Showing papers by "Payal Kapur published in 2013"

Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: A retrospective analysis with independent validation

Abstract: Summary Background Clear-cell renal-cell carcinomas display divergent clinical behaviours. However, the molecular genetic events driving these behaviours are unknown. We discovered that BAP1 is mutated in about 15% of clear-cell renal-cell carcinoma, and that BAP1 and PBRM1 mutations are largely mutually exclusive. The aim of this study was to investigate the clinicopathological significance of these molecular subtypes and to determine whether patients with BAP1 -mutant and PBRM1 -mutant tumours had different overall survival. Methods In this retrospective analysis, we assessed 145 patients with primary clear-cell renal-cell carcinoma and defined PBRM1 and BAP1 mutation status from the University of Texas Southwestern Medical Center (UTSW), TX, USA, between 1998 and 2011. We classified patients into those with BAP1 -mutant tumours and those with tumours exclusively mutated for PBRM1 ( PBRM1 -mutant). We used a second independent cohort (n=327) from The Cancer Genome Atlas (TCGA) for validation. In both cohorts, more than 80% of patients had localised or locoregional disease at presentation. Overall both cohorts were similar, although the TCGA had more patients with metastatic and higher-grade disease, and more TCGA patients presented before molecularly targeted therapies became available. Findings The median overall survival in the UTSW cohort was significantly shorter for patients with BAP1 -mutant tumours (4·6 years; 95% CI 2·1–7·2), than for patients with PBRM1 -mutant tumours (10·6 years; 9·8–11·5), corresponding to a HR of 2·7 (95% CI 0·99–7·6, p=0·044). Median overall survival in the TCGA cohort was 1·9 years (95% CI 0·6–3·3) for patients with BAP1 -mutant tumours and 5·4 years (4·0–6·8) for those with PBRM1 -mutant tumours. A HR similar to the UTSW cohort was noted in the TCGA cohort (2·8; 95% CI 1·4–5·9; p=0·004). Patients with mutations in both BAP1 and PBRM1 , although a minority (three in UTSW cohort and four in TCGA cohort), had the worst overall survival (median 2·1 years, 95% CI 0·3–3·8, for the UTSW cohort, and 0·2 years, 0·0–1·2, for the TCGA cohort). Interpretation Our findings identify mutation-defined subtypes of clear-cell renal-cell carcinoma with distinct clinical outcomes, a high-risk BAP1 -mutant group and a favourable PBRM1 -mutant group. These data establish the basis for a molecular genetic classification of clear-cell renal-cell carcinoma that could influence treatment decisions in the future. The existence of different molecular subtypes with disparate outcomes should be considered in the design and assessment of clinical studies. Funding Cancer Prevention and Research Institution of Texas and National Cancer Institute.

GATA-3 immunohistochemistry in the differential diagnosis of adenocarcinoma of the urinary bladder.

Abstract: GATA-3 is a newly described marker that labels urothelial and breast carcinoma. However, no prior study has evaluated the expression of GATA-3 in primary bladder adenocarcinoma. Tissue microarrays (TMAs) containing 46 primary bladder adenocarcinomas were constructed. They contained 19 signet ring cell (SRC) and 27 conventional adenocarcinomas. Three additional cases of SRC using routine sections were included resulting in a total of 22 SRCs. In addition, TMAs containing 32 primary gastric signet ring adenocarcinomas and 36 primary lobular breast carcinomas were evaluated. The TMAs were subjected to immunohistochemical analysis for GATA-3, with nuclear labeling scored by intensity and percentage labeling. Breast and urothelial TMAs were also labeled for estrogen receptor, progesterone receptor, and gross cystic duct fluid protein. Diffuse nuclear GATA-3 labeling was seen in 9/22 (41.0%) SRCs and in 2/27 (7.0%) conventional adenocarcinomas (P=0.01). Extracellular mucin production was seen in 12 SRCs. One of 12 (8.0%) SRCs with extracellular mucin was GATA-3 positive, and 8/10 SRCs without extracellular mucin was GATA-3 positive (P=0.005). No nuclear GATA-3 labeling was seen in any gastric signet ring carcinoma. Diffuse, moderate to strong nuclear GATA-3 labeling was seen in 36/36 (100%) primary lobular breast carcinomas. Nuclear GATA-3 labeling is a useful marker for primary adenocarcinomas of the urinary bladder with signet ring features and can be helpful in distinguishing primary signet ring carcinomas of the urinary bladder from gastric signet ring carcinomas. GATA-3 is rarely positive in bladder adenocarcinomas that lack signet ring features and in SRCs displaying extracellular mucin production.

Vulvar Fibroadenoma with Lactational Changes in Ectopic Breast Tissue

Abstract: Ectopic breast tissue represents any type of breast tissue found outside its normal location in the pectoral region. The second most common location for ectopic breast tissue after axilla is the vulvar region. We present a case of a healthy 20-year-old female, G1P1, who presented to the Emergency Department with a sudden increase in size of a painful mass located in her vulva, which started 4 days after a spontaneous vaginal delivery and 3 days after initiation of breast-feeding of her newborn. She reported a stable, smaller, painless mass in the same location for almost 2 years prior to this episode. After surgical excision, a fibroadenoma with lactation changes within ectopic breast tissue was confirmed.

Phospho-mTOR is not upregulated in metastatic SDHB paragangliomas

Abstract: Background Pheochromocytomas (PCCs)/paragangliomas (PGLs) are neuroendocrine tumours that may cause arrhythmia and death if untreated. Treatment for patients with metastatic tumours is lacking. As new PCC/PGL susceptibility genes are discovered that are associated with the mTOR pathway, treatment targets focusing on this pathway are being intensively explored. Design Twenty-one human PCC/PGLs were analysed from two tertiary care centres. Immunohistochemistry (IHC) analysis was performed for phospho-mTOR (pmTOR), phospho-S6K (pS6K), phosphoinositide 3-kinase (PI3K), phospho-4EBP1 (p4EBP1), HIF1α and MIB-1 in 6 metastatic SDHB PCC/PGLs, 15 nonmetastatic PCC/PGLs, (including 1 TMEM127 PCC and 1 nonmetastatic SDHB PGL) and 6 normal adrenal medullas. The product of the intensity of stain and percentage of cells stained was calculated as an H score. Results Using a two-sample t-test and paired t-test, pmTOR and pS6K had significantly higher H scores in nonmetastatic PCC/PGLs than in metastatic SDHB PCC/PGLs. HIF1α had significantly higher H scores in metastatic SDHB PCC/PGLs compared with nonmetastatic PCC/PGLs and normal adrenal medulla. No difference in H scores was seen with p4EBP1, PI3K and MIB-1 when comparing metastatic SDHB PCC/PGLs and nonmetastatic PCC/PGLs. Significantly higher difference in pS6K was seen in normal adrenal medullas compared to nonmetastatic PCC/PGLs and metastatic SDHB PCC/PGLs. Conclusion The present results suggest that the use of mTOR inhibitors alone for metastatic SDHB PCC/PGLs may not achieve good therapeutic efficacy in patients.

Rapid progression of a germ cell tumor encasing the inferior vena cava and aorta following a radical orchiectomy

Abstract: Early stage testicular germ cell tumors are highly curable malignancies, but the need for close radiologic and biomarker surveillance is pivotal. Even in the setting of recurrence, rescue therapy has been successfully implemented. The present report describes a patient that had rapid and aggressive recurrence after radical orchiectomy for a testicular germ cell tumor and presented with bulky disease necessitating reconstruction of the inferior vena cava at the time of salvage retroperitoneal debulking.