Andrew E Horvai

University of California, San Francisco, San Francisco, California, United States

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Publications (51)201.81 Total impact

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    ABSTRACT: We report a case of longstanding, large tumor involving spinal nerve roots of the cauda equina. The tumor showed small round cells arranged in nests and cords and immunophenotypic features of glomus tumor, along with infrequent mitoses and a low Ki-67 labeling index, but exhibited some rosette-like structures, CD99 and focal Neu-N expression. Subsequent molecular analysis showed the presence of an EWSR1-WT1 gene fusion by FISH, which was confirmed by RT-PCR. To our knowledge, this is the first case reported with EWSR1-WT1 fusion in a small round blue cell tumor with smooth muscle differentiation and an indolent course.
    Human pathology 10/2014; · 2.81 Impact Factor
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    ABSTRACT: Purpose To serially monitor bone remodeling in the swine femur after magnetic resonance (MR) imaging-guided high-intensity focused ultrasound ( HIFU high-intensity focused ultrasound ) ablation with MR imaging, computed tomography (CT), sodium fluorine 18 (Na(18)F)-positron emission tomography (PET), and histopathologic examination, as a function of sonication energy. Materials and Methods Experimental procedures received approval from the local institutional animal care and use committee. MR imaging-guided HIFU high-intensity focused ultrasound was used to create distal and proximal ablations in the right femurs of eight pigs. The energy used at the distal target was higher (mean, 419 J; range, 390-440 J) than that used at the proximal target (mean, 324 J; range, 300-360 J). Imaging was performed before and after ablation with 3.0-T MR imaging and 64-section CT. Animals were reevaluated at 3 and 6 weeks with MR imaging (n = 8), CT (n = 8), Na(18)F-PET (n = 4), and histopathologic examination (n = 4). Three-dimensional ablation lengths were measured on contrast material-enhanced MR images, and bone remodeling in the cortex was measured on CT images. Results Ablation sizes at MR imaging 3 and 6 weeks after MR imaging-guided HIFU high-intensity focused ultrasound ablation were similar between proximal (low-energy) and distal (high-energy) lesions (average, 8.7 × 21.9 × 16.4 mm). However, distal ablation lesions (n = 8) demonstrated evidence of subperiosteal new bone formation at CT, with a subtle focus of new ossification at 3 weeks and a larger focus of ossification at 6 weeks. New bone formation was associated with increased uptake at Na(18)F-PET in three of four animals; this was confirmed at histopathologic examination in four of four animals. Conclusion MR imaging-guided HIFU high-intensity focused ultrasound ablation of bone may result in progressive remodeling, with both subcortical necrosis and subperiosteal new bone formation. This may be related to the use of high energies. MR imaging, CT, and PET are suitable noninvasive techniques to monitor bone remodeling after MR imaging-guided HIFU high-intensity focused ultrasound ablation. © RSNA, 2014 Online supplemental material is available for this article.
    Radiology 10/2014; · 6.21 Impact Factor
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    ABSTRACT: Cellular schwannoma is an uncommon, but well-recognized, benign peripheral nerve sheath tumor, which can be misdiagnosed as malignant peripheral nerve sheath tumor. To develop consensus diagnostic criteria for cellular schwannoma, we reviewed 115 malignant peripheral nerve sheath tumor and 26 cellular schwannoma cases from two institutions. Clinical data were retrieved from the electronic medical records, and morphologic features, maximal mitotic counts, Ki67 labeling indices, and immunohistochemical profiles (SOX10, SOX2, p75NTR, p16, p53, EGFR, and neurofibromin) were assessed. Several features distinguish cellular schwannoma from malignant peripheral nerve sheath tumor. First, in contrast to patients with malignant peripheral nerve sheath tumor, no metastases or disease-specific deaths were found in patients with cellular schwannoma. More specifically, 5-year progression-free survival rates were 100 and 18%, and 5-year disease-specific survival rates were 100 and 32% for cellular schwannoma and malignant peripheral nerve sheath tumor, respectively. Second, the presence of Schwannian whorls, a peritumoral capsule, subcapsular lymphocytes, macrophage-rich infiltrates, and the absence of fascicles favored the diagnosis of cellular schwannoma, while the presence of perivascular hypercellularity, tumor herniation into vascular lumens, and necrosis favor malignant peripheral nerve sheath tumor. Third, complete loss of SOX10, neurofibromin or p16 expression, or the presence of EGFR immunoreactivity was specific for malignant peripheral nerve sheath tumor (P<0.001 for each). Expression of p75NTR was observed in 80% of malignant peripheral nerve sheath tumors compared with 31% of cellular schwannomas (P<0.001). Fourth, Ki-67 labeling indices ≥20% were highly predictive of malignant peripheral nerve sheath tumor (87% sensitivity and 96% specificity). Taken together, the combinations of these histopathological and immunohistochemical features provide useful criteria to distinguish between malignant peripheral nerve sheath tumor and cellular schwannoma with high sensitivity and specificity. Additional retrospective and prospective multicenter studies with larger data sets will be required to validate these findings.Modern Pathology advance online publication, 5 September 2014; doi:10.1038/modpathol.2014.109.
    Modern Pathology 09/2014; · 6.36 Impact Factor
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    ABSTRACT: The Ewing sarcoma family of tumors (EFT) is a group of highly malignant small round blue cell tumors occurring in children and young adults. We report here the largest genomic survey to date of 101 EFT (65 tumors and 36 cell lines). Using a combination of whole genome sequencing and targeted sequencing approaches, we discover that EFT has a very low mutational burden (0.15 mutations/Mb) but frequent deleterious mutations in the cohesin complex subunit STAG2 (21.5% tumors, 44.4% cell lines), homozygous deletion of CDKN2A (13.8% and 50%) and mutations of TP53 (6.2% and 71.9%). We additionally note an increased prevalence of the BRCA2 K3326X polymorphism in EFT patient samples (7.3%) compared to population data (OR 7.1, p = 0.006). Using whole transcriptome sequencing, we find that 11% of tumors pathologically diagnosed as EFT lack a typical EWSR1 fusion oncogene and that these tumors do not have a characteristic Ewing sarcoma gene expression signature. We identify samples harboring novel fusion genes including FUS-NCATc2 and CIC-FOXO4 that may represent distinct small round blue cell tumor variants. In an independent EFT tissue microarray cohort, we show that STAG2 loss as detected by immunohistochemistry may be associated with more advanced disease (p = 0.15) and a modest decrease in overall survival (p = 0.10). These results significantly advance our understanding of the genomic and molecular underpinnings of Ewing sarcoma and provide a foundation towards further efforts to improve diagnosis, prognosis, and precision therapeutics testing.
    PLoS Genetics 07/2014; 10(7):e1004475. · 8.52 Impact Factor
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    Andrew E Horvai, Richard C Jordan
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    ABSTRACT: The canonical Wnt/β-catenin pathway is involved in the formation of craniofacial skeleton and oral tissues. Aberrant nuclear localization of β-catenin protein has been described in several human diseases including a subset of odontogenic tumors thereby suggesting an important role in tumor development. Fibro-osseous lesions of the craniofacial skeleton comprise several neoplastic, and reactive mesenchymal proliferations in which β-catenin status is unknown. To study this, we immunostained 171 fibro-osseous lesions for β-catenin protein and, for lesions with nuclear positivity, sequenced exon 3 of the CTNNB1 gene and exon 15 of the APC gene. Nuclear β-catenin immunostaining was detected in 34 (20 %) tumors with no correlation between nuclear positivity and either age, gender, or tissue decalcification status (p = 0.2, 0.17, 0.12, respectively). Absent nuclear β-catenin in fibrous dysplasia was the only diagnostically significant finding (p = 0.0034). A single point mutation at Asp56 of CTNNB1 was identified in one case of ossifying fibroma. A second ossifying fibroma and one desmoplastic fibroma demonstrated point mutations (Glu1229 and Tyr1475, respectively) in the APC gene. These findings show that apart from fibrous dysplasia where nuclear β-catenin is rare, nuclear β-catenin staining has limited utility in discriminating among the craniofacial fibro-osseous lesions. The molecular mechanisms underlying nuclear β-catenin accumulation in the positive tumors is unlikely to be mediated by CTNNB1 exon 3 or APC exon 15 mutations in most cases.
    Head and Neck Pathology 03/2014;
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    ABSTRACT: Targeted therapies are increasingly being evaluated for patients with Ewing sarcoma (EWS). Optimal strategies for quantifying key signaling proteins in EWS remain unclear. We sought to quantify tumor expression of signaling pathway proteins in EWS using 3 methodologies. A total of 46 blocks of formalin-fixed paraffin-embedded tissue were obtained from 40 patients with EWS. Tumor was evaluated for the expression of proteins in the insulin-like growth factor type 1 receptor (IGF-1R), epithelial growth factor receptor (EGFR), and mTOR pathways using standard immunohistochemical analysis (IHC), automated quantitative analysis (AQUA) immunohistochemical analysis, and mass spectrometry quantification. The mean age at diagnosis was 14 years (range, 1 to 49 y). About 67.5% were male and 57.5% had localized disease. Samples displayed a wide range of expression by AQUA: mean (range) IGF-1R=10,702 (393 to 14,424); EGFR=2750 (672 to 9798); and phosphatase and tensin homolog (PTEN)=2250 (251 to 6557). Mean IGF-1R expression by AQUA did not differ between standard IHC expression categories (low IHC=11,255; medium IHC=11,070; high IHC=11,023; P=0.98). Mean PTEN expression by AQUA was higher in the medium and high IHC categories (low IHC=1229; medium IHC=2715; high IHC=2940; P=0.064). Only 2 samples expressed EGFR by standard IHC. Mass spectrometry trended toward correlation with standard IHC but did not yield interpretable results in the majority of samples. This study demonstrates that the relative quantification of signaling protein expression in EWS is dependent on the methodology used. Optimization and validation of these tools are necessary before clinical application for risk stratification of patients or measurement of biomarker expression.
    Applied immunohistochemistry & molecular morphology: AIMM / official publication of the Society for Applied Immunohistochemistry 02/2014; · 1.63 Impact Factor
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    ABSTRACT: Pulmonary metastasectomy has become a standard approach for sarcoma, but uncertainty remains regarding risk factors that accurately assess postoperative prognosis and can be used to guide surgical decision making. We identified 145 patients who underwent 204 consecutive pulmonary metastasectomies for sarcoma between 1996 and 2009, and examined 174 complete resections in 118 patients. Predictors included surgical procedure, number/size of lesions, repeat resection, intervals to metastasis and to recurrence, chemotherapy, sarcoma subtype, distribution of pulmonary and extrapulmonary metastasis, and patient age/sex. Survival estimates were based on Kaplan-Meier analysis and compared using a log-rank test. Predictors were compared using univariate and multivariate Cox proportional hazards modeling. Among patients undergoing R0 resections, median survival was 35 months (95% confidence interval, 22-60 months), with 3-, 5- and 10-year survival of 48%, 42%, and 31%, respectively. The number or size of lesions did not influence survival. Metastasis synchronous to the primary tumor, but not disease-free interval, was a significant predictor of worse survival on single variable and adjusted modeling (hazard ratio, 3.0; 95% confidence interval, 1.4-6.6; P = .005); the presence of extrapulmonary metastasis and a need for anatomic resection were also likely predictors (P = .06 and P = .07). Recurrence of pulmonary metastasis was not associated with a reduction in survival if completely resected, and a more aggressive and less invasive surgical approach during the later half of the study period was not associated with a significant decline in survival. Evolving surgical practice may allow an increasingly aggressive approach to pulmonary sarcoma metastasis, which may be facilitated by increased use of a minimally invasive approach.
    The Journal of thoracic and cardiovascular surgery 01/2014; · 3.41 Impact Factor
  • The American journal of surgical pathology 10/2013; 37(10):1627-30. · 4.59 Impact Factor
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    ABSTRACT: Precise regulation of bone resorption is critical for skeletal homeostasis. We report a 32-year-old man with a panostotic expansile bone disease and a massive hemorrhagic mandibular tumor. Originally from Mexico, he was deaf at birth and became "bow-legged" during childhood. There was no family history of skeletal disease. Puberty occurred normally, but during adolescence, he experienced difficulty straightening his limbs, sustained multiple fractures, and developed a bony tumor on his chin. By age 18 years, all limbs were misshapen. The mandibular mass grew and protruded from the oral cavity, extending to the level of the lower ribs. Other bony defects included a similar maxillary mass and serpentine limbs. Upon referral at age 27 years, biochemical studies showed serum alkaline phosphatase of 1760 U/L (Nl: 29-111) and other elevated bone turnover markers. Radiography of the limbs showed medullary expansion and cortical thinning with severe bowing. Although the jaw tumors were initially deemed inoperable, mandibular mass excision and staged partial maxillectomy were eventually performed. Tumor histopathology showed curvilinear trabeculae of woven bone on a background of hypocellular fibrous tissue. Fibrous dysplasia of bone was suspected, but there was no mutation in codon 201 of GNAS in samples from blood or tumor. His clinical findings, elevated serum markers, and disorganized bone histology suggested amplified receptor activator of nuclear factor-κβ (RANK) signaling, even though his presentation differed from conditions with known constitutive activation of RANK signaling (e.g., familial expansile osteolysis). We found a unique 12 base-pair duplication in the signal peptide of TNFRSF11A, the gene that encodes RANK. No exon or splice site mutations were found in the genes encoding RANK-ligand or osteoprotegerin. Alendronate followed by pamidronate therapies substantially decreased his serum alkaline phosphatase activity. This unique patient expands the known phenotypes of the disorders of RANK signaling activation.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 09/2013; · 6.04 Impact Factor
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    ABSTRACT: Ewing sarcoma (ES) is a malignancy of bone and soft tissue in children and adults. Previous registry-based studies indicate that Latino patients with ES have inferior outcomes compared to non-Latino patients, though an etiology for this difference could not be identified. To explore possible differences that might underlie this disparity, we conducted a retrospective study to compare clinical characteristics, tumor features, healthcare access, and treatment outcomes between Latino and non-Latino patients with ES. Primary data for 218 ES patients treated at two academic medical centers between 1980 and 2010 were collected. Categorical data were compared using Fisher exact tests; Wilcoxon rank-sum tests were used for continuous variables. Survival was estimated using Kaplan-Meier analysis and compared using log-rank testing. Latino patients were diagnosed at a younger age (P = 0.014). All other clinical and histological data were similar between groups, including radiologic and histologic response to neoadjuvant chemotherapy. Latino patients had lower socioeconomic status (P = 0.001), were less likely to have insurance (P = 0.001), and were more likely to present to the emergency room at onset of symptoms (P = 0.031) rather than to primary care physicians. Five-year event free survival (EFS) and overall survival (OS) were similar between Latino and non-Latino patients (EFS: 60.5% vs. 50.9% P = 0.37; OS: 77.6% vs. 68.6% P = 0.54). Latino patients with ES present at a younger age, and have evidence of impaired access to healthcare. Response to initial therapy appears similar between Latino and non-Latino patients. Pediatr Blood Cancer © 2013 Wiley Periodicals, Inc.
    Pediatric Blood & Cancer 08/2013; 61(2). · 2.35 Impact Factor
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    ABSTRACT: Synovial sarcoma and malignant peripheral nerve sheath tumor pose a significant diagnostic challenge given similar histomorphology. The distinction is further complicated by similar immunophenotype and especially by occasional synovial sarcomas that present as intraneural tumors. Although the presence of a t(X;18) rearrangement or expression of TLE1 can help confirm the diagnosis of synovial sarcoma, negative results for these tests are not diagnostic of malignant peripheral nerve sheath tumor. The SOX10 transcription factor, a putative marker of neural crest differentiation, may have diagnostic utility in this differential, but immunohistochemical data are limited. The goal of the present study was to determine the diagnostic utility of SOX10 to discriminate between synovial sarcoma and malignant peripheral nerve sheath tumor. Forty-eight cases of malignant peripheral nerve sheath tumor, all from patients with documented neurofibromatosis, and 97 cases of genetically confirmed synovial sarcoma, including 4 intraneural synovial sarcomas, were immunohistochemically stained for SOX10. The stain was scored for intensity and fraction of cells staining. Thirty-two of 48 malignant peripheral nerve sheath tumors (67%) were SOX10-positive. The majority of malignant peripheral nerve sheath tumors showed ≥2+ staining, but staining did not correlate with grade. By contrast, only 7/97 (7%) synovial sarcomas were SOX10-positive. Only three synovial sarcomas showed ≥2+ staining but, importantly, two of these were intraneural synovial sarcoma. Therefore, SOX10 is a specific (93%), albeit not very sensitive (67%), diagnostic marker to support a diagnosis of malignant peripheral nerve sheath tumor over synovial sarcoma. Furthermore, the stain needs to be interpreted with caution in intraneural tumors in order to avoid a potential diagnostic pitfall. It remains to be determined whether SOX10-positive cells in intraneural synovial sarcoma represent entrapped Schwann cells, synovial sarcoma cells or both.Modern Pathology advance online publication, 9 August 2013; doi:10.1038/modpathol.2013.115.
    Modern Pathology 08/2013; · 6.36 Impact Factor
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    ABSTRACT: The purpose of our study was to assess the chondrogenic potential and the MR signal effects of GadofluorineM-Cy labeled matrix associated stem cell implants (MASI) in pig knee specimen. Human mesenchymal stem cells (hMSCs) were labeled with the micelle-based contrast agent GadofluorineM-Cy. Ferucarbotran-labeled hMSCs, non-labeled hMSCs and scaffold only served as controls. Chondrogenic differentiation was induced and gene expression and histologic evaluation were performed. The proportions of spindle-shaped vs. round cells of chondrogenic pellets were compared between experimental groups using the Fisher's exact test. Labeled and unlabeled hMSCs and chondrocytes in scaffolds were implanted into cartilage defects of porcine femoral condyles and underwent MR imaging with T1- and T2-weighted SE and GE sequences. Contrast-to-noise ratios (CNR) between implants and adjacent cartilage were determined and analyzed for significant differences between different experimental groups using the Kruskal-Wallis test. Significance was assigned for p<0.017, considering a Bonferroni correction for multiple comparisons. Collagen type II gene expression levels were not significantly different between different groups (p>0.017). However, hMSC differentiation into chondrocytes was superior for unlabeled and GadofluorineM-Cy-labeled cells compared with Ferucarbotran-labeled cells, as evidenced by a significantly higher proportion of spindle cells in chondrogenic pellets (p<0.05). GadofluorineM-Cy-labeled hMSCs and chondrocytes showed a positive signal effect on T1-weighted images and a negative signal effect on T2-weighted images while Ferucarbotran-labeled cells provided a negative signal effect on all sequences. CNR data for both GadofluorineM-Cy-labeled and Ferucarbotran-labeled hMSCs were significantly different compared to unlabeled control cells on T1-weighted SE and T2*-weighted MR images (p<0.017). hMSCs can be labeled by simple incubation with GadofluorineM-Cy. The labeled cells provide significant MR signal effects and less impaired chondrogenesis compared to Ferucarbotran-labeled hMSCs. Thus, GadoflurineM-Cy might represent an alternative MR cell marker to Ferucarbotran, which is not distributed any more in Europe or North America.
    PLoS ONE 12/2012; 7(12):e49971. · 3.53 Impact Factor
    This article is viewable in ResearchGate's enriched format
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    ABSTRACT: We report a case of primary malignant mixed tumor (MMT) of bone in an 18-year-old boy with X-ray, CT, MR, scintigraphic, FDG PET, and pathologic correlation. Primary MMT of bone is a highly aggressive tumor and presents both a diagnostic and clinical treatment challenge. This tumor is extremely rare and to the best of our knowledge, this is the first report of the diagnostic imaging findings for primary MMT arising from bone in a patient of this age group.
    Journal of Bone Oncology. 12/2012; 1(3):101–105.
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    ABSTRACT: Second malignant neoplasms (SMNs) are therapy-induced malignancies and a growing problem in cancer survivors, particularly survivors of childhood cancers. The lack of experimental models of SMNs has limited understanding of their pathogenesis. It is currently not possible to predict or prevent this devastating late complication. Individuals with Neurofibromatosis I (NF1) are at increased risk of developing therapy-induced cancers for unclear reasons. To model SMNs, we replicated clinical radiotherapy and delivered fractionated abdominal irradiation to Nf1+/- and wildtype mice. Similar to irradiated cancer survivors, irradiated wildtype and Nf1+/- mice developed diverse in-field malignancies. In Nf1+/- mice, fractionated irradiation promoted both classical NF1-associated malignancies and malignancies unassociated with the NF1 syndrome but typical of SMNs. Nf1 heterozygosity potentiated the mutagenic effects of irradiation, as evidenced by the significantly reduced survival after irradiation and tumor development that was often characterized by synchronous primary tumors. Interestingly, diverse radiation-induced tumors arising in wildtype and Nf1+/- mice shared a genetic signature characterized by monoallelic loss of Nf1 and the adjacent Trp53 allele. These findings implicate Nf1 loss as mediating tumorigenesis in a broad range of cell types and organs extending beyond the classical NF1 tumor histologies. Examining clinical SMN samples, we found LOH of NF1 in SMNs from non-NF1 patients. Nf1 heterozygosity confers broad susceptibility to genotoxin-induced tumorigenesis and this paradigm serves as an experimental platform for future studies of SMNs.
    Cancer Research 10/2012; · 9.28 Impact Factor
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    ABSTRACT: OBJECTIVE: Our objective is to understand the biological and mechanical pathways linking cartilage, bone, and marrow changes in the progression of osteoarthritis (OA). The aim of the present study was to evaluate bone structure and composition within bone marrow edema-like lesion (BMEL) regions associated with knee OA. METHODS: Tibial plateau specimens (n = 18) were collected from 10 subjects with knee OA scheduled for total knee arthroplasty (TKA). Magnetic resonance (MR) imaging was used to identify BMEL and quantify metrics of cartilage composition. Micro-computed tomography (μCT) and high-resolution peripheral quantitative computed tomography (HR-pQCT) were used to quantify density and microstructure of the subchondral trabecular bone. Fourier transform infrared (FTIR) spectroscopy was used to quantify tissue composition. RESULTS: Trabecular bone within BMEL was higher in volume fraction, with more and thicker trabeculae that were more plate-like in structure compared to unaffected regions. BMEL trabecular tissue composition had decreased phosphate and carbonate content. Marrow infiltration by a fibrous collagen network and evidence of increased bone remodeling were present. Structural and compositional changes were specifically localized to regions underlying cartilage degradation. CONCLUSION: These results support the paradigm of focal interactions among bone, marrow, and cartilage in the progression of knee OA. Quantitative evaluation of tissue changes and interactions may aid in the understanding of disease pathophysiology and provide imaging markers for disease progression.
    Osteoarthritis and Cartilage 09/2012; · 4.26 Impact Factor
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    ABSTRACT: The molecules Indian hedgehog (IHH), SP7 (also known as osterix), sex-determining region Y-box 9 (SOX9), runt-related transcription factor 2 (RUNX2) and TWIST1 regulate the normal differentiation of osteo- and chondrogenic cells from precursors during skeletal development and remodeling. The aberrant function of the same molecules has been implicated in the pathogenesis of bone tumors. Preliminary studies suggest that antibodies against these molecules have practical, diagnostic or prognostic utility in tumors. However, a comprehensive analysis of the expression of these molecules in a large, diverse set of bone tumors has yet to be reported. The goals of this study were to compare the immunohistochemical profiles of IHH, SP7, SOX9, RUNX2 and TWIST1 among bone tumors and to determine the optimum panel for diagnostic utility. Tissue microarrays prepared from 206 undecalcified tumors (71 osteosarcomas, 26 osteoblastomas/osteoid osteomas, 50 giant cell tumors, 5 chondromyxoid fibromas and 54 chondroblastomas) were stained with antibodies to IHH, SP7, SOX9, RUNX2 and TWIST1. The stains were scored for intensity (0-3+) and distribution. The results were analyzed by cluster analysis. Optimum antibody panels for diagnostic sensitivity and specificity were calculated. Analysis revealed six main clusters that corresponded well to tumor types and suggested a close relationship between the stromal cells of giant cell tumor and the osteoblasts of osteosarcoma. The expression profile of chondromyxoid fibroma and chondroblastoma also suggested related differentiation. The distribution of osteoblastomas and osteoid osteomas was more heterogeneous. RUNX2, SOX9 and TWIST1 represented the most sensitive and specific immunohistochemical panel to distinguish among these diagnoses with the limitation that no result could discriminate between chondroblastoma and chondromyxoid fibroma. IHH and SP7 did not yield additional utility.Modern Pathology advance online publication, 6 July 2012; doi:10.1038/modpathol.2012.110.
    Modern Pathology 07/2012; · 6.36 Impact Factor
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    ABSTRACT: The purpose of this study was to (1) compare three different techniques for ferumoxide labeling of mesenchymal stem cells (MSCs), (2) evaluate if ferumoxide labeling allows in vivo tracking of matrix-associated stem cell implants (MASIs) in an animal model, and (3) compare the magnetic resonance imaging (MRI) characteristics of ferumoxide-labeled viable and apoptotic MSCs. MSCs labeled with ferumoxide by simple incubation, protamine transfection, or Lipofectin transfection were evaluated with MRI and histopathology. Ferumoxide-labeled and unlabeled viable and apoptotic MSCs in osteochondral defects of rat knee joints were evaluated over 12 weeks with MRI. Signal to noise ratios (SNRs) of viable and apoptotic labeled MASIs were tested for significant differences using t-tests. A simple incubation labeling protocol demonstrated the best compromise between significant magnetic resonance signal effects and preserved cell viability and potential for immediate clinical translation. Labeled viable and apoptotic MASIs did not show significant differences in SNR. Labeled viable but not apoptotic MSCs demonstrated an increasing area of T2 signal loss over time, which correlated to stem cell proliferation at the transplantation site. Histopathology confirmed successful engraftment of viable MSCs. The engraftment of iron oxide-labeled MASIs by simple incubation can be monitored over several weeks with MRI. Viable and apoptotic MASIs can be distinguished via imaging signs of cell proliferation at the transplantation site.
    Molecular Imaging 06/2012; 11(3):197-209. · 3.41 Impact Factor
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    ABSTRACT: Although pathologic response to neoadjuvant chemotherapy is highly correlated with survival among patients with osteosarcoma, there are currently no established molecular markers to predict response to chemotherapy. The objective of this study was to investigate the relationship of P16 expression in pretreatment osteosarcoma tumors to pathologic necrotic response after neoadjuvant chemotherapy. A tissue microarray was created from paraffin-embedded pretreatment biopsy specimens of 40 patients with osteosarcoma. Immunohistochemistry was performed with commercially available P16 monoclonal mouse antibody. Expression of P16 was defined as nuclear staining in 30% or greater of cells. Percent tumor necrosis was measured in postchemotherapy resection specimens per established protocols, and 90% or greater tumor necrosis was considered "good." Data were abstracted on age, sex, tumor site, and histologic subtype. Univariate and multivariate analyses were performed. The median age was 15 years, 52% were female, and 35% of tumors were located in the femur. P16 expression was present in 62%. Median posttreatment tumor necrosis was 90%, and 55% of patients experienced "good" chemotherapy response (≥90% necrosis). On univariate analysis, P16 expression correlated positively with median percent necrosis and "good" chemotherapy response (P = .004 and .003, respectively). On logistic regression analysis, P16 expression was independently associated with chemotherapy response after controlling for age, subtype, sex, and location (odds ratio, 43.5; 95% confidence interval, 2.64-708.9; P = .008). In summary, immunohistochemical expression of P16 significantly correlates with chemotherapy response in osteosarcoma. P16 expression may be a useful biomarker to guide treatment selection.
    Human pathology 05/2012; 43(11):1948-54. · 2.81 Impact Factor
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    ABSTRACT: Ewing sarcoma (ES) is a malignant tumor of bone and soft tissue of children and young adults. Patients with ES are treated with intensive chemotherapy regimens. We describe predictors of acute chemotherapy-associated toxicity in this population. In this retrospective cohort study, records of ES patients treated at two academic medical centers between 1980 and 2010 were reviewed. Grade 3 and 4 non-hematologic chemotherapy-associated toxicities during frontline therapy were recorded for each patient, along with potential clinical and demographic predictors of toxicity. Bivariate analyses were performed using the Fisher exact test. Multivariate analysis was performed using logistic regression. The cohort included 142 patients with ES and toxicity data. In bivariate analyses, age <12 years at diagnosis, Latino ethnicity, low family income, and treatment on a clinical trial were associated with higher incidence of toxicity (P < 0.01). Tumor size, site, stage, mode of local control, body mass index, overall chemotherapy exposure and dose-intensity were not associated with toxicity. In multivariate analysis, low income (odds ratio (OR) 4.97, 95% confidence interval (CI) 1.9-13.1), clinical trial enrollment (OR 3.67, 95% CI 1.2-10.9), pelvic tumor site (OR 3.88, 95% CI 1.17-12.88), and age <12 years (OR 2.8, 95% CI 1.0-7.5) were independent predictors of toxicity. ES patients who are younger, of Latino ethnicity, have pelvic tumors or low income have higher rates of toxicity that may require increased supportive care. Treatment on a clinical trial was also associated with higher rates of toxicity, though this finding may reflect better reporting in these patients.
    Pediatric Blood & Cancer 12/2011; 59(4):611-6. · 2.35 Impact Factor
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    ABSTRACT: We present the case of a 59-year-old woman with a history of plastic surgery at the forehead who complained of progressive indentations at the frontal skull. CT and MR scans revealed significant bone thinning, presenting as lytic skull lesions, which progressed over a period of 3 years. Biopsies were obtained from the lytic lesions and histology showed fibrotic tissue, synthetic residue of previous cosmetic procedure, and no evidence of infection or neoplasm. Progressive cranial bone resorption places the patient at increased risk for cerebral injury. This case highlights a potential complication after cosmetic facial surgery, with bony resorption resulting in both skull deformation and increased risk for cerebral injury.
    Skeletal Radiology 11/2011; 41(4):477-81. · 1.74 Impact Factor

Publication Stats

339 Citations
201.81 Total Impact Points


  • 2003–2014
    • University of California, San Francisco
      • • Department of Pathology
      • • Department of Laboratory Medicine
      San Francisco, California, United States
  • 2013
    • Memorial Sloan-Kettering Cancer Center
      New York City, New York, United States
  • 2012–2013
    • Stanford University
      • • Department of Medicine
      • • Department of Radiology
      Palo Alto, California, United States
    • University of Cologne
      Köln, North Rhine-Westphalia, Germany
    • San Francisco VA Medical Center
      San Francisco, California, United States
  • 2011
    • Tan Tock Seng Hospital
      Tumasik, Singapore
  • 2006
    • Mayo Clinic - Rochester
      Rochester, Minnesota, United States