Chemical peelings for the treatment of actinic keratosis: a systematic review and meta-analysis.

BACKGROUND: Actinic keratosis (AK) is a common precancerous lesion of the skin that may be treated with chemical peelings. Despite their long-standing usage and clinical experience, no evidence-based recommendation regarding the efficacy and safety of chemical peelings for AK exists. OBJECTIVES: To systematically review and synthesize the current knowledge on chemically exfoliative peelings as interventions for AK. METHODS: We performed a systematic literature research in Medline, Embase and CENTRAL and hand-searched pertinent trial registers for eligible records until 5 August 2019. Results from individual studies were pooled using a random-effects model or described in a qualitative synthesis. The risk of bias was estimated with the tools provided by the Cochrane Collaboration (randomized and non-randomized trials) and the Evidence Project (single-arm trials). RESULTS: Four randomized controlled trials, two non-randomized controlled trials and two single-arm studies with a total sample size of n = 170 patients were included. Trichloroacetic acid (TCA) plus Jessner's solution showed significantly lower participant complete clearance (RR 0.36, 95% CI: 0.14-0.90, two studies, I2  = 0%, P = 0.03) and lower lesion clearance (RR 0.92, 95% CI: 0.85-0.99, one study, P = 0.03) compared to 5-fluorouracil (5-FU) 5% cream. TCA as monotherapy showed lower lesion complete clearance (RR 0.75, 95% CI: 0.69-0.82, two studies, I2  = 7%, P < 0.001) and lower mean lesion reduction per patient compared to conventional photodynamic therapy (cPDT) (MD -20.48, 95% CI: -31.55 to -9.41, two studies, I2  = 43%, P = 0.0003). Pain was more pronounced in patients treated with cPDT in comparison with TCA (MD -1.71 95% CI: -3.02 to -0.41, two studies, I2  = 55%, P = 0.01). In the single-arm studies, 5-FU plus glycolic acid showed 92% lesion clearance and phenol peeling 90.6% participant complete clearance. All studies showed a high risk for bias. CONCLUSIONS: Future high-quality studies and a standardization of peeling protocols are warranted to determine the value of chemical peelings in the treatment of AK.

The more the better? An appraisal of combination therapies for actinic keratosis.

Actinic keratoses (AK) are common precancerous lesions of the skin. Numerous interventions exist for the treatment of AK, including lesion- and field-directed approaches. In daily practice, different treatment modalities are often combined to maximize clearance rates. However, whether a combination therapy is preferable to monotherapy in terms of efficacy and safety has been subject of intense debate. In this review, we summarize the current knowledge on the efficacy and safety of local combination therapies for the treatment of patients with AK. Combination approaches of cryosurgery followed by photodynamic therapy (PDT), laser-assisted PDT, PDT in combination with topical interventions and microneedling-assisted PDT have shown slightly better efficacy results with similar tolerability compared to the respective monotherapy. However, the individual usage of combination therapies should be checked on a case-by-case basis and take into account individual patient- and lesion-specific aspects as more resources are needed and because the individual monotherapies are already highly effective.

[Actinic keratosis]. / Aktinische Keratosen.

Actinic keratoses (AK) are common precancerous cutaneous lesions in fair-skinned individuals as a result of cumulative exposure to ultraviolet radiation. Due to their high prevalence, AK account for a large disease burden, in particular in older persons. As AK may potentially progress into invasive cutaneous squamous cell carcinoma, guidelines recommend early and consequent treatment. Numerous lesion- and field-directed interventions with different efficacy and safety profiles are currently licensed in Germany. The appropriate intervention should be chosen together with the patient based on his or her motivation and expectations towards the treatment.

[Actinic keratoses : Current guideline and practical recommendations]. / Aktinische Keratosen : Aktuelle Leitlinie und praxisbezogene Empfehlungen.

The S3 guideline "Actinic keratosis and squamous cell carcinoma of the skin" was published on 30 June 2019. Subsequently, publications, reviews and meta-analyses appeared with new questions regarding the comparability of study data and heterogeneity of the evaluations, which are caused, among other things, by divergent measurement parameters as well as insufficient consideration of pretreatments and combined treatments. This concise overview was written in the context of criticism and in view of necessary developments and research. Topics include epidemiology, pathogenesis, prevention, clinical presentation, therapy and BK5103. Therapy is divided into local destructive procedures and topical applications. Recommendations with quotation marks are based on the actual guideline. Corresponding evidence levels are given. For the implementation in daily routine basic data, side effects and features of therapeutic options are mentioned. The current developments and questions concerning actinic keratoses become clear.

[Cutaneous squamous cell carcinoma]. / Kutanes Plattenepithelkarzinom.

Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers of the Caucasian population and accounts for 20% of all skin tumours. An S3 guideline of the German Guideline Program in Oncology has been available since 2019. The diagnosis is based on the clinical examination. Excision and histological confirmation is required for all clinically suspicious lesions to allow prognostic assessment and correct treatment. The therapy of first choice is complete excision with histological control of the surgical margin. In cSCC with risk factors such as tumor thickness >6 mm, sentinel lymph node biopsy may be discussed, but there is currently no clear evidence of its prognostic and therapeutic relevance. Adjuvant radiation therapy may be considered in cases of high risk of recurrence and should be tested in cases of inoperable tumors. The indication for electrochemotherapy should also be considered in the treatment of local or locoregional recurrence. The immune checkpoint inhibitor cemiplimab is approved for the treatment of inoperable or metastasized cSCC. In case of contraindications, chemotherapeutic agents, epidermal growth factor receptor (EGFR) inhibitors or palliative radiotherapy can be used. Since the evidence is low in these cases, a systemic therapy should be used preferentially within clinical studies. Follow-up care should be risk-adapted and includes a dermatological control, supplemented by ultrasound examinations in high-risk patients.

Cryosurgery combined with topical interventions for actinic keratosis: a systematic review and meta-analysis.

BACKGROUND: Actinic keratoses (AKs) are early in situ carcinomas of the skin caused by cumulative sun exposure. Cryosurgery is an easy and practicable lesion-directed approach for treatment of isolated lesions. OBJECTIVES: To investigate whether an upfront combination of cryosurgery with a topical intervention is superior to cryosurgery alone for treatment of AK. METHODS: We performed a systematic literature search in MEDLINE, Embase and CENTRAL and hand searched pertinent trial registers for eligible randomized controlled trials until 17 July 2018. Results from individual studies were pooled using a random effects model. The risk of bias was estimated with the Cochrane Risk of Bias Tool and the quality of evidence of the outcomes with the GRADE approach. RESULTS: Out of 1758 records initially identified, nine studies with a total sample size of 1644 patients were included. Cryosurgery in combination with a topical approach showed significantly higher participant complete clearance rates than monotherapy [risk ratio (RR) 1·74, 95% confidence interval (CI) 1·25-2·43, I2 = 73%, eight studies]. The participant partial clearance rate was not statistically different (RR 1·64, 95% CI 0·88-3·03, I2 = 77%, three studies). The number of patients who completed the study protocol and did not withdraw due to adverse events was equal in both groups (RR 0·98, 95% CI 0·95-1·01, I2 = 75%, seven studies). The studies were estimated to have high risk for selective reporting bias. CONCLUSIONS: Our results suggest the superiority of a combination regimen for AK clearance, with equal tolerability. This study highlights the importance of a field-directed approach in patients with multiple AKs or field cancerization.

Local interventions for actinic keratosis in organ transplant recipients: a systematic review.

BACKGROUND: Actinic keratosis (AK) in organ transplant recipients (OTRs) has a high risk of progressing to invasive squamous cell carcinoma of the skin. Thus, early and consequent treatment of AKs is warranted in OTRs. OBJECTIVES: To summarize the current evidence for nonsystemic treatments of AKs in OTRs. METHODS: We performed a systematic literature search in MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (CENTRAL) and hand-searched pertinent trial registers up to 22 August 2018. Randomized controlled trials (RCTs) evaluating nonsystemic interventions for AKs in OTRs were included. The risk of bias was estimated using the Cochrane Risk of Bias Tool. RESULTS: Of 663 records initially identified, eight RCTs with 242 OTRs were included in a qualitative synthesis. Most studies evaluated methyl aminolaevulinate photodynamic therapy (MAL-PDT), followed by ablative fractional laser (AFXL) and diclofenac sodium 3% in hyaluronic acid, imiquimod 5% cream and 5-fluorouracil 5% cream (5-FU). MAL-PDT showed the highest rates of participant complete clearance (40-76·4%), followed by imiquimod (27·5-62·1%), diclofenac (41%) and 5-FU (11%). Similar results were observed for lesion-specific clearance rates. Treatment with AFXL alone revealed low lesion clearance (5-31%). Local skin reactions were most intense in participants treated with a combination of AFXL and daylight MAL-PDT. There were no therapy-related transplant rejections or worsening of graft function in any trial. The overall risk of bias was high. CONCLUSIONS: Limited evidence is available for the treatment of AKs in OTRs. MAL-PDT is currently the best-studied intervention. Lesion-specific regimens may not be sufficient to achieve disease control. Field-directed regimens are preferable in this high-risk population.

Comparison of guidelines for the management of patients with high-risk and advanced cutaneous squamous cell carcinoma - a systematic review.

The management of high-risk cutaneous squamous cell carcinoma (cSCC) can be a challenge as evidence from high quality clinical trials is rare. Guideline developers are challenged to provide practical and useful guidance for clinicians even in the absence of good evidence. In order to compare treatment recommendations for high-risk and advanced cSCC among national and international guidelines and to extract the most precise guidance provided, a systematic search was carried out in guideline databases Medline and Embase with a cutoff of 4 March 2019. Treatment recommendations for predefined clinical scenarios were extracted from selected guidelines and compared qualitatively. Five guidelines published from 2015 to 2018 were included. Excision of high-risk tumours with margin assessment was recommended in all guidelines. A safety margin of at least 6 mm was suggested in four guidelines. There was no clear recommendation to perform a sentinel lymph node biopsy in any guideline. Lymph node dissection was uniformly recommended in the presence of nodal disease. Treatment for metastatic cSCC was poorly characterized and restricted to the use of chemotherapy and epidermal growth factor receptor inhibitors. Recommendations for the management of high-risk and advanced cSCC were limited. We propose that guidelines should be updated to reflect recent advances in checkpoint blockade for metastatic cSCC.

Efficacy of photodynamic therapy combined with topical interventions for the treatment of actinic keratosis: a meta-analysis.

BACKGROUND: Photodynamic therapy (PDT) is a highly effective treatment option for patients with actinic keratoses (AK). However, efficacy can be reduced by insufficient illumination or hyperkeratotic nature of lesions. OBJECTIVES: To investigate if PDT combined with a topical intervention is superior to monotherapy in terms of efficacy and tolerability. METHODS: A systematic literature research was conducted in Medline, Embase and CENTRAL. Pertinent trial registers were hand-searched for eligible randomized controlled trials (RCTs) until 20 August 2018. Results were pooled using a random effects model to calculate relative risks (RR) or mean differences. The risk of bias was assessed with the Cochrane Risk of Bias Tool. The quality of evidence was estimated for each outcome of interest according to GRADE. RESULTS: Out of 1800 references initially identified, 10 RCTs with a total sample size of n = 277 were included. Four studies investigated a combination of PDT with imiquimod cream, three with 5-fluorouracil cream and one each with ingenol mebutate gel, tazarotene gel and calcipotriol ointment, respectively. Patients treated with a combination showed higher participant complete (RR 1.63; 95% CI 1.15-2.33; P = 0.007) and partial clearance rates (RR 1.19; 95% CI 0.84-1.67; P = 0.33). Similarly, the lesion-specific clearance was higher for PDT plus topical intervention compared to monotherapy (RR 1.48; 95% CI 1.04-2.11; P = 0.03). A subgroup analysis was performed for PDT combined with imiquimod, revealing an increased participant complete clearance rate compared to monotherapy (RR 1.57, 95% CI 1.09-2.25, P = 0.02). PDT-induced pain and local skin reactions after treatment were poorly reported. The studies were estimated at high risk for performance and detection bias. CONCLUSION: The combination of PDT with another topical drug intervention does improve AK clearance rates compared to either monotherapy alone. This study highlights that the sequential application of two field-directed treatments represents an efficient approach in patients with multiple AK and field cancerization.

Influence of TNF-alpha inhibitors and fumaric acid esters on male fertility in psoriasis patients.

OBJECTIVE: Is there any influence of a therapy with TNF-alpha inhibitors or fumaric acid esters and of disease activity status on male fertility and sperm quality in patients with psoriasis? METHODS: In this monocentric, open-label, prospective study, semen samples were collected from patients receiving either TNF-alpha inhibitors or fumaric acid esters for moderate-to-severe plaque psoriasis. Semen was analysed at baseline before onset of the systemic therapy and monitored every 3 months under therapy. Sperm parameters were assessed according to the current WHO definitions. RESULTS: In total, 101 semen specimens from 27 patients were obtained. Mean Psoriasis Area and Severity Index (PASI) score at baseline was 11.05. Only 14.8% of patients showed a normozoospermia without any other abnormal seminal values. 85.2% of patients had at least one sperm/seminal abnormality, including two patients showing an azoospermia. Interestingly, 48.1% showed sperm parameters indicative of genital tract inflammation. Therapy with TNF-alpha inhibitors or fumaric acid esters did not have any negative effects on relevant sperm parameters such as mean total sperm number, sperm concentration, total and progressive motility. No major gonadal dysfunction was observed in any patient. CONCLUSION: At baseline, many patients with psoriasis showed abnormal semen/sperm parameters and remarkably elevated leukocytes and values of seminal polymorphonuclear elastase, indicating a genital tract inflammation. Thus, genital tract inflammation may represent an important comorbidity of psoriasis, little attention paid to so far. Regarding treatment with TNF-alpha inhibitors or fumaric acid esters, no major negative (side-) effects on sperm quality were observed.

Transient memory impairment and transient global amnesia induced by photodynamic therapy.

Photodynamic therapy (PDT) is a commonly used and effective treatment option for nonmelanoma skin cancer. Apart from local side-effects such as pain, oedema and erythema, no major adverse events occur in the majority of cases. Here we report on five patients who developed memory deficits such as transient global amnesia immediately after PDT for actinic keratosis. All PDT treatments were performed according to standard therapy protocols. The reported patients had a memory gap for the entire procedure, as well as for the consecutive emergency medical care. Other common neurological causes such as stroke or epileptic seizures were excluded. No focal neurological deficits were detectable. The symptoms had a fairly rapid onset following red-light illumination and were reversible without sequelae within 1-24 h. No correlation of the condition and pain during the illumination could be revealed. Magnetic resonance imaging of the brain revealed punctuated lesions in the hippocampus as a potential morphological correlate in one patient. The association between amnestic syndromes and PDT is novel and has not previously been reported. Even though PDT is considered a safe treatment modality, the possibility of neurological adverse events, albeit rare, should be kept in mind.

Human papillomavirus status, anal cytology and histopathological outcome in HIV-positive patients.

BACKGROUND: Human papillomavirus (HPV) are responsible for a broad spectrum of mucocutaneous infections and may cause squamous cell carcinoma following long-standing infection . Oncogenic HPV, most commonly HPV 16, are detectable in over 90% of cervical intraepithelial neoplasia and anal intraepithelial neoplasia (AIN). Human immunodeficiency virus (HIV) infection is strongly associated with a higher prevalence of chronic HPV infection, a higher incidence of AIN and an increased risk for anal cancer (AC). In September 2013, guidelines concerning prevention, screening and treatment of AIN for patients affected by HIV were issued by the German AIDS society. OBJECTIVE: In order to validate the suggested screening procedure, we analysed data from 123 male and female patients with HIV infection that regularly present in our outpatient clinic. METHODS: Anal cytology, HPV typing and high-resolution anoscopy (HRA) were performed. RESULTS: Our results show that screening by anal cytology only identifies a minority of patients with high grade AIN (AIN 3) histology. Patients with normal cytology (NILM, cytology graded negative for intraepithelial lesion or malignancy; n = 5, 29.4%), atypical squamous cells of undetermined significance (ASCUS; n = 5, 71.4%) and low grade squamous intraepithelial lesion (LSIL; n = 8, 44.5%) showed highly dysplastic lesions (AIN 2 and 3) in the histological workup more frequently than expected. Additionally, high-grade squamous intraepithelial lesion (HSIL) was strongly associated with detection of high-risk oncogenic HPV. CONCLUSION: Anal cytology as the solitary screening tool for anal cancer fails to detect anal dysplasia in a considerable number of patients. Additionally, HPV typing and possibly further biomarkers might be applied to identify those patients with a higher risk of developing anal carcinoma, in order to monitor them more closely or directly transfer them to HRA.

Oral isotretinoin as the most effective treatment in folliculitis decalvans: a retrospective comparison of different treatment regimens in 28 patients.

BACKGROUND: Folliculitis decalvans leads to scarring alopecia through inflammatory destruction of the hair follicle. Currently, antibiotics are most commonly used to treat this disease. However, treatment regimens with antibiotics feature a high relapse rate and encourage the development of resistant bacteria. OBJECTIVE: To evaluate the outcome of different treatment options for folliculitis decalvans. METHODS: Retrospective study to compare the efficacy of different treatment regimens in 28 patients with folliculitis decalvans. RESULTS: The success of treatment with clindamycin and rifampicin, clarithromycin, dapsone and isotretinoin was analysed. The evaluation of the combination of clindamycin and rifampicin showed the lowest success rate in achieving long-term remission, since 80% of the patients relapsed shortly after end of treatment. Clarithromycin and dapsone were more successful with long-term and stable remission rates of 33% and 43% respectively. Treatment with isotretinoin was the most successful oral treatment in our analysis with 90% of the patients experiencing stable remission during and up to two years after cessation of the treatment. CONCLUSION: The common use of antibiotics as first-line therapy in folliculitis decalvans needs to be re-evaluated critically and oral isotretinoin should be considered as valid treatment alternative.