The Neutrophil-to-Lymphocyte Ratio as a Biomarker in Cutaneous Oncology: A Systematic Review of Evidence beyond Malignant Melanoma.

With the ongoing progress of basic research along with the introduction of new pharmaceutical options spanning almost all therapeutic areas, the need for biomarkers that will be implemented into the personalized medical approach is higher than ever. Their use can be incorporated into clinical practice and can be applied to the classification of disorders and the evaluation of disease severity but also to the monitoring of the progress of therapeutic/pharmaceutical interventions. This systematic review collects the findings of hematologic biomarkers in various cutaneous malignancies, excluding malignant melanoma, to support their potential use in the prognosis but also in the assessment of therapeutic strategies for the specific category of skin disorders.

BCC and Immunocryosurgery scar differentiation through computational resolution-enhanced OCT images and skin optical attenuation: A proof-of-concept study.

Monitoring medical therapy remains a challenging task across all non-surgical skin cancer treatment modalities. In addition, confirmation of residual tumours after treatment is essential for the early detection of potential relapses. Optical coherence tomography (OCT), a non-invasive method for real-time cross-sectional imaging of living tissue, is a promising imaging approach for assessing relatively flat, near-surface skin lesions, such as those that occur in most basal cell carcinomas (BCCs), at the time of diagnosis. However, the skin's inherent property of strong light scattering impedes the implementation of OCT in these cases due to the poor image quality. Furthermore, translating OCT's optical parameters into practical use in routine clinical settings is complicated due to substantial observer subjectivity. In this retrospective pilot study, we developed a workflow based on the upscale of the OCT images resolution using a deep generative adversarial network and the estimation of the skin optical attenuation coefficient. At the site of immunocryosurgery-treated BCC, the proposed methodology can extract optical parameters and discriminate objectively between tumour foci and scar tissue.

The Promise of Semantic Segmentation in Detecting Actinic Keratosis Using Clinical Photography in the Wild.

AK is a common precancerous skin condition that requires effective detection and treatment monitoring. To improve the monitoring of the AK burden in clinical settings with enhanced automation and precision, the present study evaluates the application of semantic segmentation based on the U-Net architecture (i.e., AKU-Net). AKU-Net employs transfer learning to compensate for the relatively small dataset of annotated images and integrates a recurrent process based on convLSTM to exploit contextual information and address the challenges related to the low contrast and ambiguous boundaries of AK-affected skin regions. We used an annotated dataset of 569 clinical photographs from 115 patients with actinic keratosis to train and evaluate the model. From each photograph, patches of 512 × 512 pixels were extracted using translation lesion boxes that encompassed lesions in different positions and captured different contexts of perilesional skin. In total, 16,488 translation-augmented crops were used for training the model, and 403 lesion center crops were used for testing. To demonstrate the improvements in AK detection, AKU-Net was compared with plain U-Net and U-Net++ architectures. The experimental results highlighted the effectiveness of AKU-Net, improving upon both automation and precision over existing approaches, paving the way for more effective and reliable evaluation of actinic keratosis in clinical settings.

Image Perceptual Similarity Metrics for the Assessment of Basal Cell Carcinoma.

Efficient management of basal cell carcinomas (BCC) requires reliable assessments of both tumors and post-treatment scars. We aimed to estimate image similarity metrics that account for BCC's perceptual color and texture deviation from perilesional skin. In total, 176 clinical photographs of BCC were assessed by six physicians using a visual deviation scale. Internal consistency and inter-rater agreement were estimated using Cronbach's α, weighted Gwet's AC2, and quadratic Cohen's kappa. The mean visual scores were used to validate a range of similarity metrics employing different color spaces, distances, and image embeddings from a pre-trained VGG16 neural network. The calculated similarities were transformed into discrete values using ordinal logistic regression models. The Bray-Curtis distance in the YIQ color model and rectified embeddings from the 'fc6' layer minimized the mean squared error and demonstrated strong performance in representing perceptual similarities. Box plot analysis and the Wilcoxon rank-sum test were used to visualize and compare the levels of agreement, conducted on a random validation round between the two groups: 'Human-System' and 'Human-Human.' The proposed metrics were comparable in terms of internal consistency and agreement with human raters. The findings suggest that the proposed metrics offer a robust and cost-effective approach to monitoring BCC treatment outcomes in clinical settings.

A Fiber Optic Sensor for Monitoring the Spectral Alterations and Depth in Ex Vivo and In Vivo Cryosurgery.

This article discusses how to monitor the freezing depth during cryotherapy using a fiber optic array sensor. The sensor was used to measure the backscattered and transmitted light from frozen and unfrozen ex vivo porcine tissue and in vivo human skin tissue (finger). The technique exploited the variations in optical diffusion properties of the frozen and unfrozen tissues to determine the extent of freezing. Ex vivo and in vivo measurements yielded comparable results, despite spectral variations attributable to the hemoglobin absorption peak in the human frozen and unfrozen tissues. However, because the spectral fingerprints of the freeze-thaw process in the ex vivo and in vivo experiments were similar, we could extrapolate the maximum depth of freezing. Therefore, this sensor has the potential to be utilized for monitoring cryosurgery in real time.

Flagellate dermatitis in a patient with testicular germ cell neoplasia on bleomycin.

Bleomycin, an antineoplastic antibiotic that inhibits DNA synthesis, is used to treat various malignant tumors such as Hodgkin's lymphoma, squamous cell carcinoma, and germ cell tumors. Flagellate erythema is a rare rash with a linear pattern that has been observed in association with bleomycin treatment. Herein, we present a 43-year-old patient with metastatic testicular cell neoplasms who developed a whiplash rash during treatment with a chemotherapy regimen that included bleomycin. A typical case of bleomycin-related flagellate dermatitis has been diagnosed and the main features of this characteristic adverse drug event are briefly discussed.

A Meta-Analysis on the Impact of the COVID-19 Pandemic on Cutaneous Melanoma Diagnosis in Europe.

The COVID-19 pandemic has been the epicenter of healthcare attention globally for the past two years, and large-scale adaptations in healthcare provision have been required. This study aimed to investigate the impact of the pandemic and the resulting lockdowns on cutaneous melanoma diagnosis and tumor burdens in Europe. A relevant literature search in electronic databases was conducted from inception to September 2022. The inclusion criteria were: controlled studies published in a peer-reviewed journal evaluating cutaneous melanoma in Europe and reporting data on melanoma characteristics from diagnoses. The quality of studies was evaluated using the Cochrane ROBINS-I tool for assessing bias in non-randomized studies. Meta-analysis was conducted utilizing a random effects model to synthesize the data. A total of 25 studies involving 32,231 patients were included in the data analysis models. Statistically significant increases in mean Breslow thickness (0.29 mm (0.03-0.55 mm)), ulceration rates (OR = 1.66 (1.29-2.13)), and resultant tumor staging were observed in the PostCovid group, with subgroup analysis revealing that lockdown-derived data were responsible for this trend. This meta-analysis reported on the impact of COVID-19 restrictions on melanoma diagnosis in Europe, emphasizing the higher tumor burden and disease progression state provoked by healthcare adaptations in the pandemic period.

The Feasibility of Immunocryosurgery in the Treatment of Non-Superficial, Facial Basal Cell Carcinoma That Relapsed after Standard Surgical Excision: An Experience Report from Two Centers.

In this retrospective, chart review study, we evaluated the feasibility of immunocryosurgery in facial, non-superficial basal cell carcinomas (BCC) that had relapsed after standard surgery. Inclusion criteria were (a) 'biopsy confirmed relapse of facial BCC', (b) known 'calendar year of surgical excision(s)', and (c) 'relapse within 10 years after the last surgical excision'. Tumors treated from 1 January 2011 to 31 December 2020 with a standard 5-week immunocryosurgery cycle (daily imiquimod application for 5 weeks and a cryosurgery session at day 14) were included. Descriptive statistics, Kaplan-Meier method, and Cox proportional hazards model were calculated with significance at p < 0.05. From the n = 27 BCC evaluated, n = 20 (74.1 ± 8.4%) cleared after one immunocryosurgery cycle. Two of the remaining cases cleared completely after a repeat cycle, one patient favored surgery, and four BCC did not clear despite additional immunocryosurgery cycles (feasibility 81.5 ± 7.5%). Of the 22 tumors with clinical outcome 'complete clearance with immunocryosurgery', three BCC relapsed at 9, 28, and 50 months. Overall, the 5-year treatment efficacy rate was 60.2 ± 13.4% (mean follow-up 94.6 ± 15.1 months). In total, 20/27 BCC relapses after surgery (74.1%) were tumor-free at the end of personalized follow-up times (66.7 ± 12.4% tumor free patients at 5-year follow-up). Number of tumor relapses before immunocryosurgery was the single predictor of tumor progression after immunocryosurgery (p = 0.012). Conclusively, immunocryosurgery could be further evaluated as an alternative, definitive treatment of selected facial BCC relapsing after surgery.

Immunocryosurgery is a safe and feasible treatment for basal cell carcinoma and Bowen disease in renal transplant recipients.

Keratinocyte skin carcinomas (squamous cell carcinoma, basal cell carcinoma [BCC], Bowen disease [BD]) inflict significant morbidity and constitute a treatment challenge in renal transplant recipients (RTR). Immunocryosurgery has shown efficacy >95% in the treatment of BCC and BD in immunocompetent patients. The present study evaluated the safety, feasibility and efficacy, of immunocryosurgery in the treatment of BCC and BD in a series of RTR. During a 3-year period, biopsy-confirmed cases of BCC and BD were treated with a standard immunocryosurgery cycle (5 weeks daily imiquimod and a session of cryosurgery at day 14). Safety was evaluated by comparing graft function markers between immunocryosurgery treated RTR patients and matched controls. Ten BCC (8 nodular, 1 basosquamous, 1 superficial; diameter 6-14 mm; mean 9.2 mm) and nine BD disease lesions in nine patients (7 men, 2 women; age range: 54-70 years, mean: 62.1 years) were treated with immunocryosurgery and followed-up for two to 5 years. Five BCC were located on the "H area" of the face. No patient showed clinical or laboratory signs of transplant dysfunction during treatment or follow-up. Seven out of 10 BCC lesions cleared completely after one 5-week immunocryosurgery cycle, two cleared after repeat and intensified treatment cycles and one responded only partially (clearance rate: 90%). Seven out of nine BD lesions cleared after one 5-week immunocryosurgery cycle and one lesion after two cycles (clearance rate: 88.9%). In conclusion, immunocryosurgery is a safe, feasible and effective minimally invasive treatment alternative to standard surgical modalities for BCC and BD in RTR.

Paraneoplastic Syndromes in Patients with Keratinocyte Skin Cancer.

A variety of well-characterized cutaneous paraneoplastic syndromes (PNS) are diagnosed during internal malignancies; however, the spectrum of keratinocyte skin neoplasms (KSC) related to PNS is still obscure. The aim of the present review is to compile and evaluate the literature data on PNS associated with a keratinocyte skin neoplasm (KSC). Employing Pubmed, MEDLINE was searched for KSC-associated PNS reports. Forty relevant entries were assembled, reporting a total of 41 PNS cases associated with a KSC (34 male). No review paper compiling this topic was found. Six distinct PNS entities were identified, and malignancy associated hypercalcemia (MAH; 78%), anemia (10%) and Bazex syndrome (5%) were the most frequently reported among them. 85% of the PNS were reported in association with SCC, 10% with BCC, and the rest with adnexal tumors. The median age of the patients at the time of PNS diagnosis was 58 years (range: five-83 years). In most cases the PNS was diagnosed either concurrently or after the KSC diagnosis. KSC predisposing conditions, as scars (22%) or hidradenitis suppurativa (20%), were reported in >70% of the PNS cases. Most PNS resolved after KSC treatment. In conclusion, PNS of a rather limited spectrum of entities are reported in association with KSC. They also seem to be rare, possibly reflecting a limited capacity of KSC to provoke overt PNS.

Application of a burn scar assessment tool for the evaluation of visual scarring following immunocryosurgery for facial basal cell carcinoma

Background: The therapeutic interventions for basal cell carcinoma (BCC) impact facial cosmesis. Objectives: Our aim was to assess the aesthetic burden of facial BCC treatment by evaluating the extent of the tumour site visually based on clinical images before and after immunocryosurgery; a minimally invasive combination treatment of topical imiquimod and cryosurgery. Materials & Methods: A three-item (texture, height, colour) burn scar scale was independently applied by four physicians (two dermatologists and two plastic surgeons) on archival semi-standardized clinical images of facial BCC before and one year after immunocryosurgery. The score assessments were compared using non-parametric statistical tests; internal consistency (reliability) and inter-rater agreement were assessed using Cronbach's α and Gwet's AC2, respectively. Results: Images (before and one year after treatment) of 27 BCCs from 26 patients (15 males) were analysed. The reliability was good (α>0.80) for all items before surgery and for colour after surgery. The inter-rater agreement was acceptable (AC2>0.70) for all items except for height pre-treatment (AC2 = 0.482). Based on averaging of all raters, cosmesis improved significantly after treatment at all tumour sites (p<0.001, Wilcoxon signed ranks test). The main limitations of the study are the inclusion of cases from a single centre and its retrospective nature. Conclusion: The evaluated burn scar scale can be reliably used to compare the extent of the BCC site visually before therapy and after resultant scars have formed. In this way, the impact of therapeutic interventions on cosmesis (from tumour to scar) can be evaluated, particularly for less aggressive facial skin tumours, such as most BCC.

Characterizing Malignant Melanoma Clinically Resembling Seborrheic Keratosis Using Deep Knowledge Transfer.

Malignant melanomas resembling seborrheic keratosis (SK-like MMs) are atypical, challenging to diagnose melanoma cases that carry the risk of delayed diagnosis and inadequate treatment. On the other hand, SK may mimic melanoma, producing a 'false positive' with unnecessary lesion excisions. The present study proposes a computer-based approach using dermoscopy images for the characterization of SΚ-like MMs. Dermoscopic images were retrieved from the International Skin Imaging Collaboration archive. Exploiting image embeddings from pretrained convolutional network VGG16, we trained a support vector machine (SVM) classification model on a data set of 667 images. SVM optimal hyperparameter selection was carried out using the Bayesian optimization method. The classifier was tested on an independent data set of 311 images with atypical appearance: MMs had an absence of pigmented network and had an existence of milia-like cysts. SK lacked milia-like cysts and had a pigmented network. Atypical MMs were characterized with a sensitivity and specificity of 78.6% and 84.5%, respectively. The advent of deep learning in image recognition has attracted the interest of computer science towards improved skin lesion diagnosis. Open-source, public access archives of skin images empower further the implementation and validation of computer-based systems that might contribute significantly to complex clinical diagnostic problems such as the characterization of SK-like MMs.

A Review of Immunocryosurgery and a Practical Guide to Its Applications.

Immunocryosurgery is a minimally invasive combinational therapeutic procedure that has been designed, developed, and evaluated in the Dermatology Department of the University of Ioannina from 2004. In a fixed time protocol, this approach combines immune stimulatory therapy with imiquimod and cryosurgery, i.e., cryosurgery is applied during continuous imiquimod treatment. Laboratory findings in tissue and blood level credit the efficacy to the synergy of imiquimod and cryosurgery. The synergy has been established through clinical trials and the excellent feasibility and efficacy demonstrated in clinical practice. Immunocryosurgery has extensive proof of excellent efficacy, comparable to surgery, in the treatment of basal cell carcinoma. It has also been evaluated in cases of Bowen's disease, keratoacanthoma, Merkel cell carcinoma, lentigo maligna, and cutaneous squamous cell carcinoma with or without the addition of adjuvants. The aims of this review are to detail the immunocryosurgery protocol with the addition of daily practice clinical tips, compile data on the mechanism of action of immunocryosurgery, and delineate indications and possible future applications. Most of the available data originate from the treatment of BCC, of all histological types and localizations, and the principles reported mainly reflect on evidence related to the treatment of this common skin cancer.

Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial.

BACKGROUND: Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy. METHODS: We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants. FINDINGS: Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8-18). An objective response per independent central review was observed in 26 (31%; 95% CI 21-42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths. INTERPRETATION: Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy. FUNDING: Regeneron Pharmaceuticals and Sanofi.

Advanced keratinocyte skin cancer is a tumor with considerable disease burden and aggressiveness.

In a 2013 study published in this Journal, Dacosta Byfield et al. used MediCare data to extract reliable estimations of the incidence (I = 6.16) and prevalence (P = 10.31) rates of advanced keratinocyte skin cancer (aKSC) per 100,000 US population. These data unmask a considerable disease burden of aKSC (tumor stages ≥ 3) compared to the corresponding projected SEER predictions in 2019 of all invasive cases (tumor stages ≥ 1). According to its incidence, aKSC ranks 19th out of 29 major SEER registered neoplasms and has an average disease duration of 1.67 years, which is the second shortest disease duration next only to pancreatic carcinoma. Furthermore, in support of the high disease aggressiveness of aKSC and using a calibration approach, we calculated a mortality estimate of 4.64 per 100,000 and a 5-year survival rate of 21.8% for this tumor, which corresponds to positions of 13th and 5th out of 29 cancers among the SEER tracked malignancies, respectively. Taken together, these data indicate a considerable disease burden and biologic aggressiveness of aKSC.

Aeromonas hydrophila Survives the Treatment of Posttraumatic Cellulitis in the Shelter of an Obscured Fish-Bone Fragment.

Fish bone and/or spine puncture injuries can result in infection of the upper extremities with aquatic bacterial pathogens. Additionally, in such injuries, the inoculation of foreign organic material is frequent and may further complicate the clinical presentation and course of the resulting infection. We describe the case of a 45-year-old female patient with a minimal fish rostrum puncture trauma acquired during preparation of fresh fish meal, which resulted in a galloping hand cellulitis. The alarming clinical presentation and the prompt response of the skin infection to clindamycin obscured the presence of inoculated fish rostrum remnants in the tissue that, three weeks later, gave rise to a foreign body granuloma, from which Aeromonas hydrophila was isolated. Final resolution was achieved with an additional two-week doxycycline treatment. In conclusion, the reported case highlights the potential of the accidentally implanted organic material, as are fish bones, not only to transfer uncommon pathogens but also to offer a sanctuary that favors microbial survival despite antibiotic therapy thus enabling latent or recurrent infections.