Inflammation markers on benign breast biopsy are associated with risk of invasive breast cancer in African American women.

PURPOSE: Markers of inflammation, including crown-like structures of the breast (CLS-B) and infiltrating lymphocytes (IL), have been identified in breast tissue and associated with increased risk of breast cancer (BrCa), however most of this work has been performed in primarily non-Hispanic white women. Here, we examined whether CLS-B and IL are associated with invasive BrCa in African American (AA) women. METHODS: We assessed breast biopsies from three 5-year age-matched groups: BrCa-free AA women (50 Volunteer) from the Komen Normal Tissue Bank (KTB) and AA women with a clinically-indicated biopsy diagnosed with benign breast disease (BBD) from our Detroit cohort who developed BrCa (55 BBD-cancer) or did not develop BrCa (47 BBD only, year of biopsy matched to BBD-cancer). Mean adipocyte diameter and total adipose area were estimated from digital images using the Adiposoft plugin from ImageJ. Associations between CLS-B, IL, and BrCa among KTB and Detroit biopsies were assessed using multivariable multinomial and conditional logistic regression models. RESULTS: Among all biopsies, Volunteer and BBD only biopsies did not harbor CLS-B or IL at significantly different rates after adjusting for logarithm of adipocyte area, adipocyte diameter, and BMI. Among clinically-indicated BBD biopsies, BBD-cancer biopsies were more likely to exhibit CLS-B (odds ratio (OR) = 3.36, 95% Confidence Interval (CI): 1.33-8.48) or IL (OR = 4.95, 95% CI 1.76-13.9) than BBD only biopsies after adjusting for total adipocyte area, adipocyte diameter, proliferative disease, and BMI. CONCLUSIONS: CLS-B and IL may serve as histological markers of BrCa risk in benign breast biopsies from AA women.

Disseminated cryptococcosis presenting with cutaneous involvement in an immunocompromised patient.

Cryptococcosis is a fungal infection that typically affects immunocompromised patients. It most commonly affects the lungs and may then disseminate to the central nervous system, bone, skin, and adrenal glands. Herein, we describe a 69-year-old man who presented with skin lesions as the initial manifestation of disseminated cryptococcosis. Initial workup led to an assumption that the patient was immunocompetent. Later in the clinical course, idiopathic depletion of CD4 T cells was discovered. This case highlights that disseminated cryptococcosis may present with cutaneous symptoms even when there is no evidence of pulmonary or central nervous system involvement and may be the first sign of an underlying cellular immune dysfunction.

To Debride or Not to Debride: A Review of Wound Management for Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are immune-mediated skin reactions with high mortality as a result of severely compromised skin barrier function. Currently, there is no consensus on the topical management of these conditions. Some advocate for surgical debridement of affected skin as a means of preventing infection and facilitating reepithelialization with synthetic and biological wound coverage. Others prefer a conservative approach that relies on leaving the blistered skin in situ. A consensus is lacking, primarily due to the rarity of the disease and the lack of high-quality evidence supporting one particular form of management. The goal of this review is to explore and compare the two treatment approaches for SJS and TEN, namely conservative management and surgical debridement.

Step-by-Step Guide to the Punch Removal Technique for Dermal Piercing: A Surgical Pearl.

While dermal piercings have become increasingly popular, there is limited dermatologic literature detailing a standard removal technique. Dermal piercings are often removed in the emergency department using non-serrated hemostats and a rocking motion until the anchor can be pulled through the skin. Removal by these means may lead to unnecessary damage to the skin, infections, and scarring. This article describes a straightforward technique for extracting dermal piercings that does not require the patient to know the size or type of dermal anchor. A detailed description, with corresponding images, is provided as a step-by-step guide on implementing a punch removal technique for dermal piercings. Dermatologists can implement this technique to remove piercings without knowing the underlying anchor type. This punch removal technique offers a solution for removing a variety of dermal piercings and subsequent scar tissue while minimizing scar formation and leaving patients with more cosmetically appealing skin.

Hyper IgE syndrome-related disease treated with dupilumab: A case report.

Phosphoglucomutase 3 (PGM3) catalyzes the glycosylation of immune system precursor proteins. Its impairment leads to severe infections and other developmental, musculoskeletal, and nervous system defects. We present a case of a 2-month-old female patient with recurrent infections and diffuse eczematous dermatitis recalcitrant to corticosteroids. A next-generation sequencing NGS gene panel for inherited immune dysfunction syndromes revealed multiple variants of unknown significance in key immune regulators, specifically heterozygous mutation c.337C⟩G (p.Pro113Ala) on exon 4 of PGM3 as a novel variant in the PGM3 associated diseases. Off-label use of dupilumab resulted in rapid improvement.

Next-generation sequencing in dermatology.

Over the past decade, Next-Generation Sequencing (NGS) has advanced our understanding, diagnosis, and management of several areas within dermatology. NGS has emerged as a powerful tool for diagnosing genetic diseases of the skin, improving upon traditional PCR-based techniques limited by significant genetic heterogeneity associated with these disorders. Epidermolysis bullosa and ichthyosis are two of the most extensively studied genetic diseases of the skin, with a well-characterized spectrum of genetic changes occurring in these conditions. NGS has also played a critical role in expanding the mutational landscape of cutaneous squamous cell carcinoma, enhancing our understanding of its molecular pathogenesis. Similarly, genetic testing has greatly benefited melanoma diagnosis and treatment, primarily due to the high prevalence of BRAF hot spot mutations and other well-characterized genetic alterations. Additionally, NGS provides a valuable tool for measuring tumor mutational burden, which can aid in management of melanoma. Lastly, NGS demonstrates promise in improving the sensitivity of diagnosing cutaneous T-cell lymphoma. This article provides a comprehensive summary of NGS applications in the diagnosis and management of genodermatoses, cutaneous squamous cell carcinoma, melanoma, and cutaneous T-cell lymphoma, highlighting the impact of NGS on the field of dermatology.

Integrative deep learning analysis improves colon adenocarcinoma patient stratification at risk for mortality.

BACKGROUND: Colorectal cancers are the fourth most diagnosed cancer and the second leading cancer in number of deaths. Many clinical variables, pathological features, and genomic signatures are associated with patient risk, but reliable patient stratification in the clinic remains a challenging task. Here we assess how image, clinical, and genomic features can be combined to predict risk. METHODS: We developed and evaluated integrative deep learning models combining formalin-fixed, paraffin-embedded (FFPE) whole slide images (WSIs), clinical variables, and mutation signatures to stratify colon adenocarcinoma (COAD) patients based on their risk of mortality. Our models were trained using a dataset of 108 patients from The Cancer Genome Atlas (TCGA), and were externally validated on newly generated dataset from Wayne State University (WSU) of 123 COAD patients and rectal adenocarcinoma (READ) patients in TCGA (N = 52). FINDINGS: We first observe that deep learning models trained on FFPE WSIs of TCGA-COAD separate high-risk (OS < 3 years, N = 38) and low-risk (OS > 5 years, N = 25) patients (AUC = 0.81 ± 0.08, 5 year survival p < 0.0001, 5 year relative risk = 1.83 ± 0.04) though such models are less effective at predicting overall survival (OS) for moderate-risk (3 years < OS < 5 years, N = 45) patients (5 year survival p-value = 0.5, 5 year relative risk = 1.05 ± 0.09). We find that our integrative models combining WSIs, clinical variables, and mutation signatures can improve patient stratification for moderate-risk patients (5 year survival p < 0.0001, 5 year relative risk = 1.87 ± 0.07). Our integrative model combining image and clinical variables is also effective on an independent pathology dataset (WSU-COAD, N = 123) generated by our team (5 year survival p < 0.0001, 5 year relative risk = 1.52 ± 0.08), and the TCGA-READ data (5 year survival p < 0.0001, 5 year relative risk = 1.18 ± 0.17). Our multicenter integrative image and clinical model trained on combined TCGA-COAD and WSU-COAD is effective in predicting risk on TCGA-READ (5 year survival p < 0.0001, 5 year relative risk = 1.82 ± 0.13) data. Pathologist review of image-based heatmaps suggests that nuclear size pleomorphism, intense cellularity, and abnormal structures are associated with high-risk, while low-risk regions have more regular and small cells. Quantitative analysis shows high cellularity, high ratios of tumor cells, large tumor nuclei, and low immune infiltration are indicators of high-risk tiles. INTERPRETATION: The improved stratification of colorectal cancer patients from our computational methods can be beneficial for treatment plans and enrollment of patients in clinical trials. FUNDING: This study was supported by the National Cancer Institutes (Grant No. R01CA230031 and P30CA034196). The funders had no roles in study design, data collection and analysis or preparation of the manuscript.

Accuracy and Reproducibility of Frozen Section Diagnosis in Ovarian Tumors.

CONTEXT.­: Intraoperative consultation-frozen section diagnosis (FSD)-determines tumor pathology and guides the optimal surgical management of ovarian neoplasms intraoperatively. OBJECTIVE.­: To evaluate the diagnostic accuracy of the FSD and analyze the discrepancy between the FSD and final diagnosis. DESIGN.­: This is a retrospective study of 618 ovarian neoplasm FSDs from 2009 to 2018 at a tertiary health care center. The discrepant cases were reviewed and reevaluated by gynecologic and general surgical pathologists. The outcomes of interest were performing unnecessary procedure, returning for a second surgery, and 30-day postoperative mortality. RESULTS.­: The sensitivity and the positive predictive value of the FSD were lower in borderline tumors than in benign and malignant epithelial ovarian tumors. Major and minor discrepancies were identified in 5.3% (33 of 618) and 12.3% of (76 of 618) cases, respectively. A root cause analysis of the major discrepant cases showed that sampling error accounted for 43% (14 of 33). The discrepancy distributions of gynecologic and general surgical pathologists were statistically similar in the overall cohort (P = .65). The overall κ for diagnostic agreement among gynecologic pathologists, general surgical pathologists, and final diagnosis was 0.18 (0.10-0.26, P < .001), implying only a slight overall agreement. Of the major discrepant cases, only 3 had a clinical implication. One overdiagnosed patient underwent an unecessary procedure, and 2 underdiagnosed patients were recommended to return for a second surgery. No patient had 30-day postoperative mortality. CONCLUSIONS.­: Frozen section diagnosis remains a definitive diagnostic tool in ovarian neoplasms and plays a crucial role in guiding intraoperative surgical management.

Calcium channel blockers for neuroleptic-induced tardive dyskinesia.

BACKGROUND: Schizophrenia and related disorders affect a sizable proportion of any population. Neuroleptic (antipsychotic) medications are the primary treatment for these disorders. Neuroleptic medications are associated with a variety of side effects including tardive dyskinesia. Dyskinesia is a disfiguring movement disorder of the orofacial region that can be tardive (having a slow or belated onset). Tardive dyskinesia is difficult to treat, despite experimentation with several treatments. Calcium channel blockers (diltiazem, nifedipine, nimodipine, verapamil) have been among these experimental treatments. OBJECTIVES: To determine the effects of calcium-channel blocker drugs (diltiazem, nifedipine, nimodipine, verapamil) for treatment of neuroleptic-induced tardive dyskinesia in people with schizophrenia, schizoaffective disorder or other chronic mental illnesses. SEARCH STRATEGY: We updated previous searches in May 2010 by searching the Cochrane Schizophrenia Group Register using the Cochrane Schizophrenia Group search strategy. SELECTION CRITERIA: Randomised clinical trials comparing calcium-channel blockers with placebo, no intervention or any other intervention for people with both tardive dyskinesia and schizophrenia or serious mental illness. DATA COLLECTION AND ANALYSIS: We planned to extract and analyse data on an intention-to-treat (ITT) basis. We intended to calculate the relative risk (RR) and 95% confidence intervals (CI) of homogeneous dichotomous data using a random-effects model, and, where possible, calculate the number needed to treat. We planned to calculate mean differences (MD) for continuous data. MAIN RESULTS: We did not include any trials in this review. We excluded 15 studies; eight were not randomised, one did not use calcium channel blockers, five small, randomised, studies reported no usable data and one did not include people with both tardive dyskinesia and schizophrenia. AUTHORS' CONCLUSIONS: The effects of calcium-channel blockers for antipsychotic induced tardive dyskinesia are unknown. Their use is experimental and should only be given in the context of well designed randomised clinical trials.

Revisiting the pathobiology of scurvy: a review of the literature in the context of a challenging case.

Scurvy is a nutritional disorder resulting from vitamin C deficiency. Although rare in developing countries, scurvy continues to develop in settings of limited dietary intake such as post-gastrointestinal surgery and restrictive dietary habits. The disease primarily affects the skin and soft tissue. As the state of deficiency persists, hematological and immunological sequelae may develop. The classic signs of scurvy are not always present and can be altered by the presence of other comorbidities. In this article, we present a challenging case of scurvy in an older male from an urban tertiary healthcare setting. We review the atypical and uncommon clinical and pathological findings of scurvy including those seen in the skin, blood, and bone marrow. We also review contemporary research findings that provide a better understanding of the pathogenicity and clinical manifestations of vitamin C deficiency.

Improvement of steatotic rat liver function with a defatting cocktail during ex situ normothermic machine perfusion is not directly related to liver fat content.

There is a significant organ shortage in the field of liver transplantation, partly due to a high discard rate of steatotic livers from donors. These organs are known to function poorly if transplanted but make up a significant portion of the available pool of donated livers. This study demonstrates the ability to improve the function of steatotic rat livers using a combination of ex situ machine perfusion and a "defatting" drug cocktail. After 6 hours of perfusion, defatted livers demonstrated lower perfusate lactate levels and improved bile quality as demonstrated by higher bile bicarbonate and lower bile lactate. Furthermore, defatting was associated with decreased gene expression of pro-inflammatory cytokines and increased expression of enzymes involved in mitochondrial fatty acid oxidation. Rehabilitation of marginal or discarded steatotic livers using machine perfusion and tailored drug therapy can significantly increase the supply of donor livers for transplantation.