Does Genetics Play a Role in Acute Liver Injury After Amoxicillin Exposure?

Amoxicillin-clavulanate has long been associated with drug-induced liver injury (DILI) and although approximately 4 times less common, amoxicillin has also been implicated. Many studies have associated possible genetic factors with susceptibility to DILI, but there is currently no literature with evidence of instances of DILI within the same family. Two sisters presented with similar symptoms and signs of liver injury including jaundice, scleral icterus, abdominal pain, and anorexia with transaminitis and abnormal coagulation studies. Both sisters were started on amoxicillin approximately 2-3 weeks before presentation. They both had progression of the liver injury, and on biopsies, they had similar findings indicative of DILI as well.

Keratin 17 is a sensitive and specific biomarker of urothelial neoplasia.

There is a clinical need to identify novel biomarkers to improve diagnostic accuracy for the detection of urothelial tumors. The current study aimed to evaluate keratin 17 (K17), an oncoprotein that drives cell cycle progression in cancers of multiple anatomic sites, as a diagnostic biomarker of urothelial neoplasia in bladder biopsies and in urine cytology specimens. We evaluated K17 expression by immunohistochemistry in formalin-fixed, paraffin embedded tissue specimens of non-papillary invasive urothelial carcinoma (UC) (classical histological cases), high grade papillary UC (PUC-LG), low grade papillary UC (PUC-HG), papillary urothelial neoplasia of low malignant potential (PUNLMP), and normal bladder mucosa. A threshold was established to dichotomize K17 status in tissue specimens as positive vs. negative, based on the proportion of cells that showed strong staining. In addition, K17 immunocytochemistry was performed on urine cytology slides, scoring positive test results based on the detection of K17 in any urothelial cells. Mann-Whitney and receiver operating characteristic analyses were used to compare K17 expression between histologic diagnostic categories. The median proportion of K17 positive tumor cells was 70% (range 20-90%) in PUNLMP, 30% (range 5-100%) in PUC-LG, 20% (range 1-100%), in PUC-HG, 35% (range 5-100%) in UC but staining was rarely detected (range 0-10%) in normal urothelial mucosa. Defining cases in which K17 was detected in ≥10% of cells were considered positive, the sensitivity of K17 in biopsies was 89% (95% CI: 80-96%) and the specificity was 88% (95% CI: 70-95%) to distinguish malignant lesions (PUC-LG, PUC-HG, and UC) from normal urothelial mucosa. Furthermore, K17 immunocytochemistry had a sensitivity of 100% and a specificity of 96% for urothelial carcinoma in 112 selected urine specimens. Thus, K17 is a sensitive and specific biomarker of urothelial neoplasia in tissue specimens and should be further explored as a novel biomarker for the cytologic diagnosis of urine specimens.

Keratin 17 Is a Prognostic Biomarker in Endocervical Glandular Neoplasia.

OBJECTIVES: Previous work in our laboratory identified keratin 17 (K17) as a specific and sensitive biomarker for high-grade squamous intraepithelial lesions and cervical squamous cell carcinoma (SCC). K17, however, has not been previously evaluated in endocervical glandular neoplasia. Based on the similar pathogenesis of squamous and glandular lesions of the cervix, we hypothesized that K17 overexpression could also be a diagnostic and/or prognostic biomarker for endocervical neoplasia. METHODS: Cases of endocervical adenocarcinoma (n = 90), adenocarcinoma in situ (AIS) (n = 32), benign glandular lesions (n = 36), and normal endocervical mucosa (n = 5) were selected from Stony Brook Medicine and the University of Massachusetts from 2002 to 2013. Immunohistochemical staining for K17 was performed by an indirect immunoperoxidase method and was scored based on the proportion of cells that showed strong (2+) staining. RESULTS: K17 was highly expressed in 21 (65.6%) of 32 AIS and in 75 (83.0%) of 90 adenocarcinoma cases. In adenocarcinomas, K17 staining was detected in a mean of 33.9% of malignant cells. Staining tended to be strongest at the periphery of pseudoglandular groups and at the invasive front of tumors. K17 was not detected in the epithelial cells of benign glandular lesions, but groups of cuboidal cells, residing beneath the epithelial layer of benign glands, were frequently positive for K17, especially in cases of microglandular hyperplasia. High levels of K17 expression were significantly associated with decreased patient survival. CONCLUSIONS: K17 is highly expressed in most cases of both invasive adenocarcinoma and in AIS and is a powerful, negative prognostic marker for patient survival.

Immunocytochemical colocalization of P16(INK4a) and Ki-67 predicts CIN2/3 and AIS/adenocarcinoma.

BACKGROUND: Although previous studies have shown that p16(INK4a) and Ki-67 are sensitive and specific markers for high-grade lesions (≥CIN2) on cervical biopsies, limited information is available regarding the performance of a dual-staining approach as a diagnostic adjunct in cervical cytology. We evaluated a dual p16(INK4a)/Ki-67 immunocytochemistry (ICC) assay to determine its sensitivity and specificity versus that of high-risk HPV (HR-HPV) in a US-based pilot cytology study. METHODS: ThinPrep specimens from 122 cervical cytology specimens encompassing 23 negative (NILM), 20 ASC-US, 22 LSIL, 17 ASCH, 22 HSIL, and 18AGC cases were processed for multiplexed ICC staining using a CINtec Plus Kit. Dual-positive assay results were defined based on the detection of 1 or more epithelial cells that were stained for both p16INK4a and Ki-67 without regard to cellular morphology. HR-HPV testing was performed by multiplex PCR with capillary electrophoresis genotyping. RESULTS: Dual staining for p16(INK4a) and Ki-67 was frequently detected in HSIL and AGC but was rarely detected in NILM cases. The HR-HPV assay showed a sensitivity of 76.2% and a specificity of 55.8% for the detection of clinically significant cervical squamous or endometrial lesions. In contrast, the colocalization of p16(INK4a) plus Ki-67 maintained a high sensitivity of 81.8% and improved specificity to 81.8% for biopsy-confirmed CIN2/3, endocervical adenocarcinoma, or endometrial adenocarcinoma. CONCLUSIONS: Dual staining for p16(INK4a)/Ki-67 immunocytochemistry dramatically increased specificity and maintained high-level sensitivity for the diagnosis of CIN2/3 or glandular lesions compared with PCR-based testing for HR-HPV.