Skin cancer: Primary, secondary, and tertiary prevention. Part II.

Skin cancer is the most commonly diagnosed cancer worldwide. Understanding the natural history of skin cancer will provide a framework for the creation of prevention and control strategies that aim to reduce skin cancer burden. The strategies include health promotion, primary prevention, secondary prevention, and tertiary prevention. Health promotion and primary prevention were covered in the first part of this 2-part review. The second part covers the secondary and tertiary prevention of skin cancer. In particular, preventive strategies centered on the early detection of skin cancer, the prevention of disease progression, clinical surveillance, and educational and behavioral interventions are highlighted. The summaries of existing recommendations, challenges, opportunities, and future directions are discussed.

A Non-Surgical and Cost-Effective Treatment Approach Employing Topical Imiquimod, 5-Fluorouracil, and Tretinoin for Primary Non-Melanoma Skin Cancers.

BACKGROUND: Minimally invasive alternative approaches to treat non-melanoma skin cancers remain limited and unproven. OBJECTIVE: We aim to assess the efficacy of varying combinations of anti-tumor agents—imiquimod 5% cream, 5-fluorouracil 2% solution, and tretinoin 0.1% cream—with brief cryotherapy in treating non-melanoma skin cancers. METHODS: This retrospective study included 690 cases of non-melanoma skin cancers in 480 patients who received a diagnosis of a basal cell carcinoma or squamous cell carcinoma during a ten-year period. During treatment period, patients applied 30 applications of one of three combinations (imiquimod/tretinoin, 5-fluorouracil/tretinoin, or imiquimod/5-fluorouracil/tretinoin) and had cryotherapy every 2 weeks. Each patient had a clinical examination at least three years post-treatment or documented treatment failure. Clearance was defined by a lack of persistence or recurrence for 3 years following the completion of treatment. The likelihood of lesion clearance was evaluated using multivariable logistic regression analysis. RESULTS: A total of 186 cases (97; basal cell carcinoma and 89; squamous cell carcinoma) in 133 patients [37% women and 63% men; median (interquartile range) age, 77 (69, 83) years] met the inclusion criteria. Multivariable logistic regression analysis adjusting for clinical and lesion variables demonstrated that, relative to the imiquimod/5-fluorouracil/tretinoin treatment approach, imiquimod/ tretinoin (odds ratio, 0.05; 95% confidence interval, 0.00-0.99) and 5-fluorouracil/tretinoin (0.02; 0.00–0.45) were associated with lower likelihoods of lesion clearance. Likewise, morpheaform basal cell carcinoma had a lower probability of clearance (0.05; 0.00–0.72). CONCLUSIONS: The combination of imiquimod/5-fluorouracil/tretinoin with cryotherapy had high clearance rates and was the most effective treatment regimen. J Drugs Dermatol. 2021;20(3):260-267. doi:10.36849/JDD.5427.

A Biologically Based Approach to Acne and Rosacea.

Complementary and alternative medicine (CAM) therapies are increasing in popularity in the field of dermatology. Natural products and holistic approaches are in high demand among patients and research has begun to support their roles in acne and rosacea pathophysiology. In this article, commonly utilized biologically based complementary and alternative therapies for acne and rosacea are reviewed from an evidence-based perspective. Therapies discussed include vitamin C, nicotinamide, zinc, tea tree oil, green tea, resveratrol, curcumin, feverfew, licorice, chamomile, polypodium leucotomos, and nutrition-based approaches. J Drugs Dermatol. 2018;17(6):611-617.

Widespread Skin Necrosis Secondary to Gemcitabine Therapy.

Gemcitabine, a pyrimidine nucleoside analogue, is an oncologic agent used in the treatment of cutaneous T-cell lymphoma (CTCL). Common dermatologic reactions associated with gemcitabine include alopecia, mild skin rash, and mucositis but skin necrosis is exceptional. Herein we present an unusual case of widespread skin necrosis mimicking toxic epidermal necrolysis in a 45-year-old woman receiving gemcitabine therapy for stage IIIA cutaneous T-cell lymphoma. This is the first reported case of a TEN-like reaction subsequent to gemcitabine treatment. J Drugs Dermatol. 2018;17(5):582-585.

Phaeohyphomycosis due to Exophiala infections in solid organ transplant recipients: Case report and literature review.

This case report and literature review underscores the cutaneous presentations of phaeohyphomycosis in the solid organ transplant population. Increased cognizance with prompt identification is critical. The therapy and clinical outcomes of phaeohyphomycosis, caused by the Exophiala genus, in the solid organ transplant population, is analyzed to examine optimal care. This review highlights the inherent difficulties in providing the appropriate duration of antifungal therapy to avoid relapsing infections in immunosuppressed patients.

Spesolimab for generalized pustular psoriasis: a review of two key clinical trials supporting initial US regulatory approval.

Generalized pustular psoriasis (GPP) is a chronic, rare, and potentially life-threatening inflammatory disease, characterized by the rapid and widespread eruption of small, sterile pustules with surrounding skin erythema. Abnormal signaling of the interleukin-36 (IL-36) pathway appears to have a central role in GPP immunopathology, and provides a rational therapeutic target. Spesolimab is a first-in-class humanized monoclonal antibody that binds specifically to the IL-36 receptor, and antagonizes IL-36 signaling. Spesolimab obtained regulatory approval in the United States (US) in September 2022 for use in the treatment of GPP flares in adults, and was subsequently approved for GPP flare treatment in many other countries across the world. Recently, regulatory approval was granted for subcutaneous dosing of spesolimab for treatment of GPP when not experiencing a flare. Here, we review data from two key clinical trials that supported the initial US regulatory approval; namely, the phase 1 proof-of-concept trial (ClinicalTrials.gov ID, NCT02978690), and Effisayil™ 1 (NCT03782792), which remains the largest and only randomized clinical trial in patients experiencing GPP flares published to date. In the phase 1 proof-of-concept trial, a Generalized Pustular Psoriasis Physician Global Assessment (GPPGA) score of 0 or 1 (clear or almost clear skin) was attained in 5/7 (71%) patients by week 1 and in all 7 patients by week 4; and the mean percent improvement in the Generalized Pustular Psoriasis Area and Severity Index (GPPASI) score from baseline was 59.0% at week 1, 73.2% at week 2, and 79.8% at week 4. In Effisayil™ 1, a GPPGA pustulation subscore of 0 (no visible pustules) was achieved in 19/35 (54%) patients receiving spesolimab at the end of week 1, versus 1/18 (6%) receiving placebo (difference, 49 percentage points; 95% confidence interval [CI], 21 to 67; P<0.001); and a GPPGA total score of 0 or 1 was achieved by 15/35 (43%) patients in the spesolimab group, versus 2/18 (11%) patients in the placebo group (difference, 32 percentage points; 95% CI, 2 to 53; P = 0.02). Infections at week 1 were reported in 6/35 (17%) patients receiving spesolimab and in 1/18 (6%) patients receiving placebo. These data demonstrate the efficacy and safety of spesolimab in providing rapid and sustained clinical improvement for patients with GPP flares, which translates into improved quality of life, by offering a targeted therapy for GPP.

Therapeutic Response to Treatment of a Papillomatous Ocular Surface Squamous Neoplasia With Intramuscular Human Papillomavirus Vaccine.

PURPOSE: The purpose of this study was to describe the response of a papillomatous ocular surface squamous neoplasia (OSSN) to the intramuscular (IM) 9-valent human papillomavirus (HPV) vaccine after failed medical and surgical interventions. METHODS: A 79-year-old White man with a conjunctival lesion underwent a biopsy which revealed OSSN and positivity for high-risk HPV. Initially treated with medical therapy and surgical excisions, the patient developed a recurrence and refused further surgery. He was given 4 doses of IM HPV vaccine at the 6-week interval. RESULTS: A dramatic reduction in lesion size and reduced epithelial thickening and hyperreflectivity was noted on slitlamp examination and high-resolution anterior segment optical coherence tomography after receiving the IM HPV vaccine. Although lesion size was markedly reduced, the therapy did not achieve total resolution, resulting in further treatment with topical 1% 5-fluorouracil (5-FU) eye drops and later 0.04% mitomycin C eye drops. The patient then elected to discontinue further treatment and solely observe. CONCLUSIONS: This case report adds to the growing literature demonstrating the potential therapeutic use of vaccines in cancer treatment. Although HPV vaccination is currently approved for prophylaxis, the use of HPV vaccines as a therapeutic option for various HPV-mediated diseases, including OSSN, should be further explored. The HPV vaccine yielded significant initial improvement in this patient who refused further surgical interventions. The use of IM HPV vaccine as an adjunctive treatment of papillomatous OSSN may represent a potential therapeutic option in cases refractory to standard treatment modalities.

Reelin promotes neuronal orientation and dendritogenesis during preplate splitting.

The secreted ligand Reelin is thought to regulate the translocation and positioning of prospective layer 6 (L6) neurons into the preplate, a plexus of neurons overlying the ventricular zone. We examined wild type and Reelin-deficient cortices and found that L6 neurons were equivalently positioned beneath the pia during the period of preplate splitting and initial cortical plate (CP) formation. The absence of detectable L6 ectopia in "reeler" cortices at this developmental time point indicates that Reelin-signaling might not regulate L6 neuron migration or gross positioning during preplate splitting. To explore the acute response of L6 neurons to Reelin, subpial injections of Reelin were made into Reelin-deficient explants. Reelin injection caused L6 neurons to orient their nuclei and polarize their Golgi toward the pia while initiating exuberant dendritic (MAP2+) outgrowth within 4 h. This rapid Reelin-dependent neuronal orientation and alignment created CP-like histology without any significant change in the mean position of the population of L6 neurons. Conversely, subplate cells and chondroitin sulfate proteoglycan immunoreactivity were found at significantly deeper positions from the pial surface after injection, suggesting that Reelin partially rescues preplate splitting within 4 h. Thus, Reelin has a direct role in promoting rapid morphological differentation and orientation of L6 neurons during preplate splitting.

Treating Melanoma in Situ During a Pandemic with Telemedicine and a Combination of Imiquimod, 5-Fluorouracil, and Tretinoin.

The recent coronavirus disease 2019 (COVID-19) pandemic has created a quandary for the physician in terms of evaluating and treating cutaneous skin cancers, particularly melanomas. At the onset of the pandemic, many planned medical and surgical visits for skin cancers were postponed. Physicians and patients have had to balance the risk of exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with that of worsening morbidity and mortality due to delays in skin cancer treatments. We present a male patient who had two melanoma-in-situs (MISs) that were treated during the COVID-19 pandemic with a combination of topical imiquimod 5% cream, 5-fluorouracil 2% solution, and tretinoin 0.1% cream. The successful treatments occurred without in-person visits and with the aid of telemedicine. Although surgery is the standard for the treatment of melanoma in situ, this case demonstrates an effective viable treatment modality for MIS during a pandemic situation.

A Genetic Variant in the BCL2 Gene Associates with Adalimumab Response in Hidradenitis Suppurativa Clinical Trials and Regulates Expression of BCL2.

Hidradenitis suppurativa is a chronic skin disease with a significant genetic component and prevalence from 0.5% to 4%. Adalimumab is the only treatment approved by either the European Medicines Agency or the U.S. Food and Drug Administration for the management of moderate to severe hidradenitis suppurativa. To identify genetic variants associated with adalimumab response, we performed a genome-wide association study (GWAS) from the most extensive two phase 3 hidradenitis suppurativa clinical trials (PIONEER I and II) to date. Through direct genotyping and imputation, we tested almost 7 million genetic variants with minor allele frequency > 5% and identified one single linkage disequilibrium block, located in the intron of the BCL2 gene, which reached genome-wide significance (lead single-nucleotide polymorphism, rs59532114; P = 2.35E-08). Bioinformatic analysis and functional genomics experiments suggested a correlation of the most strongly associated single-nucleotide polymorphism minor allele with increased BCL2 gene and protein expressions in hair follicle tissues. In reciprocal knockdown experiments, we found that BCL2 is down-regulated by TNF inhibition. These results highlight a pathway that involves BCL2 in response to adalimumab. Further work is required to determine how this pathway influences adalimumab effectiveness in patients with hidradenitis suppurativa.

Comparison of slow and fast neocortical neuron migration using a new in vitro model.

BACKGROUND: Mutations, toxic insults and radiation exposure are known to slow or arrest the migration of cortical neurons, in most cases by unknown mechanisms. The movement of migrating neurons is saltatory, reflecting the intermittent movement of the nucleus (nucleokinesis) within the confines of the plasma membrane. Each nucleokinetic movement is analogous to a step. Thus, average migration speed could be reduced by lowering step frequency and/or step distance. RESULTS: To assess the kinetic features of cortical neuron migration we developed a cell culture system that supports fiber-guided migration. In this system, the majority of fiber-apposed cells were neurons, expressed age-appropriate cortical-layer specific markers and migrated during a 30 min imaging period. Comparison of the slowest and fastest quartiles of cells revealed a 5-fold difference in average speed. The major determinant of average speed in slower cells (6-26 microm/hr) was step frequency, while step distance was the critical determinant of average speed in faster cells (>26 microm/hr). Surprisingly, step distance was largely determined by the average duration of the step, rather than the speed of nucleokinesis during the step, which differed by only 1.3-fold between the slowest and fastest quartiles. CONCLUSION: Saltatory event frequency and duration, not nucleokinetic speed, are the major determinants of average migration speed in healthy neurons. Alteration of either saltatory event frequency or duration should be considered along with nucleokinetic abnormalities as possible contributors to pathological conditions.

Complementary and Alternative Medicine Therapies for Psoriasis: A Systematic Review.

Importance: Up to 51% of patients with psoriasis report the use of complementary and alternative medicine (CAM) in their treatment regimen, although it is unclear which CAM therapies are effective for treatment of psoriasis. Objective: This review compiles the evidence on the efficacy of the most studied CAM modalities for treatment of patients with plaque psoriasis and discusses those therapies with the most robust available evidence. Evidence Review: PubMed, Embase, and ClinicalTrials.gov searches (1950-2017) were used to identify all documented CAM psoriasis interventions in the literature. The criteria were further refined to focus on those treatments identified in the first step that had the highest level of evidence for plaque psoriasis with more than 1 randomized clinical trial supporting their use. This excluded therapies lacking randomized clinical trial (RCT) data or showing consistent inefficacy. Findings: Primary CAM therapy searches identified 457 articles, of which 107 articles were retrieved for closer examination. Of those articles, 54 were excluded because the CAM therapy did not have more than 1 RCT on the subject or showed consistent lack of efficacy. An additional 7 articles were found using references of the included studies, resulting in a total of 44 RCTs (17 double-blind, 13 single-blind, and 14 nonblind), 10 uncontrolled trials, 2 open-label nonrandomized controlled trials, 1 prospective controlled trial, and 3 meta-analyses. Compared with placebo, application of topical indigo naturalis, studied in 5 RCTs with 215 participants, showed significant improvements in the treatment of psoriasis. Treatment with curcumin, examined in 3 RCTs (with a total of 118 participants), 1 nonrandomized controlled study, and 1 uncontrolled study, conferred statistically and clinically significant improvements in psoriasis plaques. Fish oil treatment was evaluated in 20 studies (12 RCTs, 1 open-label nonrandomized controlled trial, and 7 uncontrolled studies); most of the RCTs showed no significant improvement in psoriasis, whereas most of the uncontrolled studies showed benefit when fish oil was used daily. Meditation and guided imagery therapies were studied in 3 single-blind RCTs (with a total of 112 patients) and showed modest efficacy in treatment of psoriasis. One meta-analysis of 13 RCTs examined the association of acupuncture with improvement in psoriasis and showed significant improvement with acupuncture compared with placebo. Conclusions and Relevance: The CAM therapies with the most robust evidence of efficacy for treatment of psoriasis are indigo naturalis, curcumin, dietary modification, fish oil, meditation, and acupuncture. This review will aid practitioners in advising patients seeking unconventional approaches for treatment of psoriasis.

Combined Systemic and Intratumoral Administration of Human Papillomavirus Vaccine to Treat Multiple Cutaneous Basaloid Squamous Cell Carcinomas.

Importance: Squamous cell carcinoma (SCC) is the second most common form of skin cancer, and its incidence is increasing. When surgical management is not an option, finding a safe and efficacious treatment is a challenge. Mounting evidence suggests that the human papillomavirus (HPV) is involved in the pathogenesis of some SCCs. Objective: To assess whether the 9-valent HPV vaccine could be an effective treatment strategy for cutaneous SCC. Design, Setting, and Participants: A woman in her 90s with multiple, inoperable cutaneous basaloid SCCs was successfully treated at a university-based outpatient dermatology clinic with a combination of systemic and intratumoral delivery of the 9-valent HPV vaccine from March 17, 2016, through February 27, 2017, and then followed up through May 21, 2018. Main Outcomes and Measures: Reduction in tumor size and number after a combination of systemic and intratumoral administration of the HPV vaccine. Results: All tumors resolved 11 months after the first intratumoral injection of the vaccine. The patient remained free of tumors at the end of follow-up. Conclusions and Relevance: This is the first report, to our knowledge, of complete regression of a cutaneous malignant tumor after combined systemic and direct intratumoral injection of the 9-valent HPV vaccine. This report suggests that the HPV vaccine may have therapeutic utility for SCCs in patients who are poor surgical candidates, have multiple lesions, or defer surgery.

An Open-Label Evaluator Blinded Study of the Efficacy and Safety of a New Nutritional Supplement in Androgenetic Alopecia: A Pilot Study.

Objective: To evaluate the effectiveness of a novel oral supplement, Forti5®, containing green tea extract, omega 3 and 6 fatty acids, cholecalciferol, melatonin, beta-sitosterol, and soy isoflavones, and in the management of subjects with androgenetic alopecia. Design: A prospective case series of 10 subjects. Setting: Open-label, evaluator-blinded, proof-of-concept study. Participants: Ten adult subjects with androgenetic alopecia completed the study. Subjects were not allowed to use oral or topical hair growth products in the 24 weeks preceding the study or during the study. The nutritional supplement was administered at a dosage of two tablets daily for 24 weeks. Measurements: Clinical evaluations were performed at baseline and at 24 weeks. Efficacy was evaluated using hair mass index measured by cross section trichometer, terminal hair count measured with dermoscopy and Investigator Global Photography Assessment. Results: Overall 80 percent of subjects (8/10) were rated as improved after 24 weeks of supplementation (mean change of +1.4 equivalent to slightly-to-moderately increased). Forty percent of subjects (4/10) were rated as moderately improved (2+), and 10 percent (1/10) were rated as greatly improved (3+). There was a significant improvement in terminal hair count (mean increase of 5.9% or 4.2 more terminal hairs in the area examined, p=0.014) and in Hair Mass Index (mean increase of 9.5% or 4.5 higher Hair Mass Index, p=0.003). Conclusion: These preliminary results indicate that Forti5® a novel nutritional supplement that contains cholecalciferol, omega 3 and 6 fatty acids, melatonin, antioxidants, and botanical 5-alpha reductase inhibitors, may be a useful adjunct in the treatment of androgenetic alopecia.

Association of Human Papillomavirus Vaccine With the Development of Keratinocyte Carcinomas.

Importance: Keratinocyte carcinomas (KCs), consisting of squamous cell carcinomas (SCCs) and basal cell carcinomas (BCCs), are the most common human malignant neoplasms. Several risk factors have been implicated in KC development. For some SCCs, particularly those in immunocompromised patients, human papillomavirus (HPV) may be an important factor. Objective: To determine whether quadrivalent HPV vaccination would affect the development of KCs in immunocompetent patients with a history of multiple KCs. Design, Setting, and Participants: Two patients with a history of multiple KCs-a man in his 70s (patient 1) and a woman in her 80s (patient 2)-were treated in a private dermatology practice. Each patient received 3 doses of the quadrivalent HPV vaccine at 0, 2, and 6 months in 2013, and both patients underwent full-body skin examinations at least every 3 months. Biopsy-proven skin cancers were recorded for 16 months (for patient 1) or 13 months (for patient 2) after the first dose of vaccine and then compared with the number of biopsy-proven skin cancers recorded over a similar period before the first dose of vaccine. The period of observation was from October 18, 2011, to June 21, 2014. Main Outcomes and Measures: The numbers of new SCCs and BCCs after the first dose of the quadrivalent HPV vaccine. Results: Patient 1 had a mean of 12 new SCCs and 2.25 new BCCs per year before vaccination. After vaccination, he developed 4.44 SCCs and 0 BCCs per year, a 62.5% reduction in SCCs and a 100% reduction in BCCs. Patient 2 had a mean of 5.5 new SCCs and 0.92 new BCCs per year before vaccination. After vaccination, she developed 1.84 SCCs and 0 BCCs per year, a 66.5% reduction in SCCs and a 100% reduction in BCCs. The quadrivalent HPV vaccine was well tolerated by both patients and had no adverse effects. Conclusions and Relevance: A reduction of SCCs and BCCs was observed in 2 patients after administration of the quadrivalent HPV vaccine. These findings highlight the possibility that cutaneous SCC development, and perhaps BCC development, may be driven in part by HPV in immunocompetent patients. Human papillomavirus vaccination may represent an efficacious, cost-effective, readily available, and well-tolerated strategy for preventing KCs.