Surgical excision versus clinical follow-up: Outcomes of benign intraductal papillomas diagnosed on core needle biopsy.

OBJECTIVE: To compare outcomes between benign intraductal papillomas diagnosed on core need biopsy that were excised (BIP-E) versus those that were followed-up (BIP-F) at our institution. METHODS: Patients were identified by an electronic data base search from January 2010 to October 2016. After exclusions, clinical, radiological and histologic variables were evaluated and biopsy and excision slides reviewed. RESULTS: 110 BIP from 104 females were analyzed. 84 BIP were excised and 26 BIP were followed up (mean 43.3 months, range 7-93 months).11 patients in BIP-E group had atypia on excision. There were no statistically significant differences between BIP-E with atypia and BIP-E without, except for clinical presentation with pain/discomfort (p â€‹= â€‹0.015) in the former. There were no true upgrades to malignancy in both groups on follow up. One patient from each group developed a new breast cancer distant from IP site after nearly 4 years of uneventful follow-up. CONCLUSION: Clinical follow up is an oncologically safe alternative for radiologically concordant BIP. Excision may be considered if a diagnosis of atypia would impact surveillence and chemoprevention recommendations.

Synchronous Basal Cell Carcinoma and Squamous Cell Carcinoma of Nasal Vestibule With Novel Unique Variants Identified by Whole-exome Sequencing.

BACKGROUND/AIM: It is estimated that nonmelanoma skin cancer (NMSC), including basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), affects more than 3 million Americans each year. Translation of next-generation sequencing (NGS) data into identification of new potential targets for therapeutic applications may be helpful. Whole-exome sequencing (WES) is a widely used NGS method that involves sequencing the protein-coding regions of the genome. CASE REPORT: We report a case of a 65-year-old female smoker who was found to have two 6 mm lesions in her left nasal vestibule. Biopsies demonstrated synchronous BCC and SCC. The patient underwent surgical excision of both cancers with safe margins followed by plastic reconstruction. WES was performed on both cancers and 16 alterations including BRCA2 (p.P389S), FAM5C (S420L), KMT2A (P855L), and SMO (L412F), as unique for BCC, and 4 alterations including TP53 (p.H179Q) and CDKN2A (p.P114L), as unique for SCC, were identified. CONCLUSION: We report the first documented case with unique genetic alterations in two distinct and synchronous skin BCC and SCC arising from the same nasal vestibule of a patient. This adds to the growing field of data regarding genetic variants in characterizing malignancies and potentially for targeted therapies.

Single-cell expression quantitative trait loci (eQTL) analysis of SLE-risk loci in lupus patient monocytes.

BACKGROUND: We performed expression quantitative trait locus (eQTL) analysis in single classical (CL) and non-classical (NCL) monocytes from patients with systemic lupus erythematosus (SLE) to quantify the impact of well-established genetic risk alleles on transcription at single-cell resolution. METHODS: Single-cell gene expression was quantified using qPCR in purified monocyte subpopulations (CD14++CD16- CL and CD14dimCD16+ NCL) from SLE patients. Novel analysis methods were used to control for the within-person correlations observed, and eQTLs were compared between cell types and risk alleles. RESULTS: The SLE-risk alleles demonstrated significantly more eQTLs in NCLs as compared to CLs (p = 0.0004). There were 18 eQTLs exclusive to NCL cells, 5 eQTLs exclusive to CL cells, and only one shared eQTL, supporting large differences in the impact of the risk alleles between these monocyte subsets. The SPP1 and TNFAIP3 loci were associated with the greatest number of transcripts. Patterns of shared influence in which different SNPs impacted the same transcript also differed between monocyte subsets, with greater evidence for synergy in NCL cells. IRF1 expression demonstrated an on/off pattern, in which expression was zero in all of the monocytes studied from some individuals, and this pattern was associated with a number of SLE risk alleles. We observed corroborating evidence of this IRF1 expression pattern in public data sets. CONCLUSIONS: We document multiple SLE-risk allele eQTLs in single monocytes which differ greatly between CL and NCL subsets. These data support the importance of the SPP1 and TNFAIP3 risk variants and the IRF1 transcript in SLE patient monocyte function.

Distinct Single Cell Gene Expression in Peripheral Blood Monocytes Correlates With Tumor Necrosis Factor Inhibitor Treatment Response Groups Defined by Type I Interferon in Rheumatoid Arthritis.

Previously, we demonstrated in test and validation cohorts that type I IFN (T1IFN) activity can predict non-response to tumor necrosis factor inhibitors (TNFi) in rheumatoid arthritis (RA). In this study, we examine the biology of non-classical and classical monocytes from RA patients defined by their pre-biologic treatment T1IFN activity. We compared single cell gene expression in purified classical (CL, n = 342) and non-classical (NC, n = 359) monocytes. In our previous work, RA patients who had either high IFNß/α activity (>1.3) or undetectable T1IFN were likely to have EULAR non-response to TNFi. In this study comparisons were made among patients grouped according to their pre-biologic treatment T1IFN activity as clinically relevant: "T1IFN undetectable (T1IFN ND) or IFNß/α >1.3" (n = 9) and "T1IFN detectable but IFNß/α ≤ 1.3" (n = 6). In addition, comparisons were made among patients grouped according to their T1IFN activity itself: "T1IFN ND," "T1IFN detected and IFNß/α ≤ 1.3," and "IFNß/α >1.3." Major differences in gene expression were apparent in principal component and unsupervised cluster analyses. CL monocytes from the T1IFN ND or IFNß/α >1.3 group were unlikely to express JAK1 and IFI27 (p < 0.0001 and p 0.0005, respectively). In NC monocytes from the same group, expression of IFNAR1, IRF1, TNFA, TLR4 (p ≤ 0.0001 for each) and others was enriched. Interestingly, JAK1 expression was absent in CL and NC monocytes from nine patients. This pattern most strongly associated with the IFNß/α>1.3 group. Differences in gene expression in monocytes among the groups suggest differential IFN pathway activation in RA patients who are either likely to respond or to have no response to TNFi. Additional transcripts enriched in NC cells of those in the T1IFN ND and IFNß/α >1.3 groups included MYD88, CD86, IRF1, and IL8. This work could suggest key pathways active in biologically defined groups of patients, and potential therapeutic strategies for those patients unlikely to respond to TNFi.

Desmoplasia and Detached Papillae in Early Esophageal Adenocarcinoma: A Histologic Study on Endoscopic Submucosal Dissection Specimens.

BACKGROUND: Desmoplasia and detached papillae were only rarely mentioned in intramucosal adenocarcinoma of esophagus or stomach. This study aimed to examine these two features in early esophageal adenocarcinoma. METHODS: All endoscopic submucosal dissections specimens performed for Barrett's esophagus neoplasm during the year 2013 to 2016 were reviewed. These 44 cases included in this study were eight Barrett's esophagus with high-grade dysplasia, 21 intramucosal adenocarcinoma, and 15 submucosally or beyond invasive adenocarcinoma. RESULTS: Desmoplasia occurred in 73% submucosally or beyond invasive adenocarcinoma, higher than intramucosal adenocarcinoma (24%) and high-grade dysplasia (0%) (P < 0.00001 for each). The frequency of detached papillae in intramucosal adenocarcinoma and submucosally or beyond invasive adenocarcinoma specimens was 71.4% and 73.3%, higher than high-grade dysplasia (0%, P < 0.0001 for both). Univariate analysis identified desmoplasia as risk factors for lymphovascular invasion in intramucosal adenocarcinoma specimens (odds ratio 12, P = 0.048), and desmoplasia and tumor thickness for lymphovascular invasion in intramucosal adenocarcinoma and submucosally or beyond invasive adenocarcinoma specimens combined (odds ratio 9.0, P = 0.005; odds ratio 2.7, P = 0.01, respectively). Age, gender, the largest dimension and the average thickness of endoscopic submucosal dissection specimens, tumor size, detached papillae, and poor differentiation were not associated with lymphovascular invasion (P ≥ 0.05 for all). Multivariate analysis confirmed that only desmoplasia was predictive of lymphovascular invasion (odds ratio 8.0, P = 0.02) in intramucosal adenocarcinoma and submucosally or beyond invasive adenocarcinoma specimens combined. CONCLUSIONS: In conclusion, desmoplasia occurs in about a quarter of esophageal intramucosal adenocarcinomas and three quarters of submucosally or beyond invasive adenocarcinomas, and is associated with lymphovascular invasion in early esophageal adenocarcinoma.

Single-cell gene expression patterns in lupus monocytes independently indicate disease activity, interferon and therapy.

OBJECTIVES: Important findings can be masked in gene expression studies of mixed cell populations. We examined single-cell gene expression in SLE patient monocytes in the context of clinical and immunological features. METHODS: Monocytes were purified from patients with SLE and controls, and individually isolated for single-cell gene expression measurement. A panel of monocyte-related transcripts were measured in individual classical (CL) and non-classical (NCL) monocytes. RESULTS: Analyses of both CL and NCL monocytes demonstrated that many genes had a lower expression rate in SLE monocytes than in controls. Unsupervised hierarchical clustering of the CL and NCL data sets demonstrated independent clusters of cells from the patients with SLE that were related to disease activity, type I interferon (IFN) and medication use. Thus, each of these factors exerted a different impact on monocyte gene expression that could be identified separately, and a number of genes correlated uniquely with disease activity. We found within-cell correlations between genes directly induced by type I IFN-induced and other non-IFN-induced genes, suggesting the downstream biological effects of type I IFN in individual human SLE monocytes which differed between CLs and NCLs. CONCLUSIONS: In summary, single-cell gene expression in monocytes was associated with a wide range of clinical and biological features in SLE, providing much greater detail and insight into the cellular biology underlying the disease than previous mixed-cell population studies.

Widely divergent transcriptional patterns between SLE patients of different ancestral backgrounds in sorted immune cell populations.

Systemic lupus erythematosus (SLE) is a complex autoimmune disease of uncertain etiology. Patients from different ancestral backgrounds demonstrate differences in clinical manifestations and autoantibody profiles. We examined genome-wide transcriptional patterns in major immune cell subsets across different ancestral backgrounds. Peripheral blood was collected from African-American (AA) and European-American (EA) SLE patients and controls. CD4 T-cells, CD8 T-cells, monocytes, and B cells were purified by flow sorting, and each cell subset from each subject was run on a genome-wide expression array. Cases were compared to controls of the same ancestral background. The overlap in differentially expressed gene (DEG) lists between different cell types from the same ancestral background was modest (<10%), and only 5-8% overlap in DEG lists was observed when comparing the same cell type between different ancestral backgrounds. IFN-stimulated gene (ISG) expression was not up-regulated synchronously in all cell types from a given patient, for example a given subject could have high ISG expression in T and B cells, but not in monocytes. AA subjects demonstrated more concordance in ISG expression between cell types from the same individual, and AA patients demonstrated significant down-regulation of metabolic gene expression which was not observed in EA patients. ISG expression was significantly decreased in B cells in patients taking immunosuppressants, while ISGs in other cell types did not differ with medication use. In conclusion, gene expression was strikingly different between immune cell subsets and between ancestral backgrounds in SLE patients. These findings emphasize the critical importance of studying multiple ancestral backgrounds and multiple cell types in gene expression studies. Ancestral backgrounds which are not studied will not benefit from personalized medicine strategies in SLE.

Pyogenic bacterial infections in humans with MyD88 deficiency.

MyD88 is a key downstream adapter for most Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 deficiency in mice leads to susceptibility to a broad range of pathogens in experimental settings of infection. We describe a distinct situation in a natural setting of human infection. Nine children with autosomal recessive MyD88 deficiency suffered from life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease. However, these patients were otherwise healthy, with normal resistance to other microbes. Their clinical status improved with age, but not due to any cellular leakiness in MyD88 deficiency. The MyD88-dependent TLRs and IL-1Rs are therefore essential for protective immunity to a small number of pyogenic bacteria, but redundant for host defense to most natural infections.