Staphylococcus aureus induces drug resistance in cancer T cells in Sézary syndrome.

ABSTRACT: Patients with Sézary syndrome (SS), a leukemic variant of cutaneous T-cell lymphoma (CTCL), are prone to Staphylococcus aureus infections and have a poor prognosis due to treatment resistance. Here, we report that S aureus and staphylococcal enterotoxins (SE) induce drug resistance in malignant T cells against therapeutics commonly used in CTCL. Supernatant from patient-derived, SE-producing S aureus and recombinant SE significantly inhibit cell death induced by histone deacetylase (HDAC) inhibitor romidepsin in primary malignant T cells from patients with SS. Bacterial killing by engineered, bacteriophage-derived, S aureus-specific endolysin (XZ.700) abrogates the effect of S aureus supernatant. Similarly, mutations in major histocompatibility complex (MHC) class II binding sites of SE type A (SEA) and anti-SEA antibody block induction of resistance. Importantly, SE also triggers resistance to other HDAC inhibitors (vorinostat and resminostat) and chemotherapeutic drugs (doxorubicin and etoposide). Multimodal single-cell sequencing indicates T-cell receptor (TCR), NF-κB, and JAK/STAT signaling pathways (previously associated with drug resistance) as putative mediators of SE-induced drug resistance. In support, inhibition of TCR-signaling and Protein kinase C (upstream of NF-κB) counteracts SE-induced rescue from drug-induced cell death. Inversely, SE cannot rescue from cell death induced by the proteasome/NF-κB inhibitor bortezomib. Inhibition of JAK/STAT only blocks rescue in patients whose malignant T-cell survival is dependent on SE-induced cytokines, suggesting 2 distinct ways SE can induce drug resistance. In conclusion, we show that S aureus enterotoxins induce drug resistance in primary malignant T cells. These findings suggest that S aureus enterotoxins cause clinical treatment resistance in patients with SS, and antibacterial measures may improve the outcome of cancer-directed therapy in patients harboring S aureus.

Primary cutaneous lymphoma: recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC.

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

Ethical considerations for artificial intelligence in dermatology: a scoping review.

The field of dermatology is experiencing the rapid deployment of artificial intelligence (AI), from mobile applications (apps) for skin cancer detection to large language models like ChatGPT that can answer generalist or specialist questions about skin diagnoses. With these new applications, ethical concerns have emerged. In this scoping review, we aimed to identify the applications of AI to the field of dermatology and to understand their ethical implications. We used a multifaceted search approach, searching PubMed, MEDLINE, Cochrane Library and Google Scholar for primary literature, following the PRISMA Extension for Scoping Reviews guidance. Our advanced query included terms related to dermatology, AI and ethical considerations. Our search yielded 202 papers. After initial screening, 68 studies were included. Thirty-two were related to clinical image analysis and raised ethical concerns for misdiagnosis, data security, privacy violations and replacement of dermatologist jobs. Seventeen discussed limited skin of colour representation in datasets leading to potential misdiagnosis in the general population. Nine articles about teledermatology raised ethical concerns, including the exacerbation of health disparities, lack of standardized regulations, informed consent for AI use and privacy challenges. Seven addressed inaccuracies in the responses of large language models. Seven examined attitudes toward and trust in AI, with most patients requesting supplemental assessment by a physician to ensure reliability and accountability. Benefits of AI integration into clinical practice include increased patient access, improved clinical decision-making, efficiency and many others. However, safeguards must be put in place to ensure the ethical application of AI.

The use of artificial intelligence (AI) in dermatology is rapidly increasing, with applications in dermatopathology, medical dermatology, cutaneous surgery, microscopy/spectroscopy and the identification of prognostic biomarkers (characteristics that provide information on likely patient health outcomes). However, with the rise of AI in dermatology, ethical concerns have emerged. We reviewed the existing literature to identify applications of AI in the field of dermatology and understand the ethical implications. Our search initially identified 202 papers, and after we went through them (screening), 68 were included in our review. We found that ethical concerns are related to the use of AI in the areas of clinical image analysis, teledermatology, natural language processing models, privacy, skin of colour representation, and patient and provider attitudes toward AI. We identified nine ethical principles to facilitate the safe use of AI in dermatology. These ethical principles include fairness, inclusivity, transparency, accountability, security, privacy, reliability, informed consent and conflict of interest. Although there are many benefits of integrating AI into clinical practice, our findings highlight how safeguards must be put in place to reduce rising ethical concerns.

Paediatric-onset lymphomatoid papulosis: results of a multicentre retrospective cohort study on behalf of the EORTC Cutaneous Lymphoma Tumours Group (CLTG).

BACKGROUND: Lymphomatoid papulosis (LyP) is a rare cutaneous T-cell lymphoproliferative disorder. Comprehensive data on LyP in the paediatric population are scarce. OBJECTIVES: To characterize the epidemiological, clinical, histopathological and prognostic features of paediatric LyP. METHODS: This was a retrospective multicentre international cohort study that included 87 children and adolescents with LyP diagnosed between 1998 and 2022. Patients aged ≤ 18 years at disease onset were included. LyP diagnosis was made in each centre, based on clinicopathological correlation. RESULTS: Eighty-seven patients from 12 centres were included. Mean age at disease onset was 7.0 years (range 3 months-18 years) with a male to female ratio of 2 : 1. Mean time between the onset of the first cutaneous lesions and diagnosis was 1.3 years (range 0-14). Initial misdiagnosis concerned 26% of patients. LyP was most often misdiagnosed as pityriasis lichenoides et varioliformis acuta, insect bites or mollusca contagiosa. Erythematous papules or papulonodules were the most frequent clinical presentation. Pruritus was specifically mentioned in 21% of patients. The main histological subtype was type A in 55% of cases. When analysed, monoclonal T-cell receptor rearrangement was found in 77% of skin biopsies. The overall survival rate was 100%, with follow-up at 5 years available for 33 patients and at 15 years for 8 patients. Associated haematological malignancy (HM) occurred in 10% of cases (n = 7/73), including four patients with mycosis fungoides, one with primary cutaneous anaplastic large cell lymphoma (ALCL), one with systemic ALCL and one with acute myeloid leukaemia. If we compared incidence rates of cancer with the world population aged 0-19 years from 2001 to 2010, we estimated a significantly higher risk of associated malignancy in general, occurring before the age of 19 years (incidence rate ratio 87.49, 95% confidence interval 86.01-88.99). CONCLUSIONS: We report epidemiological data from a large international cohort of children and adolescents with LyP. Overall, the disease prognosis is good, with excellent survival rates for all patients. Owing to an increased risk of associated HM, long-term follow-up should be recommended for patients with LyP.

Lymphomatoid papulosis is a very rare skin condition caused by an abnormal increase in white blood cells (called 'lymphocytes') in the skin. The condition rarely affects children, so most of the scientific data published about this disease focuses on adults. This study involved 12 academic dermatology centres in Europe, the Middle East and North America, and gathered data from about 87 children who presented with symptoms of lymphomatoid papulosis before the age of 19 years. The aim of this study was to better describe this disease in the paediatric population and discuss its treatment options and evolution. We found that the presentation of the disease in children is roughly the same as in adults. Safe and effective treatment options exist. The disease is not life threatening, but it requires investigation by a dermatologist, both to make a careful diagnosis and to monitor it as sometimes associated cancers that originate from blood cells can occur, mostly on the skin.

Febrile Ulceronecrotic Mucha-Habermann Disease Associated With Hemophagocytic Lymphohistiocytosis: A Case Report and Review of the Literature.

ABSTRACT: Mucha-Habermann disease (MHD) is an inflammatory skin disease characterized by polymorphous eruptions of erythematous, necrotic macules that have been reported for similarities to cutaneous T-cell lymphoma. Febrile ulceronecrotic MHD (FUMHD) represents a severe variant of MHD, marked by ulcers, hemorrhagic bullae, and systemic symptoms. Herein, we report a case of a severely atypical lymphomatoid expression of FUMHD associated with hemophagocytic lymphohistiocytosis (HLH). A previously healthy 21-year-old woman was admitted to the hospital with a rapidly progressive necrotic papular rash. Physical examination revealed right orbital swelling, bilateral hemorrhagic auricular bullae, and multiple ulcerative purpuric papulonodules on the trunk, face, and extremities. Biopsy indicated a dermal and subcutaneous infiltrate of atypical CD8 + lymphocytes with loss of CD5 and reduction in CD7 expression, along with features of lymphomatoid vasculitis. A diagnosis of a severely atypical lymphomatoid expression of FUMHD was made. The patient also met 7 of 9 HLH-2004 criteria, leading to a diagnosis of HLH. Positron emission tomography/computed tomography, flow cytometry, and rheumatologic workup were unremarkable. Treatment with an eight-week course of etoposide and dexamethasone for HLH led to rapid clinical improvement. Over time, her skin lesions regressed and eventually scabbed over to leave hyperpigmented scars, confirming the diagnosis of MHD. She has remained stable, off therapy for 4 years. Although potentially fatal, FUMHD often exhibits favorable outcomes and may resolve without recurrence, as in our patient. FUMHD should be considered in the differential diagnosis for patients presenting with cutaneous CD8 + necrotizing angiocentric lymphoproliferative disease complicated by HLH.

Extragenital lichen sclerosus et atrophicus-morphea overlap as an initial presentation of genital lichen sclerosus.

Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory disorder, most often characterized by atrophic skin plaques located on female genitalia. Infrequently, LSA may present extragenitally; however, much is unknown about the temporal relationship between genital and extragenital LSA. Morphea, also known as localized scleroderma, is a rare inflammatory skin condition characterized by sclerotic plaques. Investigators debate whether LSA and morphea exist on the same spectrum of disease, with LSA representing a superficial variant of morphea involving genitalia, or if they are distinct but coincidental entities. Although researchers have described LSA and morphea occurring in different locations on the same patient, few reports describe LSA and morphea occurring in the same lesion and in the inguinal folds. Herein, we report a case of a 62-year-old woman with extragenital LSA-morphea overlap in the inguinal folds, who three months later developed genital LSA. Extragenital LSA-morphea in the same plaque, with no signs of genital lesions on initial exam, with later development of genital LSA, is especially uncommon. The temporal progression of extragenital LSA-morphea overlap to genital LSA over a three-month period is an important contribution to the literature, as the temporal relationship between extragenital and genital LSA is not previously discussed.

Multimodal single-cell analysis of cutaneous T-cell lymphoma reveals distinct subclonal tissue-dependent signatures.

Cutaneous T-cell lymphoma (CTCL) is a heterogeneous group of mature T-cell neoplasms characterized by the accumulation of clonal malignant CD4+ T cells in the skin. The most common variant of CTCL, mycosis fungoides (MF ), is confined to the skin in early stages but can be accompanied by extracutaneous dissemination of malignant T cells to the blood and lymph nodes in advanced stages of disease. Sézary syndrome (SS), a leukemic form of disease, is characterized by significant blood involvement. Little is known about the transcriptional and genomic relationship between skin- and blood-residing malignant T cells in CTCL. To identify and interrogate malignant clones in matched skin and blood from patients with leukemic MF and SS, we combine T-cell receptor clonotyping with quantification of gene expression and cell surface markers at the single cell level. Our data reveal clonal evolution at a transcriptional and genetic level within the malignant populations of individual patients. We highlight highly consistent transcriptional signatures delineating skin- and blood-derived malignant T cells. Analysis of these 2 populations suggests that environmental cues, along with genetic aberrations, contribute to transcriptional profiles of malignant T cells. Our findings indicate that the skin microenvironment in CTCL promotes a transcriptional response supporting rapid malignant expansion, as opposed to the quiescent state observed in the blood, potentially influencing efficacy of therapies. These results provide insight into tissue-specific characteristics of cancerous cells and underscore the need to address the patients' individual malignant profiles at the time of therapy to eliminate all subclones.

Surgical management of dermatofibrosarcoma protuberans.

Dermatofibrosarcoma protuberans (DFSP) is an uncommon, locally aggressive cutaneous malignancy. Complete resection is the primary treatment but there is debate over the optimal method. Wide local excision was traditionally the standard of care; however, National Comprehensive Cancer Network guidelines now recommend Mohs micrographic surgery as the preferred approach. Medical therapy with imatinib can be used in advanced or unresectable disease. This review will discuss the current management of DFSP, focusing on optimal surgical approach.

Identifying unmet needs and challenges in the definition of a plaque in mycosis fungoides: An EORTC-CLTG/ISCL survey.

BACKGROUND: Consensus about the definition and classification of 'plaque' in mycosis fungoides is lacking. OBJECTIVES: To delineate a comprehensive view on how the 'plaque' entity is defined and managed in clinical practice; to evaluate whether the current positioning of plaques in the TNMB classification is adequate. METHODS: A 12-item survey was circulated within a selected panel of 22 experts (pathologists, dermatologists, haematologists and oncologists), members of the EORTC and International Society for Cutaneous Lymphoma. The questionnaire discussed clinical and histopathological definitions of plaques and its relationship with staging and treatment. RESULTS: Total consensus and very high agreement rates were reached in 33.3% of questions, as all panellists regularly check for the presence of plaques, agree to evaluate the presence of plaques as a potential separate T class, and concur on the important distinction between plaque and patch for the management of early-stage MF. High agreement was reached in 41.7% of questions, since more than 50% of the responders use Olsen's definition of plaque, recommend the distinction between thin/thick plaques, and agree on performing a biopsy on the most infiltrated/indurated lesion. High divergence rates (25%) were reported regarding the possibility of a clinically based distinction between thin and thick plaques and the role of histopathology to plaque definition. CONCLUSIONS: The definition of 'plaque' is commonly perceived as a clinical entity and its integration with histopathological features is generally reserved to specific cases. To date, no consensus is achieved as for the exact definition of thin and thick plaques and current positioning of plaques within the TNMB system is considered clinically inadequate. Prospective studies evaluating the role of histopathological parameters and other biomarkers, as well as promising diagnostic tools, such as US/RM imaging and high-throughput blood sequencing, are much needed to fully integrate current clinical definitions with more objective parameters.

Cutaneous type IV hypersensitivity reaction following tebentafusp treatment for uveal melanoma.

Tebentafusp is a bispecific protein that recently underwent FDA approval for the treatment of metastatic uveal melanoma that functions by redirecting cytotoxic T cells to glycoprotein-100, a protein highly expressed in melanoma. Although clinical trials have demonstrated that rashes are common in the first few days of treatment, little is known about skin reactions that develop later in the treatment course. Herein, we describe a type IV hypersensitivity reaction and vitiligo-like depigmentation that developed six weeks into treatment and discuss the possible mechanisms underlying these reactions. The type IV hypersensitivity reaction resolved without intervention within seven weeks of onset, suggesting that tebentafusp can be safely continued in select patients who develop this cutaneous reaction.

Genome-wide transcriptome analysis of the STAT6-regulated genes in advanced-stage cutaneous T-cell lymphoma.

The signal transducer and activator of transcription 6 (STAT6) is a critical up-stream mediator of interleukin-13 (IL-13) and IL-4 signaling and is constitutively activated in malignant lymphocytes from Sezary syndrome (SS) and mycosis fungoides (MF), the most common subtypes of cutaneous T-cell lymphomas. By combining genome-wide expression profiling with pharmacological STAT6 inhibition, we have identified the genes regulated by STAT6 in MF/SS tumors. We found that STAT6 regulates several common pathways in MF/SS malignant lymphocytes that are associated with control of cell-cycle progression and genomic stability as well as production of Th2 cytokines. Using ex vivo skin explants from cutaneous MF tumors as well as Sezary cells derived from the blood of SS patients, we demonstrated that inhibition of STAT6 activation downregulates cytokine production and induces cell-cycle arrest in MF/SS malignant lymphocytes, inhibiting their proliferation but not their survival. Furthermore, we show that STAT6 promotes the protumoral M2-like phenotype of tumor-associated macrophages in the tumor microenvironment of advanced stage MF by upregulating the expression of genes associated with immunosuppression, chemotaxis, and tumor matrix remodeling. Thus, we show STAT6 to be a major factor in the pathogenesis and progression of MF/SS, promoting proliferation and invasion of the malignant lymphocytes while inducing a progressive depression of the antitumor immune response. Together, our results provide new insights into disease pathogenesis and offer new prospective targets for therapeutic intervention.

Biomarkers in melanoma and non-melanoma skin cancer prevention and risk stratification.

The rates of melanoma and non-melanoma skin cancer (NMSC) have been increasing over the last twenty years in the United States, and this has been attributed to increased ultraviolet radiation exposure (UVR). Given these rising rates, preventative measures have become increasingly important to reduce the incidence and promote early detection of these cancers. Skin cancer prevention remains a challenging task to accomplish mainly due to the lack of reliable and sensitive methods to provide objective risk information that can educate and motivate individuals to avoid sunburn. Currently, minimal erythema dose (MED) is used as a marker of UVR. However, it is not an ideal marker because significant cancer-related molecular damage can occur after UVR exposure that cannot be detected by MED. Thus, over the recent years there has been significant interest in development of biomarkers indicative of exposure to UVR to improve early detection of cutaneous malignancies. Here, we will discuss emerging biomarkers for melanoma and NMSC that can help with risk stratification and targeted prevention and treatment.

Repetitive expanded T-cell receptor clonotypes impart the classic T helper 2 Sézary cell phenotype.

Six out of 12 Sézary patients shared one clonotype (TRAV13-1*01-TRAJ49*01-TRBV20-1*01-TRBJ2-3*01). TRBV20-1*01 (also known as Vb2) that binds toxic shock syndrome toxin-1 was utilized by Sézary cells among half of the cohort, which would be expected for a common unifying origin.

Antibiotics and Imiquimod for Cutaneous T-Cell Lymphoma in Veterans: A Patient Population with Agent Orange Exposure.

LESSONS LEARNED: Staphylococcus aureus infection in cutaneous T-cell lymphoma (CTCL) is thought to contribute to disease progression; thus, adjunctive treatment with antibiotics warrants further investigation. This trial of antibiotic therapy followed by imiquimod in early stage CTCL was not completed because of difficulties with patient accrual. BACKGROUND: Cutaneous T-cell lymphoma (CTCL), a form of non-Hodgkin lymphoma, is a heterogeneous group of malignancies of mature memory T lymphocytes. It has an annual age-adjusted incidence of 7.5 per million persons in the U.S. population [1]. The etiology of CTCL is unknown, but epidemiological studies have reported potential associations with environmental and occupational factors, including Agent Orange exposure in Vietnam Veterans [2]. Both topical and systemic therapies have been identified as effective in CTCL; the choice of treatment is dependent on disease stage, with the overall goal of improving symptoms given the chronic and recurrent nature of the disease. Several studies have suggested that CTCL is exacerbated by the presence of Staphylococcus aureus in the skin and can be ameliorated by treatment with antibiotics [3]. METHODS: Our study was designed to assess the effects of antibiotics and imiquimod on early stage CTCL. Patients between the ages of 30-89 years with stage I and II CTCL were eligible for enrollment. They could not be receiving concurrent therapy, and the study design included a 14-day washout period after discontinuation of CTCL therapy. The washout period was followed by doxycycline 100 mg p.o. b.i.d. for 14 days and then two packets (250 mg per packet) of imiquimod 5% cream topically to the most clinically active lesions 3 days a week (Monday, Wednesday, and Friday) for 28 days. Skin lesions were measured using the modified Severity Weighted Assessment Tool (mSWAT). RESULTS: Our study enrolled only two patients with early stage CTCL because of difficulty locating patients with active CTCL able to discontinue all therapy. The two enrolled patients completed all therapy. One patient had a complete response after imiquimod, whereas the other patient had stable disease. CONCLUSION: Antibiotics and imiquimod have reported activity as single agents in CTCL; we did not enroll enough patients to assess value in the sequence of antibiotic therapy followed by imiquimod.

UV biomarker genes for classification and risk stratification of cutaneous actinic keratoses and squamous cell carcinoma subtypes.

Currently, there is no sensitive molecular test for identifying transformation-prone actinic keratoses (AKs) and aggressive squamous cell carcinoma (SCC) subtypes. Biomarker-based molecular testing represents a promising tool for risk stratifying these lesions. We evaluated the utility of a panel of ultraviolet (UV) radiation-biomarker genes in distinguishing between benign and transformation-prone AKs and SCCs. The expression of the UV-biomarker genes in 31 SCC and normal skin (NS) pairs and 10 AK/NS pairs was quantified using the NanoString nCounter system. Biomarker testing models were built using logistic regression models with leave-one-out cross validation in the training set. The best model to classify AKs versus SCCs (area under curve (AUC) 0.814, precision score 0.833, recall 0.714) was constructed using a top-ranked set of 13 UV-biomarker genes. Another model based on a 15-gene panel was developed to differentiate histologically concerning from less concerning SCCs (AUC 1, precision score 1, recall 0.714). Finally, 12 of the UV-biomarker genes were differentially expressed between AKs and SCCs, while 10 genes were uniquely expressed in the more concerning SCCs. UV-biomarker gene subsets demonstrate dynamic utility as molecular tools to classify and risk stratify AK and SCC lesions, which will complement histopathologic diagnosis to guide treatment of high-risk patients.

Management of Mycosis Fungoides with Topical Chlormethine/Mechlorethamine Gel: A Columbia University Cutaneous Lymphoma Center Experience.

Mycosis fungoides is a type of cutaneous T-cell lymphoma, which accounts for the majority of cases of cutaneous T-cell lymphoma. Mycosis fungoides can be classified as early-stage (IA-IIA) or late-stage (IIB or greater) disease. In early-stage mycosis fungoides, skin-directed therapies are commonly used to manage the disease. Chlormethine, or mechlorethamine, is a topical chemotherapeutic, which has been in use for over 60 years. In 2013, the US Food and Drug Administration approved chlormethine/mechlorethamine gel (Valchlor®) for treatment of stage IA and IB mycosis fungoides. Chlormethine/mechlorethamine gel is an effective therapy; however, its use may be limited by the development of adverse cutaneous reactions. Off-label dosing modifications, as well as co-administration of topical steroids and an aggressive moisturization regimen, can be used to reduce these side-effects. We report here 4 cases of mycosis fungoides treated with chlormethine/mechlorethamine gel at the Comprehensive Skin Cancer Center at Columbia University Irving Medical Center, which provide insights into the use of this therapy in clinical practice.

CD8+ Lymphogranulomatous Dermatitis as a Manifestation of Malignancy-Associated Immunodeficiency: Rethinking Paraneoplastic Granulomas.

ABSTRACT: Paraneoplastic granulomatous disease occurs in approximately 7.3% of patients with non-Hodgkin lymphoma, most commonly among patients with chronic lymphocytic leukemia (CLL). These lesions are often reported to appear similar to sarcoidosis in clinical presentation and under light microscopy. However, comprehensive descriptions of the cytomorphologic characteristics of these paraneoplastic granulomas are lacking, and the mechanisms involved in their formation remain ill-defined. Noninfectious dermal granulomatous reactions have also been reported in many primary immunodeficiencies, including common variable immune deficiency and ataxia-telangiectasia. We present a case of noninfectious CD8+ predominant granulomatous dermatitis with ocular involvement occurring in the setting of CLL and marked hypogammaglobulinemia. Based on the analysis of shared factors in patients with primary immunodeficiencies and CLL, we conclude that the presence of pan-humoral immunodeficiency could itself be a risk factor for developing a CD8+ lymphogranulomatous reaction. This report and associated discussion evince that CD8+ predominant granulomatous reactions, distinct from sarcoidosis, may represent a previously unappreciated segment of the paraneoplastic granulomas observed in hematologic malignancies.

An Autopsy Review: "COVID Toes".

ABSTRACT: "Severe acute respiratory syndrome coronavirus-2" (SARS-CoV-2) infection has variable described dermatologic manifestations. "COVID (coronavirus disease) toes" became a hallmark of the disease in young and largely asymptomatic patients, who may have negative test results for SARS-CoV-2. Pernio (chilblains)-like lesions are seen mostly in infected pediatric patients and are purple painful, frequently bilateral, ill-defined plaques with prominent inflammation on histological examination. In contrast to pernio-like presentation in children, critically ill adult patients with SARS-CoV-2 develop "purple" digits that may be sharply demarcated and may demonstrate asymmetric areas of ischemia. These 2 contrasting entities are sometimes grouped together as "COVID toes" due to some similarities in clinical appearance and presentation. Here, we summarize histopathologic examination from an autopsy, including the cutaneous lesions from the affected and normal contralateral toes and correlate them with systemic findings. In contrast to pernio-like lesions, the skin of the affected necrotic toes contained thrombi in vessels without prominent inflammation, suggestive of an embolic event. This is further supported by the clinical history of and autopsy findings of popliteal artery thrombus and multiple subsegmental pulmonary emboli. Our findings suggest that critically ill patients with SARS-CoV-2 have different pathological processes affecting skin at peripheral sites (ie, fingers, toes, ears, and nose), which may be due to thromboembolic events. The skin is a mirror of the body and skin pathology may shed light into overall pathogenesis of systemic illness and processes.

A Case Report of Papillary Digital Adenocarcinoma With BRAFV600E Mutation and Quantified Mutational Burden.

ABSTRACT: Papillary digital adenocarcinoma (PDA) is a rare eccrine tumor that is most often found on the digits. Few case reports have described PDAs located on atypical sites. It is now accepted that PDAs cannot be distinguished from benign adenomas based on histological features, and it is recommended to excise all of these lesions. Even with excision, recurrence and metastasis rates are high. Only limited genomic analyses have been performed to date, and no driver mutations have been identified. We report a case of a 63-year-old woman with a PDA on the right forearm. Biopsy showed moderate cytologic atypia and mitotic figures. Next-generation DNA sequencing of the tumor showed a BRAFV600E mutation and high tumor mutational burden (5.51 mutations/Mb). This mutation is known for its response to small molecular inhibitors of BRAF and Mitogen-activated protein kinase kinase. Such therapy may be a consideration should our patient develop recurrent unresectable disease.

Oncolytic Viruses for the Treatment of Metastatic Melanoma.

OPINION STATEMENT: There is an unmet need for additional treatments for metastatic melanoma, besides anti-PD1 antibodies which are FDA approved for adjuvant therapy for stage III or resected stage IV melanoma. Talimogene laherparepvec (T-VEC) is the first and only FDA-approved oncolytic virus for the treatment of melanoma. New viral vectors including coxsackieviruses, HF-10, adenovirus, reovirus, echovirus, and newcastle disease virus are currently under active development and investigation with varying degrees of efficacy in targeting melanoma. The use of T-VEC as a neoadjuvant therapy is emerging, but more data is needed at this point. T-VEC has also shown promise for use in combination therapy with ipilimumab, as T-VEC plus ipilimumab has a significantly higher objective response compared to ipilimumab alone. Data comparing T-VEC in combination with PD-1 checkpoint inhibitors is awaited, and a phase III trial is underway. It is likely that oncolytic viruses will have long-term application in the treatment of melanoma and that T-VEC in particular will continue to have a role in the treatment of patients with readily accessible cutaneous lesions both for local control and synergistic induction of antitumor immunity as part of combination therapies.