Janis M Taube

Johns Hopkins University, Baltimore, Maryland, United States

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Publications (61)325.61 Total impact

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    ABSTRACT: To evaluate programmed death ligand 1 (PD-L1) expression in urothelial carcinoma of the bladder in relationship with tumor-infiltrating CD8+ T cells. Tissue microarrays were prepared from 56 cystectomy specimens performed at our hospital (1994-2002). PD-L1 immunoexpression was assessed using the murine antihuman PD-L1 monoclonal antibody 5H1. Extent of membranous PD-L1 expression was assigned in each spot. Spots showing ≥5% expression were considered positive. Average PD-L1 expression per tumor was also calculated (5% positivity cutoff). "High CD8 density" was defined as the presence of ≥60 CD8+ intraepithelial lymphocytes per high power field in a given spot. A tumor was considered high density if ≥50% of its spots were of high density. PD-L1 expression was positive in approximately 20% of tumors. None of the benign urothelium spots expressed PD-L1. High CD8 density was observed in approximately 20% of cases. CD8 density did not correlate with PD-L1 expression. Overall survival (OS) and disease-specific survival (DSS) rates were 14% and 28%, respectively (median follow-up, 31.5 months). PD-L1 expression was associated with age at cystectomy (P = .01). Remaining clinicopathologic parameters were not associated with PD-L1 expression or CD8 density. High CD8 density was associated with favorable OS (P = .02) and DSS (P = .02). The same was true when CD8 density was adjusted for demographic and clinicopathologic parameters. There was no correlation between PD-L1 expression and outcome. High intratumoral CD8+ T cell density is associated with better OS and DSS in invasive urothelial carcinoma of the bladder. We found no correlation between PD-L1 expression and outcome. Copyright © 2015 Elsevier Inc. All rights reserved.
    Urology 03/2015; 85(3):703.e1-6. DOI:10.1016/j.urology.2014.10.020 · 2.13 Impact Factor
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    ABSTRACT: PD-L1 expression in melanoma correlates with response to PD-1 pathway blocking antibodies. Aberrant tumor cell PD-L1 expression may be oncogene-driven and/or induced by interferon-gamma (IFN-g). Melanomas express PD-L1 in association with tumor infiltrating lymphocytes (TILs), but the potential contribution of the BRAF V600E mutation (BRAFmut) to induced PD-L1 expression has not been determined. Fifty-two archival melanocytic lesions were simultaneously assessed for PD-L1 expression, TIL infiltration and BRAFmut. IFN-g-induced PD-L1 expression in cultured melanomas was also assessed according to BRAF status. Melanocyte PD-L1 expression was observed in 40% of specimens, and BRAFmut was observed in 42% of specimens, but there was no significant concordance between these variables. Almost all melanocytes displaying PD-L1 expression were observed adjacent to TILs, irrespective of BRAF status. TIL(-) lesions were not more likely to be associated with BRAFmut, compared to TIL(+) lesions. Baseline expression of PD-L1 by melanoma cell lines was virtually nil regardless of BRAFmut status, and the intensity of interferon-induced PD-L1 expression in melanoma cell lines likewise did not correlate with BRAF mutational status. PD-L1 expression in melanocytic lesions does not correlate with the BRAFmut. Thus, distinct populations of melanoma patients will likely benefit from BRAF inhibitors vs. PD-1 pathway blockade.
    11/2014; DOI:10.1158/2326-6066.CIR-14-0145
  • Journal of the American Academy of Dermatology 11/2014; 71(5):e206-e207. DOI:10.1016/j.jaad.2014.04.005 · 5.00 Impact Factor
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    ABSTRACT: We examined the immune microenvironment of primary colorectal cancer (CRC) using immunohistochemistry, laser capture microdissection/qRT-PCR, flow cytometry and functional analysis of tumor infiltrating lymphocytes. A subset of CRC displayed high infiltration with activated CD8+ CTL as well as activated Th1 cells characterized by IFN-γ production and the Th1 transcription factor Tbet. Parallel analysis of tumor genotypes revealed that virtually all of the tumors with this active Th1/CTL microenvironment had defects in mismatch repair, as evidenced by microsatellite instability (MSI). Counterbalancing this active Th1/CTL microenvironment, MSI tumors selectively demonstrated highly up-regulated expression of multiple immune checkpoints, including five - PD-1, PD-L1, CTLA-4, LAG-3 and IDO - currently being targeted clinically with inhibitors. These findings link tumor genotype with the immune microenvironment, and explain why MSI tumors are not naturally eliminated despite a hostile Th1/CTL microenvironment. They further suggest that blockade of specific checkpoints may be selectively efficacious in the MSI subset of CRC.
    Cancer Discovery 10/2014; 5(1). DOI:10.1158/2159-8290.CD-14-0863 · 15.93 Impact Factor
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    ABSTRACT: Chordomas are rare malignant tumors that are postulated to arise from remnants of the notochord. Currently, the interaction between chordomas and the host immune system is poorly understood. The checkpoint protein, PD-1 is expressed by circulating lymphocytes and is a marker of activation and exhaustion. Its ligands, PD-L1 (B7-H1, CD274) and PD-L2 (B7-DC, CD273), are expressed on a variety of human cancers; however this pathway has not been previously reported in chordomas. We used flow cytometric and RT-PCR analysis in three established primary and recurrent chordoma cell lines (U-CH1, U-CH2, and JHC7) as well as immunohistochemical analysis of chordoma tissues from 10 patients to identify and localize expression of PD-1 pathway proteins. PD-1 ligands are not constitutively expressed by chordoma cells, but their expression is induced in the setting of pro-inflammatory cytokines in all cell lines examined. In paraffin embedded tissues, we found that tumor infiltrating lymphocytes expressed PD-1 in 3/6 cases. We also found that, although chordoma cells did not express significant levels of PD-L1, PD-L1 expression was observed on tumor-infiltrating macrophages and tumor infiltrating lymphocytes. Our study suggests that PD-1, PD-L1, and PD-L2 are present in the microenvironment of a subset of chordomas analyzed. Future studies are needed to evaluate the contribution of the PD-1 pathway to the immunosuppressive microenvironment of chordomas.
    Journal of Neuro-Oncology 10/2014; 121(2). DOI:10.1007/s11060-014-1637-5 · 2.79 Impact Factor
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    ABSTRACT: Primary effusion lymphoma (PEL) is a rare and aggressive lymphoma that arises in the context of immunosuppression and is characterized by co-infection with Epstein-Barr virus (EBV) and Human Herpesvirus-8/Kaposi sarcoma-associated herpesvirus (HHV-8/KSHV). It was originally described as arising in body cavity effusions, but presentation as a mass lesion (extracavitary PEL) is now recognized. Here we describe a case of PEL with an initial presentation as an intravascular lymphoma with associated skin lesions. The patient was a 53 year-old man with HIV/AIDS who presented with fevers, weight loss, and skin lesions concerning for Kaposi sarcoma (KS). A skin biopsy revealed no evidence of KS; however, dermal vessels contained large atypical cells that expressed CD31 and plasma cell markers but lacked most B and T cell antigens. The atypical cells expressed EBV and HHV-8. The patient subsequently developed a malignant pleural effusion containing the same neoplastic cell population. The findings in this case highlight the potential for unusual intravascular presentations of PEL in the skin as well as the importance of pursuing microscopic diagnosis of skin lesions in immunosuppressed patients.
    Journal of Cutaneous Pathology 10/2014; DOI:10.1111/cup.12405 · 1.56 Impact Factor
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    ABSTRACT: Objectives BRAF mutations have substantial therapeutic, diagnostic, and prognostic significance, so detecting and specifying them is an important part of the workload of molecular pathology laboratories. Pyrosequencing assays are well suited for this analysis but can produce complex results. Therefore, we introduce a pyrosequencing lookup table based on Pyromaker that assists the user in generating hypotheses for solving complex pyrosequencing results. Methods The lookup table contains all known mutations in the sequenced region and the positions in the dispensation sequence at which changes would occur with those mutations. We demonstrate the lookup table using a homebrew dispensation sequence for BRAF codons 596 to 605 as well as a commercially available kit-based dispensation sequence for codons 599 to 600. Results These results demonstrate that the homebrew dispensation sequence unambiguously identifies all known BRAF mutations in this region, whereas the kit-based dispensation sequence has one unresolvable degeneracy that could be solved with the addition of two injections. Conclusions Using the lookup table and confirmatory virtual pyrogram, we unambiguously solved clinical pyrograms of the complex mutations V600K (c.1798_1799delGTinsAA), V600R (c.1798_1799delGTinsAG), V600D (c.1799_1800delTGinsAT), V600E (c.1799_1800delTGinsAA), and V600_K601delinsE (c.1799_1801delTGA). In addition, we used the approach to hypothesize and confirm a new mutation in human melanoma, V600_K601delinsEI (c.1799_1802delTGAAinsAAAT).
    American Journal of Clinical Pathology 05/2014; 141(5):639-47. DOI:10.1309/AJCPVWH1K2ZIHHTV · 3.01 Impact Factor
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    ABSTRACT: Immunomodulatory drugs differ in mechanism-of-action from directly cytotoxic cancer therapies. Identifying factors predicting clinical response could guide patient selection and therapeutic optimization. Patients (N=41) with melanoma, non-small cell lung carcinoma (NSCLC), renal cell carcinoma (RCC), colorectal carcinoma or castration-resistant prostate cancer were treated on an early phase trial of anti-PD-1 (nivolumab) at one institution and had evaluable pre-treatment tumor specimens. Immunoarchitectural features including PD-1, PD-L1, and PD-L2 expression, patterns of immune cell infiltration, and lymphocyte subpopulations, were assessed for interrelationships and potential correlations with clinical outcomes. Membranous (cell surface) PD-L1 expression by tumor cells and immune infiltrates varied significantly by tumor type and was most abundant in melanoma, NSCLC, and RCC. In the overall cohort, PD-L1 expression was geographically associated with infiltrating immune cells (p<0.001), although lymphocyte-rich regions were not always associated with PD-L1 expression. Expression of PD-L1 by tumor cells and immune infiltrates was significantly associated with expression of PD-1 on lymphocytes. PD-L2, the second ligand for PD-1, was associated with PD-L1 expression. Tumor cell PD-L1 expression correlated with objective response to anti-PD-1 therapy, when analyzing either the specimen obtained closest to therapy or the highest scoring sample among multiple biopsies from individual patients. These correlations were stronger than borderline associations of PD-1 expression or the presence of intratumoral immune cell infiltrates with response. Tumor PD-L1 expression reflects an immune-active microenvironment and, while associated other immunosuppressive molecules including PD-1 and PD-L2, is the single factor most closely correlated with response to anti-PD-1 blockade.
    Clinical Cancer Research 04/2014; 20(19). DOI:10.1158/1078-0432.CCR-13-3271 · 8.19 Impact Factor
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    ABSTRACT: Basal cell carcinoma (BCC) of the vulva is rare and may be confused with the much more commonly encountered high-risk human papillomavirus (HPV)-related basaloid squamous cell carcinoma (SCC). The HPV status of BCCs is not well established. This study assesses the utility of p16 and BerEP4 expression patterns and high-risk HPV detection for distinction of these tumors. Thirteen cases of vulvar BCC were analyzed by immunohistochemistry for p16 and BerEP4 expression. HPV status was assessed by in situ hybridization (ISH) with a high-risk HPV wide-spectrum probe and HPV 16 and 18 type-specific probes. All tumors (13/13) demonstrated patchy p16 positivity, with <50% of tumor cells expressing p16 in all cases. None demonstrated the diffuse p16 expression characteristic of high-risk HPV-associated lesions. No high-risk HPV was detected by ISH (0/13). Eleven of 13 (85%) vulvar BCCs showed diffuse, intense expression of BerEP4. The 2 BerEP4-negative cases were notably squamatized. The lack of diffuse p16 expression and failure to detect high-risk HPV by ISH in vulvar BCCs indicate that these tumors are unrelated to high-risk HPV. Thus, these ancillary techniques, particularly p16 immunohistochemistry, are useful for distinguishing vulvar BCCs from basaloid forms of high-risk HPV-related vulvar SCC. BerEP4 expression can help in distinction of these tumors except in cases of BCC with extensive squamatization. Distinction of vulvar BCC from basaloid SCC is important because of differences in extent of surgical treatment for these entities.
    The American journal of surgical pathology 04/2014; 38(4):542-7. DOI:10.1097/PAS.0000000000000143 · 4.59 Impact Factor
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    ABSTRACT: Background: Treatment with a blocking αPD-1 antibody recently showed clinical efficacy for various tumors types. In this study, we characterized the expression profile of PD-1/PD-L1 and the potential of PD-1 blockade in human papilloma virus (HPV)-negative head and neck squamous cell carcinoma (HNSCC).Methods: Lymphocytes from peripheral blood, draining lymph nodes and the tumor were phenotyped for PD-1 expression, and their proliferative activity was assessed in the presence of blocking αPD-1 treatment. Primary tumor expression of PD-L1 was also analyzed using immunohistochemistry.Results: Lymphocyte PD-1 expression was abundant with highest expression in the tumor and in vitro mixed lymphocyte reaction demonstrated that PD-1 blockade could induce T cell proliferation. Furthermore, tumor cells were found to have three distinct patterns of PD-L1 expression with over 82% of the specimens demonstrating strong PD-L1 positivity.Conclusions: Our data strongly supports the use of αPD-1 blockade in HPV-negative HNSCC patients that are refractory to standard treatments. Head Neck, 2014
    Head & Neck 04/2014; DOI:10.1002/hed.23706 · 3.01 Impact Factor
  • Janis M Taube
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    ABSTRACT: The cooperation of tumor infiltrating lymphocytes and tertiary lymphoid tissue in early stage colorectal carcinoma further corroborates the strong immune influences on tumor progression and patient outcome. Immune factors in the tumor microenvironment may warrant inclusion in pathology reports and staging systems for prognostication and prediction of therapeutic response.
    Clinical Cancer Research 03/2014; 20(8). DOI:10.1158/1078-0432.CCR-14-0328 · 8.19 Impact Factor
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    ABSTRACT: Detection of BRAF mutations is an established standard of care to predict small-molecule inhibitor (vemurafenib) response in metastatic melanoma. Molecular assays should be designed to detect not only the most common p.V600E mutation, but also p.V600K and other non-p.V600E mutations. The purpose of this study was to assess if tumor cellularity can function as a quality assurance (QA) measure in molecular diagnostics. Potential causes of discrepancy between the observed and predicted mutant allele percentage were also explored. We correlated pathologist-generated estimates of tumor cellularity versus mutant allele percentage via pyrosequencing as a QA measure for BRAF mutation detection in formalin-fixed, paraffin-embedded melanoma specimens. BRAF mutations were seen in 27/62 (44 %) specimens, with 93 % p.V600E and 7 % non-p.V600E. Correlation between p.V600E mutant percentage and tumor cellularity was poor-moderate (r = -0.02; p = 0.8), primarily because six samples showed a low p.V600E signal despite high tumor cellularity. A QA investigation revealed that our initial pyrosequencing assay showed a false positive, weak p.V600E signal in specimens with a p.V600K mutation. A redesigned assay detected BRAF mutations in 50/131 (38 %) specimens, including 30 % non-p.V600E. This revised assay showed strong correlation between p.V600E BRAF mutant percentage and tumor cellularity (r = 0.76; p ≤ 0.01). Re-evaluation of the previously discordant samples by the revised assay confirmed a high level of p.V600K mutation in five specimens. Pathologists play important roles in molecular diagnostics, beyond identification of correct cells for testing. Accurate evaluation of tumor cellularity not only ensures sufficient material for required analytic sensitivity, but also provides an independent QA measure of the molecular assays.
    03/2014; 18(4). DOI:10.1007/s40291-014-0091-6
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    ABSTRACT: Programmed cell death 1 (PD-1) is an inhibitory receptor expressed by activated T cells that downmodulates effector functions and limits the generation of immune memory. PD-1 blockade can mediate tumor regression in a substantial proportion of patients with melanoma, but it is not known whether this is associated with extended survival or maintenance of response after treatment is discontinued. Patients with advanced melanoma (N = 107) enrolled between 2008 and 2012 received intravenous nivolumab in an outpatient setting every 2 weeks for up to 96 weeks and were observed for overall survival, long-term safety, and response duration after treatment discontinuation. Median overall survival in nivolumab-treated patients (62% with two to five prior systemic therapies) was 16.8 months, and 1- and 2-year survival rates were 62% and 43%, respectively. Among 33 patients with objective tumor regressions (31%), the Kaplan-Meier estimated median response duration was 2 years. Seventeen patients discontinued therapy for reasons other than disease progression, and 12 (71%) of 17 maintained responses off-therapy for at least 16 weeks (range, 16 to 56+ weeks). Objective response and toxicity rates were similar to those reported previously; in an extended analysis of all 306 patients treated on this trial (including those with other cancer types), exposure-adjusted toxicity rates were not cumulative. Overall survival following nivolumab treatment in patients with advanced treatment-refractory melanoma compares favorably with that in literature studies of similar patient populations. Responses were durable and persisted after drug discontinuation. Long-term safety was acceptable. Ongoing randomized clinical trials will further assess the impact of nivolumab therapy on overall survival in patients with metastatic melanoma.
    Journal of Clinical Oncology 03/2014; 32(10). DOI:10.1200/JCO.2013.53.0105 · 17.88 Impact Factor
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    ABSTRACT: Intravascular lymphomas are rare and aggressive hematolymphoid tumors. Here, we describe a human herpesvirus type-8 (HHV-8)/Kaposi sarcoma-associated herpesvirus-positive and Epstein-Barr virus (EBV)-positive intravascular lymphoma. The patient was a 59-year-old human immunodeficiency virus-positive man who presented with diarrhea, abdominal pain, fevers, night sweats, and weight loss. Radiographic studies of the abdomen and pelvis revealed numerous subcentimeter nodules within the subcutaneous fat that lacked connection to the skin. An excisional biopsy demonstrated large atypical cells within vessels in the deep subcutaneous fat, and many of the vessels contained extensive organizing thrombi. The atypical cells lacked strong expression of most B-cell markers but were positive for MUM-1 and showed partial expression of several T-cell markers. An immunohistochemical stain for HHV-8 and an in situ hybridization for EBV were both positive in the neoplastic cells. The disease had a rapidly progressive and fatal course. This lymphoma appears to represent an entirely intravascular form of primary effusion lymphoma and highlights the propensity for HHV-8 and EBV-positive lymphoid neoplasms to show aberrant expression of T-cell markers, illustrates the utility of skin biopsies for the diagnosis of intravascular lymphoma, and suggests that biopsies to evaluate for intravascular lymphoma should be relatively deep and include subcutaneous fat.
    The American journal of surgical pathology 03/2014; 38(3):426-32. DOI:10.1097/PAS.0000000000000128 · 4.59 Impact Factor
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    ABSTRACT: Numerous complications can be observed in the post-transplant period among recipients of hematopoietic stem cells including graft-versus-host disease (GVHD), which is associated with significant morbidity and mortality. On the other hand, graft versus tumor (GVT) effect is a well-described phenomenon in patients with hematologic malignancies and has also been reported in renal cell cancer, ovarian cancer, breast carcinoma, and melanoma. We describe spontaneous regression of a cutaneous invasive squamous cell carcinoma and multifocal atypical intraepidermal proliferations in a patient with chronic graft-versus-host disease following initiation of extracorporeal photopheresis (ECP). This observation raises questions regarding the GVT in cutaneous neoplasms and potential immunomodulatory effects of ECP.
    Dermatology online journal 01/2014; 20(5):22614.
  • Journal of Translational Medicine 01/2014; 12(Suppl 1):O8. DOI:10.1186/1479-5876-12-S1-O8 · 3.99 Impact Factor
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    ABSTRACT: Chordomas constitute a slowly growing malignant tumor of mesenchymal origin. They grow along the craniospinal axis but they are much more frequent at its two ends (skull base and sacral region). They can be locally invasive and not infrequently give remote metastases. Despite aggressive therapy that consists of en block resection of the tumor with or without radiation the patients experience very often recurrence with an overall 10 year survival rate of 39%. Despite an extensive genetic analysis, gene expression and molecular analysis of possible cellular pathways involved in the chordoma progression, very little is known about the interaction of chordomas with the immune system. The lack of a sufficient mouse model that recapitulates the human disease and the rarity of these tumors among the general population have left unexplored the immune system reaction to chordomas. The immune checkpoints are a group of surface proteins and secreted molecules that inhibit the activation and expansion of immune cells towards a robust antitumor response. Programmed death 1 (PD-1) with its two ligands (PDL1, PDL2) are an example of immune checkpoint inhibitors that has been shown to play a crucial role in the progression of other types of cancer. We explored the potential of PD-1 - PDL1, PDL2 pathway in the involvement of immunosuppression in chordomas. For this purpose we used established chordoma cell lines and chordoma human samples to evaluate the expression of these surface markers in chordomas. We also sought to assess the inducible expression of PDL1, PDL2 in human chordoma cell lines to establish a mechanistic basis by which these two molecules may be differentially expressed in human chordoma samples.
    Society of Neurooncology (SNO/WFNO), San Francisco; 11/2013
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    ABSTRACT: Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade.
    Oncotarget 10/2013; 4(11). · 6.63 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):446-446. DOI:10.1158/1538-7445.AM2013-446 · 9.28 Impact Factor
  • Cancer Research 08/2013; 73(8 Supplement):4619-4619. DOI:10.1158/1538-7445.AM2013-4619 · 9.28 Impact Factor

Publication Stats

2k Citations
325.61 Total Impact Points


  • 2008–2015
    • Johns Hopkins University
      • • Department of Pathology
      • • Department of Surgery
      Baltimore, Maryland, United States
  • 2006–2014
    • Johns Hopkins Medicine
      • • Department of Otolaryngology - Head and Neck Surgery
      • • Department of Dermatology
      • • Department of Pathology
      Baltimore, Maryland, United States
  • 2010
    • Stanford Medicine
      • Department of Pathology
      Stanford, California, United States