The Complex Interplay between Nevi and Melanoma: Risk Factors and Precursors.

One effort to combat the rising incidence of malignant melanoma is focused on early detection by the clinical and dermoscopic screening of melanocytic nevi. However, the interaction between nevi, which are congenital or acquired benign melanocytic proliferations, and melanoma is still enigmatic. On the one hand, the majority of melanomas are thought to form de novo, as only a third of primary melanomas are associated with a histologically identifiable nevus precursor. On the other hand, an increased number of melanocytic nevi is a strong risk factor for developing melanoma, including melanomas that do not derive from nevi. The formation of nevi is modulated by diverse factors, including pigmentation, genetic risk factors, and environmental sun exposure. While the molecular alterations that occur during the progression of a nevus to melanoma have been well characterized, many unanswered questions remain surrounding the process of nevus to melanoma evolution. In this review, we discuss clinical, histological, molecular, and genetic factors that influence nevus formation and progression to melanoma.

Efficacy of ultraviolet A1 phototherapy for inflammatory, sclerotic and neoplastic dermatological diseases: A 10-year tertiary referral center experience.

BACKGROUND: Ultraviolet (UV) A1 phototherapy is considered a beneficial treatment for various inflammatory, sclerotic, malignant, and other skin conditions. However, the available data regarding its efficacy for different indications, the potential side effects, and the recommended treatment protocols are sparse. OBJECTIVES: To assess the efficacy of UVA1 phototherapy and identify correlation between different indications and treatment protocols to response rates. METHODS: We performed a retrospective study of a cohort of 335 patients treated with UVA1 phototherapy at the Department of Dermatology at Hadassah Medical Center, Jerusalem, Israel, between 2008 and 2018. RESULTS: The study population included 163 patients with inflammatory diseases (mainly atopic dermatitis and other types of eczema), 67 patients with sclerotic diseases (morphea and graft versus host disease), nine patients with neoplastic diseases (cutaneous T cell lymphoma), and 188 patients with other cutaneous disorders. Response rates ranged between 85% and 89% across indications, without differences in response rates among the indication groups (p = .941). In a multivariant logistic regression model, increased number of treatments and higher maximal dosages were associated with response to treatment (p < .001). Using ROC analysis, a cut-off of 8 UVA1 phototherapy treatments was chosen as predictive for beneficial response (86.4% sensitivity, 78% specificity). A cut-off of 40 J/cm2 was chosen as an optimal maximal dosage for differentiating between responders and non-responders (51.1% sensitivity, 83.1% specificity). CONCLUSIONS: UVA1 phototherapy is an effective treatment for a variety of skin conditions. In most patients, at least eight treatments of a medium-high dosage are required for clinical response.

Dermatological adverse events under programmed cell death-1 inhibitors as a prognostic marker in metastatic melanoma.

Melanoma is widely treated with programmed cell death-1 (PD-1) inhibitors. As part of their anti-tumor immunity effect, they increase the susceptibility to cutaneous immune-related adverse events (cIRAE) among other autoimmune effects. To characterize the manifestations of cIRAE in melanoma patients treated with PD-1 inhibitors, and evaluate the correlation with tumor response. A retrospective study of 95 metastatic malignant melanoma patients treated with PD-1 inhibitors at the Hadassah Medical Center during 2013-2016. The most common cIRAE was pruritus reported by 39 (41%) patients. All other cIRAE were noted in 34 patients (35.8%), of which the most common cutaneous manifestation was vitiligo, demonstrated in 17 patients (17.9%) followed by various rashes (7.4%, including erythema multiforme, oral lichen planus, photosensitive rash, insect bite-like reaction, and urticaria), psoriasiform rash (3.2%), bullous pemphigoid (3.2%), and eczema (1%). Interestingly, higher response rates to immunotherapy were demonstrated in patients who developed pruritus (85%) and cIRAE (88%), with lower mortality rates in the cIRAE group (38.2%) versus the non-cIRAE group (70.5%, p = 0.002). cIRAE are common among malignant melanoma patients treated with PD-1 inhibitors and may be a marker for favorable prognosis.

The role of immune checkpoint receptors in the malignant phenotype of cutaneous T cell lymphoma.

Immune checkpoint receptors (ICR) modulate the immune response and are critical hubs for immunotherapy. However, data on their role in T lymphoid malignancies, such as cutaneous T cell lymphoma (CTCL), is sparse. We aimed to explore the role of ICR in the malignant features of transformed T lymphocytes and evaluate the effect of ICR-targeting monoclonal antibodies, often used as immunotherapy for solid tumors. We used the CTCL cell line HH and the Sézary cell line Hut78 to examine ICR expression and the effects of ICR inhibition on cell viability and proliferation. Despite their shared T cell progeny, the different CTCL cell lines exhibit markedly different ICR expression profiles. Programmed cell death-ligand 1 (PD-L1) was expressed by both cell lines, while programmed death-1 (PD-1) was expressed only by the HH cell line. Common to all malignant T cells was an autonomous hyper-proliferative state that did not require T cell receptor stimulation. A monoclonal antibody blocking PD-1 had a small but statistically significant augmenting effect on T cell proliferation. Of note, when the cells were exposed to ionizing radiation, healthy lymphocytes and those derived from the HH cell line were salvaged by anti-PD-L1. We show a regulatory role of ICR, mainly PD-1 and its ligand PD-L1, on cutaneous T cell malignancy.

LGR5 expressing skin fibroblasts define a major cellular hub perturbed in scleroderma.

Systemic sclerosis (scleroderma, SSc) is an incurable autoimmune disease with high morbidity and mortality rates. Here, we conducted a population-scale single-cell genomic analysis of skin and blood samples of 56 healthy controls and 97 SSc patients at different stages of the disease. We found immune compartment dysfunction only in a specific subtype of diffuse SSc patients but global dysregulation of the stromal compartment, particularly in a previously undefined subset of LGR5+-scleroderma-associated fibroblasts (ScAFs). ScAFs are perturbed morphologically and molecularly in SSc patients. Single-cell multiome profiling of stromal cells revealed ScAF-specific markers, pathways, regulatory elements, and transcription factors underlining disease development. Systematic analysis of these molecular features with clinical metadata associates specific ScAF targets with disease pathogenesis and SSc clinical traits. Our high-resolution atlas of the sclerodermatous skin spectrum will enable a paradigm shift in the understanding of SSc disease and facilitate the development of biomarkers and therapeutic strategies.

Acrofacial necrotic ulcers in an infant: An undiagnosed presentation.

Acral necrotic ulcers in infancy are rare but have been described in type I interferonopathies. Herein, we present a case of an 8-year-old child who presented at the age of one month with severe ulceronecrotic lesions on the face and limbs with exacerbations following exposure to cold weather. Despite extensive investigation the case remains undiagnosed to this day. We hypothesize that this case represents a novel and yet unknown autoinflammatory disease.

Allergic Rhinitis and Asthma Among Adolescents with Psoriasis: A Population-based Cross-sectional Study.

Few studies have reported an association between psoriasis and atopic comorbidity in adults. A population-based cross-sectional study was performed to investigate the possible association of psoriasis with allergic rhinitis or asthma among adolescents. Adolescents (16-18 years of age) medically evaluated for military service between 1999 and 2014 were included. Medical records were obtained from the database of the Israeli Defense Forces. Of the 887,765 adolescents studied, 3,112 patients had psoriasis (56.1% mild; 43.9% moderate-to-severe). Psoriasis was significantly associated with allergic rhinitis (adjusted odds ratio (aOR) 1.3; 95% confidence interval (CI) 1.2-1.5) and asthma (aOR 1.2; 95% CI 1.0-1.3), compared with controls without psoriasis. Moderate-to-severe psoriasis was associated with allergic rhinitis (aOR 1.3; 95% CI 1.1-1.5) and asthma (aOR 1.5; 95% CI 1.2-1.7), while mild psoriasis was only associated with allergic rhinitis (aOR 1.4; 95% CI 1.2-1.6). In conclusion, amongst adolescents, psoriasis was found to be associated with allergic rhinitis and asthma.

Epidemiology and Comorbidities of Psoriasis among Israeli Adolescents: A Large Cross-Sectional Study.

BACKGROUND AND AIMS: Although psoriasis can develop at any age, the data regarding its characteristics in adolescents are sparse. This study was designed to determine the psoriasis prevalence and its associations with the body mass index (BMI), lipid profile, and comorbidities in adolescents. METHODS: This was a nationwide population-based cross-sectional retrospective study of adolescents (16-18 years old) evaluated for military service between January 1999 and January 2014. RESULTS: Our database included 887,765 adolescents (57.1% males), of whom 3,112 (0.35%) were diagnosed with psoriasis. During the 15-year study period, the psoriasis prevalence increased by 1.4-fold, from 0.3 to 0.42% (1.25-fold for the males and 1.63-fold for the females). Certain comorbidities, such as contact dermatitis, hyperhidrosis, and arthritis, were significantly associated with psoriasis (odds ratios [ORs] of 2.26, 1.51, and 5.3, respectively). The adolescents with psoriasis had significantly elevated BMI and triglyceride values. We found increased ORs of 1.34 (95% confidence interval [CI] = 1.25-1.56) and 1.56 (95% CI = 1.32-1.83) for the overweight and obese adolescents, respectively, while a lower BMI (<20) had an opposite effect with psoriasis (OR = 0.8). CONCLUSIONS: Based on our results, the psoriasis prevalence in Israeli adolescents is rising. Dermatological comorbidities and an increased BMI were associated with psoriasis in these adolescents. A better understanding of the distinctive epidemiological characteristics of juvenile psoriasis may allow for the early detection of comorbidities and improve its management.

Cutaneous Chronic Graft Versus Host Disease Following Allogeneic Haematopoietic Stem Cell Transplantation in Children: A Retrospective Study.

Chronic graft versus host disease (cGVHD) is a complication of allogeneic haematopoietic stem cell transplantation (HSCT). The aim of this study was to clinically characterize childhood cutaneous cGVHD. A retrospective study of children treated with HSCT at 2 tertiary medical centres in Israel between 2011 and 2014 was performed. A total of 112 children were included. Cutaneous cGVHD developed in 18% of subjects. Risk factors were older age, HSCT from peripheral blood and acute lymphoblastic leukaemia. The eruption was lichenoid in 90% of subjects, of whom one-third progressed to sclerosis. Topical treatments were usually sufficient in localized disease. Widespread eruption necessitated phototherapy, extracorporeal photopheresis and/or systemic immunosuppressants. Patients presenting with palmoplantar keratoderma, developed sclerosis. To the best of our knowledge, this is the first study describing childhood cutaneous cGVHD. Lichenoid eruption is the most common cutaneous pattern of cGVHD in children. Sclerotic changes may be associated with prior keratoderma. cGVHD poses a therapeutic challenge and better treatments should be sought.

Prevalence of Sharing Access Credentials in Electronic Medical Records.

OBJECTIVES: Confidentiality of health information is an important aspect of the physician patient relationship. The use of digital medical records has made data much more accessible. To prevent data leakage, many countries have created regulations regarding medical data accessibility. These regulations require a unique user ID for each medical staff member, and this must be protected by a password, which should be kept undisclosed by all means. METHODS: We performed a four-question Google Forms-based survey of medical staff. In the survey, each participant was asked if he/she ever obtained the password of another medical staff member. Then, we asked how many times such an episode occurred and the reason for it. RESULTS: A total of 299 surveys were gathered. The responses showed that 220 (73.6%) participants reported that they had obtained the password of another medical staff member. Only 171 (57.2%) estimated how many time it happened, with an average estimation of 4.75 episodes. All the residents that took part in the study (45, 15%) had obtained the password of another medical staff member, while only 57.5% (38/66) of the nurses reported this. CONCLUSIONS: The use of unique user IDs and passwords to defend the privacy of medical data is a common requirement in medical organizations. Unfortunately, the use of passwords is doomed because medical staff members share their passwords with one another. Strict regulations requiring each staff member to have it's a unique user ID might lead to password sharing and to a decrease in data safety.

Atopic Dermatitis in Israeli Adolescents from 1998 to 2013: Trends in Time and Association with Migraine.

BACKGROUND: Recent data have shown an increasing occurrence of atopic dermatitis (AD) in children and adolescents, as well as in adults. Most of the epidemiologic research on AD is limited to pediatric and youth populations and is based on self-reported questionnaires. METHODS: A nationwide, population-based, cross-sectional retrospective study of adolescents with AD was performed to estimate its prevalence, trends, and association with demographic factors and comorbidities. The study included all Israeli teens going through medical evaluation as part of the assessment before being conscripted into the military from 1998 to 2013. RESULTS: A total of 1,187,757 adolescents were included in the study population, with an overall prevalence of AD of 0.64% in boys and 0.9% in girls. Over the study period, the prevalence of AD steadily increased, especially in the mild disease group. A greater risk of AD was found in subjects with high predicted socioeconomic status (male: odds ratio [OR] 1.14 [95% confidence interval {CI} 1.11, 1.16]; female: OR 1.08, [95% CI 1.05, 1.10]) and Israeli-born subjects (male: OR 1.34 [95% CI 1.21, 1.48]; female: OR 1.12 [95% CI 1.01, 1.23]). Allergic conditions such as asthma, conjunctivitis, and contact dermatitis were more prevalent in subjects with AD. There was a significantly higher prevalence of migraine in patients with AD (male: OR 1.35 [95% CI 1.18, 1.54]; female: OR 1.51 [95% CI 1.30, 1.74]). CONCLUSION: This large cross-sectional study demonstrates the increasing prevalence of AD in adolescents and its relation to other allergic diseases and migraine. It is hoped that greater awareness of the distinctive epidemiologic characteristics of this population will lead to better recognition and management of the disease and its comorbidities.

Janus kinase inhibitors in dermatology: A systematic review.

BACKGROUND: Janus kinase (JAK) inhibitors are emerging as a promising new treatment modality for many inflammatory conditions. OBJECTIVE: Our aim was to systematically review the available data on the use of JAK inhibitors in cutaneous diseases. METHODS: This is a systematic review of PubMed and ClinicalTrials.gov. RESULTS: One hundred thirty-four articles matched our search terms, of which 78 were original articles and 12 reports on adverse events. Eighteen clinical trials were found. JAK inhibitors have been extensively studied for psoriasis, showing beneficial results that were comparable to the effects achieved by etanercept. Favorable results were also observed for alopecia areata. Promising preliminary results were reported for vitiligo, dermatitis, graft versus host disease, cutaneous T cell lymphoma, and lupus erythematosus. The most common adverse events reported were infections, mostly nasopharyngitis and upper respiratory tract infections. LIMITATIONS: It was not possible to perform a meta-analysis of the results. CONCLUSIONS: This systematic review shows that while JAK inhibitors hold promise for many skin disorders, there are still gaps regarding the correct dosing and safety profile of these medications for dermatologic indications. Additional trials are necessary to address these gaps.

Identification of Dormancy-Associated MicroRNAs for the Design of Osteosarcoma-Targeted Dendritic Polyglycerol Nanopolyplexes.

The presence of dormant, microscopic cancerous lesions poses a major obstacle for the treatment of metastatic and recurrent cancers. While it is well-established that microRNAs play a major role in tumorigenesis, their involvement in tumor dormancy has yet to be fully elucidated. We established and comprehensively characterized pairs of dormant and fast-growing human osteosarcoma models. Using these pairs of mouse tumor models, we identified three novel regulators of osteosarcoma dormancy: miR-34a, miR-93, and miR-200c. This report shows that loss of these microRNAs occurs during the switch from dormant avascular into fast-growing angiogenic phenotype. We validated their downregulation in patients' tumor samples compared to normal bone, making them attractive candidates for osteosarcoma therapy. Successful delivery of miRNAs is a challenge; hence, we synthesized an aminated polyglycerol dendritic nanocarrier, dPG-NH2, and designed dPG-NH2-microRNA polyplexes to target cancer. Reconstitution of these microRNAs using dPG-NH2 polyplexes into Saos-2 and MG-63 cells, which generate fast-growing osteosarcomas, reduced the levels of their target genes, MET proto-oncogene, hypoxia-inducible factor 1α, and moesin, critical to cancer angiogenesis and cancer cells' migration. We further demonstrate that these microRNAs attenuate the angiogenic capabilities of fast-growing osteosarcomas in vitro and in vivo. Treatment with each of these microRNAs using dPG-NH2 significantly prolonged the dormancy period of fast-growing osteosarcomas in vivo. Taken together, these findings suggest that nanocarrier-mediated delivery of microRNAs involved in osteosarcoma tumor-host interactions can induce a dormant-like state.