Cutaneous squamous cell carcinoma (cSCC), the second most common skin cancer, remains a major health burden worldwide. The WW domain-containing oxidoreductase (WWOX) is frequently altered in cancer; however, its role in epidermal biology and skin carcinogenesis remains undefined. Here, we uncover an essential function for WWOX in safeguarding epithelial identity and restraining cSCC progression. Using conditional knockout mice, we demonstrate that WWOX loss accelerates p53-driven cSCC, resulting in early, highly penetrant, and poorly differentiated tumors. Transcriptomic profiling revealed that WWOX deficiency drives epithelial-to-mesenchymal transition (EMT) and transcriptional plasticity, hallmarks of aggressive disease. Mechanistically, proximity ligation assays together with biochemical and cellular analyses support a close association between WWOX and p63 and imply that WWOX contributes to p63 stabilization; loss of WWOX reduces p63 protein levels and diminishes its binding to epithelial target genes, thereby disrupting epidermal transcriptional programs. Human tissue microarrays confirmed a concordant reduction of WWOX and p63 in advanced cSCC, correlating with poor differentiation. Functional assays in human keratinocytes and cSCC cells further showed that WWOX depletion enhances EMT plasticity, invasiveness, and metastatic colonization. Together, these findings identify WWOX as a critical regulator of epidermal integrity and reveal a previously unrecognized WWOX-p63 axis that constrains EMT and tumor progression in cSCC.

<p>PDF file - 118K, Supplementary Figure S1. Species specificity of p14ARF and p19ARF antibodies. Supplementary Figure S2. Increase in SAβGal-positive cell numbers in control mice during early aging. Supplementary Figure S3. Rb and p130 dephosphorylation upon p14ARF induction. Supplementary Figure S4. Effects of p14ARF induction on skin histology. Supplementary Figure S5. p14ARF induces hair-follicle stem cell dysfunction through p53. Supplementary Figure S6. Senescence in TPA-treated mice.</p>

<p>Supplementary Table S1 - Patient Characteristics Supplementary Fig. S1 - IR-induced morphology and inflammatory responses Supplementary Fig. S2 - Apoptosis following IR Supplementary Fig. S3 - Morphology, Aquaporin and ??H2AX in Acini following IR Supplementary Fig. S4 - IL-6 is crucial for persistence of DDR Supplementary Fig. S5 - IL-6 infusion induces IL-6 upregulation. Supplementary Fig. S6 - IL-6 and HIL-6 pretreatment reduces persistent DDR Supplementary Fig. S7 - IL-6 pretreatment accelerates DNA damage repair Supplementary Fig. S8 - IL-6 deficiency does not affect DDR Supplementary Fig. S9 - HIL-6 pretreatment does not affect distal tumor radiotherapy Supplementary Figure Legends Supplementary Materials and Methods</p>

Permanent chemotherapy-induced alopecia (pCIA) is the absence of hair regrowth after more than 6 months of treatment discontinuation.1 pCIA has a profound impact on patients’ quality of life.1 Data on the pathophysiology and treatment of pCIA are scarce.1 We describe a patient who developed pCIA after hematopoietic stem cell transplantation and responded to low-dose oral minoxidil (LDOM) with full hair regrowth.

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.

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.

BACKGROUND:We report a clinically challenging and unusual case of L. donovani oral mucosal leishmaniasis.CASE PRESENTATION:Israeli resident with a former travel to central and North Africa, with no documented or prior cutaneous lesions presented with oral lesions of the maxillary gingiva and the upper lip. A delay in diagnosis and treatment have led to progression of the maxillary gingival lesions towards the hard palatal and the soft palate that could have potentially compromised the upper airway.CONCLUSIONS:This case highlights the importance of early diagnosis of leishmaniasis in patients with oral lesions and the laboratory workup necessary to appropriately characterize and treat the disease.

the present epidemiological context, we emphasize the importance of high clinical suspicion to avoid undetected cases in order to interrupt the chains of transmission. Considering the steady increase of cases reported in Africa since 1970 and present-day globalization, it would be wise to consider monkeypox in the differential diagnosis when evaluating genital ulcer diseases. Finally, we would like to highlight our patient’s remarkable improvement after one day of antibiotherapy with doxycycline, with resolution of fever and lymphadenopathy reduction. A case report of MPXV treated with doxycycline for suspected rickettsial infection has been described in the literature, where the patient presented fever resolution within the first 24 h of treatment. This clinical improvement could be explained by the natural evolution of the disease, by the antiinflammatory properties of doxycycline or by an unknown mechanism.

Introduction: Immune-checkpoint inhibitors have demonstrated a significant survival benefit in metastatic and non-resectable head and neck squamous cell carcinoma (HNSCC). Patients with a combined positivity score (CPS) of 20 and higher benefit the most from therapy. Inaccurate definition of the CPS category might lead to the incorrect stratification of patients to immunotherapy. This study’s main aim was to investigate programmed death-ligand 1 (PD-L1) antigen expression in HNSCC in diverse clinical situations and histological settings. Materials and Methods: This is a prospective cohort study conducted in a tertiary referral medical center. Tissues were investigated for PD-L1 expression using the FDA-approved 22C3 immunohistochemistry assay (Dako). We analyzed potential associations between the CPS category and meaningful demographic, clinical, and outcome metrics. Furthermore, we investigated morphologically separate sites for CPS scores in whole surgical tissue specimens and matched preoperative biopsies. Results: We analyzed 36 patients, of whom 26 had oral cavity SCC and 10 had laryngeal SCC. The overall, disease-specific, and progression-free survival of the HNSCC group of patients were not associated with the CPS category (p = 0.45, p = 0.31, and p = 0.88, respectively). There was a significant (18%, 95% CI 0.65–0.9) inconsistency between the CPS category determined in biopsies versus whole carcinoma analyses. We also found an uneven distribution of whole-tumor CPS attributed to spatial carcinoma invasiveness, tumor differentiation, and inflammatory cell infiltration heterogeneity. Discussion and Conclusions: Our data suggest that careful selection of tumor area for CPS analysis is important. PD-L1 antigen expression, clinically represented by CPS, may be up- or down-categorized in different clinical and pathological circumstances. The high whole-tissue CPS category scatter may clinically result in potential treatment modifications. We argue that CPS analysis requires not only adequacy (at least 100 viable tumor cells), but also correct representation of the tumor microenvironment.

INTRODUCTION:Heterotopia is the presence of a particular tissue / tumor at a non-physiological / ectopic site. The study primary goals: To review the current data investigating heterotopic, normal appearing, and diseased salivary gland tumors, in lymph nodes. To describe the meticulous pathological investigation and multidisciplinary decision-making process of a heterotopic carcinoma ex pleomorphic adenoma arising in an intra-parotid lymph node.MATERIALS AND METHODS:A literature search in the "PubMed" database using key words "carcinoma ex pleomorphic adenoma", "parotid lymph node", "salivary gland" and "heterotopia" was conducted. We describe the thorough pathological investigation and clinical decision-making process, focusing TNM staging system limitations.RESULTS:A few case reports presented either normal appearing salivary tissue, benign tumors or low and high-grade salivary malignancies arising in lymph nodes. We present the investigation, controversies and treatment decision process of a 46-year-old man with CXPA in intra-parotid lymph node.CONCLUSIONS:The staging scheme does not distinguish between nodal spread and primary tumor arising in a lymph node. Multidisciplinary input regarding prognosis and follow-up plans, may consider heterotopia differently from the usual pattern of nodal spread.

Citation: Goldberger T, Levi SS, Armoni G, Ben-Shushan S, Maly A, Ramot Y. Granuloma annulare located on striae distensae. Dermatol Pract Concept. 2021;11(2):e2021018. DOI: https://doi.org/10.5826/dpc.1102a18

The current National Institutes of Health (NIH) consensus paper excluded "white hyperkeratotic plaque" from the diagnostic criteria for oral chronic graft-versus-host disease (cGVHD) in order to ensure malignant transformation is not overlooked. Therefore, an isolated oral white plaque is recommended to be subjected to biopsy and pathologic examination. The cases described in this paper shed a new light on the clinical approach to oral white plaque post-hematopoietic stem cell transplantation. The objectives of this article are to demonstrate that a white plaque does not contradict a diagnosis of oral cGVHD, and to highlight the clinical considerations for taking a biopsy.

Pityriasis rubra pilaris induced by PD-1 inhibitor nivolumab Dear Editor, A 28-year-old with relapsed Hodgkin lymphoma was treated with PD-1 inhibitor nivolumab for 2 years and 6 months. The treatment was halted because of pneumonitis and was resumed 6 months later. Four months after the renewal of immunotherapy, the patient developed a widespread rash, consisting of widespread reddish-orange colored scaling plaques, scattered follicular papules with islands of spared skin (Fig. 1). A punch biopsy from a scaling plaque demonstrated alternating orthokeratosis and parakeratosis, keratotic plugs, hypergranulosis, and mild acanthosis (Fig. 2). Differential diagnosis included other papulosquamous eruptions, such as psoriasis. However, the clinical and histological features were typical for pityriasis rubra pilaris (PRP)-like eruption, which was secondary to PD-1 inhibitor treatment. The rash was classified as grade 3 skin toxicity. Accordingly, nivolumab was stopped, and the patient was treated with topical and systemic corticosteroids and with methotrexate. The patient was intolerant to phototherapy and was not interested in acitretin because of planned future pregnancies. Over the following 3 months, the rash gradually faded. However, the lymphoma continued to progress until the patient passed away because of a severe infection.

Background Treatment regimens for patients with metastatic or recurrent post-radiation, locoregional, unresectable salivary cancer are limited. An inverse correlation between somatostatin receptor 2 (SSTR2) and the proliferating marker Ki-67 in neuroendocrine tumors has enabled a treatment plan for metastatic disease, utilizing peptide receptor radionuclide therapy. Interestingly, healthy salivary glands express high levels of SSTR2. In this study, the presence of SSTR2, its correlation with Ki-67 in glandular salivary carcinomas and the clinical applicability thereof was determined. Methods In the retrospective part of this study, 76 adequate tumor tissue specimens obtained from patients diagnosed with primary or metastatic salivary carcinomas between 1988 and 2016, were collected for tissue array and histologically classified. Immunohistochemistry was performed to determine the presence, relative expression and potential correlation of SSTR2 and Ki-67. The clinical significance of SSTR2 expression was determined by prospectively assessing 68 Ga-DOTATATE uptake using PET-CT imaging, in patients diagnosed with metastatic salivary gland malignant tumors between 2015 and 2016. Results Sixty-three primary cancer tumors and 14 metastatic tumors were tested. All tumor subtypes were found to express SSTR2 to some extent. The highest expression was seen in Mucoepidermoid carcinoma (MEC) tissues where the majority of specimens (86.4%) expressed SSTR2. A relatively strong immunohistochemical staining score for SSTR2 was observed in MEC, adenoid cystic carcinoma and polymorphous adenocarcinoma. Interestingly, an inverse correlation between SSTR2 and Ki-67 expressions was observed (44%) in MEC tissue. Uptake of 68 Ga-DOTATATE was visualized using PET-CT imaging in 40% of patients, across metastatic MEC and ACC. All observations were found to be statistically significant. Conclusion This study confirms the expression of SSTR2 in glandular salivary carcinomas and an inverse correlation in expression levels between SSTR2 and Ki-67. This lays a foundation for novel treatment options in salivary metastatic cancers where SSTR2 may be a potential novel therapeutic target.

International Journal of DermatologyVolume 60, Issue 5 p. e181-e183 Clinicopathologic challenge Multiple brown papules on the chest in a zosteriform distribution Stav Hartshtark MD, Stav Hartshtark MD Department of, Dermatology, The Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelSearch for more papers by this authorYuval Ramot MD, MSc, Corresponding Author Yuval Ramot MD, MSc yramot@gmail.com orcid.org/0000-0002-8606-8385 Department of, Dermatology, The Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel Correspondence Yuval Ramot, md, MSc Department of Dermatology The Faculty of Medicine Hadassah Medical Center Hebrew University of Jerusalem Jerusalem 9112001 Israel E-mail: yramot@gmail.comSearch for more papers by this authorAlexander Maly MD, Alexander Maly MD Department of, Pathology, The Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelSearch for more papers by this authorLaurent Klapholz MD, Laurent Klapholz MD Department of, Dermatology, The Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelSearch for more papers by this author Stav Hartshtark MD, Stav Hartshtark MD Department of, Dermatology, The Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelSearch for more papers by this authorYuval Ramot MD, MSc, Corresponding Author Yuval Ramot MD, MSc yramot@gmail.com orcid.org/0000-0002-8606-8385 Department of, Dermatology, The Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, Israel Correspondence Yuval Ramot, md, MSc Department of Dermatology The Faculty of Medicine Hadassah Medical Center Hebrew University of Jerusalem Jerusalem 9112001 Israel E-mail: yramot@gmail.comSearch for more papers by this authorAlexander Maly MD, Alexander Maly MD Department of, Pathology, The Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelSearch for more papers by this authorLaurent Klapholz MD, Laurent Klapholz MD Department of, Dermatology, The Faculty of Medicine, Hadassah Medical Center, Hebrew University of Jerusalem, Jerusalem, IsraelSearch for more papers by this author First published: 27 October 2020 https://doi.org/10.1111/ijd.15276 Conflict of interest: None. Funding source: None. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume60, Issue5May 2021Pages e181-e183 RelatedInformation

Acta Derm Venereol 2020; 100: adv00350 This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta doi: 10.2340/00015555-3716 Society for Publication of Acta Dermato-Venereologica A 12-year-old boy with no significant past medical history presented with multiple nasal papules over the nasal bridge since the age of 3 years. The parents and patient observed aggravation with sweat and heat. Neither pruritus nor hyperhidrosis were reported. His family history was unremarkable. Physical examination revealed 1–3-mm skin-coloured to bluish papulo-vesicles on the middle and lower nasal bridge (Fig. 1A). Dermoscopy showed, in addition to freckles, a homogeneous bluish pattern (Fig. 1B). A 2-mm punch biopsy from one of the lesions was performed and sent for histopathological evaluation (Fig. 2).

We present three children who presented with papules and plaques over the knuckles, mimicking Gottron's papules of juvenile dermatomyositis, as well as subcutaneous nodules over the joints of the extremities that were initially thought to represent calcinosis cutis. However, thorough clinical and laboratory evaluation, as well as imaging, failed to support this diagnosis. Skin biopsies were consistent with a diagnosis of subcutaneous granuloma annulare. This unique phenotype of granuloma annulare should be recognized in order to prevent erroneous diagnosis and treatment.

p16INK4a (CDKN2A) is a central tumor suppressor, which induces cell-cycle arrest and senescence. Cells expressing p16INK4a accumulate in aging tissues and appear in premalignant lesions, yet their physiologic effects are poorly understood. We found that prolonged expression of transgenic p16INK4a in the mouse epidermis induces hyperplasia and dysplasia, involving high proliferation rates of keratinocytes not expressing the transgene. Continuous p16INK4a expression increases the number of epidermal papillomas formed after carcinogen treatment. Wnt-pathway ligands and targets are activated upon prolonged p16INK4a expression, and Wnt inhibition suppresses p16INK4a-induced hyperplasia. Senolytic treatment reduces p16INK4a-expressing cell numbers, and inhibits Wnt activation and hyperplasia. In human actinic keratosis, a precursor of squamous cell carcinoma, p16INK4a-expressing cells are found adjacent to dividing cells, consistent with paracrine interaction. These findings reveal that chronic p16INK4a expression is sufficient to induce hyperplasia through Wnt-mediated paracrine stimulation, and suggest that this tumor suppressor can promote early premalignant epidermal lesion formation.

The current National Institutes of Health (NIH) consensus paper excluded “white hyperkeratotic plaque” from the diagnostic criteria for oral chronic graft-versus-host disease (cGVHD) in order to ensure malignant transformation is not overlooked. Therefore, an isolated oral white plaque is recommended to be subjected to biopsy and pathologic examination. The cases described in this paper shed a new light on the clinical approach to oral white plaque post hematopoietic stem cell transplantation. The objectives of this article are to demonstrate that a white plaque does not contradict a diagnosis of oral cGVHD, and to highlight the clinical considerations for taking a biopsy.