Importance of Both Clinical and Dermoscopic Findings in Predicting High-Risk Histopathological Subtype in Facial Basal Cell Carcinomas.

INTRODUCTION: Being able to recognize high-risk facial basal cell carcinoma (BCC) may lead to fewer incomplete excisions and inappropriate treatments. OBJECTIVES: We sought to investigate clinical and dermoscopic criteria for predicting facial BCC subtypes, analyze the interobserver agreement between readers, and develop a diagnostic algorithm to predict high-risk histopathological subtype. METHODS: In this single-center, retrospective investigation, 6 independent readers evaluated predefined clinical and dermoscopic criteria in images of histopathologically verified primary facial BCCs including: topography, border demarcation, vessels, ulceration, white porcelain areas, shiny white blotches and strands, and pigmented structures and vessels within ulceration. RESULTS: Overall, 297 clinical and dermoscopic image pairs were analyzed. The strongest associations with high-risk subtype were: "bumpy" topography (OR 3.8, 95% CI, 3.1-4.7), ill-defined borders (OR 3.4, 95% CI 3.1-4.7), white porcelain area (OR 3.5, 95% CI 2.8-4.5), and vessels within ulceration (OR 3.1, 95% CI 2.4-4.1). Predominantly focused vessels were a positive diagnostic criterium for either nodular (OR 1.7, 95% CI 1.3-2.2) or high-risk (OR 2.0, 95% CI 1.6-2.5) subtypes and a strong negative diagnostic criterium for superficial BCC (OR 14.0, 95% CI 9.6-20.8). Interobserver agreement ranged from fair to substantial (κ=0.36 to 0.72). A diagnostic algorithm based on these findings demonstrated a sensitivity of 81.4% (95% CI, 78.9-83.7%) and a specificity of 53.3% (95% CI, 49.7-56.9%) for predicting high-risk BCC subtype. CONCLUSIONS: Integration of both clinical and dermoscopic features (including novel features such as topography and vessels within ulceration) are essential to improve subtype prediction of facial BCCs and management decisions.

Basal cell carcinoma: Epidemiological impact of clinical versus histopathological diagnosis.

BACKGROUND: Low-risk basal cell carcinomas (BCCs) are to an increasing extent diagnosed by dermatologists through dermoscopic examination only and treated with non-surgical methods. Reports on increasing incidence as well as trends regarding subtypes, anatomical sites and differences related to gender are based solely on histopathologically verified tumours. How unreported clinically diagnosed BCCs affect the epidemiological data has not been sufficiently investigated. OBJECTIVES: To analyse the tumour and patient characteristics of clinically diagnosed versus histopathologically confirmed primary BCCs and to make a gross estimate on how unreported BCCs could influence the total number of new cases. METHODS: We retrospectively reviewed all primary BCCs diagnosed in 2016 at the Department of Dermatology, Sahlgrenska University Hospital in Gothenburg, Sweden. We also reviewed all histopathologically verified primary BCCs at the two largest pathology laboratories in Western Sweden during the same year to estimate the proportion of BCCs diagnosed by dermatologists. RESULTS: In total, 2365 primary BCCs were diagnosed at our centre. More than half of these tumours were clinically diagnosed (55.8%). Superficial subtype (41.7%), location on the trunk (46.3%) and destructive treatment methods (60.0%) were most common. The reports from the two pathology laboratories showed that histopathologically verified BCCs (n = 5837) were more commonly of the infiltrative or nodular subtype and located in the head and neck area. Dermatologists managed 56.0% of them. CONCLUSIONS: This study indicates that a substantial number of BCCs are not visualized in the official statistics which are solely based on reports from pathology laboratories. When taking clinically diagnosed tumours into account, truncal location and superficial subtype are more common than previously believed. Further, based on the regional calculations, the real burden of BCC in Sweden might be up to 70% higher than what is reported in official statistics.

Evaluation of Melanoma Thickness with Clinical Close-up and Dermoscopic Images Using a Convolutional Neural Network.

Convolutional neural networks (CNNs) have shown promise in discriminating between invasive and in situ melanomas. The aim of this study was to analyse how a CNN model, integrating both clinical close-up and dermoscopic images, performed compared with 6 independent dermatologists. The secondary aim was to address which clinical and dermoscopic features dermatologists found to be suggestive of invasive and in situ melanomas, respectively. A retrospective investigation was conducted including 1,578 cases of paired images of invasive (n = 728, 46.1%) and in situ melanomas (n = 850, 53.9%). All images were obtained from the Department of Dermatology and Venereology at Sahlgrenska University Hospital and were randomized to a training set (n = 1,078), a validation set (n = 200) and a test set (n = 300). The area under the receiver operating characteristics curve (AUC) among the dermatologists ranged from 0.75 (95% confidence interval 0.70-0.81) to 0.80 (95% confidence interval 0.75-0.85). The combined dermatologists' AUC was 0.80 (95% confidence interval 0.77-0.86), which was significantly higher than the CNN model (0.73, 95% confidence interval 0.67-0.78, p = 0.001). Three of the dermatologists significantly outperformed the CNN. Shiny white lines, atypical blue-white structures and polymorphous vessels displayed a moderate interobserver agreement, and these features also correlated with invasive melanoma. Prospective trials are needed to address the clinical usefulness of CNN models in this setting.

Pancreatic Cancer From the Patient Perspective: The Time to Act is Now.

Pancreatic cancer is a disease requiring urgent attention from governments and policymakers. Recently, a state of emergency has been declared for this cancer-being the fourth most common cause of cancer deaths in the European Union, it has the lowest survival rate of all common cancers. One of the major reasons pancreatic cancer is associated with such poor outcomes is because it is usually diagnosed at a late stage. Also, investment in research for effective targeted therapies is lacking. This is the perspective of a white paper developed by Digestive Cancers Europe, an umbrella organisation representing European patient organisations. It has been developed after consultation with pancreatic cancer patients, representatives of cancer patient organisations and leading pancreatic cancer healthcare professionals. The purpose of the paper is to highlight the key urgent unmet needs in pancreatic cancer from the patient perspective, ultimately with a view to improve patient care and outcomes in this very challenging disease.

The impact of nutrition on the lives of patients with digestive cancers: a position paper.

Nutritional intervention is an essential part of cancer treatments. Research and clinical evidence in cancer have shown that nutritional support can reduce length of hospitalisation, diminish treatment-related toxicity, and improve nutrient intake, quality of life, and physical function. Nutritional intervention can improve outcomes and help patients in the successful completion of oncological treatments by preventing malnutrition. Malnutrition is a very common hallmark in patients with cancers. Almost one-fourth of cancer patients are at risk of dying because of the consequences of malnutrition, rather than cancer itself. Patients with digestive cancers are at higher risk of suffering malnutrition due to the gastrointestinal impairment caused by their disease. They are at high nutritional risk by definition, yet the majority of them have insufficient or null access to nutritional intervention.Inadequate resources are dedicated to implementing nutritional services in Europe. Universal access to nutritional support for digestive cancer patients is not a reality in many European countries. To change this situation, health systems should invest in qualified staff to reinforce or create nutritional teams' experts in digestive cancer treatments. We aim to share the patient community's perspective on the status and the importance of nutritional intervention. This is an advocacy manuscript presenting data on the topic and analysing the current situations and the challenges for nutrition in digestive cancers. It highlights the importance of integrative nutrition in the treatment of digestive cancers and advocates for equitable and universal access to nutritional intervention for all patients.

Interobserver Agreement on Dermoscopic Features and their Associations with In Situ and Invasive Cutaneous Melanomas.

Several melanoma-specific dermoscopic features have been described, some of which have been reported as indicative of in situ or invasive melanomas. To assess the usefulness of these features to differentiate between these 2 categories, a retrospective, single-centre investigation was conducted. Dermoscopic images of melanomas were reviewed by 7 independent dermatologists. Fleiss' kappa (κ) was used to analyse interobserver agreement of predefined features. Logistic regression and odds ratios were used to assess whether specific features correlated with melanoma in situ or invasive melanoma. Overall, 182 melanomas (101 melanoma in situ and 81 invasive melanomas) were included. The interobserver agreement for melanoma-specific features ranged from slight to substantial. Atypical blue-white structures (κ=0.62, 95% confidence interval 0.59-0.65) and shiny white lines (κ=0.61, 95% confidence interval 0.58-0.64) had a substantial interobserver agreement. These 2 features were also indicative of invasive melanomas >1.0 mm in Breslow thickness. Furthermore, regression/peppering correlated with thin invasive melanomas. The overall agreement for classification of the lesions as invasive or melanoma in situ was moderate (κ=0.52, 95% confidence interval 0.49-0.56).

Discrimination Between Invasive and In Situ Melanomas Using Clinical Close-Up Images and a De Novo Convolutional Neural Network.

Background: Melanomas are often easy to recognize clinically but determining whether a melanoma is in situ (MIS) or invasive is often more challenging even with the aid of dermoscopy. Recently, convolutional neural networks (CNNs) have made significant and rapid advances within dermatology image analysis. The aims of this investigation were to create a de novo CNN for differentiating between MIS and invasive melanomas based on clinical close-up images and to compare its performance on a test set to seven dermatologists. Methods: A retrospective study including clinical images of MIS and invasive melanomas obtained from our department during a five-year time period (2016-2020) was conducted. Overall, 1,551 images [819 MIS (52.8%) and 732 invasive melanomas (47.2%)] were available. The images were randomized into three groups: training set (n = 1,051), validation set (n = 200), and test set (n = 300). A de novo CNN model with seven convolutional layers and a single dense layer was developed. Results: The area under the curve was 0.72 for the CNN (95% CI 0.66-0.78) and 0.81 for dermatologists (95% CI 0.76-0.86) (P < 0.001). The CNN correctly classified 208 out of 300 lesions (69.3%) whereas the corresponding number for dermatologists was 216 (72.0%). When comparing the CNN performance to each individual reader, three dermatologists significantly outperformed the CNN. Conclusions: For this classification problem, the CNN was outperformed by the dermatologist. However, since the algorithm was only trained and validated on 1,251 images, future refinement and development could make it useful for dermatologists in a real-world setting.

Can Dermoscopy Be Used to Predict if a Melanoma Is In Situ or Invasive?

BACKGROUND: The preoperative prediction of whether melanomas are invasive or in situ can influence initial management. OBJECTIVES: This study evaluated the accuracy rate, interobserver concordance, sensitivity and specificity in determining if a melanoma is invasive or in situ, as well as the ability to predict invasive melanoma thickness based on clinical and dermoscopic images. METHODS: In this retrospective, single-center investigation, 7 dermatologists independently reviewed clinical and dermoscopic images of melanomas to predict if they were invasive or in situ and, if invasive, their Breslow thickness. Fleiss' and Cohen's kappa (κ) were used for interobserver concordance and agreement with histopathological diagnosis. RESULTS: We included 184 melanomas (110 invasive and 74 in situ). Diagnostic accuracy ranged from 67.4% to 76.1%. Accuracy rates for in situ and invasive melanomas were 57.5% (95% confidence interval [CI], 53.1%-61.8%) and 81.7% (95% CI, 78.8%-84.4%), respectively. Interobserver concordance was moderate (κ = 0.47; 95% CI, 0.44-0.51). Sensitivity for predicting invasiveness ranged from 63.6% to 91.8% for 7 observers, while specificity was 32.4%-82.4%. For all correctly predicted invasive melanomas, agreement between predictions and correct thickness over or under 1.0 mm was moderate (κ = 0.52; 95% CI, 0.45-0.58). All invasive melanomas incorrectly predicted by any observer as in situ had a thickness <1.0 mm. All 32 melanomas >1.0 mm were correctly predicted to be invasive by all observers. CONCLUSIONS: Accuracy rates for predicting thick melanomas were excellent, melanomas inaccurately predicted as in situ were all thin, and interobserver concordance for predicting in situ or invasive melanomas was moderate. Preoperative dermoscopy of suspected melanomas is recommended for choosing appropriate surgical margins.

Incomplete Excisions of Melanocytic Lesions: Rates and Risk Factors.

Incomplete excisions of melanocytic lesions occur despite the intention of complete removal. The aim of this study was to determine the incomplete excision rates for benign and malignant melanocytic lesions and the associated risk factors. Demographic, clinical, and histo-pathological data possibly associated with incomplete excision were collected from 2,782 consecutive excisions between 2014 and 2015. Of these, 269 melanocytic lesions (9.7%) were incompletely excised. Multivariate analysis revealed the following risk factors for significantly higher incomplete excision rates: lesions located in the head and neck area (odds ratio (OR) 3.95, 95% confidence interval (95% CI) 2.35-6.65), surgery performed by general practitioners (OR 3.01, 95% CI 2.16-4.19), the use of a punch excision technique (OR 2.83, 95% CI 1.96-4.08), and excision of non-dysplastic naevi (OR 1.58, 95% CI 1.11-2.23). In conclusion, more caution should be taken when excising melanocytic lesions in the head and neck area, general practitioners require more surgical training, and punch excisions of melanocytic lesions should be avoided.

Nonsurgical Options for the Treatment of Basal Cell Carcinoma.

OBJECTIVES: The aim of this review article is to summarize the effectiveness, potential adverse events, and indications of the main nonsurgical treatment alternatives for basal cell carcinoma. METHODS: An extensive literature review was carried out. The most relevant articles were discussed and selected by the authors in order to provide a brief but evidence-based overview of the most common nonsurgical methods used for treating basal cell carcinoma. RESULTS: Although surgery and Mohs micrographic surgery are often considered the optimal treatment options for basal cell carcinoma, these tumors can also be treated successfully with destructive techniques (eg, curettage alone, cryosurgery, or electrodesiccation), photodynamic therapy, topical drugs (eg, 5-fluorouracil, imiquimod, or ingenol mebutate), radiotherapy, or hedgehog pathway inhibitors. When choosing between these alternatives, physicians must take into consideration the tumor's size, location, and histopathological subtype. Special care should be taken when treating recurrent tumors. Furthermore, physician experience is of great importance when using destructive techniques. Finally, patient preference, potential adverse events, and cosmetic outcome should also be considered. CONCLUSIONS: Dermatologists and physicians treating basal cell carcinoma should have knowledge of and experience with the large arsenal of therapeutic alternatives available for the successful, safe, and individualized management of patients with basal cell carcinoma.

Smartphone teledermoscopy referrals: a novel process for improved triage of skin cancer patients.

In this open, controlled, multicentre and prospective observational study, smartphone teledermoscopy referrals were sent from 20 primary healthcare centres to 2 dermatology departments for triage of skin lesions of concern using a smartphone application and a compatible digital dermoscope. The outcome for 816 patients referred via smartphone teledermoscopy was compared with 746 patients referred via the traditional paper-based system. When surgical treatment was required, the waiting time was significantly shorter using teledermoscopy for patients with melanoma, melanoma in situ, squamous cell carcinoma, squamous cell carcinoma in situ and basal cell carcinoma. Triage decisions were also more reliable with teledermoscopy and over 40% of the teledermoscopy patients could potentially have avoided face-to-face visits. Only 4 teledermoscopy referrals (0.4%) had to be excluded due to poor image quality. Smartphone teledermoscopy referrals allow for faster and more efficient management of patients with skin cancer as compared to traditional paper referrals.

Development of interleukin-1 receptor antagonist mutants with enhanced antagonistic activity in vitro and improved therapeutic efficacy in collagen-induced arthritis.

Interleukin-1 receptor antagonist (IL-1Ra) is a naturally occurring inhibitor of the pro-inflammatory interleukin-1-mediated activation of the interleukin-1 receptor (IL-1R). Although wild-type IL-1Ra is used for treatment of inflammatory diseases, its effect is moderate and/or short-lived. The objective of this study was to generate IL-1Ra mutants with enhanced antagonistic activity for potential therapeutic use. Using a directed evolution approach in which libraries of IL-1Ra gene mutants were generated and screened in functional assays, mutants with desired properties were identified. Initially, diversity was introduced into the IL-1Ra using random mutagenesis. Mutations resulting in enhanced antagonistic activity were identified by screening in a reporter cell assay. To further enhance the antagonistic activity, selected mutations were recombined using the DNA recombination technology Fragment-INduced Diversity (FIND). Following three rounds of FIND recombination, several mutants with up to nine times enhanced antagonistic activity (mean IC50 +/- SEM value: 0.78 +/- 0.050 vs. 6.8 +/- 1.1 ng/ml for mutant and wild-type, respectively) were identified. Sequence analysis identified the mutations D47N, E52R and E90Y as being most important for this effect, however, the mutations P38Y, H54R, Q129L and M136N further enhanced the antagonistic function. Analysis of identified mutations in protein models based on the crystal structure of the IL-1Ra/IL-1R complex suggested that mutations found to enhance the antagonistic activity had a stabilizing effect on the IL-1Ra mutants or increased the affinity for the IL-1R. Finally, the therapeutic effect of one mutant was compared to that of wild-type IL-1Ra in collagen-induced arthritis in mice. Indeed, the enhanced antagonistic effect of the mutants observed in vitro was also seen in vivo. In conclusion, these results demonstrate that directed evolution of IL-1Ra is an effective means of generating highly potent therapeutic proteins.

A new perspective: molecular motifs on oxidized LDL, apoptotic cells, and bacteria are targets for chronic lymphocytic leukemia antibodies.

The restricted immunoglobulin (Ig) repertoire found in B-cell chronic lymphocytic leukemia (CLL) implies a role for antigen(s) in the leukemogenesis. The nature of the antigens has, however, not been characterized, although examples of autoantigens have been demonstrated. We have analyzed a panel of 28 CLL cell lines and primary cultures, producing monoclonal Ig with different Ig heavy-chain variable region gene usage and mutational status, including several complementarity determining region 3 homology subset members. Using mass-spectrometry, immunoassays, or protein macroarrays, we have discovered novel antigens binding to CLL Igs. These antigens included cytoskeletal proteins vimentin, filamin B, and cofilin-1, but also phosphorylcholine-containing antigens (eg, Streptococcus pneumoniae polysaccharides and oxidized low-density lipoprotein [oxLDL]). Additional new antigens identified were cardiolipin and proline-rich acidic protein-1. Remarkably, these antigens represent molecular motifs exposed on apoptotic cells/blebs and bacteria, and several CLL Igs bound to apoptotic Jurkat cells. In conclusion, these intriguing data, showing a limited target structure recognition, indicate that CD5+ CLL B cells are derived from a cell compartment that produces "natural antibodies," which may be instrumental in elimination and scavenging of apoptotic cells and pathogenic bacteria.

Thioredoxin, produced by stromal cells retrieved from the lymph node microenvironment, rescues chronic lymphocytic leukemia cells from apoptosis in vitro.

BACKGROUND AND OBJECTIVES: The redox-regulatory protein thioredoxin has several functions including transcriptional regulation, and antioxidant, cytokine, and chemokine activities. We have previously shown that extracellular thioredoxin protects B-cell chronic lymphocytic leukemia (CLL) cells from apoptosis in vitro. In this study we were interested to determine whether thioredoxin is produced by cells surrounding the CLL cells in the in vivo microenvironment and whether this cell-derived thioredoxin has any leukemia growth-promoting effect in vitro. DESIGN AND METHODS: Lymph nodes from CLL patients (n=25) were analyzed for thioredoxin expression by immunohistology. Stromal cells purified from the lymph nodes were analyzed for thioredoxin secretion at the single cell level using an ELIspot assay. The survival effect of the stromal-derived thioredoxin was tested by co-culturing stromal- and CLL cells with and without Fab-fragments of an anti-thioredoxin antibody. RESULTS: The results indicated that the thioredoxin production correlated with the amount of proliferating cells and was mainly localized to the proliferation centers (pseudofollicles) in the CLL lymph nodes. The leukemia cells per se showed minimal thioredoxin levels; in contrast, stromal cells strongly expressed thioredoxin. Purified primary stromal cells, which secreted extracellular thioredoxin, significantly protected the CLL cells from undergoing apoptosis in 72 h co-cultures. Interestingly, this anti-apoptotic effect could be abrogated by addition of Fab-fragments of an anti- thioredoxin antibody. INTERPRETATION AND CONCLUSIONS: In conclusion, we have shown that stromal cells in the lymph node microenvironment produce thioredoxin and that the thioredoxin production is localized to the proliferation centers of the CLL lymph nodes. In addition, thioredoxin produced by purified stromal cells rescued CLL cells from apoptosis in vitro.

Quantitative EMG and muscle tension in painful muscles in fibromyalgia.

Examinations were performed in 22 female fibromyalgic patients and in 9 healthy controls. The biceps brachii, trapezius, and tibial anterior muscles were examined electromyographically. The changes found were minor and non-specific. This implies that there is no important loss of motor units and no conspicuous muscle fiber degeneration in fibromyalgia. Our investigation also failed to demonstrate any electrically detectable muscle activity in muscles where the patients during the examination reported pain (paraspinal, trapezius and tibial anterior muscles). This means that muscle tension cannot be a prominent pathogenetic factor in fibromyalgia and that factors other than muscle tension are responsible for maintaining the pain in fibromyalgia.