Ghee-Young Kwon

Fine needle aspiration cytology of cystic hypersecretory carcinoma of the breast. A case report.

BACKGROUND Cystic hypersecretory carcinoma (CHC) of the breast is a rare variant of intraductal carcinoma. It is characterized by a multicystic, yellow-brown lesion with gelatinous material grossly and cystically dilated ducts with an eosinophilic secretion microscopically. The histologic or cytologic features can be deceptively bland. CASE A 37-year-old female presented with an 8-cm-diameter, firm mass in the breast. Radical mastectomy was performed after fine needle aspiration (FNA). The moderately cellular smear had a characteristic background of proficient, intensely staining secretion with bubbling. The cellular components were various, ranging from sheets of benign hyperplastic ductal cells to three-dimensional clusters or papillae of frankly malignant ductal cells, with varying degrees of secretory activity. The background consisted of inflammatory cells, naked nuclei and foamy histiocytes. The cytologic findings correlated well with the histologic features of the tumor, which showed both micropapillary intraductal carcinoma with apocrine metaplasia and focal high grade invasive carcinoma in a background of cystic hypersecretory hyperplasia. CONCLUSION This was the first reported case of FNA cytology of an invasive form of CHC. CHC has characteristic features on FNA, and so a reliable diagnosis can be made.

Overexpression of CD24: association with invasiveness in urothelial carcinoma of the bladder.

CONTEXT CD24, originally described as a B-cell marker, has gained considerable attention in tumor research. High rates of CD24 expression have been found in several types of carcinomas that are significantly associated with a more aggressive course of the disease. To our knowledge, the expression of CD24 in urothelial carcinoma (UC) of the bladder has not been previously reported. OBJECTIVE To determine the expression of CD24 in UCs and the association between CD24 levels and tumor grade and stage. DESIGN Urothelial carcinomas (48 cystectomy, 87 transurethral biopsy), including 56 pTa, 29 pT1, 19 pT2, and 31 pT3, were analyzed immunohistochemically using an anti-CD24 monoclonal antibody. The intensity of CD24 staining was semiquantitatively scored as high-level or low-level expression. RESULTS In normal urothelium, CD24 was localized to the cytoplasm of the luminal cell layer with very low intensity. CD24 expression was upregulated in noninvasive UCs, and a high level of expression was correlated with the tumor grade (P = .003). Invasive UCs demonstrated strong diffuse cytoplasmic overexpression of CD24 and the difference in CD24 expression between invasive and noninvasive UC was statistically significant (P < .001). CONCLUSIONS CD24 protein is overexpressed in a significant number of bladder UCs. The high level of CD24 expression with loss of apical localization is a marker for stromal invasion and high tumor grade in UC. This study provides the basis for future investigations of CD24 as a potential serum marker or target of antibody-based therapeutics in bladder UC.

Effect of nicotinamide on early graft failure following intraportal islet transplantation

Intraportal islet transplantation (IPIT) may potentially cure Type 1 diabetes mellitus; however, graft failure in the early post-transplantation period presents a major obstacle. In this study, we tested the ability of nicotinamide to prevent early islet destruction in a syngeneic mouse model. Mice (C57BL/6) with chemically-induced diabetes received intraportal transplants of syngeneic islet tissue in various doses. Islets were cultured for 24 h in medium with or without 10 mM nicotinamide supplementation. Following IPIT, islet function was confirmed by an intraperitoneal glucose tolerance test (IPGTT) and hepatectomy. The effects of nicotinamide were evaluated by blood glucose concentration, serum monocyte chemoattractant protein-1 (MCP-1) concentration, and immunohistology at 3 h and 24 h after IPIT. Among the various islet doses, an infusion of 300 syngeneic islets treated with nicotinamide exhibited the greatest differences in glucose tolerance between recipients of treated and untreated (i.e., control) islets. One day after 300 islet equivalent (IEQ) transplantation, islets treated with nicotinamide were better granulated than the untreated islets (P = 0.01), and the recipients displayed a slight decrease in serum MCP-1 concentration, as compared to controls. After 15 days, recipients of nicotinamide-pretreated islets showed higher levels of graft function (as measured by IPGTT) than controls. The pretreatment also prolonged graft survival (> 100 days) and function; these were confirmed by partial hepatectomy, which led to the recurrence of diabetes. Pretreatment of islet grafts with nicotinamide may prevent their deterioration on the early period following IPIT in a syngeneic mouse model.

Beneficial effects of simultaneous treatment with 15-deoxyspergualin and monoclonal antibodies to CD45RB and CD154 on murine islet transplantation recipients.

Background. Treatment of transplant recipients with either 15-deoxyspergualin (DSG) or monoclonal antibodies (mAbs) to T-cell proteins CD45RB and CD154 (a two-signal blockade) has been shown to prolong islet graft survival. Therefore, we investigated the combined effect of DSG, anti-CD45RB, and anti-CD154 in murine islet model. Methods. Chemically induced diabetic C57BL/6 mice underwent allografting with islets from BALB/c mice or xenografting with rat islets. After transplantation, they were treated with either DSG, the two-signal blockade, or both (the triple treatment). The tolerogenic effects of the posttransplant treatments were measured with an intraperitoneal glucose tolerance test (IPGTT), immunohistology, enzyme-linked immunosorbent assays, and flow cytometry. Results. Blood glucose profiles measured after glucose challenges were improved in all islet recipients. Enhancement of xenograft survival in triple-treated groups was not statistically significant (P=0.08), compared to graft survival in group received only the two-signal blockade. However, 15 days after transplantation, xenografts in the triple-treated group showed a significant decrease in the proportion of CD4+, CD8+, and CD4+CD45RBhigh T-cells, and in the expression of interleukin-10 and interferon-&ggr;, relative to grafts in the other treatment groups. In addition, reduced infiltration of the xenografts by CD3+ T-cells was observed in groups that had received either the two-signal blockade or the triple treatment. With long-term (>248 days) xenografts, only those in the triple-treated group were free of inflammatory infiltrates. These grafts also exhibited larger islet clusters and contained more insulin- and glucagon-positive cells, relative to grafts in the other treatment groups. Conclusion. Triple treatment has a beneficial effect in murine islet xenotransplantation.

Nuclear and cytoplasmic localization of β-catenin in the nail-matrix cells and in an onychomatricoma.

β‐catenin plays an important role in hair morphogenesis. Previously, the nuclear and cytoplasmic localizations of β‐catenin were identified in hair‐matrix cells. To evaluate β‐catenin expression in the nail matrix, we obtained human nail units. Immunohistochemistry for β‐catenin was used to evaluate sections of normal nail units and of sections from a single case of onychomatricoma. In the nail unit, β‐catenin was expressed in the nucleus and cytoplasm of the suprabasal nail‐matrix cells. Of the other epithelial‐cell types, only the cell membrane was β‐catenin‐positive. In the nail tissue from the onychomatricoma case, β‐catenin was expressed in the nucleus and cytoplasm of the upper epithelial layers. Our result suggests that β‐catenin plays an important role in nail formation. In addition, β‐catenin expression in onychomatricoma supports the presence of nail‐matrix cells in this condition. To our knowledge, this is the first report of β‐catenin expression in the nucleus and cytoplasm of the nail matrix.

Molecular Characterization of Urothelial Carcinoma of the Bladder and Upper Urinary Tract

PURPOSE: A better understanding of the molecular basis of urothelial carcinoma (UC) is needed to refine the clinical decision-making process. METHODS AND MATERIALS: We performed next-generation sequencing to investigate the mutational and transcriptional profiles of commonly mutated genes in UC using Ampliseq v2. Copy number variations (CNVs) were detected with nCounter assay. Genetic alterations between upper tract UC (UTUC) and urinary bladder UC (UBUC) were compared. RESULTS: Tumor samples from 31 UTUC and 61 UBUC patients were included in analysis. The two groups showed similar clinicopathologic features including tumor grade and stage. Median survival was longer in UTUC than UBUC patients, though this was statistically nonsignificant (59 vs 41 months, P = .137). In total, we found 982 genetic alterations from 92 samples: single nucleotide variants were the most common type of somatic mutation (479/508, 94.3%). Frequently detected somatic mutations included TP53 (68.5%), KDR (41.3%), and PIK3CA (17.4%). Notably, RB1 mutations were the only mutations significantly different between the UBUC and UTUC groups (19.7% vs. 0%, P = .020). The most common types of CNVs included amplifications (56/62, 90.3%): 17.7% of patients identified amplifications in NOTCH1. We also identified five translocations in the entire study population, including one case with FGFR3-TACC3 (Chr4) fusion. CONCLUSION: Within a small study population, we identified similar genetic alterations in both UTUC and UBUC patients, indicating a basis for similar management strategies.

Giant Cell Myocarditis Associated With Coxsackievirus Infection

doi:10.1016/j.jacc.2009.10.096 J. Am. Coll. Cardiol. 2010;56;e19 Mirae Lee, Ghee-Young Kwon, June-Soo Kim, and Eun-Seok Jeon Giant Cell Myocarditis Associated With Coxsackievirus Infection This information is current as of April 11, 2012 http://content.onlinejacc.org/cgi/content/full/56/10/e19 located on the World Wide Web at: The online version of this article, along with updated information and services, isDownloaded from content.onlinejacc.org

Development of Novel Patient-Derived Preclinical Models from Malignant Effusions in Patients with Tyrosine Kinase Inhibitor–Resistant Clear Cell Renal Cell Carcinoma

PURPOSE: Although targeting angiogenesis with tyrosine kinase inhibitors (TKIs) has become standard of care in the treatment of clear cell renal cell carcinoma (RCC), resistance mechanism are not fully understood, and there is a need to develop new therapeutic options overcoming them. METHODS AND MATERIALS: To develop a preclinical model that predicts clinical activity of novel agents in 19 RCC patients, we established patient-derived cell (PDC) and xenograft (PDX) models derived from malignant effusions or surgical specimen. RESULTS: Successful PDCs, defined as cells that maintained growth following two passages, were established in 5 of 15 malignant effusions and 1 of 4 surgical specimens. One PDC, clinically refractory to TKIs, was implanted and engrafted in mice, resulting in a comparable histology to the primary tumor. The PDC-PDX model also showed similar genomic features when tested using targeted sequencing of cancer-related genes. When we examined the drug effects of the PDX model, the tumor cells showed resistance to TKIs and everolimus in vitro. CONCLUSION: The results suggest that the PDC-PDX preclinical model we developed using malignant effusions can be a useful preclinical model to interrogate sensitivity to targeted agents based on genomic alterations.

Fibroblast growth factor receptor 3 (FGFR3) aberrations in muscle-invasive urothelial carcinoma

BackgroundRecent studies suggest that FGFR3 is a potential therapeutic target in urothelial carcinoma (UC). The purpose of this study was to evaluate the rates and types of FGFR3 aberrations in patients with muscle-invasive UC who received radical resection.MethodsWe analyzed surgical tumor samples from 74 UC patients who had received radical cystectomy (n = 40) or ureteronephrectomy (n = 34). Ion AmpliSeq Cancer Hotspot Panel v2 and nCounter Copy Number Variation Assay were used to detect FGFR3 aberrations.ResultsFifty-four patients (73%) had high-grade tumors, and 62% had lymph node involvement. Sixteen patients (22%) harbored FGFR3 alterations, the most common of which was FGFR3 mutations (n = 13): Y373C (n = 3), N532D (n = 3), R248C (n = 2), S249C (n = 1), G370C (n = 1), S657S (n = 1), A797P (n = 1), and 746_747insG (n = 1). Three additional patients had a FGFR3-TACC3 rearrangement. The frequency of FGFR3 aberrations was higher in bladder UC (25%) than in UC of the renal pelvis and ureter (18%) but the difference was not statistically significant (P = 0.444). Genes that were co-aberrant with FGFR3 included APC (88%), PDGFRA (81%), RET (69%), and TP53 (69%).ConclusionsWe report the frequency and types of FGFR3 aberrations in Korean patients with UC. Patients with FGFR3 mutations or FGFR3-TACC3 fusion may constitute potential candidates for a novel FGFR-targeted therapy in the perioperative setting.