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Concept: Skin biopsy

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BACKGROUND: Sarcoidosis is a systemic disease characterized by the formation of noncaseating granulomas in various tissues. Cutaneous involvement occurs in 20 to 35 percent of the patients and may be the initial manifestation of the disease. Our study was performed to discriminate the clinical, laboratory, and prognostic differences between patients with specific and nonspecific cutaneous involvement. The second aim was to asses the diagnostic usefulness of punch biopsy in sarcoidosis. METHODS: The clinical, laboratory, pathological features, and skin biopsy results of 120 patients with cutaneous sarcoidosis were evaluated. The patients fulfilled clinical, radiologic or both features of sarcoidosis supported by the histopathologic evidence of noncaseating granulomas.Skin involvement was the initial finding in 30% of the patients. Erythema nodosum and lupus pernio were the most common skin lesions. Almost all of the patients with LP were either stage 0 or 1. Respiratory symptoms occurred in 72.2% of the patients with specific skin involvement. BronchoalveolarLavage (BAL) lymphocytosis, high ratio of CD4/CD8 and elevated serum Angiotensin Converting Enzyme (ACE) were more frequent in patients with specific cutaneous lesions. The frequency of progressive disease was significantly higher in this group. Punch skin biopsy was diagnostic in 81.6% of the patients with a complication rate of 4%. CONCLUSIONS: Specific cutaneous lesions along with BAL lymphocytosis, high CD4/CD8 ratio and elevated serum ACE levels may be predictors of progressive disease in sarcoidosis. Punch biopsy is a simple technique with a high diagnostic yield and a low complication rate for cutaneous sarcoidosis.

Concepts: Granuloma, Skin biopsy, Pathology, Biopsy, Medical terms, Lupus pernio, Erythema nodosum, Sarcoidosis

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BACKGROUND: Skin involvement is of major prognostic value in systemic sclerosis (SSc) and often the primary outcome in clinical trials. Nevertheless, an objective, validated biomarker of skin fibrosis is lacking. Optical coherence tomography (OCT) is an imaging technology providing high-contrast images with 4 μm resolution, comparable with microscopy (‘virtual biopsy’). The present study evaluated OCT to detect and quantify skin fibrosis in SSc. METHODS: We performed 458 OCT scans of hands and forearms on 21 SSc patients and 22 healthy controls. We compared the findings with histology from three skin biopsies and by correlation with clinical assessment of the skin. We calculated the optical density (OD) of the OCT images employing Matlab software and performed statistical analysis of the results, including intraobserver/interobserver reliability, employing SPSS software. RESULTS: Comparison of OCT images with skin histology indicated a progressive loss of visualisation of the dermal-epidermal junction associated with dermal fibrosis. Furthermore, SSc affected skin showed a consistent decrease of OD in the papillary dermis, progressively worse in patients with worse modified Rodnan skin score (p<0.0001). Additionally, clinically unaffected skin was also distinguishable from healthy skin for its specific pattern of OD decrease in the reticular dermis (p<0.001). The technique showed an excellent intraobserver and interobserver reliability (intraclass correlation coefficient >0.8). CONCLUSIONS: OCT of the skin could offer a feasible and reliable quantitative outcome measure in SSc. Studies determining OCT sensitivity to change over time and its role in defining skin vasculopathy may pave the way to defining OCT as a valuable imaging biomarker in SSc.

Concepts: Covariance and correlation, Optics, Skin biopsy, Skin, Biopsy, Scleroderma, Optical coherence tomography, Dermis

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A 57-year-old man presented with crusted lesions on his nose that had developed over a period of 2 months. He had occasional bloody discharge, without pain. Multiple skin biopsies eventually confirmed cutaneous T-cell lymphoma.

Concepts: T-cell lymphoma, Non-Hodgkin lymphoma, Mammal, Skin biopsy, Skin, Types of cancer, Biopsy, Lymphoma

3

Valid and reliable biomarkers can play an important role in clinical trials as indicators of biological or pathogenic processes or as a signal of treatment response. Currently, there are no biomarkers for pain qualified by the US Food and Drug Administration or the European Medicines Agency for use in clinical trials. This article summarizes an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) meeting in which 3 potential biomarkers were discussed for use in the development of analgesic treatments: (1) sensory testing, (2), skin punch biopsy, and (3) brain imaging. The empirical evidence supporting the use of these tests is described within the context of the 4 categories of biomarkers: (1) diagnostic, (2) prognostic, (3) predictive, and (4) pharmacodynamic. Although sensory testing, skin punch biopsy, and brain imaging are promising tools for pain in clinical trials, additional evidence is needed to further support and standardize these tests for use as biomarkers in pain clinical trials.

Concepts: The Canon of Medicine, Pharmaceutical industry, Pharmacology, Medicine, Pain, Skin biopsy, Food and Drug Administration, Biopsy

3

Lyme disease is the most important vector-borne disease in the Northern hemisphere and represents a major public health challenge with insufficient means of and reliable diagnosis. Skin is rarely investigated in proteomics but constitutes in the case of Lyme disease the key interface where the pathogens can enter, persist and multiply. Therefore, we investigated proteomics on skin samples to detect Borrelia proteins directly in cutaneous biopsies in a robust and specific way. We first set up a discovery Ge-LC-MS/MS approach on a murine model infected by B. burgdorferi sensu stricto that allowed the identification of 25 Borrelia proteins among more than 1300 mouse proteins. Then we developed a targeted Ge-LC-SRM assay to detect 9/33 Borrelia proteins/peptides in mice skin tissue samples using heavy labeled synthetic peptides. We successfully transferred this assay from the mouse model to human skin biopsies - naturally infected by Borrelia - and we were able to detect two Borrelia proteins: OspC and flagellin. Considering the extreme variability of OspC, we developed an extended SRM assay to target a large set of variants. This assay afforded the detection of nine peptides belonging to either OspC or flagellin in human skin biopsies. We further shortened the sample preparation and showed that Borrelia is detectable in mouse and human skin biopsies by directly using a liquid digestion followed by LC-SRM analysis without any prefractionation. This study thus shows that a targeted SRM approach is a promising tool for the early direct diagnosis of Lyme disease with high sensitivity (<10 fmol OspC per mg of human skin biopsy).

Concepts: Protein, Mouse, Skin biopsy, Borrelia, Skin, Lyme disease, Biopsy, Borrelia burgdorferi

1

Inherited epidermolysis bullosa (EB) comprises a highly heterogeneous group of rare diseases characterized by exacerbated skin and/or mucosal fragility and blister formation after minor mechanical trauma. Level of cleavage in the skin, clinical features with immunofluorescence antigen mapping and/or electron microscopy examination of a skin biopsy and/or gene involved, type(s) of mutation present and sometimes specific mutation(s), allow to define the EB type and subtype. This family of genodermatoses exposes patients to several complications, cutaneous squamous cell carcinoma (cSCC) being the most severe of them.

Concepts: DNA, Squamous epithelium, Skin biopsy, Skin, Protein, Epidermolysis bullosa, Cancer, Squamous cell carcinoma

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Purpose: CUDC-101 is a small molecule that simultaneously inhibits the epidermal growth factor receptor (EGFR), human growth factor receptor 2 (HER2), and histone deacetylase (HDAC) with preclinical activity in head and neck squamous cell cancer (HNSCC). The primary objective of this investigation is to determine the maximum tolerated dose (MTD) of CUDC-101 with cisplatin-radiation in the treatment of HNSCC. Experimental Design: CUDC-101 monotherapy was administered intravenously thrice weekly (M/W/F) for a 1-week run-in, then continued with concurrent cisplatin (100 mg/m2 every 3 weeks) and external beam radiation (70 Gy to gross disease) over 7 weeks. Results: Twelve patients with intermediate or high risk HNSCC enrolled. Eleven were p16INKa (p16) negative. The MTD of CUDC-101 based combination therapy was established at 275 mg/m2/dose. Five patients discontinued CUDC-101 due to an adverse event (AE); only one was considered a dose limiting toxicity (DLT), at the MTD. Pharmacokinetic evaluation suggested low accumulation with this dosing regimen. HDAC inhibition was demonstrated by pharmacodynamic analyses in peripheral blood mononuclear cells (PBMCs), tumor biopsies, and paired skin biopsies. Paired tumor biopsies demonstrated a trend of EGFR inhibition. At 1.5 years of median follow-up, there has been one recurrence and two patient deaths (neither attributed to CUDC-101). The remaining 9 patients are free of progression. Conclusions: CUDC-101, cisplatin and radiation was feasible in intermediate/high risk patients with HNSCC, with no unexpected patterns of AE. Although the MTD was identified, a high rate of DLT-independent discontinuation of CUDC-101 suggests a need for alternate schedules or routes of administration.

Concepts: Skin biopsy, Enzyme inhibitor, Epidermal growth factor, Growth factor, Histone deacetylase, Epidermal growth factor receptor, Cancer, Squamous cell carcinoma

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Mucosal biopsies from the head and neck are often small and poorly oriented, which impedes diagnostic interpretation, especially in patients with a history of cancer, being monitored for recurrence. A cocktail of antibodies targeted against DNA topoisomerase IIA and mini-chromosome maintenance protein 2 (MCM2/TOP2A, ProExC), markers of aberrant S-phase induction, have been used with success as a diagnostic adjunct in the evaluation of squamous dysplasia of the uterine cervix. We tested the utility in head and neck biopsies to see if ProExC could be used to discriminate reactive/inflammatory from true pre-neoplasia. Sixty-four archival biopsies were selected from patients who presented to the surgeon with an indication for biopsy to “rule out” dysplasia. Histologically, all biopsies showed nonspecific atypia that was difficult to discriminate from dysplasia. Twenty-three of the patients progressed to squamous carcinoma and the rest remained benign over five years follow-up. Cases stained with ProExC by IHC methods showed a significant pattern of expression (p=0.026). The staining was greatest in patients without a history of prior head and neck cancer but was not significant. Our results show that ProExC, used in conjunction with the H&E slide, can enhance the predictive power of a mucosal biopsy in a cohort of patients.

Concepts: Skin biopsy, Uterus, Cervix, Head and neck cancer, DNA, Squamous cell carcinoma, Vagina, Cancer

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The objectives of the study were to characterize the clinical picture of paradoxical skin lesions in SAPHO patients treated with anti-TNF-α agents and to explore its pathogenesis. Patients treated with anti-TNF-α therapy were identified from a cohort of 164 SAPHO patients. The clinical data and skin biopsies were collected. The usage, efficacy, and side effects of anti-TNF-α therapy were recorded. Forty-one (25.0%) patients received anti-TNF-α therapy, of which seven (17.1%) developed paradoxical skin lesions after 1 to 14 infusions. Patients with such lesions were older at onset of skin lesions than those without (p = 0.034). Expression of TNF-α in palmoplantar pustulosis increased after anti-TNF-α therapy in the two examined patients with exacerbated skin lesions. Anti-TNF-α therapy induces paradoxical skin lesions in 17.1% SAPHO patients. Late onset of skin manifestations is associated with an increased risk of such lesions. The paradoxical elevation of TNF-α expression in lesions may contribute to this phenomenon.

Concepts: Pathology, Induced demand, Skin biopsy, SAPHO syndrome, Biopsy, Immune system, Effectiveness

0

Most patients with mycosis fungoides (MF) remain in early disease stages but some progress to tumor stage. The individual course of the disease cannot be predicted. We wanted to assess the clinical and histological characteristics of the first available biopsy. An end-of-spectrum approach with two groups was used, comparing MF remaining long-term stable in T1a (‘MF stable’) and MF with later tumor development or present T3 stage (‘MF tumor’). The clinical and histomorphological features of the initial skin biopsy were compared. Patients in the ‘MF tumor’ group presented initially with higher disease stages. The first biopsies of ‘MF tumor’ patients showed significantly higher infiltrate density and depth, more large cells and a higher proliferative index. In summary, long-term stable MF seems to differ in clinical and histopathological parameters from MF with T3 evolution/presence already at the time point of the initial biopsy. Our findings might indicate a predetermined biologic behavior.

Concepts: Pathology, Skin biopsy, Cancer staging, Biopsy, Time, Anatomical pathology, Mycosis fungoides, Cancer