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Publications (11)42.76 Total impact

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    ABSTRACT: BACKGROUND: Lymphoma with signet ring cell features (LSF) is a rare morphologic variant of non-Hodgkin lymphoma. Although it has been well documented in the surgical pathology literature, to the best of the authors's knowledge, the features of LSF in fine-needle aspiration (FNA) samples have rarely been reported. An accurate cytologic diagnosis of LSF is of important therapeutic significance. METHODS: The authors retrospectively reviewed 7 FNA cases of LSF for cytologic features, ancillary studies, corresponding histologic findings, and the patients' clinical and radiologic information to illustrate the diagnostic clues and potential pitfalls. RESULTS: The final diagnoses, based on a multidisciplinary approach, were follicular lymphoma (5 patients), large B-cell lymphoma of follicular center cell origin (1 patient), and low-grade B-cell lymphoma with plasmacytoid features (1 patient). FNAs were obtained from both lymph node and extranodal sites. Common cytologic features included various percentages of signet ring cells in a background of nonvacuolated lymphomatous cells, lymphoglandular bodies, and cytoplasmic rings. The majority of signet ring cells contained a single, large, clear intracytoplasmic vacuole that pushed the nucleus laterally whereas fewer cells contained ≥ 2 vacuoles that indented the nucleus into a scalloped or stellate configuration. These cells resemble, to some degree, other lesions with signet ring cell features. One of the diagnostic clues of LSF was the similarity in nuclear details between signet ring cells and surrounding nonvacuolated lymphoid cells. CONCLUSIONS: Familiarity with cytologic features, correlation with clinical/radiologic information, and ancillary studies are important for an accurate diagnosis of LSF and for distinguishing it from other lesions with signet ring cell features in FNA samples. Cancer (Cancer Cytopathol) 2013. © 2013 American Cancer Society.
    Cancer Cytopathology 03/2013; · 4.43 Impact Factor
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    ABSTRACT: Notch pathway signaling has critical roles in differentiation, proliferation, and survival, and has oncogenic or tumor suppressor effects in a variety of malignancies. The goal of this study was to evaluate the effects of Notch activation on human neuroblastoma cells. Quantitative RT-PCR, immunoblots, and immunohistochemistry were used to determine the expression of Notch receptors (Notch1-4), cleaved Notch1 (ICN1), and downstream targets (HES1-5) in human neuroblastoma cell lines and patient tumor samples. Notch pathway signaling was induced using intracellular Notch (ICN1-3) and HES gene constructs or direct culture on Notch ligands. Quantitative methylation-specific PCR was used to quantify methylation of the HES gene promoters, and the effects of treatment with decitabine were measured. Neuroblastoma cells express varying levels of Notch receptors and low levels of HES genes at baseline. However, no endogenous activation of the Notch pathway was detected in neuroblastoma cell lines or patient tumor samples. Expression of activated Notch intracellular domains and HES gene products led to growth arrest. The HES2 and HES5 gene promoters were found to be heavily methylated in most neuroblastoma lines, and HES gene expression could be induced through treatment with decitabine. We report that neuroblastoma cell lines express multiple Notch receptors, which are inactive at baseline. Activation of the Notch pathway via ligand binding consistently resulted in growth arrest. HES gene expression appears to be regulated epigenetically and could be induced with decitabine. These findings support a tumor suppressor role for Notch signaling in neuroblastoma.
    Pediatric Blood & Cancer 07/2011; 58(5):682-9. · 2.35 Impact Factor
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    ABSTRACT: The repressor element-1 silencing transcription factor (REST) is a repressor of neuronal genes. Its expression is associated with poor neuronal differentiation in many neuroblastoma patient samples and cell lines. Because retinoic acid promotes neuronal differentiation, the authors postulated that it involves modulation of REST expression. The expression of REST and of an S-phase kinase-associated protein 1/cullin 1/F-box (SCF) protein complex that contains the F-box protein β-transducin repeat-containing protein (β-TRCP) (SCF(β-TRCP) ) in neuroblastoma tumor samples and cell lines was analyzed by immunofluorescence and Western blot analysis. SK-N-SH and SK-N-AS cells were treated with retinoic acid and MG-132 to measure proteasomal degradation of REST by Western blot and quantitative real-time polymerase chain reaction analyses. Immunoprecipitation and coimmunoprecipitation assays were done in SK-N-AS cells that were transfected either with a control plasmid or with an enhanced green fluorescent protein-SCF(β-TRCP) -expressing plasmid. Several neuroblastoma patient samples and cell lines displayed elevated REST expression. Although, REST transcription increased upon retinoic acid treatment in SK-N-SH and SK-N-AS cells, REST protein levels declined, concomitant with the induction of neuronal differentiation, in SK-N-SH cells but not in SK-N-AS cells. MG-132 treatment countered the retinoic acid-mediated decline in REST protein. SCF(β-TRCP) , a known REST-specific E3-ligase, was poorly expressed in many neuroblastoma samples, and its expression increased upon retinoic acid treatment in SK-N-SH cells but declined in SK-N-AS cells. Ectopic expression of SCF(β-TRCP) in SK-N-AS cells promoted REST ubiquitination and degradation and neuronal differentiation. The current results indicated that elevated transcription of REST compounded by its impaired degradation by SCF(β-TRCP) may contribute to the failure of these tumors to differentiate in response to retinoic acid.
    Cancer 04/2011; 117(22):5189-202. · 5.20 Impact Factor
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    ABSTRACT: The aim of this study was to validate clinical utilization of routinely prepared cytology specimens for molecular testing to detect EGFR or KRAS mutations in lung cancer. From September 2009 to April 2010, the authors collected 209 cytology specimens from patients with lung cancer at the MD Anderson Cancer Center Department of Pathology. The specimens included 99 cases of endobronchial ultrasound-guided (EBUS) fine-needle aspiration (FNA), 67 cases of computed tomography (CT)-guided FNA, 27 cases of body fluid, 10 cases of ultrasound-guided of superficial FNA, and 6 cases of other cytology specimens. DNA sequencing for EGFR exons 18-21 and KRAS codons 12, 13, and 61 was performed. The overall specimen insufficiency rate was low (6.2%). EBUS (4%) and body-fluid cases (3.7%) showed lower insufficiency rates than the other cases. Similar insufficiency rates were observed in smears (6.1%) and cell-block sections (6.4%). EGFR mutations were detected in 19.4% (34 of 175) of nonsmall cell lung carcinoma (NSCLC) with a significantly higher frequency in adenocarcinoma (29%, 29 of 100) than in nonadenocarcinoma (7%, 5 of 75, P = .002). KRAS mutations were detected in 23.6% (41 of 174) of NSCLCs with no statistical differences between adenocarcinoma (26%, 26 of 102) and nonadenocarcinoma (21%, 17 of 72, P = .86). Higher frequencies of EGFR mutations in exons 19 and 21 (65%) than in exons 18 and 20 were detected. Our findings support clinical utilization of routinely prepared cytology specimens, including EBUS, CT/US. FNAs and body fluid specimens, as a reliable source for molecular testing to detect EGFR or KRAS mutations in patients with NSCLC.
    Cancer Cytopathology 03/2011; 119(2):111-7. · 4.43 Impact Factor
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    ABSTRACT: Wilms tumor (WT) is a genetically heterogeneous childhood kidney tumor. Several genetic alterations have been identified in WT patients, including inactivating mutations in WT1 and loss of heterozygosity or loss of imprinting at 11p15, which results in biallelic expression of IGF2. However, the mechanisms by which one or a combination of genetic alterations results in tumorigenesis has remained challenging to determine, given the lack of a mouse model of WT. Here, we engineered mice to sustain mosaic, somatic ablation of Wt1 and constitutional Igf2 upregulation, mimicking a subset of human tumors. Mice with this combination of genetic alterations developed tumors at an early age. Mechanistically, Wt1 ablation blocked mesenchyme differentiation, and increased Igf2 expression upregulated ERK1/2 phosphorylation. Importantly, a subset of human tumors similarly displayed upregulation of ERK1/2 phosphorylation, which suggests ERK signaling might contribute to WT development. Thus, we have generated a biologically relevant mouse model of WT and defined one combination of driver alterations for WT. This mouse model will provide a powerful tool to study the biology of WT initiation and progression and to investigate therapeutic strategies for cancers with IGF pathway dysregulation.
    The Journal of clinical investigation 01/2011; 121(1):174-83. · 15.39 Impact Factor
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    ABSTRACT: Both 22- and 25-gauge needles are used for endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) of lesions, yet limited data exist on whether either offers an advantage over the other in terms of specimen cellularity and quality. The aim of this study was to compare sample quality for 22- and 25-gauge needles in EUS-guided FNA of pancreatic and peri-pancreatic lesions. Between October 2005 and June 2006, 12 patients with pancreatic or peripancreatic lesions underwent EUS-guided FNA with both 22- and 25-gauge Wilson-Cook Echotip needles. All procedures were performed with an Olympus linear echoendoscope by the same endoscopist to eliminate operator-dependent variability. Needle order was selected randomly, and two passes were made with each needle, consisting of ten uniform to-and-fro movements on each pass with 10-ml syringe suction. The specimens were immediately stained and independently reviewed by two cytopathologists, who were blinded to the needle used. Cellularity was graded as 0 to 6, with 6 being most cellular. No statistically significant difference in cellularity was detected between the two needle size groups by cytologist 1 (mean difference, 0.04; 95% confidence interval [CI], -1.22 to 1.30; p = 0.94) or by cytologist 2 (mean difference, 0.2; 95% CI, -1.23 to 1.65; p = 0.76). When the data from both cytologists were combined, no significant difference in cellularity was detected between the two needle sizes (mean difference, 0.125; 95% CI, -1.22 to 1.47; p = 0.84). No significant difference in cellularity was detected between cytologists 1 and 2 (mean difference, 0.17; 95% CI, -0.15 to 0.48; p = 0.27). When the order in which needles were used was compared, no significant difference in cellularity was detected (p = 0.75). Three mechanical failures occurred with 25-gauge needles, but none occurred with 22-gauge needles. The visibility of the needles on EUS did not differ. Cytologic diagnoses were achieved in all cases: seven pancreatic adenocarcinomas, one pancreatic giant cell carcinoma, one pancreatic neuroendocrine tumor, one metastatic non-small cell carcinoma, one metastatic colon carcinoma, and one pancreatitis. There were no procedure-related complications. Both FNA needles provided accurate diagnoses in all patients. There was no significant difference between the 22- and 25-gauge needle groups in the independent interpretation of two cytopathologists with respect to cellular yield and ability to render a diagnosis.
    Digestive Diseases and Sciences 09/2009; 54(10):2274-81. · 2.26 Impact Factor
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    ABSTRACT: Radical surgery for malignant pleural mesothelioma does not improve survival in patients with nodal metastases. Imaging is poor at predicting nodal involvement and mediastinoscopy, though frequently used, is of low sensitivity. As endobronchial ultrasound (EBUS) and esophageal endoscopic ultrasound (EUS) are accurate for nodal staging of lung cancer, we hypothesized that they would be at least as sensitive as cervical video-mediastinoscopy for nodal staging of mesothelioma. Eighty-five patients with mesothelioma who were potential candidates for radical surgery underwent preoperative staging with mediastinoscopy (n = 50) or EBUS (n = 38). Eleven patients also underwent EUS. Diagnostic yield (specimens containing lymphocytes or tumor cells) was 100% for mediastinoscopy and 84% for EBUS (p < 0.001). Mediastinoscopy identified 7 of 50 (14%) patients with nodal metastases. Thirty-eight (76%) mediastinoscopy-negative patients underwent surgery with nodal sampling and there were 18 false negatives. Endobronchial ultrasound identified 13 of 38 (34%) patients with nodal metastases. Twenty-two (58%) EBUS-negative patients underwent surgery with nodal sampling and there were 10 false negatives. Sensitivity and negative predictive value for mediastinoscopy were 28% and 49%, and 59% and 57% for EBUS. Eleven patients had EUS preoperatively, which revealed infradiaphragmatic nodal metastases in 5 patients. Although this study is retrospective, EBUS had higher sensitivity than either mediastinoscopy or imaging studies for detection of nodal metastases. Nevertheless, the ability to accurately identify nodal involvement preoperatively in patients with mesothelioma remains suboptimal. Esophageal ultrasound may complement EBUS particularly in cases where infradiaphragmatic nodal metastases are suspected.
    The Annals of thoracic surgery 09/2009; 88(3):862-8; discussion 868-9. · 3.45 Impact Factor
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    ABSTRACT: Frasier syndrome is characterized by a 46 XY disorder of sex development, nephropathy, and increased risk for gonadoblastoma due to Wilms tumor 1(WT1) mutation in the donor splice site of intron-9, resulting in the splice form +KTS. Germ cell tumors and gonadoblastomas have been reported previously in Frasier syndrome. We present the clinical, radiological, and genetic (WT1 mutation analysis) of a 46 XY phenotypic female with Frasier syndrome with bilateral gonadoblastoma with dysgerminoma who developed pilocytic astrocytoma.
    Pediatric Blood & Cancer 09/2009; 53(7):1349-51. · 2.35 Impact Factor
  • Gastrointestinal Endoscopy - GASTROINTEST ENDOSCOP. 01/2007; 65(5).
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    ABSTRACT: We retrospectively reviewed the cytologic features of metastatic prostatic ductal carcinoma (PDC) in 23 cases, clinical manifestations, and clinical outcomes. Cytologic smears typically showed tumor cells with abundant cytoplasm and oval nuclei arranged in papillary groups or flat and folded sheets, some of which showed peripheral nuclear palisading. However, these features could be focal, subtle, and even indistinguishable from those of acinar carcinoma, particularly when the ductal component was predominantly of a cribriform and solid pattern or coexisted with acinar carcinoma. A determination of a prostatic origin of a metastatic PDC, based on cytomorphologic features alone, could be difficult. Immunostaining for prostate-specific antigen and prostatic acid phosphatase proved helpful in determining a definitive diagnosis. The median followup of patients was 82 months, the median overall survival was 77 months, and the 5-year overall survival rate was 72%. Tumor growth pattern did not correlate with prognosis, but visceral metastasis conveyed a poor prognosis. The correlation with clinical and radiologic findings, a high index of suspicion, and the use of immunoperoxidase studies are important in making an accurate diagnosis.
    American Journal of Clinical Pathology 09/2006; 126(2):302-9. · 2.88 Impact Factor
  • Nancy P. Caraway, John Stewart
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    ABSTRACT: Primary effusion lymphoma (PEL) is a rare, aggressive lymphoma that involves 1 or more of the serous (pleural, peritoneal, and peritoneal) cavities without other tumor masses and is associated with the human herpesvirus 8 (HHV-8), often in the setting of immunodeficiency. PEL occurs predominantly in men with acquired immunodeficiency syndrome (AIDS) but can be seen in iatrogenically immunosuppressed transplant patients and elderly individuals. The effusions show a dispersed population of large pleomorphic cells with eccentrically located nuclei, 1 or more prominent nucleoli, a perinuclear pallor, and moderately abundant cytoplasm. Binucleated and multinucleated cells and mitotic figures are seen commonly. This lymphoma frequently has an indeterminate immunophenotype that is not clearly B cell or T cell in origin, but it is often positive for CD45, CD30, and epithelial membrane antigen. In addition to HHV-8 positivity, many patients also have seropositive results for HIV and Epstein-Barr virus. PEL usually exhibits a complex karyotype without a characteristic aberration. The differential diagnosis typically includes other high-grade lymphomas that occur in HIV-infected patients, immunosuppressed patients, and elderly individuals. The prognosis of this high-grade lymphoma is usually poor, with a survival of only a few months, even with chemotherapy.
    Pathology Case Reviews 02/2006; 11(2):78-84.