Chart review study of real-world clinical outcomes in patients with cutaneous T-cell lymphoma treated with extracorporeal photopheresis in the US in 2017-2019.

BACKGROUND: Response rates of approved systemic therapies for cutaneous T-cell lymphoma (CTCL) hover near 30%, suggesting unmet need. This study describes real-world treatment patterns and response rates of extracorporeal photopheresis (ECP) in CTCL patients. METHODS: A chart review was conducted in the United States of adults with CTCL who initiated ECP between January 1, 2017, and February 28, 2019, and received at least three months of ECP treatment as monotherapy or concomitant therapy. Clinical outcomes were collected quarterly for up to 18 months. RESULTS: The 52 patients were predominantly Caucasian. Half were male; median age was 69 years. Most patients had Sézary syndrome (50%) or mycosis fungoides (36.5%). Nearly 40% of patients had stage IV disease; 33% had lymph node involvement. Nineteen patients (36.5%) achieved response (>50% reduction in BSA affected); median time to response was 6.5 months. The percentage of patients rated as at least minimally improved was 59.5% at 6 months (N = 22), 75.0% at 9 months (N = 24), and 60.0% at 12 months (N = 15) after ECP initiation. CONCLUSIONS: Despite the ECP treated population in this study being older and having more advanced-stage disease than recent trials, response rates were comparable. These real-world findings support ECP as an effective treatment option for CTCL patients.

Managing longitudinal melanonychia.

Longitudinal melanonychia (LM) is a pigmented band extending from the matrix to the distal edge of a nail. It is caused by increased production of melanin within the matrix, and integration into the nail plate. The origin of this production is usually benign, due to activation, hyperplasia or proliferation of melanocytes normally present in the matrix. In some cases, however, LM is the manifestation of a subungual melanoma, the diagnosis of which must be made early. Biographical, clinical and dermoscopic criteria make it possible to suspect melanoma and decide whether to perform biopsy. None of these criteria, however, are specific and definitive diagnosis requires pathologic examination of a matrix biopsy. The biopsy technique should enable reliable histological study while limiting the risk of secondary nail dystrophy. Initial resection should ideally involve the entire lesion. Complete elevation of the nail plate enables the lesion to be precisely located. Lesions up to 3 mm can be removed by longitudinal resection biopsies without significant sequelae. In more extensive lesions, incision or tangential ("shave") biopsy can be performed without impairing prognosis. In clinical presentations strongly suggestive of melanoma, immediate complete resection of the entire nail unit may be proposed.

When does a melanoma metastasize? Implications for management.

Selecting which patients with clinically-localized melanoma require treatment other than wide excision of the primary tumor is based on the risk or presence of metastatic disease. This in turn is linked to survival. Knowing if and when a melanoma is likely to metastasize is therefore of great importance. Several studies employing a range of different methodologies have suggested that many melanomas metastasize long before the primary lesion is diagnosed. Therefore, waiting for dissemination of metastatic disease to become evident before making systemic therapy available to these patients may be less effective than giving them post-operative adjuvant therapy initially if the metastatic risk is high. The identification of these high-risk patients will assist in selecting those to whom adjuvant systemic therapy can most appropriately be offered. Further studies are required to better identify high-risk patients whose primary melanoma is likely to have already metastasized.

The role of macrophage migration inhibitory factor family and CD74 in the pathogenesis of melanoma.

Melanoma is an aggressive tumour with poor prognosis that arises from the malignant transformation of melanocytes. Over the past few decades, intense research into the pathogenesis of melanoma has led to the development of BRAF and immune checkpoint inhibitors, including antibodies against programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which have shown clinically significant efficacy. However, some tumours do not respond to these therapies initially or become treatment resistant. Most melanoma tissues appear to possess biological characteristics that allow them to evade these treatments, and identifying these characteristics is one of the major challenges facing cancer researchers. One such characteristic that has recently gained attention is the role of macrophage migration inhibitory factor (MIF) and its receptor CD74. This review outlines the cellular and molecular functions of CD74, MIF and their family of proteins. We then review their roles in tumours based on previous reports, highlight their pathological significance in melanoma and discuss their potential as therapeutic targets.

C1s targeting antibodies inhibit the growth of cutaneous squamous carcinoma cells.

Cutaneous squamous cell carcinoma (cSCC) is the most common metastatic skin cancer. The incidence of cSCC is increasing globally and the prognosis of metastatic disease is poor. Currently there are no specific targeted therapies for advanced or metastatic cSCC. We have previously shown abundant expression of the complement classical pathway C1 complex components, serine proteases C1r and C1s in tumor cells in invasive cSCCs in vivo, whereas the expression of C1r and C1s was lower in cSCCs in situ, actinic keratoses and in normal skin. We have also shown that knockdown of C1s expression results in decreased viability and growth of cSCC cells by promoting apoptosis both in culture and in vivo. Here, we have studied the effect of specific IgG2a mouse monoclonal antibodies TNT003 and TNT005 targeting human C1s in five primary non-metastatic and three metastatic cSCC cell lines that show intracellular expression of C1s and secretion of C1s into the cell culture media. Treatment of cSCC cells with TNT003 and TNT005 significantly inhibited their growth and viability and promoted apoptosis of cSCC cells. These data indicate that TNT003 and TNT005 inhibit cSCC cell growth in culture and warrant further investigation of C1s targeted inhibition in additional in vitro and in vivo models of cSCC.

Co-occurrence of posterior chest wall pilonidal sinus with melanocytic nevus: a challenging presentation: a case report.

INTRODUCTION: To date, only a limited number of case reports have documented the co-occurrence of PNS and melanocytic nevus in the medical literature. This study aims to report an exceptionally rare case of posterior chest wall PNS in conjunction with a melanocytic nevus. CASE PRESENTATION: A 46-year-old female presented with a long-standing black lesion on her left upper posterior chest wall, that had become painful in the two months prior to presentation. There was a painful, dark blue, non-erythematous, and non-tender nodule on the left upper posterior chest wall. Based on the patient's desire for cosmetic purposes, the lesion was excised totally with primary closure under local anaesthesia. Histopathological examination revealed intradermal melanocytic nevus with inflamed pilonidal sinus. DISCUSSION: The rarity of posterior chest wall PNS associated with nevi poses unique diagnostic and therapeutic challenges for clinicians. The distinct anatomical location, different from the conventional region, and the rare association between the two conditions may delay accurate diagnosis and result in mismanagement or inappropriate interventions. CONCLUSION: The posterior chest wall PNS is another type of atypical PNS that is extremely rare. The association between PNS and blue nevus is a fascinating medical finding that deserves further investigation.

Case report: Pilomatrix carcinoma with PDL1 expression and CDKN2A aberrant.

Case report: A 55-year-old male patient developed a mass in the left inguinal area with left lower limb swelling and first visited a local hospital 3 months earlier because of unrelieved pain. An MRI scan suggested left suprapubic branch and left acetabular bone destruction, abnormal soft tissue signals within the iliopsoas muscle of the anterior edge of the left iliac bone, and enlarged lymph nodes in the left iliac fossa and left inguinal region. The patient subsequently underwent left pelvic lesion open biopsy and inguinal lymph node resection biopsy. According to pathological reports, the left inguinal mass was considered to be a malignant tumor of cutaneous accessory origin (pilomatrix carcinoma) with extensive vitreous changes. The suprapupubis branch mass was considered to be a bone metastatic pilomatrix carcinoma. Immunohistochemistry (IHC) revealed a PDL1 combined positive score (CPS) of 8. DNA next-generation sequencing (NGS) showed CDKN2A L65Rfs*53 mutation. The patient received three cycles of gemcitabine and nedaplatin. However, the lesion progressed. Conclusion: Chemotherapy is not effective for treating pilomatrix carcinoma. PDL1 antibodies and CDK4/6 inhibitors might be treatment options for pilomatrix carcinoma.

The small tumor antigen of Merkel cell polyomavirus accomplishes cellular transformation by uniquely localizing to the nucleus despite the absence of a known nuclear localization signal.

BACKGROUND: Merkel Cell Carcinoma (MCC) is an aggressive skin cancer that is three times deadlier than melanoma. In 2008, it was found that 80% of MCC cases are caused by the genomic integration of a novel polyomavirus, Merkel Cell Polyomavirus (MCPyV), and the expression of its small and truncated large tumor antigens (ST and LT-t, respectively). MCPyV belongs to a family of human polyomaviruses; however, it is the only one with a clear association to cancer. METHODS: To investigate the role and mechanisms of various polyomavirus tumor antigens in cellular transformation, Rat-2 and 293A cells were transduced with pLENTI MCPyV LT-t, MCPyV ST, TSPyV ST, HPyV7 ST, or empty pLENTI and assessed through multiple transformation assays, and subcellular fractionations. One-way ANOVA tests were used to assess statistical significance. RESULTS: Soft agar, proliferation, doubling time, glucose uptake, and serum dependence assays confirmed ST to be the dominant transforming protein of MCPyV. Furthermore, it was found that MCPyV ST is uniquely transforming, as the ST antigens of other non-oncogenic human polyomaviruses such as Trichodysplasia Spinulosa-Associated Polyomavirus (TSPyV) and Human Polyomavirus 7 (HPyV7) were not transforming when similarly assessed. Identification of structural dissimilarities between transforming and non-transforming tumor antigens revealed that the uniquely transforming domain(s) of MCPyV ST are likely located within the structurally dissimilar loops of the MCPyV ST unique region. Of all known MCPyV ST cellular interactors, 62% are exclusively or transiently nuclear, suggesting that MCPyV ST localizes to the nucleus despite the absence of a canonical nuclear localization signal. Indeed, subcellular fractionations confirmed that MCPyV ST could achieve nuclear localization through a currently unknown, regulated mechanism independent of its small size, as HPyV7 and TSPyV ST proteins were incapable of nuclear translocation. Although nuclear localization was found to be important for several transforming properties of MCPyV ST, some properties were also performed by a cytoplasmic sequestered MCPyV ST, suggesting that MCPyV ST may perform different transforming functions in individual subcellular compartments. CONCLUSIONS: Together, these data further elucidate the unique differences between MCPyV ST and other polyomavirus ST proteins necessary to understand MCPyV as the only known human oncogenic polyomavirus.

A Case of Gallbladder Metastasis of Malignant Melanoma.

In the clinical course of malignant melanoma, which can metastasize to multiple organs, gallbladder metastases are rarely detected. A 69-year-old man who underwent resection of a primary malignant melanoma was subsequently treated with nivolumab for lung metastases and achieved complete response. Seven years after surgery, multiple nodules were found in the gallbladder, and he underwent laparoscopic cholecystectomy. The postoperative diagnosis was metastases of malignant melanoma. He has been recurrence-free 8 months after surgery. If radical resection is possible, such surgery should be performed for gallbladder metastases found in patients with other controlled lesions of malignant melanoma.

RARRES1 identified by comprehensive bioinformatic analysis and experimental validation as a promising biomarker in Skin Cutaneous Melanoma.

Skin cutaneous melanoma (SKCM) is a highly malignant form of skin cancer, known for its unfavorable prognosis and elevated mortality rate. RARRES1, a gene responsive to retinoic acid receptors, displays varied functions in various cancer types. However, the specific role and underlying mechanisms of RARRES1 in SKCM are still unclear. GSE15605 was utilized to analyze the expression of RARRES1 in SKCM. Subsequently, the TCGA and GEO databases were employed to investigate the relationships between RARRES1 and clinicopathological parameters, as well as the prognostic implications and diagnostic efficacy of RARRES1 in SKCM. GO, KEGG, and GSEA analyses were conducted to explore the potential functions of RARRES1. Furthermore, the associations between RARRES1 and immune infiltration were examined. Genomic alterations and promoter methylation levels of RARRES1 in SKCM were assessed using cBioPortal, UALCAN, and the GEO database. Finally, RARRES1 expression in SKCM was validated through immunohistochemistry, and its functional role in SKCM progression was elucidated via in vivo and in vitro experiments. We found that RARRES1 was downregulated in SKCM compared with normal tissues, and this low expression was associated with worse clinicopathological features and poor prognosis of SKCM. The diagnostic efficacy of RARRES1, as determined by ROC analysis, was 0.732. Through GO, KEGG, and GSEA enrichment analysis, we identified 30 correlated genes and pathways that were mainly enriched in the tumor immune microenvironment, proliferation, apoptosis, and autophagy. Additionally, RARRES1 expression was found to be positively related to the infiltration of various immune cells in SKCM, particularly macrophages and T helper cells, among others. Analysis of genomic alterations and promoter methylation revealed that shallow deletion and hypermethylation of the RARRES1 promoter could lead to reduced RARRES1 expression. IHC validation confirmed the downregulation of RARRES1 in SKCM. Moreover, overexpression of RARRES1 inhibited the proliferation and migration of A375 cells, promoted apoptosis, and inhibited autophagic flux. In the mouse xenograft model, RARRES1 overexpression also suppressed SKCM tumor growth. Collectively, these findings suggest that RARRES1 may function as a suppressor and could potentially serve as a prognostic biomarker and therapeutic target for SKCM.

Prognostic and therapeutic roles of SETD2 in cutaneous melanoma.

BACKGROUND: Cutaneous melanoma (CM) is an aggressive form of skin cancer with limited treatment options for advanced stages. Prognostic markers that accurately predict patients' outcomes and guide therapeutic strategies are crucial for improving melanoma management. SETD2 (SET Domain-Containing Protein 2), a histone methyltransferase involved in chromatin remodeling and gene regulation, has recently emerged as a tumor suppressor. Its dysfunction is involved in oncogenesis in some cancers, but little is known about its functions in progression and therapeutic response of melanoma. METHODS: RNA-seq and clinical data from public database were used to evaluate the survival analysis, gene set enrichment, IC50 of therapeutics and immunotherapy response. SETD2 knock-out A375 cell line (A375SETD2ko) was developed by Crispr/cas9 and CCK-8 analysis and nude mice used to evaluate the proliferation and invasion of melanoma cells in vitro and in vivo, while Western blotting tested the MMR-related protein. RESULTS: SETD2 was commonly down-regulated in melanoma samples which demonstrated an unfavorable survival. Cells without SETD2 expression tend to have a more progressive and invasive behavior, with resistance to chemotherapy. However, they are more sensitive to tyrosine kinase inhibitors (TKIs). They also exhibit inflamed features with lower TIDE (Tumor Immune Dysfunction and Exclusion) score and higher tumor mutation burden (TMB), showing that these patients may benefit from immunotherapy. CONCLUSIONS: This study revealed that SETD2 dysfunction in melanoma implied a poor prognosis and chemotherapy resistance, but highly sensitive to TKIs and immunotherapy, highlighting the prognostic and therapeutic value of SETD2 in cutaneous melanoma.