Jennifer R Grandis

University of Pittsburgh, Pittsburgh, Pennsylvania, United States

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Publications (288)1755.39 Total impact

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    ABSTRACT: Aberrant activation of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) 3 has been implicated in cell proliferation and survival of many cancers including head and neck squamous cell carcinoma (HNSCC). AZD1480, an orally active pharmacologic inhibitor of JAK1/JAK2, has been tested in several cancer models. In the present study, the in vitro and in vivo effects of AZD1480 were evaluated in HNSCC preclinical models to test the potential use of JAK kinase inhibition for HNSCC therapy. AZD1480 treatment decreased HNSCC proliferation in HNSCC cell lines with half maximal effective concentration (EC50) values ranging from 0.9 to 4 μM in conjunction with reduction of pSTAT3Tyr705 expression. In vivo antitumor efficacy of AZD1480 was demonstrated in patient-derived xenograft (PDX) models derived from two independent HNSCC tumors. Oral administration of AZD1480 reduced tumor growth in conjunction with decreased pSTAT3Tyr705 expression that was observed in both PDX models. These findings suggest that the JAK1/2 inhibitors abrogate STAT3 signaling and may be effective in HNSCC treatment approaches. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Neoplasia (New York, N.Y.) 03/2015; 3(3). DOI:10.1016/j.neo.2015.01.003 · 5.40 Impact Factor
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    ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) accounts for more than 5% of all cancers worldwide. The mortality rate of HNSCC has remained unchanged (approximately 50%) over the last few decades. Ubiquitous overexpression of wild type EGFR in many solid tumors has led to the development of EGFR targeted therapies. EGFR can be constitutively activated via several mechanisms including the truncated, EGFR variant III isoform (EGFRvIII). EGFRvIII lacks exons 2-7 and has been reported to be present in up to 20-40% of HNSCC. EGFRvIII has been shown to contribute to cetuximab resistance. The mechanisms leading to EGFRvIII expression in HNSCC are unknown. The present investigation was undertaken to determine the etiology of EGFRvIII in HNSCC. Fixed HNSCC and glioma tissues were analyzed by fluorescence in situ hybridization for EGFR amplification. DNA and RNA from fresh frozen specimens were used to determine the presence of EGFRvIII transcripts and the mechanisms of expression via PCR, RT-PCR and RNA sequencing. Unlike glioma, EGFRvIII expression in HNSCC did not correlate with EGFR amplification. We found evidence of genomic deletion of the exon 2-7 in 6 of 7 HNSCC cases examined, however, the presence of genomic deletion did not always result in mRNA expression of EGFRvIII. RNA sequencing with automated alignment did not identify EGFRvIII due to microhomology between intron 1 and exon 8. RNA sequencing analyzed by manual alignment methods did not correlate well with RT-PCR and PCR findings. These findings suggest that genomic deletion as well as additional regulatory mechanisms may contribute to EGFRvIII expression in HNSCC. Further, large scale automated alignment of sequencing are unlikely to identify EGFRvIII and an assay specifically designed to detect EGFRvIII may be necessary to detect this altered form of EGFR in HNSCC tumors.
    PLoS ONE 02/2015; 10(2):e0117781. DOI:10.1371/journal.pone.0117781 · 3.53 Impact Factor
  • Peter S Hammerman, D Neil Hayes, Jennifer R Grandis
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    ABSTRACT: Large and comprehensive genomic surveys of head and neck squamous cell carcinomas (HNSCC) are now greatly increasing our understanding of the diversity of this disease and the key genomic changes that drive these tumors. The results from these studies are beginning to inform the introduction of novel therapies for patients with HNSCCs. Here, we review some of the key findings from recent genomic studies of head and neck cancers, including the most comprehensive study to date from The Cancer Genome Atlas Network. Cancer Discov; 5(3); 1-6. ©2015 AACR. ©2015 American Association for Cancer Research.
    Cancer Discovery 02/2015; 5(3). DOI:10.1158/2159-8290.CD-14-1205 · 15.93 Impact Factor
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    ABSTRACT: EGFR polymorphisms have not been thoroughly evaluated for association with head and neck squamous cell carcinoma (HNSCC) risk. We genotyped 578 HNSCC patients and 588 cancer-free controls for 60 EGFR single nucleotide polymorphisms (SNPs) and tested associations with HNSCC risk. EGFR intronic SNPs rs12535536, rs2075110, rs1253871, rs845561 and rs6970262 and synonymous SNP rs2072454 were associated with HNSCC risk among all subjects (p<0.05). SNPs rs12538371, rs845561, and rs6970262 were significantly associated with HNSCC risk (p<0.05) among never tobacco users. We identified EGFR variants that likely modify risk for HNSCC including three variants that contribute to tobacco-independent risk. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
    Cancer Letters 12/2014; 357(2). DOI:10.1016/j.canlet.2014.12.008 · 5.02 Impact Factor
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    ABSTRACT: BACKGROUND Earlier detection and diagnosis of head and neck squamous cell carcinoma (HNSCC) should lead to improved outcomes. However, to the authors' knowledge, no effective screening strategy has been identified to date. In the current study, the authors evaluated whether it would be useful to screen subjects targeted for lung cancer screening for HNSCC as well.METHODS Medical records, death certificates, and cancer registry and questionnaire data were used to determine the number of observed incident HNSCC cases in the Pittsburgh Lung Screening Study (PLuSS), a cohort of current and former smokers aged ≥50 years with a ≥12.5 pack-year smoking history. The expected number of cases was estimated using stratum-specific incidence rates obtained from Surveillance, Epidemiology, and End Results data for 2000 through 2011. The standardized incidence ratio was calculated to examine the difference between the observed and expected number of cases.RESULTSOf the 3587 at-risk participants in the PLuSS, 23 (0.64%) developed HNSCC over a total of 32,201 person-years of follow-up. This finding was significantly higher than expected based on incidence rates obtained from the Surveillance, Epidemiology, and End Results program (13.70 cases expected; standardized incidence ratio, 1.68 [95% confidence interval, 1.06-2.52]). The excess burden of HNSCC in the PLuSS was 28.9 cases per 100,000 person-years. Observed incident cases were significantly more often male, had started smoking at a younger age, smoked more per day, and had more pack-years of smoking than the rest of the PLuSS at-risk participants.CONCLUSIONS The results of the current study provide a rationale for offering head and neck cancer screening along with computed tomography screening for lung cancer. Randomized controlled trials that assess the effectiveness of adding examination of the head and neck area to lung cancer screening programs are warranted. Cancer 2015. © 2015 American Cancer Society.
    Cancer 12/2014; 121(9). DOI:10.1002/cncr.29189 · 4.90 Impact Factor
  • Netanya I Pollock, Jennifer R Grandis
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    ABSTRACT: The majority of patients with head and neck squamous cell carcinoma (HNSCC) present with advanced-stage disease. Current standard of care is surgery followed by adjuvant radiation therapy with or without chemotherapy or chemoradiation alone. The addition of cetuximab for the treatment of patients with locally advanced or recurrent/metastatic HNSCC has improved overall survival and locoregional control; however, responses are often modest, and treatment resistance is common. A variety of therapeutic strategies are being explored to overcome cetuximab resistance by blocking candidate proteins implicated in resistance mechanisms such as HER2. Several HER2 inhibitors are in clinical development for HNSCC, and HER2-targeted therapy has been approved for several cancers. This review focuses on the biology of HER2, its role in cancer development, and the rationale for clinical investigation of HER2 targeting in HNSCC. Copyright © 2014, American Association for Cancer Research.
    Clinical Cancer Research 11/2014; 21(3). DOI:10.1158/1078-0432.CCR-14-1432 · 8.19 Impact Factor
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    Yu Du, Jennifer R Grandis
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    ABSTRACT: Protein tyrosine phosphatases (PTPs) play an important role in regulating cell signaling events in coordination with tyrosine kinases to control cell proliferation, apoptosis, survival, migration, and invasion. Receptor-type protein tyrosine phosphatases (PTPRs) are a subgroup of PTPs that share a transmembrane domain with resulting similarities in function and target specificity. In this review, we summarize genetic and epigenetic alterations including mutation, deletion, amplification, and promoter methylation of PTPRs in cancer and consider the consequences of PTPR alterations in different type of cancers. We also summarize recent developments using PTPRs as prognostic or predictive biomarkers and/or direct targets. Increased understanding of the role of PTPRs in cancer may provide opportunities to improve therapeutic approaches.
    Ai zheng = Aizheng = Chinese journal of cancer 10/2014; 34(2). DOI:10.5732/cjc.014.10146
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    ABSTRACT: Previous studies have established that a subset of head and neck tumors contains human papillomavirus (HPV) sequences and that HPV-driven head and neck cancers display distinct biological and clinical features. HPV is known to drive cancer by the actions of the E6 and E7 oncoproteins, but the molecular architecture of HPV infection and its interaction with the host genome in head and neck cancers have not been comprehensively described. We profiled a cohort of 279 head and neck cancers with next generation RNA and DNA sequencing and show that 35 (12.5%) tumors displayed evidence of high-risk HPV types 16, 33, or 35. Twenty-five cases had integration of the viral genome into one or more locations in the human genome with statistical enrichment for genic regions. Integrations had a marked impact on the human genome and were associated with alterations in DNA copy number, mRNA transcript abundance and splicing, and both inter- and intrachromosomal rearrangements. Many of these events involved genes with documented roles in cancer. Cancers with integrated vs. nonintegrated HPV displayed different patterns of DNA methylation and both human and viral gene expressions. Together, these data provide insight into the mechanisms by which HPV interacts with the human genome beyond expression of viral oncoproteins and suggest that specific integration events are an integral component of viral oncogenesis.
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    ABSTRACT: Synthesis and SAR investigation of 2-guanidinoquinazolines, initially identified in a high content screen for selective STAT3 pathway inhibitors, led to a more potent analog (11c) that demonstrated improved anti-proliferative activity against a panel of HNSCC cell lines.
    Bioorganic & Medicinal Chemistry Letters 09/2014; 24(21). DOI:10.1016/j.bmcl.2014.09.001 · 2.33 Impact Factor
  • Noah D Peyser, Jennifer R Grandis
    Pharmacogenomics 09/2014; 15(12):1553-5. DOI:10.2217/pgs.14.122 · 3.43 Impact Factor
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    ABSTRACT: PurposeIntratumoral metabolic heterogeneity may increase the likelihood of treatment failure due to the presence of a subset of resistant tumor cells. Using a head and neck squamous cell carcinoma (HNSCC) xenograft model and a real-time fluorescence imaging approach, we tested the hypothesis that tumors are metabolically heterogeneous, and that tumor hypoxia alters patterns of glucose uptake within the tumor.Experimental DesignCal33 cells were grown as xenograft tumors (n = 16) in nude mice after identification of this cell line's metabolic response to hypoxia. Tumor uptake of fluorescent markers identifying hypoxia, glucose import, or vascularity was imaged simultaneously using fluorescent molecular tomography. The variability of intratumoral 2-deoxyglucose (IR800-2-DG) concentration was used to assess tumor metabolic heterogeneity, which was further investigated using immunohistochemistry for expression of key metabolic enzymes. HNSCC tumors in patients were assessed for intratumoral variability of 18F-fluorodeoxyglucose (18F-FDG) uptake in clinical PET scans.ResultsIR800-2-DG uptake in hypoxic regions of Cal33 tumors was 2.04 times higher compared to the whole tumor (p = 0.0001). IR800-2-DG uptake in tumors containing hypoxic regions was more heterogeneous as compared to tumors lacking a hypoxic signal. Immunohistochemistry staining for HIF-1α, carbonic anhydrase 9, and ATP synthase subunit 5β confirmed xenograft metabolic heterogeneity. We detected heterogeneous 18F-FDG uptake within patient HNSCC tumors, and the degree of heterogeneity varied amongst tumors.ConclusionHypoxia is associated with increased intratumoral metabolic heterogeneity. 18F-FDG PET scans may be used to stratify patients according to the metabolic heterogeneity within their tumors, which could be an indicator of prognosis.
    PLoS ONE 08/2014; 9(8):e102452. DOI:10.1371/journal.pone.0102452 · 3.53 Impact Factor
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    ABSTRACT: Purpose: Treatment with cisplatin or cetuximab combined with radiotherapy each yield superior survival in locally advanced squamous cell head and neck cancer (LA-SCCHN) compared with radiotherapy alone. Eastern Cooperative Oncology Group Trial E3303 evaluated the triple combination. Experimental Design: Patients with stage IV unresectable LA-SCCHN received a loading dose of cetuximab (400 mg/m(2)) followed by 250 mg/m(2)/week and cisplatin 75 mg/m(2) q 3 weeks x3 cycles concurrent with standard fractionated radiotherapy. In the absence of disease progression or unacceptable toxicity, patients continued maintenance cetuximab for 6 to 12 months. Primary endpoint was 2-year progression-free survival (PFS). Patient tumor and blood correlates, including tumor human papillomavirus (HPV) status, were evaluated for association with survival. Results: A total of 69 patients were enrolled; 60 proved eligible and received protocol treatment. Oropharyngeal primaries constituted the majority (66.7%), stage T4 48.3% and N2-3 91.7%. Median radiotherapy dose delivered was 70 Gy, 71.6% received all three cycles of cisplatin, and 74.6% received maintenance cetuximab. Median PFS was 19.4 months, 2-year PFS 47% [95% confidence interval (CI), 33%-61%]. Two-year overall survival (OS) was 66% (95% CI, 53%-77%); median OS was not reached. Response rate was 66.7%. Most common grade >= 3 toxicities included mucositis (55%), dysphagia (46%), and neutropenia (26%); one attributable grade 5 toxicity occurred. Only tumor HPV status was significantly associated with survival. HPV was evaluable in 29 tumors; 10 (all oropharyngeal) were HPV positive. HPV+ patients had significantly longer OS and PFS (P = 0.004 and P = 0.036, respectively). Conclusions: Concurrent cetuximab, cisplatin, and radiotherapy were well tolerated and yielded promising 2-year PFS and OS in LA-SCCHN with improved survival for patients with HPV+ tumors. (C) 2014 AACR.
    Clinical Cancer Research 08/2014; 20(19). DOI:10.1158/1078-0432.CCR-14-0051 · 8.19 Impact Factor
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    ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is characterized by aggressive behavior with a propensity for metastasis and recurrence. Here we report a comprehensive analysis of the molecular and clinical features of HNSCC that govern patient survival. We find that TP53 mutation is frequently accompanied by loss of chromosome 3p and that the combination of these events is associated with a surprising decrease in survival time (1.9 years versus >5 years for TP53 mutation alone). The TP53-3p interaction is specific to chromosome 3p and validates in HNSCC and pan-cancer cohorts. In human papillomavirus (HPV)-positive tumors, in which HPV inactivates TP53, 3p deletion is also common and is associated with poor outcomes. The TP53-3p event is modified by mir-548k expression, which decreases survival further, and is mutually exclusive with mutations affecting RAS signaling. Together, the identified markers underscore the molecular heterogeneity of HNSCC and enable a new multi-tiered classification of this disease.
    Nature Genetics 08/2014; 46(9). DOI:10.1038/ng.3051 · 29.65 Impact Factor
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    ABSTRACT: Aberrant activation of EGFR in human cancers promotes tumorigenesis through stimulation of AKT signaling. Here, we determined that the discoidina neuropilin-like membrane protein DCBLD2 is upregulated in clinical specimens of glioblastomas and head and neck cancers (HNCs) and is required for EGFR-stimulated tumorigenesis. In multiple cancer cell lines, EGFR activated phosphorylation of tyrosine 750 (Y750) of DCBLD2, which is located within a recently identified binding motif for TNF receptor-associated factor 6 (TRAF6). Consequently, phosphorylation of DCBLD2 Y750 recruited TRAF6, leading to increased TRAF6 E3 ubiquitin ligase activity and subsequent activation of AKT, thereby enhancing EGFR-driven tumorigenesis. Moreover, evaluation of patient samples of gliomas and HNCs revealed an association among EGFR activation, DCBLD2 phosphorylation, and poor prognoses. Together, our findings uncover a pathway in which DCBLD2 functions as a signal relay for oncogenic EGFR signaling to promote tumorigenesis and suggest DCBLD2 and TRAF6 as potential therapeutic targets for human cancers that are associated with EGFR activation.
    The Journal of clinical investigation 07/2014; DOI:10.1172/JCI73093 · 13.77 Impact Factor
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    ABSTRACT: One of the greatest challenges in biomedical research, drug discovery and diagnostics is understanding how seemingly identical cells can respond differently to perturbagens including drugs for disease treatment. Although heterogeneity has become an accepted characteristic of a population of cells, in drug discovery it is not routinely evaluated or reported. The standard practice for cell-based, high content assays has been to assume a normal distribution and to report a well-to-well average value with a standard deviation. To address this important issue we sought to define a method that could be readily implemented to identify, quantify and characterize heterogeneity in cellular and small organism assays to guide decisions during drug discovery and experimental cell/tissue profiling. Our study revealed that heterogeneity can be effectively identified and quantified with three indices that indicate diversity, non-normality and percent outliers. The indices were evaluated using the induction and inhibition of STAT3 activation in five cell lines where the systems response including sample preparation and instrument performance were well characterized and controlled. These heterogeneity indices provide a standardized method that can easily be integrated into small and large scale screening or profiling projects to guide interpretation of the biology, as well as the development of therapeutics and diagnostics. Understanding the heterogeneity in the response to perturbagens will become a critical factor in designing strategies for the development of therapeutics including targeted polypharmacology.
    PLoS ONE 07/2014; 9(7):e102678. DOI:10.1371/journal.pone.0102678 · 3.53 Impact Factor
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    ABSTRACT: Purpose: Tumor metastasis is the leading cause of death in cancer patients. However, the mechanisms that underlie metastatic progression remain unclear. We examined TMEM16A (ANO1) expression as a key factor shifting tumors between growth and metastasis. Experimental Design: We evaluated 26 pairs of primary and metastatic lymph node tissue from patients with squamous cell carcinoma of the head and neck (SCCHN) for differential expression of TMEM16A. Additionally, we identified mechanisms by which TMEM16A expression influences tumor cell motility via proteomic screens of cell lines and in vivo mouse studies of metastasis. Results: Compared to primary tumors, TMEM16A expression decreases in metastatic lymph nodes of patients with SCCHN. Stable reduction of TMEM16A expression enhances cell motility and increases metastases while decreasing tumor proliferation in an orthotopic mouse model. Evaluation of human tumor tissues suggests an epigenetic mechanism for decreasing TMEM16A expression through promoter methylation that correlated with a transition between an epithelial and a mesenchymal phenotype. These effects of TMEM16A expression on tumor cell size and epithelial to mesenchymal transition (EMT) required the amino acid residue, serine 970 (S970); however, mutation of S970 to alanine does not disrupt the proliferative advantages of TMEM16A overexpression. Further, S970 mediates the association of TMEM16A with Radixin, an actin-scaffolding protein implicated in EMT. Conclusions: Together, our results identify TMEM16A, an eight trans-membrane domain Ca2+-activated Cl- channel, as a primary driver of the "Grow" or "Go" model for cancer progression, in which TMEM16A expression acts to balance tumor proliferation and metastasis via its promoter methylation.
    Clinical Cancer Research 06/2014; 20(17). DOI:10.1158/1078-0432.CCR-14-0363 · 8.19 Impact Factor
  • Julie E Bauman, Jennifer R Grandis
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    ABSTRACT: Cetuximab is a murine-human chimeric IgG1 mAb directed against the EGFR that is approved for use in patients with colorectal and head and neck carcinomas. While some patients benefit greatly from cetuximab, many do not; therefore, strategies to increase the efficacy of this drug are of great clinical interest. In this issue of the JCI, Kohrt and colleagues report a strategy for enhancing the secondary immune response to cetuximab that involves sequential targeting with an agonist mAb against CD137 expressed on NK and T cells.
    Journal of Clinical Investigation 05/2014; 124(6). DOI:10.1172/JCI76264 · 13.77 Impact Factor
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    ABSTRACT: Little is known regarding molecular markers in head and neck squamous cell carcinoma (HNSCC) that predict responsiveness to different therapeutic regimens or predict HNSCC progression. Mutations in procaspase-8 occur in 9% of HNSCC primary tumors, but the functional consequences of these mutations are poorly understood. In this study, we examined the impact of four, representative, HNSCC-associated procaspase-8 mutations on activation of the extrinsic apoptosis pathway, as well as cellular migration and invasion, and in vivo tumor growth. All four mutant proteins acted to potently inhibit activation of apoptosis following treatment with TRAIL or agonistic anti-Fas. In contrast to wild-type procaspase-8, the mutant proteins were not recruited to FADD following treatment with TRAIL or anti-Fas, but may be constitutively bound by FADD. Three of the four procaspase-8 mutants promoted enhanced cellular migration and invasion through matrigel, relative to that seen with the wild-type procaspase-8 protein. Procaspase-8 mutation also stimulated the growth of HNSCC xenograft tumors. These findings indicate that HNSCC-associated procaspase-8 mutations inhibit activation of the extrinsic apoptosis pathway and are likely to represent markers for resistance to therapeutic regimens incorporating death receptor activators. Moreover, procaspase-8 mutations may serve as markers of HNSCC tumor progression, as exemplified by enhanced migration, invasion, and tumor growth.
    Molecular oncology 04/2014; 8(7). DOI:10.1016/j.molonc.2014.03.018 · 5.94 Impact Factor
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    ABSTRACT: The epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways are upregulated in head and neck squamous cell carcinoma (HNSCC). Preclinical models indicate synergistic anti-tumor activity from dual blockade. We conducted a randomized, double-blind, placebo-controlled window trial of erlotinib, an EGFR inhibitor; erlotinib plus sulindac, a non-selective COX inhibitor, vs. placebo. Patients with untreated, operable Stage II-IVb HNSCC were randomized 5:5:3 to erlotinib, erlotinib-sulindac, or placebo. Tumor specimens were collected before and after 7-14 days of treatment. The primary endpoint was change in Ki-67 proliferation index. We hypothesized an ordering effect in Ki-67 reduction: erlotinib-sulindac > erlotinib > placebo. We evaluated tissue microarrays by immunohistochemistry for pharmacodynamic modulation of EGFR and COX-2 signaling intermediates. From 2005-2009, 47 patients were randomized for the target 39 evaluable patients. Thirty-four tumor pairs were of sufficient quality to assess biomarker modulation. Ki-67 was significantly decreased by erlotinib or erlotinib-sulindac (omnibus comparison, two-sided Kruskal-Wallis, p=0.04). Wilcoxon pairwise contrasts confirmed greater Ki-67 effect in both erlotinib groups (erlotinib-sulindac vs. placebo p=0.043; erlobinib vs. placebo, p=0.027). There was a significant trend in ordering of Ki-67 reduction: erlotinib-sulindac > erlotinib > placebo (two-sided exact Jonckheere-Terpstra, p =0.0185). Low baseline pSrc correlated with greater Ki-67 reduction (R2 = .312, p = 0.024). Brief treatment with erlotinib significantly decreased proliferation in HNSCC, with additive effect from sulindac. Efficacy studies of dual EGFR-COX inhibition are justified. pSrc is a potential resistance biomarker for anti-EGFR therapy, and warrants investigation as a molecular target.
    Clinical Cancer Research 04/2014; 20(12). DOI:10.1158/1078-0432.CCR-13-3360 · 8.19 Impact Factor
  • Molecular Cancer Therapeutics 01/2014; 12(11_Supplement):A23-A23. DOI:10.1158/1535-7163.TARG-13-A23 · 6.11 Impact Factor

Publication Stats

10k Citations
1,755.39 Total Impact Points


  • 1970–2015
    • University of Pittsburgh
      • • Department of Otolaryngology
      • • Department of Medicine
      • • Pittsburgh Cancer Institute
      Pittsburgh, Pennsylvania, United States
  • 2011
    • Broad Institute of MIT and Harvard
      • Cancer Program
      Cambridge, Massachusetts, United States
  • 2009
    • University of Wisconsin, Madison
      • Department of Human Oncology
      Madison, MS, United States
  • 2007
    • The Chinese University of Hong Kong
      Hong Kong, Hong Kong
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 2006
    • Johns Hopkins University
      Baltimore, Maryland, United States
    • Duke University
      Durham, North Carolina, United States
  • 2005
    • Universität Mannheim
      Mannheim, Baden-Württemberg, Germany
  • 2002–2003
    • Universität Heidelberg
      Heidelburg, Baden-Württemberg, Germany
  • 1998
    • Childrens Hospital of Pittsburgh
      • Division of Pediatric Otolaryngology (ENT)
      Pittsburgh, Pennsylvania, United States