searched included PubMed, CINAHL, Embase, and Web of Science. After screening and critical appraisal, subgroup meta-analysis on excision method and location of the keloid was conducted using the Miller approach for proportional meta-analysis and a random effects model. Seven studies, including 77 participants and 82 keloids were included. Meta-analysis revealed a recurrence rate of 39% (95% CI = 8.474.4%; I 2 = 87.5%) following application of Imiquimod postexcision. The use of primary excision or tangential excision did not alter the outcome. For analysis based on the location of the keloid scar, earlobe keloids had a recurrence rate of 5.4% (95% CI = 0-21.7%; I 2 = 52.9%). For keloids excised from other areas (predominantly on the trunk) recurrence rate was higher, at 76.8% (95% CI = 36.1-100%). For keloids, Imiquimod application postexcision results in highly variable recurrence rates. There is very low certainty in the effect of Imiquimod and it therefore is not recommended as a treatment option., (© 2019 by the Wound Healing Society.)

Vascular disrupting agents (VDAs) have great potential in cancer treatment. However, in addition to their direct tumoral vascular collapse effect, VDAs activate host immunological responses, which can remarkably impair their anticancer efficacy. Here, a VDA nanomedicine, poly(l-glutamic acid)- graft -methoxy poly(ethylene glycol)/combretastatin A4 (CA4-NPs), is found to induce the intratumor infiltration of immature plasmacytoid dendritic cells (pDCs), thereby curtailing anticancer immunity. To overcome this problem, hypoxia-sensitive imiquimod (hs-IMQ) is developed, which is selectively activated into imiquimod (IMQ) in treated tumors following the catalysis of CA4-NPs-induced nitroreductase (NTR). The combination of hs-IMQ and CA4-NPs causes a 6.3-fold enhancement of active IMQ concentration in tumors, as compared to hs-IMQ treatment alone. The in situ -generated IMQ alters the tumor microenvironment from a state of immunosuppression to immune activation. Hs-IMQ achieves this effect through the conversion of immature pDCs into their active form, leading to the robust infiltration and priming of natural killer cells and cytotoxic T-lymphocytes in treated tumors. Thus, the CA4-NPs and hs-IMQ combination treatment synergistically inhibits tumor growth and metastasis in 4T1 tumor-bearing mice. This work offers new approaches to harness intratumor pDCs to reverse the immune suppression resulting from VDA treatment. These findings additionally provide a mechanistic rationale for the use of VDAs in combination with TLR agonists to trigger in situ immune activation and enhance anticancer efficacy.

Objective: To generate estimates of comparative clinical effectiveness for interventions used in the treatment of anogenital warts (AGWs) through the systematic review, appraisal and synthesis of data from randomised controlled trials (RCTs)., Design: Systematic review and network meta-analysis of RCTs. Search strategies were developed for MEDLINE, Embase, the Cochrane Library and the Web of Science. For electronic databases, searches were run from inception to March 2018. The systematic review was carried out following the general principles recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement., Participants: People aged ≥16 years with clinically diagnosed AGWs (irrespective of biopsy confirmation)., Interventions: Topical and ablative treatments recommended by the British Association for Sexual Health and HIV for the treatment of AGWs, either as monotherapy or in combination versus each other., Outcome Measures: Complete clearance of AGWs at the end of treatment and at other scheduled visits, and rate of recurrence., Results: Thirty-seven RCTs met inclusion criteria. Twenty studies were assessed as being at unclear risk of bias, with the remaining studies categorised as high risk of bias. Network meta-analysis indicates that, of the treatment options compared, carbon dioxide laser therapy is the most effective treatment for achieving complete clearance of AGWs at the end of treatment. Of patient-applied topical treatments, podophyllotoxin 0.5% solution was found to be the most effective at achieving complete clearance, and was associated with a statistically significant difference compared with imiquimod 5% cream and polyphenon E 10% ointment (p<0.05). Few data were available on recurrence of AGWs after complete clearance. Of the interventions evaluated, surgical excision was the most effective at minimising risk of recurrence., Conclusion: Of the studies assessed, as a collective, the quality of the evidence is low. Few studies are available that evaluate treatment options versus each other., Trial Registration Number: CRD42013005457., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Actinic keratoses (AK) are common precancerous lesions of the skin due to cumulative sun exposure. A variety of interventions are available for the treatment; however, the majority of randomised controlled trials (RCTs) and meta-analyses focus on short-term efficacy outcomes. This network meta-analysis aims to investigate the long-term (> 12 months) efficacy of interventions for AK., Methods: To identify relevant studies, we will perform a systematic literature research in MEDLINE, Embase, and CENTRAL and hand-search pertinent trial registers. Two authors will independently screen titles and abstracts for eligibility. We will include RCTs with an inter-individual (parallel arm) design. The study population includes patients with a clinical or histopathologic diagnosis of AK. Eligibility will be restricted to the following interventions: surgical approaches, cryosurgery, ablative laser treatment, topical drug treatment with 5-fluorouracil, imiquimod, ingenol mebutate, diclofenac, or photodynamic therapy. As outcomes, we will consider the following endpoints: (1) the participant complete clearance rate, (2) the participant partial clearance rate, (3) the lesion-specific clearance, (4) the mean lesion reduction per patient, and (5) the number of withdrawals due to adverse events after at least 12 months after the end of treatment. Monotherapy or placebo will serve as a comparison. Estimates of effects from individual studies will be pooled using a random-effects model. Heterogeneity will be evaluated based on I 2 and chi-square test. The risk of bias will be estimated with the Cochrane Risk of Bias Tool by two review authors independently. The quality of evidence of the outcomes will be assessed with the GRADE approach. A network meta-analysis will be performed to combine direct and indirect evidence from the included RCTs., Discussion: The potential of interventions to achieve a sustained clearance of AK has not been assessed to date. To investigate the long-term efficacy of interventions is important as the natural disease course is highly variable and relapses occur frequently even after initial lesion clearance. This review will help to set a framework for clinical decision making in patients with AK., Systematic Review Registration: CRD42018095903 (PROSPERO).

Combination of chemotherapeutics and immunomodulators can generate synergistic anticancer efficacy, exerting efficient chemoimmunotherapy for cancer treatment. Nanoparticulate delivery systems hold great promise to promote synergistic anticancer efficacy for the codelivery of drugs. However, there remain challenges to precisely coencapsulate and deliver combinational drugs at designed ratios due to the difference of compatibility between drugs and nanocarriers. In this study, coassembled nanoparticles of lipophilic prodrugs (LPs) were designed to codeliver chemotherapeutics and immunomodulators for cancer treatment. Such nanoassemblies (NAs) could act as platforms to ratiometrically coencapsulate chemotherapeutics and immunomodulators. Based on this method, NAs formed by the self-assembly of iRGD peptide derivatives, paclitaxel (PTX) LPs, and imiquimod (R837) LPs were demonstrated to target the tumor at unified pharmacokinetics, further inducing the effective tumor inhibition and tumor recurrence prevention. This work provided an alternative to prepare chemoimmunotherapeutic NAs with advantages of ratiometric drug coencapsulation and unified pharmacokinetics, which may advance the future cancer chemoimmunotherapy.

Background: Fingolimod is used to reduce relapse rates in relapsing-remitting multiple sclerosis (MS). It is a sphingosine 1-phosphate (S1P) analogue having antagonistic effects on S1P receptors. Its immunosuppressive effect is due to reduced circulating lymphocyte numbers, and it may also be associated with impaired intrinsic cancer surveillance. Fingolimod side effects include increased rates and severity of viral infections particularly varicella zoster., Methods: We present five cases of chronic and treatment refractory warts associated with fingolimod therapy., Results: Each of the five cases presenting with chronic warts while receiving fingolimod therapy had prolonged periods of lymphopenia and improvements were seen following dose reduction or cessation of fingolimod., Conclusion: Cutaneous warts are associated with human papilloma virus (HPV) infection, suggesting an increased risk of other HPV-driven conditions such as cervical cancer following fingolimod administration. HPV viruses are responsible for approximately 90% of cervical cancers as well as a significant portion of anogenital cancers and have a high prevalence in sexually active adults. Given the reduced immune response to viral infections and potential impaired cancer surveillance in those receiving fingolimod, HPV vaccination and frequent assessment for the development of HPV-associated malignancies are recommended.

Background: Vulvar Paget disease (VPD) is a rare skin disorder that is considered premalignant., Objective: To assess the clinical course, treatment schedules, and effect of invasion and treatment on recurrence and survival in patients with VPD., Methods: Data on women with VPD were retrieved from the medical files and pathology reports in all Dutch tertiary university medical centers. Disease-free survival and 5-year disease-specific survival were estimated by using Kaplan-Meier curves., Results: Data on 113 patients whose VPD was diagnosed between 1991 and 2016 were analyzed; 77% had noninvasive VPD. Most of the women (65%) underwent a surgical procedure. Recurrences were reported in 40%. Of the women with noninvasive VPD, 8% developed invasion. There were no disease-specific deaths reported in the women with noninvasive VPD. The 5-year disease-specific survival rate was greater than 98% in noninvasive and microinvasive VPD, but significantly worse in invasive VPD (50% [P < .0005])., Limitations: The main limitations of this study are its retrospective character and the fact that original pathology samples were not available for reassessment., Conclusions: VPD is extremely rare, and the recurrence rates are high. Most patients have noninvasive VPD, which does not affect survival and should be considered a chronic disorder with limited invasive potential. In cases of invasive disease, survival decreases significantly., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Although surgical intervention remains the standard of care for nonmelanoma skin cancer, other treatment modalities have been studied and used. Nonsurgical treatment methods include cryotherapy, topical medications, photodynamic therapy, radiation therapy, Hedgehog pathway inhibitors, programmed cell death protein 1 inhibitors, and active nonintervention. Despite the favorable efficacy of surgical treatment methods, many factors, including but not limited to patient age, preference, and severity of disease, must be taken into consideration when choosing the most appropriate, patient-centered treatment approach., (Copyright © 2019 Elsevier Inc. All rights reserved.)

There are multiple, genetically distinct pathways that give rise to melanoma. Melanomas on sun-damaged skin (MSDS), including lentigo maligna and desmoplastic melanoma, have distinct genetic profiles and are uniquely linked to chronic ultraviolet exposure. In this article, we discuss the etiologies of lentigo maligna and desmoplastic melanoma, emerging diagnostic adjuncts that might be helpful for accurately identifying these lesions, and the clinical relevance of their frequent co-occurrence. We present unique and overlapping features of these entities and discuss challenges in MSDS management, including margin assessment, excision, and the potential role of nonsurgical therapy. Last, we address the role of immunotherapy in invasive disease. Understanding MSDS as distinct from melanoma arising on intermittently sun-exposed or sun-protected skin will ultimately help optimize patient outcomes., (Copyright © 2019 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background/objectives: Anogenital verrucae (AV) are benign, human papillomavirus (HPV)-induced tumors of the anogenital skin and mucosa. Medical therapy for AV in preadolescents has not been well studied. We explore the efficacy and safety profile of sinecatechins 15% ointment and imiquimod 5% cream in the treatment of AV, alone and in combination therapy with other commonly used medications., Methods: A single-institution, retrospective review of children under 12 years of age with AV treated with imiquimod 5% cream and sinecatechins 15% ointment was performed. Demographic data, side effects, and outcomes of therapy were recorded for each patient, and overall efficacy was determined., Results: A total of 37 patients met inclusion criteria. Responses were seen in 8 out of 9 patients treated with sinecatechins 15% ointment (5 full, 3 partial, and 1 no response) and 9 out of 17 patients treated with imiquimod 5% cream (4 full, 5 partial, and 8 no response). Combination therapy with one or more of the following treatments (podophyllin, cimetidine, candida antigen injection, and HPV vaccine) were evaluated, but no combination was objectively superior to the others. No significant difference was found in overall efficacy between sinecatechins and imiquimod. Side effects were mild and limited to irritation and erythema., Conclusions: Both imiquimod 5% cream and sinecatechins 15% ointment are moderately effective in the treatment of AV in preadolescent children, with a trend toward greater effectiveness of sinecatechins. Combination therapy with other treatments did not significantly increase the effectiveness of topical therapies. Each modality has a tolerable side effect profile with a low risk of serious complications., (© 2019 Wiley Periodicals, Inc.)

Background: Classic Kaposi sarcoma usually remains on the skin and has a slow progression; thus, local treatment methods are preferable. Imiquimod is an immunomodulatory agent with antiviral, antitumoural, and antiangiogenic properties that is expedient against Kaposi sarcoma., Objectives: We aimed to clarify whether imiquimod is effective on classic Kaposi sarcoma lesions by comparing imiquimod treatment with cryotherapy, which is the most-used treatment method in our department for this disease., Method: Patients with classic Kaposi sarcoma were included. All lesions of each patient were evaluated and measured by the blinded investigator considering infiltration and surface diameters. Then, lesions were categorized into 2 groups by the other investigator (nonblinded), and imiquimod 5% cream was administered 3 times per week without occlusion in 1 group. Cryotherapy was performed every 3 weeks in the other group. All lesions were reevaluated and measured at the end of 12 weeks by the blinded investigator. Initial and last measurements were compared between the treatment methods., Results: Fifty lesions of 8 patients were included in this study. Imiquimod and cryotherapy were applied to 26 and 24 lesions, respectively. At the end of the study, statistically significant decreases were detected in all scores between weeks 0 and 12 with both treatment methods. Mean percentages of change in scores were not significantly different between the methods., Conclusions: Based on a limited number of patients and lesions treated, we believe imiquimod may be a suitable option to use for the treatment of classic Kaposi sarcoma.

The importance of dermoscopy for diagnosing lentigo maligna melanoma (LMM) is well known. More recently, dermoscopy has been proposed as a useful tool also for the treatment choice and monitoring. Herein, we present an 87-year-old woman, who was successfully treated with imiquimod 5% cream after surgical persistence of residual LMM and for whom dermoscopy was helpful to assist diagnosis and assess tumor persistence after surgery and its response to topical treatment with imiquimod., (© 2019 Wiley Periodicals, Inc.)

In medical practice, physicians are sometimes faced with patients who reject the gold-standard treatment for a condition. In this hypothetical clinical scenario, we present the case of a patient who refuses Mohs micrographic surgery for management of infiltrative basal cell carcinoma and instead requests off-label therapy with imiquimod. We discuss the treating dermatologist's options in response to this patient's request and the ethical considerations surrounding the case. We conclude that the physician has the right to refuse to provide treatment that deviates from standard clinical practice but that the physician should counsel the patient on all options, provide thorough informed consent, offer contact information for the patient to pursue a second opinion or a radiation oncology referral, and ensure safe transfer of care should the patient desire treatment with a different provider.

Objectives: In HIV + -patients, routine proctological assessment is warranted due to the high incidence of human papilloma virus (HPV) infection-related anogenital lesions, such as Condylomata acuminata (C. ac.), anal intraepithelial dysplasia (AIN) and anal cancer. For C. ac. and AIN, surgical resection and topical therapy with imiquimod have been discussed as treatment options., Background: In this study, we contrasted surgical resection and topical imiquimod therapy of HPV-associated anal lesions in HIV + -patients, with a focus on healing rates and clinical outcome. We also analysed whether a synergistic treatment effect was detectable., Methods: This was a retrospective analysis of 97 HIV + patients who underwent proctological evaluation and treatment over a 10-year period (11/2004 - 11/2015) at our centre. Initial success of surgical treatment, topical imiquimod therapy and the combination of the two strategies were compared., Results: In 53/97 patients (54%), HPV-associated anal disease was diagnosed upon the first visit. In approx. 50% of the patients, the HIV infection was adequately controlled (52 patients with viral load < 40 copies [53.6%]) under cART. The mean age was 41.0 ± 11.6 years. In 7/53 patients with macroscopic C. ac., low-grade and in 18/53 patients high-grade AIN were additionally confirmed. Success rates of surgical resection, imiquimod treatment and the combination of the two were compared. Complete remission of C. ac. and AIN four weeks after treatment was considered a therapeutic success. For C. ac., success rates with imiquimod were 5/25 (20.0%) vs. surgery* 30/57 (52.6%, Mann-Whitney U test p < 0.05) vs. surgery+imiquimod 7/15 (46.7%). For AIN, success rates with imiquimod were 4/24 (16.7%) vs. surgery* 47/83 (56.7%, Mann-Whitney U test p < 0.05) vs. surgery+imiquimod 9/21 (42.8%). In 7/92 (13%) of surgical treatments, complications were reported: four minor and two significant bleeding episodes and one perianal thrombosis. No side effects of imiquimod were documented besides skin irritation., Conclusion: Surgery is more effective than topical imiquimod as initial therapy of HPV-related anogenital disease in HIV + -patients. A synergistic effect could not be demonstrated. On this basis, we recommend surgical treatment of C. ac. and AIN in HIV + -patients as first line treatment., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: Lentigo maligna (LM) may be disfiguring and can progress to LM melanoma. Surgical excision remains the mainstay of treatment, but may result in disfigurement when used for large facial lesions. Topical imiquimod is a nonsurgical alternative although data on its long-term efficacy remain limited., Aim: To assess long-term outcomes of LM treated with imiquimod cream., Methods: We collected data retrospectively for 33 patients treated with imiquimod cream for biopsy-proven LM from 2001 to 2016. Patients initially applied imiquimod once daily, 5 days/week for 6 weeks, aiming to produce a brisk local inflammatory response. If there was no response, the dose was increased to twice daily 7 days/week for 6 weeks and if again there was no response, to twice daily for 10 weeks., Results: An inflammatory response developed in 29 (88%) of the 33 patients, and of these, 4 patients stopped treatment earlier than planned because they could not tolerate the inflammatory reaction, while 3 patients reported systemic side effects. There was lesion clearance in 21 (72%) of the 29 patients, and they remained clear after a mean follow-up of 4.1 years. Eight failed to clear; in five the lesion was excised, while the remaining three were managed expectantly., Conclusions: Our results support the use of imiquimod as an alternative to surgery for the treatment of LM in selected cases. With adequate patient preparation, imiquimod is generally tolerated and can achieve excellent cosmetic results. A clinical response is more likely if there is a brisk inflammatory response, and LM will not resolve if there is no inflammatory response., (© 2019 British Association of Dermatologists.)

Immunocryosurgery, the combination modality of a cryosurgery session at day 14 of a 5-week daily imiquimod treatment cycle, has shown remarkable efficacy in the treatment of basal cell carcinoma (BCC). The modality was designed to exploit synergy of antitumor effects, including the induction of immune responses, elicited by imiquimod and cryosurgery. Herein, we report on the infiltration of the BCC by selected inflammatory cell species during an immunocryosurgery treatment cycle. The density of tissue infiltrating CD68 + , CD3 + and Foxp3 + cells was studied by immunohistochemistry in 56 BCC biopsies from 28 treated sites (26 patients) at baseline and at days 12, 16 or 28 during treatment. Immunocryosurgery induces statistically significant alterations in all three cell species (p < 0.003): The density of CD68 + increased already by day 12 and remained at a higher level during the treatment thereafter. The density of CD3 + cells increased significantly between days 12 and 16 of treatment. The density of T reg (Foxp3 + ) cells increased in the early phase of treatment (highest at day 12) to decrease significantly already 2 days after the cryosurgery session (day 16) and thereafter up to day 28 of the treatment cycle (p = 0.033). Within the tumor tissue, these alterations result in an abrupt increase in the CD3 + /Foxp3 + ratio, a finding suggesting that the cryosurgical perturbation may probably play a decisive modulating role in the cellular composition of the inflammatory infiltrate during immunocryosurgery, eventually heralding the induction of an effective tumor-destructing immune response.

Stimulation of Toll-like receptors (TLRs) and/or NOD-like receptors on immune cells initiates and directs immune responses that are essential for vaccine adjuvants. The small-molecule TLR7 agonist, imiquimod, has been approved by the FDA as an immune response modifier but is limited to topical application due to its poor pharmacokinetics that causes undesired adverse effects. Nanoparticles are increasingly used with innate immune stimulators to mitigate side effects and enhance adjuvant efficacy. In this study, a potent small-molecule TLR7 agonist, 2-methoxyethoxy-8-oxo-9-(4-carboxybenzyl)adenine (1V209), was conjugated to hollow silica nanoshells (NS). Proinflammatory cytokine (IL-6, IL-12) release by mouse bone-marrow-derived dendritic cells and human peripheral blood mononuclear cells revealed that the potency of silica nanoshells-TLR7 conjugates (NS-TLR) depends on nanoshell size and ligand coating density. Silica nanoshells of 100 nm diameter coated with a minimum of ∼6000 1V209 ligands/particle displayed 3-fold higher potency with no observed cytotoxicity when compared to an unconjugated TLR7 agonist. NS-TLR activated the TLR7-signaling pathway, triggered caspase activity, and stimulated IL-1β release, while neither unconjugated TLR7 ligands nor silica shells alone produced IL-1β. An in vivo murine immunization study, using the model antigen ovalbumin, demonstrated that NS-TLR increased antigen-specific IgG antibody induction by 1000× with a Th1-biased immune response, compared to unconjugated TLR7 agonists. The results show that the TLR7 ligand conjugated to silica nanoshells is capable of activating an inflammasome pathway to enhance both innate immune-stimulatory and adjuvant potencies of the TLR7 agonist, thereby broadening applications of innate immune stimulators.

Chemoprevention of nonmelanoma skin cancer should be considered in patients likely to develop numerous, invasive, or metastatic nonmelanoma skin cancers. This article reviews the various topical and systemic substances studied as chemopreventive agents., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Immune cells infiltrating the psoriatic skin secrete high amounts of pro-inflammatory cytokines IL-17, TNF-α, IL-21 and IL-36 resulting in chronic inflammation. However, the exact cellular and molecular mechanisms have not been fully understood. We report here elevation of IL-33 expression in psoriatic lesions. Studies in imiquimod (IMQ)-induced mice with psoriatic inflammation confirmed a critical role for IL-33 in driving the disease. IL-33 reduces the CD4 + and CD8 + cells, inhibits autophagy in IMQ-treated mouse skin, and promoted tyrosyl phosphorylation of STAT3. Thus, IL-33 appears to be a major risk factor for severity of psoriasis-like skin inflammation. Our findings may open new perspectives for understanding the mechanisms and developing a therapeutic strategy for psoriasis., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: This is an updated version of the original Cochrane Review published in Issue 10, 2013.Extramammary Paget's disease is a rare form of superficial skin cancer. The most common site of involvement is the vulva. It is seen mainly in postmenopausal white women. Paget's disease of the vulva often spreads in an occult fashion, with margins extending beyond the apparent edges of the lesion. There is a range of interventions from surgical to non-invasive techniques or treatments. The challenges of interventions are to remove or treat disease that may not be visible, without overtreatment and with minimisation of morbidity from radical surgery. There is little consensus regarding treatment. Surgery, by default, is the most common treatment, but it is challenging to excise the disease adequately, and recurrence is common, leading to repeated operations, and destruction of anatomy. Alternative treatments of photodynamic therapy, laser therapy, radiotherapy, topical treatments or even chemotherapy have been mooted, and it is important to evaluate the available evidence. It is essential to assess whether newer cell-specific treatments, such as photodynamic therapy and imiquimod, can reduce the need for radical surgery., Objectives: To evaluate the benefits and harms of different treatment modalities for the management of Paget's disease of the vulva., Search Methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (via Ovid) and Embase (via Ovid) up to 8 May 2018. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of review articles., Selection Criteria: We searched for randomised controlled trials (RCTs) and well-designed non-randomised studies that compared different interventions in women with Paget's disease of the vulva, DATA COLLECTION AND ANALYSIS: Two review authors independently assessed whether potentially relevant studies met the inclusion criteria. We found no trials and, therefore, analysed no data., Main Results: The search for the original version of the review identified 635 unique references. We found 31 references (which reported on 30 studies) in full text after inspection of titles and abstracts, but we excluded them all as they did not meet the inclusion criteria. However, we have included a comprehensive narrative account of studies where we identified an analysis of more than 10 women, as this forms the only evidence base in this rare disease. Surgery continues to be the mainstay of treatment in the current literature, with other treatments limited to case reports or treatment of inoperable or recurrent disease.This update between September 2013 and May 2018 identified 35 new studies. None of these met the inclusion criteria. There was only one prospective study of 5% imiquimod in recurrent Paget's disease of the vulva, which although of good quality only included eight women., Authors' Conclusions: Since the last version of the review was published there are many more cases in the literature reporting a clinical response to 5% imiquimod cream. There is one prospective study of eight women treated with 5% imiquimod for recurrent Paget's disease of the vulva, and one prospective trial of 20 women was due to be reported. This increasing evidence for the safety and efficacy of 5% imiquimod will be helpful for women and clinicians alike. Ideally, a multicentre RCT of reasonable size is needed, but ongoing publications of high-quality non-randomised prospective studies will enhance the current available literature.

Extramammary Paget disease is a rare neoplastic condition that more commonly affects postmenopausal Caucasian women. Although the vulvar area is the most frequently affected location, it corresponds solely to 1 to 2% of all vulvar malignancies. A 72-year-old female patient was observed in our outpatient clinic with a 2-year history of an erythematous and pruritic plaque on the vulva. Histopathology and immunohistochemistry studies were compatible with extramammary Paget disease of the vulva. Associated neoplastic conditions were excluded. Due to multiple relapses, the patient was submitted to three surgical interventions, including a total vulvectomy, and to external radiotherapy. The present case illustrates the chronic and recurrent nature of extramammary Paget disease despite aggressive procedures as well as the challenge in obtaining tumor-free resection margins., Competing Interests: The authors have no conflicts of interests to declare., (Thieme Revinter Publicações Ltda Rio de Janeiro, Brazil.)

Background: Vulval intraepithelial neoplasia (VIN) is a precancerous condition that may progress to invasive malignancy. VIN is associated with human papillomavirus (HPV) infection in most cases, and with inflammatory skin disorders in a smaller proportion of patients. Treatment of VIN has traditionally been surgical excision; however, topical treatments, including imiquimod cream, are becoming increasingly used. Patient factors influencing response to imiquimod therapy, in particular smoking, have not yet been published., Aim: To assess the impact of smoking and other patient characteristics that may influence the treatment response to topical imiquimod for VIN., Methods: This was a retrospective cohort study of 46 women treated with topical imiquimod for VIN in a single centre dermatology unit from January 2011 to July 2017., Results: Complete clinical resolution of VIN was observed in 28 of 46 patients (61%), but was significantly reduced in the smoking cohort., Conclusions: Smoking may impair response to imiquimod for VIN, and should be considered when discussing VIN treatment options with patients., (© 2019 British Association of Dermatologists.)

Introduction: Condylomas or genital warts (GW) are the most frequently diagnosed sexually transmitted infection (STI) in STI centers in Chile, but there are no population statistics available., Objectives: To describe the prevalence of GW in patients from 18-60 years of age who attend outpatient dermatology, gynecology and urology practice; the demographic characteristics of the patients and the diagnostic and treatment tools., Methods: A sample of Chilean specialists stratified by region, population and gender of patients was provided with a logbook and answered a questionnaire., Results: The GW prevalence was 2.44% for the whole group; 3.76% for the 18-34 age group and 1.29% for the 35-60 years group (p = 0.0000). The average age of patients with GW was 29.4 years in women and 32.7 years in men (p = 0.019). The distribution by age was different according to gender and health system. Visual inspection was the most frequent diagnostic method used and imiquimod cream the most common treatment, however, there were differences in the use of diagnostic and therapeutic tools according to the patient's gender, specialty of the doctor and health system., Conclusions: The high prevalence of GW confirmed the need and importance of public health interventions to address this problem.

There is a need for new, effective, and less expensive and toxic treatment for Leishmaniasis. It seems that the use of a suitable adjuvant and a delivery system is effective in inducing immune reactions for protection. Liposomes can be applied as immunoadjuvants to trigger immune reactions to different antigens. The adjuvant effects of imiquimod using DSPC liposomes containing SLA (soluble Leishmania antigens) were studied on the type and intensity of the produced immune reaction to the challenge of Leishmania major in BALB/c mice. Liposomes were produced by the lipid film procedure. BALB/C mice were immunized subcutaneously, three times at 2-week intervals and with various formulations. Lesion development and the parasite burden in the spleens and feet after the challenge with Leishmania major, Th1 cytokine (IFN-γ), and the IgG isotype titration were assessed to evaluate the induced immune reaction and the protection level. The group of mice immunized with Liposome DSPC +Imiquimod +SLA revealed less severe footpad swelling, being significantly different (P < .05) from other groups. A higher level of IgG2a and IFN-γ secretion was observed in the mice immunized with Liposome DSPC +Imiquimod +SLA than the control group. These observations imply that the DSPC liposome containing imiquimod induces the Th1 immune response that is protective against the challenge of Leishmania major., (Copyright © 2019 Elsevier B.V. All rights reserved.)

T-cell lymphomas include diverse malignancies. They are rare, some have low survival rates and they lack curative therapies. The aim of this work was to assess whether employing the TLR7 agonist imiquimod and the T-cell costimulatory molecule CD40 or the combination of both as adjuvants of a cell lysate vaccine could enhance the antitumor immune response using a murine T-cell lymphoma model. Immunization with LBC-lysate and imiquimod protected almost all vaccinated animals. A specific humoral and a Th1-type cellular immunity were induced in mice that rejected the lymphoma, characterized by an elevated number of CD4 + T-cells and secretion of IFN-γ, locally and systemically. In contrast, CD40 alone or in combination with imiquimod did not improve the protective response obtained with LBC-lysate and imiquimod. Systemic administration of imiquimod proved to have high potential to serve as a vaccine adjuvant for the treatment of T-cell lymphomas and was effective in this immunotherapy model., (Copyright © 2019. Published by Elsevier Inc.)

Primary cutaneous anaplastic large cell lymphoma (pc-ALCL) is a CD30+ subtype of cutaneous T-cell lymphoma. It typically has a very favorable prognosis; however, traditional treatment can be expensive, invasive, and associated with significant adverse events. Imiquimod is a topical toll-like receptor approved by the Food and Drug Administration (FDA) for genital warts, actinic keratosis, and primary superficial basal cell carcinoma. In previous case reports, imiquimod has been shown to be effective against pc-ALCL. We present a case of complete resolution of pc-ALCL within 8 weeks with topical imiquimod and review the current literature. J Drugs Dermatol. 2019;18(5):460-462.

Transplant recipients are at high risk of developing actinic keratosis (AK) and skin cancer. For this reason, initiating treatment at an early stage is crucial. Topical and systemic therapeutic options for AK have widely been described in studies of immunocompetent patients. However, little is known about AK management in organ transplant recipients (OTR). Photodynamic therapy (PDT), along with imiquimod, topical NSAIDs and topical 5-fluorouracil have been used on ORT patients in small non randomized studies. Although these studies seem to suggest that PDT offers best results, solid evidence is lacking. Nicotinamide and oral retinoids have also been described as reasonably effective preventive treatments in ORT patients. Management of immunosuppressive drugs is also considered as a key point for reducing the number of AK in ORT patients; an early switch for m-tor inhibitors has been shown to be protective while azathioprine, ciclosporin and tacrolimus have been shown to heighten the risk of developing AKs and skin cancer in this population. © 2019 Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Kératoses actiniques : comprendre et traiter réalisé avec le soutien institutionnel de Galderma International., (© 2019 Elsevier Masson SAS. Tous droits réservés.)

Dermatologists have many therapeutic options for the management of actinic keratoses (AK), in order to treat individual lesions or wider areas. Field cancerization is an area of sun-damaged skin, where visible and subclinical lesions co-exist, and is prone to the development of further AK lesions and sun-related skin cancers (SC). Treatments available are instrumental or medical. Resistance to treatment or atypical symptoms must lead to a biopsy for histological exam. Cryotherapy is the most frequently used method to destroy small or isolated AK, whereas photodynamic therapy (PDT), 5-fluoro-uracil (5-FU), imiquimod, ingenol mebutate and diclofenac are required for large, multiple lesions, and for the treatment of field cancerization. Side-effects of these therapies are essentially local, including pain, irritation, erythema, edema and scars. There is no randomized comparative study reviewing all these treatments, therefore physicians must also consider clinical characteristics, patient's compliance, side-effects and cost when treating AK. Medicoeconomic data of these treatments have been analyzed in several countries, and annual costs are estimated between 250 € and 2 000 €, with an uncertain cost-effective relation. Finally, beyond treatment of AK lesions, patients with AK are at high risk of developing SC, and must therefore have regular full-body examination, in order to be detected and treated precociously. © 2019 Elsevier Masson SAS. All rights reserved. Cet article fait partie du numéro supplément Kératoses actiniques : comprendre et traiter réalisé avec le soutien institutionnel de Galderma International., (© 2019 Elsevier Masson SAS. Tous droits réservés.)

Actinic keratosis (AK) develops on chronically sun-exposed skin and constitutes one of the most common diseases managed by dermatologists. The incidence of AKs continues to rise among aging as well as younger sun damaged populations worldwide, underscoring the importance of effective therapy options. Various treatments are available, including light-based therapies, topical therapies, and destructive therapies. Herein, we review the current management options for AKs and discuss emerging therapeutic agents. J Drugs Dermatol. 2019;18(5 Suppl 1):s161-166.

Background: In the warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome, variable phenotypic expression may delay diagnosis. Panleukopenia, malignancy, and chronic lung disease all affect morbidity and mortality risks. Routinely used treatments include immunoglobulins, granulocyte-colony stimulating factor (G-CSF), and antibiotics; recent trials with a target C-X-C chemokine receptor type 4 (CXCR4) antagonist show promising results., Objective: We sought to characterize the largest cohort of patients with WHIM and evaluate their diagnostic and therapeutic management., Methods: Data were collected from an international cohort of 18 patients with CXCR4 mutations., Results: The clinical features manifested at 2.2 ± 2.6 years of age, whereas the disease diagnosis was delayed until 12.5 ± 10.4 years of age. Patients with WHIM commonly presented with a severe bacterial infection (78%). Pneumonia recurrence was observed in 61% of patients and was complicated with bronchiectasis in 27%. Skin warts were observed in 61% of patients at a mean age of 11 years, whereas human papilloma virus (HPV)-related malignancies manifested in 16% of patients. All the patients had severe neutropenia (195 ± 102 cells/mm 3 at onset), whereas lymphopenia and hypogammaglobulinemia were detected in 88% and 58% of patients, respectively. Approximately 50% of patients received antibiotic prophylaxis, whereas G-CSF and immunoglobulin treatments were used in 72% and 55% of patients, respectively., Conclusions: The WHIM syndrome onsets early in life and should be suspected in patients with chronic neutropenia. Patients with WHIM need careful monitoring and timely intervention for complications, mainly lung disease and HPV-related malignancies. We suggest that immunoglobulin therapy should be promptly considered to control the frequency of bacterial infections and prevent chronic lung damage., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: There have been concerns that recurrences after noninvasive therapy for basal cell carcinoma (BCC) transform into a "more aggressive" histologic subtype., Objective: We sought to evaluate the proportion of patients with a nonsuperficial treatment failure after noninvasive therapy for superficial BCC., Methods: An observational study was performed using data from a single blind, noninferiority, randomized controlled trial (March 2008-August 2010) with 5-year follow-up in patients with primary superficial BCC treated with methylaminolevulinate-photodynamic therapy, 5-fluorouracil, or imiquimod. Data were used from 166 adults with a histologically confirmed treatment failure., Results: A nonsuperficial subtype was found in 64 of 166 treatment failures (38.6%). Proportions with a more aggressive subtype than the primary tumor were 51.3% (38/74) for early and 28.3% (26/92) for later treatment failures (P = .003). The proportion of more aggressive early failures was significantly lower after imiquimod (26.3%) compared with methylaminolevulinate-photodynamic therapy (54.8%, P = .086) and 5-fluorouracil (66.7%, P = .011)., Limitations: There was limited information on the exact time of occurrence of treatment failures., Conclusion: More aggressive treatment failure recurrences after noninvasive therapy for superficial BCC occur most often within the first 3 months posttreatment, probably indicating underdiagnosis of more aggressive components in the primary tumor rather than transformation., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The effectiveness of 5-fluorouracil compared with that of imiquimod for preventing keratinocyte carcinoma is unknown., Objective: To compare the effectiveness of 5-fluorouracil and that of imiquimod in preventing keratinocyte carcinoma in a real-world practice setting., Methods: We identified 5700 subjects who filled prescriptions for 5-fluorouracil or imiquimod for treatment of actinic keratosis in 2007. An intention-to-treat analysis controlling for potential confounding variables was used to calculate 2- and 5-year cumulative risk differences for subsequent keratinocyte carcinoma overall and in field-treated areas., Results: 5-Fluorouracil was associated with a statistically significant decreased risk of any keratinocyte carcinoma compared with imiquimod (adjusted hazard ratio [aHR], 0.86; 95% confidence interval [CI], 0.76-0.97), but there were no significant differences in risk by tumor subtype (for squamous cell carcinoma: aHR, 0.89; 95% CI, 0.74-1.07; for basal cell carcinoma: aHR, 0.87; 95% CI, 0.74-1.03) or site-specific keratinocyte carcinoma (aHR, 0.96; 95% CI, 0.81-1.14). There were no significant differences in 2- or 5-year cumulative risk of keratinocyte carcinoma among those treated with 5-fluorouracil versus with imiquimod., Limitations: Generalizability to other practice settings may be limited., Conclusions: Whereas 5-fluorouracil was more effective in reducing keratinocyte carcinoma risk overall, we found no differences in the short- or long-term risk of subsequent site-specific keratinocyte carcinoma in a real-world practice setting., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Actinic keratosis (AK) is a lesion that arises as a result of excessive exposure to solar radiation and appearing predominantly on Fitzpatrick phototype I and II skin. Given that some AKs evolve into squamous cell carcinoma, these lesions are considered premalignant in nature, occurring mostly in elderly men and immunosuppressed individuals chronically exposed to ultraviolet (UV) radiation. There are several mechanisms for the formation of AKs; among them are oxidative stress, immunosuppression, inflammation, altered proliferation and dysregulation of cell growth, impaired apoptosis, mutagenesis, and human papillomavirus (HPV). Through the understanding of these mechanisms, several treatments have emerged. Among the options for AK treatment, the most commonly used include 5-fluorouracil (5-FU), cryotherapy, diclofenac, photodynamic therapy (PDT), imiquimod (IQ), retinoids, and ingenol mebutate (IM). There have been recent advances in the treatment options that have seen the emergent use of newer agents such as resiquimod, betulinic acid, piroxicam, and dobesilate. The combination between therapies has presented relevant results with intention to reduce duration of therapy and side effects. All AK cases must be treated because of their propensity to transform into malignancy and further complicate treatment. In addition to medical or surgical care, education about sun exposure prevention remains the best and most cost-effective method for AK prevention. The objective of this article is to conduct a literature review of the clinical presentation of AK including advances in treatment options available., (© 2018 The International Society of Dermatology.)

Rationale: Condyloma acuminatum (CA) is a benign tumor primarily caused by infection with human papillomavirus (HPV) type-6 or type-11, lesions of which are most frequently found on the genital and perianal squamous mucosa and skin. CA outside the genitals is not common., Patient Concerns: A 29-year-old male presented with lesions on the left nipple and coronary sulcus after heterosexual contact., Diagnoses: Histopathological examination and HPV detection made a definite diagnosis of CA., Intervention: The patient was treated with microwave and topical imiquimod cream., Outcomes: After 6 months follow-up, there was no sign of recurrence., Lessons: This case shows that we should pay more attention to CA outside the genitals in the process of diagnosis and treatment.

Background: Without clear evidence, selecting among the existing immunotherapeutic options for warts remains challenging., Objective: Through network meta-analyses, we aimed to evaluate the comparative efficacy of different intralesional immunotherapeutic modalities., Methods: We included randomized controlled trials comparing intralesional immunotherapeutic modalities to cryotherapy, placebo, or imiquimod. All outcomes were presented as odds ratios (ORs) with 95% confidence intervals. Both conventional and network meta-analyses (with a frequentist approach) were conducted on R software. The P-score was used to rank different treatments., Results: Network meta-analysis of 17 randomized controlled trials (1676 patients) showed that PPD (purified protein derivative vaccine, OR 39.56), MMR (measles, mumps, rubella vaccine, OR 17.46) and interferon β (OR 15.55) had the highest efficacy in terms of complete recovery at the primary site compared with placebo. Regarding complete recovery at the distant site, autoinoculation (OR 79.95), PPD (OR 42.95), and MMR (OR 15.39) were all statistically superior to placebo. According to the P-score, MMR was more effective than other modalities in reducing the recurrence rate at the same site., Limitations: Relatively small sample size in some comparisons and variability in baseline characteristics., Conclusion: PPD and MMR were the most effective in achieving complete primary and distant recovery (along with autoinoculation for distant recovery) and reducing the recurrence rate at the same site compared with cryotherapy and other immunotherapeutic modalities., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)