ATM and IRAK1 orchestrate two distinct mechanisms of NF-κB activation in response to DNA damage.

DNA damage in cells induces the expression of inflammatory genes. However, the mechanism by which cells initiate an innate immune response in the presence of DNA lesions blocking transcription remains unknown. Here we find that genotoxic stresses lead to an acute activation of the transcription factor NF-κB through two distinct pathways, each triggered by different types of DNA lesions and coordinated by either ataxia-telangiectasia mutated (ATM) or IRAK1 kinases.

Metabolic Lipids in Melanoma Enable Rapid Determination of Actionable BRAF-V600E Mutation with Picosecond Infrared Laser Mass Spectrometry in 10 s.

Rapid molecular profiling of biological tissues with picosecond infrared laser mass spectrometry (PIRL-MS) has enabled the detection of clinically important histologic types and molecular subtypes of human cancers in as little as 10 s of data collection and analysis time. Utilizing an engineered cell line model of actionable BRAF-V600E mutation, we observed statistically significant differences in 10 s PIRL-MS molecular profiles between BRAF-V600E and BRAF-wt cells. Multivariate statistical analyses revealed a list of mass-to-charge (/) values most significantly responsible for the identification of BRAF-V600E mutation status in this engineered cell line that provided a highly controlled testbed for this observation.

Three Ds for diagnosing necrotizing fasciitis by front-line clinicians.

Introduction: Necrotizing fasciitis (NF) is a life-threatening infection and a surgical emergency. Not all clinicians have the experience or resources to detect NF in its early stages.

Objective: To develop a diagnostic algorithm for primary care and emergency physicians to identify patients with possible NF, including an initial approach to triaging such individuals.

Immunohistochemical Analysis of Lymphocyte Populations in Acute Skin Rejection: The University Health Network Addition to the Banff Classification.

Unlabelled: Acute rejection in vascularized composite allotransplantation has been identified using the Banff 2007 working classification. We propose an addition to this classification based on histological and immunological assessment within the skin and subcutaneous tissue.

Methods: Biopsies from vascularized composite transplant patients were obtained at scheduled visits and whenever skin changes occurred.

Picosecond Infrared Laser Mass Spectrometry Identifies a Metabolite Array for 10 s Diagnosis of Select Skin Cancer Types: A Proof-of-Concept Feasibility Study.

Currently, a large number of skin biopsies are taken for each true skin cancer case detected, creating a need for a rapid, high sensitivity, and specificity skin cancer detection tool to reduce the number of unnecessary biopsies taken from benign tissue. Picosecond infrared laser mass spectrometry (PIRL-MS) using a hand-held sampling probe is reported to detect and classify melanoma, squamous cell carcinoma, and normal skin with average sensitivity and specificity values of 86-95% and 91-98%, respectively (at a 95% confidence level) solely requiring 10 s or less of total data collection and analysis time. Classifications are not adversely affected by specimen's quantity of melanin pigments and are mediated by a number of metabolic lipids, further identified herein as potential biomarkers for skin cancer-type differentiation, 19 of which were sufficient here (as a fully characterized metabolite array) to provide high specificity and sensitivity classification of skin cancer types.

Diagnosis of the origin of an epibulbar melanocytic tumor with molecular genomics.

Background: Uveal melanoma (UM) and conjunctival melanoma (CM) are distinct entities with different etiologies and genetic background. We present a case of an atypical subconjunctival melanoma arising from a blue nevus.

Patients And Methods: A 61-year-old female presented with a partially melanocytic epibulbar mass with surrounding episcleral pigmented spots.

Early Pilomatrix Carcinoma: A Case Report With Emphasis on Molecular Pathology and Review of the Literature.

Pilomatrix carcinoma is a rare adnexal tumor with origin from the germinative matrical cells of the hair follicle. Clinically, it presents as a solitary lesion commonly found in the head and neck region and upper back. The tumors cannot be distinguished by their clinical appearance only and frequently are mistaken for cysts.

Development of a Metastatic Uveal Melanoma Prognostic Score (MUMPS) for Use in Patients Receiving Immune Checkpoint Inhibitors.

Metastatic uveal melanoma (mUM) is a rare disease. There are limited data on prognostic clinical factors for overall survival (OS) in patients with mUM treated with immune checkpoint inhibitors (ICI). Retrospective and non-randomized prospective studies have reported response rates of 0-17% for anti-PD1/L1 ± anti-CTLA4 ICI in mUM, indicating a potential benefit only in a subset of patients.

Genomic Landscape of Malignant Peripheral Nerve Sheath Tumor‒Like Melanoma.

Malignant peripheral nerve sheath tumor (MPNST)-like melanoma is a rare malignancy with overlapping characteristics of both neural sarcoma and melanoma. Although the genomics of cutaneous melanoma has been extensively studied, those of MPNST-like melanoma have not. To characterize the genomic landscape of MPNST-like melanoma, we performed a single-center, retrospective cohort study at a tertiary academic cancer center.

Biologic subtypes of melanoma predict survival benefit of combination anti-PD1+anti-CTLA4 immune checkpoint inhibitors versus anti-PD1 monotherapy.

Purpose: Anti-programmed cell death protein 1 (PD1)±anti-cytotoxic T-lymphocyte associated protein 4 (CTLA4) immune checkpoint inhibitors (ICIs) are standard therapeutic options for metastatic melanoma. We assessed whether biologic subtype according to primary tumor type or genomic subtype can function as predictive biomarkers for anti-PD1±anti-CTLA4 ICI in patients with advanced melanoma.

Methods: We performed a single-center retrospective cohort analysis of patients who received anti-PD1±anti-CTLA4 ICI for advanced melanoma between 2012 and 2019.

Pitfalls in the diagnosis of lentigo maligna and lentigo maligna melanoma, facts and an opinion.

Lentigo maligna/lentigo maligna melanoma (LM/LMM) affects chronically sun-damaged skin of the head and neck with a slow radial growth phase. It is characterised by predominantly lentiginous proliferation of small, but atypical melanocytes with occasional upward scatter in an atrophic epidermis. It is not uncommon for pathologists to receive partial or scouting biopsies to assess for LM.

Metastatic aneurysmal fibrous histiocytoma in a 20-year-old woman: A rare case report with review of the literature and discussion of its genomic features.

Aneurysmal fibrous histiocytoma is an uncommon variant of cutaneous fibrous histiocytomas with a local recurrence rate of 19%. We present a case of aneurysmal fibrous histiocytoma in a 20-year-old female with a regional lymph node metastasis and subsequent satellite nodule. The patient initially presented with a 1-month history of two palpable nodules in left lower anterior shoulder and left axilla.

Landscape mapping of shared antigenic epitopes and their cognate TCRs of tumor-infiltrating T lymphocytes in melanoma.

HLA-restricted T cell responses can induce antitumor effects in cancer patients. Previous human T cell research has largely focused on the few HLA alleles prevalent in a subset of ethnic groups. Here, using a panel of newly developed peptide-exchangeable peptide/HLA multimers and artificial antigen-presenting cells for 25 different class I alleles and greater than 800 peptides, we systematically and comprehensively mapped shared antigenic epitopes recognized by tumor-infiltrating T lymphocytes (TILs) from eight melanoma patients for all their class I alleles.

Targetoid form of polymorphic eruption of pregnancy: A case report.

Polymorphic eruption of pregnancy, formerly known as pruritic and urticarial papules and plaques of pregnancy, is an uncommon cutaneous eruption that can affect women during their third trimester of pregnancy. As its name implies, it has a variety of morphologies and it is important to consider other diagnoses, such as pemphigoid gestationis, which polymorphic eruption of pregnancy can mimic. Sometimes, as in this case, polymorphic eruption of pregnancy can have a targetoid morphology reminiscent of erythema multiforme.

Primary excision margins, sentinel lymph node biopsy, and completion lymph node dissection in cutaneous melanoma: a clinical practice guideline.

Background: For patients who are diagnosed with early-stage cutaneous melanoma, the principal therapy is wide surgical excision of the primary tumour and assessment of lymph nodes. The purpose of the present guideline was to update the 2010 Cancer Care Ontario guideline on wide local excision margins and sentinel lymph node biopsy (slnb), including treatment of the positive sentinel node, for melanomas of the trunk, extremities, and head and neck.

Methods: Using Ovid, the medline and embase electronic databases were systematically searched for systematic reviews and primary literature evaluating narrow compared with wide excision margins and the use of slnb for melanoma of the truck and extremities and of the head and neck.

Cutaneous Crohn's disease of the vulva after a total colectomy and without gastrointestinal manifestations: A case report.

Crohn's disease has many cutaneous manifestations. We report a case of a 54-year-old woman, who had non-contiguous vulvar Crohn's disease despite a total colectomy and the absence of gastrointestinal Crohn's disease on ileoscopy.

Bullous leukemia cutis: a rare clinical subtype.

Leukemia cutis represents infiltration of the skin by malignant leukocytes and typically presents as firm, red-brown papules and nodules. The bullous clinical subtype is considered a rare entity and can be a diagnostic challenge. This case describes a patient with bullous leukemia cutis mimicking vesiculobullous skin disease.

HPV-independent Vulvar Squamous Cell Carcinoma is Associated With Significantly Worse Prognosis Compared With HPV-associated Tumors.

Vulvar squamous cell carcinomas (VSCC) represent the most common carcinoma of the female external genitalia, with increasing incidence. Although high-risk human papillomavirus (HPV) infection has long been implicated in the majority of cervical and anal squamous cell carcinomas, there is uncertainty about its prevalence and prognostic impact in VSCC. In this study, we conducted a retrospective integrated morphologic and multimodal HPV analysis of a cohort of 114 VSCC cases treated at the Princess Margaret Cancer Centre/University Health Network, Toronto, Canada between 2000 and 2010.

A Case of Postpartum Anogenital Mammary-Like Gland Tumor with Focal Lactational Features: A Nomenclature Issue.

Mammary-like glands (MLG) are considered to be a normal constituent of the anogenital region and can give rise to tumors with variable morphology that may be difficult to classify. We present a case of an anogenital mammary-like gland tumor in a breastfeeding woman showing morphological variation with lactational change, an unusual finding. We discuss the differing terminology used to report these tumors and the variation in assignment of their origin to MLG or ectopic breast tissue.

Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2.

Adoptive cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown significant clinical benefit, but is limited by toxicities due to a requirement for post-infusion interleukin-2 (IL-2), for which high dose is standard. To assess a modified TIL protocol using lower dose IL-2, we performed a single institution phase II protocol in unresectable, metastatic melanoma. The primary endpoint was response rate.

Melanoma of the Vulva and Vagina: Surgical Management and Outcomes Based on a Clinicopathologic Reviewof 68 Cases.

Objective: This study sought to evaluate the clinicopathologic features, surgical management, and survival of patients over 12 years at two academic centres.

Methods: Patients diagnosed with vulvar or vaginal melanoma between 2002 and 2014 were identified through pathology databases. Clinical and pathologic data were extracted from the medical records.

Cutaneous epithelioid angiomatous nodule: a report of a series including a case with moderate cytologic atypia and immunosuppression.

Background: Cutaneous epithelioid angiomatous nodule (CEAN) is a very rare and relatively recently recognized vascular proliferation characterized usually by minimal cytological atypia and accompanying mitotic activity. As such, CEAN represents an important diagnostic pitfall, which could lead to significant misdiagnosis and unnecessary treatment.

Methods: The clinicopathologic findings of 5 cases of CEAN were reviewed including a unique case with typical findings but also moderate cytologic atypia and brisk mitotic activity in a patient on immunosuppression.

Regulatory T Cells in Ovarian Cancer Are Characterized by a Highly Activated Phenotype Distinct from that in Melanoma.

Regulatory T (Treg) cells expressing the transcription factor FOXP3 are essential for the maintenance of immunologic self-tolerance but play a detrimental role in most cancers due to their ability to suppress antitumor immunity. The phenotype of human circulating Treg cells has been extensively studied, but less is known about tumor-infiltrating Treg cells. We studied the phenotype and function of tumor-infiltrating Treg cells in ovarian cancer and melanoma to identify potential Treg cell-associated molecules that can be targeted by tumor immunotherapies.

Case Report of a 21-Year-Old Man With Epidermolysis Bullosa Acquisita.

Epidermolysis bullosa acquisita (EBA) is a rare acquired type of mechanobullous disease affecting the dermal-epidermal junction (DEJ) of trauma prone acral surfaces. It manifests as tense vesicles, bullae, and milia and typically heals as atrophic hypo- or hyperpigmented scars. Classic noninflammatory mechanobullous EBA typically presents at a mean age of 48 years.