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Context.--Accurate HER2 testing in breast cancer is crucial for appropriate precision therapy. HER2 testing is most commonly accomplished by a combination of immunohistochemistry and in situ hybridization techniques, as gene amplification is closely tied to protein overexpression. During the last 5þyears, brightfield dual in situ hybridization (DISH) has replaced fluorescence methods (fluorescence in situ hybridization [FISH]) in some laboratories. Objective.--To analyze routine HER2 DISH performance in the field. Design.--We reviewed our experience with HER2 DISH performed at outside laboratories and referred for patient care. Results.--Of 273 identified retrospective DISH results, 55 had repeated FISH testing at our institution; 7 (13%) were discordant. Additional cases had technical flaws hampering appropriate scoring. In 23 cases (42%), HER2 DISH was performed without immunohistochemistry. Slide review of a prospective cohort of 42 consecutive DISH cases revealed 14 (33%) with technical or interpretative limitations potentially jeopardizing results. Commonly identified problems include lack of or weak signals in most tumor cells, and silver precipitate or red signals outside of nuclei, resulting in false-negative or falsepositive interpretations, respectively. Further, 44% (24 of 55) of DISH reports lacked complete data, specifically average HER2 signals/cell. Conclusions.--While HER2 DISH can be an efficient and effective alternative to FISH, we illustrate pitfalls and reinforce that careful attention to slide quality and technical parameters are critically important. HER2 DISH cotesting with immunohistochemistry could help minimize false-negative or false-positive HER2 results. [ABSTRACT FROM AUTHOR]

Targeted cancer treatments offer the prospect of precise inhibition of tumor growth without the untoward off-target toxicity of traditional chemotherapies. Still, unintended, often idiosyncratic side effects, such as drug-induced liver injury, can occur. We discuss the case of a 26-year-old female with a history of ROS1-rearranged lung adenocarcinoma, undergoing treatment with the tyrosine kinase inhibitor crizotinib, who presented to our hospital with abdominal pain and scleral icterus. Liver chemistries were notable for hyperbilirubinemia (5 mg/dL total) and marked transaminasemia (AST 1736 U/L, ALT >3500 U/L); liver biopsy demonstrated acute hepatitis with extensive necrosis. There was no evidence of an infectious or autoimmune etiology. It was discovered that the patient was taking a 500 mg once daily dose of crizotinib, in lieu of the intended dose of 250 mg twice daily. After immediate cessation of crizotinib therapy upon hospital admission, there was complete biochemical resolution of the hepatitis. This case highlights the potential reversibility of fulminant crizotinib-associated hepatoxicity, possibly related to supratherapeutic dosing, when managed with abrupt stoppage of the drug and initiation of supportive care. [ABSTRACT FROM AUTHOR]

Background: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a glomerular disease defined by non-organized glomerular deposits of heavy and light chain–restricted immunoglobulin and is rarely reported in children. Methods: We characterized a series of nine pediatric patients from two academic centers with biopsy-proven PGNMID and additionally describe two patients with monotypic IgG in the setting of IgM deposition. Results: Each patient presented with hematuria and/or proteinuria; however, only five had elevated serum creatinine. Prodromal or concurrent infection was identified in six patients, low C3 in five, and alternate complement pathway gene variants in two. No monoclonal serum proteins were identified in five tested patients. Seven patients had monotypic deposits composed of IgG3-λ, two showed IgG3-κ, and one each IgG1 and IgG3 with lambda dominance in the setting of IgM deposition. The glomerular pattern was predominantly mesangial proliferative or membranoproliferative glomerulonephritis (MPGN). Treatment and outcomes were variable; four patients have recent PGNMID diagnoses and therefore minimal follow up, one had relatively stable kidney function for over a decade, and six experienced kidney failure, with four receiving transplants. Recurrent deposits of the same isotype were identified in five of six transplanted kidneys, corresponding to three of four transplanted patients. One of these patients developed PGNMID recurrences in three separate kidney allografts over a 20-year disease course. Conclusions: Our study emphasizes the need for upfront IgG subclass investigation in pediatric mesangial or MPGN with IgG deposition and monotypic or biased light-chain staining. Furthermore, this pediatric experience suggests expanded pathogenic considerations in PGNMID. [ABSTRACT FROM AUTHOR]

In the majority of children with ALF, the etiology is unknown and liver transplantation is often needed for survival. A patient case prompted us to consider that immune dysregulation may be the cause of indeterminate acute hepatitis and liver failure in children. Our study includes nine pediatric patients treated under a multidisciplinary clinical protocol to identify and treat immune-mediated acute liver injury. Patients with evidence of inflammation and no active infection on biopsy received treatment with intravenous immune globulin and methylprednisolone. Seven patients had at least one positive immune marker before or after treatment. All patients had a CD8+ T-cell predominant liver injury that completely or partially responded to immune therapy. Five of the nine patients recovered liver function and did not require liver transplantation. Three of these patients subsequently developed bone marrow failure and were treated with either immunosuppression or stem cell transplant. This series highlights the importance of this tissue-based approach to diagnosis and treatment that may improve transplant-free survival. Further research is necessary to better characterize the immune injury and to predict the subset of patients at risk for bone marrow failure who may benefit from earlier and stronger immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

Keratin 8 and 18 (K8/K18) mutations are found in patients with cryptogenic cirrhosis, but the role of keratin mutations in noncryptogenic cirrhosis and the incidence of keratin mutations in the general population are not known. We screened for K8/K18 mutations in genomic DNA isolated from 314 liver explants of patients who primarily had noncryptogenic cirrhosis, and from 349 blood bank volunteers. Seven unique K8/K18 mutations were found in 11 independent patients with biliary atresia, hepatitis B/C, alcohol, primary biliary cirrhosis, and fulminant hepatitis. Seven of the 11 patients had mutations previously described in patients with cryptogenic cirrhosis: K8 Tyr-53 → His, K8 Gly-61 → Cys, and K18 His-127 → Leu. The four remaining patients had mutations at one K8 and three other K18 new sites. Of the 349 blood bank control samples, only one contained the Tyr-53 → His and one the Gly-61 → Cys K8 mutations (P < 0.004 when comparing cirrhosis versus control groups). Two additional mutations were found in both the liver disease and blood bank groups and, hence, likely represent polymorphisms. Livers with keratin mutations had cytoplasmic filamentous deposits that were less frequent in livers without the mutations (P = 0.03). Therefore, K8/K18 are likely susceptibility genes for developing cryptogenic and noncryptogenic forms of liver disease. [ABSTRACT FROM AUTHOR]

Investigates the expression of insulin-like growth factor-I (IGF-I) and transforming growth factor-Beta in hypokalemic nephropathy in rats in the U.S. Alterations in the expression of growth factor; Isolation of RNA; Determination of messenger RNA signal in kidneys and muscles.

Reports on regulated upon activation, normal T cell expressed and secreted (RANTES) chemokine expression in cell-mediated transplant rejection of the kidney. Study in renal allograft biopsy specimens; Detection of RANTES mRNA in infiltrating mononuclear cells and renal tubular epithelium; Role of RANTES in allograft rejection.

The article presents a case of a 69-year-old woman with a phyllodes tumor arising in the vulva. It examines whether phyllodes tumor is a site-specific tumor requiring the presence of ectopic breast tissue tumorigenesis. It also discusses the tissue distribution of phyllodes and other common differential diagnoses.