Bio

Clinical Focus


  • Anatomic Pathology
  • Pathology
  • Cytopathology

Academic Appointments


Administrative Appointments


  • Assistant Service Chief, PAVAHCS (2010 - Present)
  • Associate Director, Cytopathology at PAVAHCS (2006 - Present)

Professional Education


  • Fellowship:UCSF Medical Center (2006) CA
  • Residency:Stanford University Medical Center (2005) CA
  • Board Certification: Cytopathology, American Board of Pathology (2006)
  • Board Certification: Anatomic Pathology, American Board of Pathology (2005)
  • Internship:Stanford University Medical Center (2002) CA
  • Medical Education:Rush University Medical College (2001) IL
  • --, UCSF, Cytopathology (2006)
  • --, Stanford University Hospital, Immunopathology (2005)
  • --, Stanford University Hospital, Anatomic Pathology (2004)
  • M.D., Rush Medical College, Chicago, -- (2001)

Research & Scholarship

Current Research and Scholarly Interests


Together with collaborators at Stanford and in Vancouver, British Columbia, I have worked to define an immunohistochemical correlate to a gene expression panel originally developed at Stanford, that was applied to a series of approximately 900 breast cancers on a tissue microarray and showed a similar outcome stratification (see Nielsen et al). The combination of gene and protein (immunohistochemical) expression analysis of breast cancer has redefined the clinical understanding of breast cancer biology (including description of the "basal-like" subset of tumors), and will have significant impact on future clinical diagnosis and treatment of this disease.

In addition, ongoing work arising from the initial tissue microarray immunohistochemical studies has identified an interesting expression pattern of the fatty acid synthase protein, raising the possibility that this protein may highlight a reserve cell or stem cell population in the breast. This is especially interesting, as the gene that corresponds to this protein co-clusters with genes that define the "basal-like" subtype of breast cancer, supporting the hypothesis that these particularly aggressive tumors arise from a breast stem cell population.

Ultimately, I hope to improve techniques to amplify tumor cell RNA so that gene expression studies can be performed on fine needle aspiration material. With a limited panel of genes, breast tumors could then be stratified into variious "good-acting" and "bad-acting" subtypes, information which could direct neoadjuvant treatment using a relatively non-invasive and rapid procedure (fine needle aspiration biopsy). As therapeutic targets are discovered with refined gene analysis and subsequent drug development, neoadjuvant therapy will likely play a larger role in breast cancer treatment, and diagnosis and risk stratification using material obtained from fine needle aspiration would be ideal in this setting.

While adjunct research tools are exciting and interesting, the role of traditional cytomorphologic diagnosis and correlation with imaging features cannot be underestimated, as these two tools along with clinical examination, are the mainstay of early detection and diagnosis programs. I am currently completing a project correlating radiologic features to cytologic impression and histologic diagnosis to show the overall accuracy and efficacy of ultrasound-guided fine needle aspiration biopsy with immediate cytologic adequacy assessment.

Clinical Trials


  • Vitamin D and Breast Cancer: Does Weight Make a Difference? Recruiting

    This protocol is a randomized, controlled and blinded clinical trial in obese and non-obese subjects diagnosed with breast cancer in whom we will test the effects of vitamin D supplementation in the neoadjuvant setting and evaluate changes in biomarker expression in blood and tissue comparing core breast biopsy to definitive surgical samples. Our goal is to determine whether dietary vitamin D can reverse the negative effects of obesity and insulin resistance as reflected by favorable changes in the gene expression patterns in the pathologic specimens as well as in serum biomarkers of insulin resistance and adipokine secretion. We expect that vitamin D administration will improve the breast cancer gene expression pattern from a high-risk configuration to a low-risk profile in the obese patients and will also cause improvement in the non-obese.

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  • PRospective Study Of MammaPrint in Patients With an Intermediate Recurrence Score Not Recruiting

    This is a prospective study that will assess the impact of MammaPrint on chemotherapy + endocrine versus endocrine alone treatment decisions in patients with an Oncotype Intermediate Score.

    Stanford is currently not accepting patients for this trial. For more information, please contact Annabel Castaneda, 650-498-7977 .

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  • Development of Vitamin D as a Therapy for Breast Cancer - Phase II Not Recruiting

    This study will assess whether levels of vitamin D impact the characteristics of a woman's breast cancer at diagnosis, and whether a short course of vitamin D in women with low levels of vitamin D changes the gene expression of their breast cancers.

    Stanford is currently not accepting patients for this trial. For more information, please contact Charlene Kranz, (650) 498 - 7977.

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  • Phase I Trial of Metabolic Reprogramming Therapy for Treatment of Recurrent Head and Neck Cancers Recruiting

    To determine the maximum tolerated dose of DCA in patients with recurrent head and neck cancer who have failed first-line therapy. The purpose of this study is to study the effect of the drug DCA (dichloroacetate) on recurrent head and neck cancers. Part of this study will also use EF5 PET scan to study tumor hypoxia.

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Teaching

2013-14 Courses


Publications

Journal Articles


  • Clinicopathologic Characteristics of HER2 FISH-ambiguous Breast Cancer at a Single Institution AMERICAN JOURNAL OF SURGICAL PATHOLOGY Clay, M. R., Iberri, D. J., Bangs, C. D., Cherry, A., Jensen, K. C. 2013; 37 (1): 120-127

    Abstract

    : The typical algorithm for human epidermal growth factor-2 (HER2) testing is immunohistochemistry (IHC), followed by reflex HER2 fluorescence in situ hybridization (FISH) for HER2 IHC-ambiguous (2+) cases. At our institution, HER2 FISH testing is initially performed as part of routine breast cancer testing, with HER2 FISH-ambiguous (HER2:CEP17 ratio, 1.8 to 2.2) cases reflexed to HER2 IHC. This provides a unique dataset for lesions that may not routinely undergo FISH testing. The clinicopathologic characteristics of HER2 FISH-ambiguous cases are described.: The electronic pathology database in our institution was searched for HER2 FISH-ambiguous cases from 2007 to December 2011. Review of clinical and pathologic characteristics was performed.: Sixty cases from 60 patients were reported as HER2 FISH ambiguous. Reflex HER2 IHC testing was performed on all 60 cases, of which 26 were HER2 IHC negative (0 to 1+), 18 were HER2 IHC ambiguous (2+), and 16 were HER2 IHC positive (3+). Of the 46 HER2 FISH-ambiguous patients with available clinical records, 13 (32%) pursued anti-HER2 treatment (10 IHC 3+, 1 IHC 2+, 2 IHC 0 to 1+). All were grade II or III ductal carcinomas, with 1 grade III metaplastic carcinoma.: Reflex HER2 IHC testing after initially ambiguous HER2 FISH testing provides definitive HER2 status in a majority of cases (70%). However, a substantial percentage (30%) of HER2 FISH-ambiguous cases is also HER2 IHC ambiguous, suggesting an intermediate HER2 biology. Most HER2 FISH-ambiguous patients who received trastuzumab were HER2 IHC 3+, grade III, and had associated high-grade ductal carcinoma in situ. Although not statistically significant and with only minimal follow-up, no recurrences have occurred in those patients treated with trastuzumab (P=0.5754).

    View details for DOI 10.1097/PAS.0b013e31826ab19d

    View details for Web of Science ID 000312486700015

    View details for PubMedID 23108020

  • Inhibitory effects of calcitriol on the growth of MCF-7 breast cancer xenografts in nude mice: selective modulation of aromatase expression in vivo. Hormones & cancer Swami, S., Krishnan, A. V., Wang, J. Y., Jensen, K., Peng, L., Albertelli, M. A., Feldman, D. 2011; 2 (3): 190-202

    Abstract

    Calcitriol (1,25-dihydroxyvitamin D(3)), the hormonally active metabolite of vitamin D, exerts many anticancer effects in breast cancer (BCa) cells. We have previously shown using cell culture models that calcitriol acts as a selective aromatase modulator (SAM) and inhibits estrogen synthesis and signaling in BCa cells. We have now examined calcitriol effects in vivo on aromatase expression, estrogen signaling, and tumor growth when used alone and in combination with aromatase inhibitors (AIs). In immunocompromised mice bearing MCF-7 xenografts, increasing doses of calcitriol exhibited significant tumor inhibitory effects (~50% to 70% decrease in tumor volume). At the suboptimal doses tested, anastrozole and letrozole also caused significant tumor shrinkage when used individually. Although the combinations of calcitriol and the AIs caused a statistically significant increase in tumor inhibition in comparison to the single agents, the cooperative interaction between these agents appeared to be minimal at the doses tested. Calcitriol decreased aromatase expression in the xenograft tumors. Importantly, calcitriol also acted as a SAM in the mouse, decreasing aromatase expression in the mammary adipose tissue, while increasing it in bone marrow cells and not altering it in the ovaries and uteri. As a result, calcitriol significantly reduced estrogen levels in the xenograft tumors and surrounding breast adipose tissue. In addition, calcitriol inhibited estrogen signaling by decreasing tumor ER? levels. Changes in tumor gene expression revealed the suppressive effects of calcitriol on inflammatory and growth signaling pathways and demonstrated cooperative interactions between calcitriol and AIs to modulate gene expression. We hypothesize that cumulatively these calcitriol actions would contribute to a beneficial effect when calcitriol is combined with an AI in the treatment of BCa.

    View details for DOI 10.1007/s12672-011-0073-7

    View details for PubMedID 21686077

  • Variations in stromal signatures in breast and colorectal cancer metastases JOURNAL OF PATHOLOGY Webster, J. A., Beck, A. H., Sharma, M., Espinosa, I., Weigelt, B., Schreuder, M., Montgomery, K. D., Jensen, K. C., van de Rijn, M., West, R. 2010; 222 (2): 158-165

    Abstract

    The tumour microenvironment (TME) plays an important role in tumour survival and growth, but little is known about the degree of preservation between different stromal response patterns found in primary tumours and their metastases. We have previously identified gene expression profiles for two distinct stromal signatures in breast carcinoma of fibroblast (aka DTF) and macrophage (aka CSF1) response and found them to be correlated with clinicopathological features, including outcome. In this study, we compare the DTF fibroblast and CSF1 macrophage stromal response patterns in primary breast and colorectal cancers to their matched lymph node metastases. In both breast and colorectal cancer, there was a significant positive correlation between the CSF1 macrophage signature in the primary tumours and the matched lymph node metastases, as assessed by immunohistochemical markers. No such correlation was observed for the DTF fibroblast signature. A similar result was seen in independent analysis of two published gene expression microarray datasets. The variations of these stromal reaction patterns from the primary to the metastasis shed light on the relationship between the neoplastic cells and the non-neoplastic cells in the TME. The preservation of the CSF1 macrophage response pattern in metastases lends support to targeting the CSF1 pathway in cancer.

    View details for DOI 10.1002/path.2738

    View details for Web of Science ID 000282725700006

    View details for PubMedID 20593409

  • Analysis of stromal signatures in the tumor microenvironment of ductal carcinoma in situ BREAST CANCER RESEARCH AND TREATMENT Sharma, M., Beck, A. H., Webster, J. A., Espinosa, I., Montgomery, K., Varma, S., van de Rijn, M., Jensen, K. C., West, R. B. 2010; 123 (2): 397-404

    Abstract

    Recent advances in the study of the tumor microenvironment have revealed significant interaction between tumor cells and their surrounding stroma in model systems. We have previously shown that two distinct stromal signatures derived from a macrophage (CSF1) response and a fibroblastic (DTF-like) response are present in subsets of invasive breast cancers and show a correlation with clinical outcome. In the present study we explore whether these signatures also exist in the stroma of ductal carcinoma in situ (DCIS). We studied the signatures by both gene expression profile analysis of a publically available data set of DCIS and by immunohistochemistry (IHC) on a tissue microarray of DCIS and invasive breast cancer cases. Both the gene expression and immunohistochemical data show that the macrophage response and fibroblast expression signatures are present in the stroma of subsets of DCIS cases. The incidence of the stromal signatures in DCIS is similar to the incidence in invasive breast cancer that we have previously reported. We also find that the macrophage response signature is associated with higher grade DCIS and cases which are ER and PR negative, whereas the fibroblast signature was not associated with any clinicopathologic features in DCIS. A comparison of 115 matched cases of DCIS and invasive breast cancer found a correlation between the type of stromal response in DCIS and invasive ductal carcinoma (IDC) within the same patient for both the macrophage response and the fibroblast stromal signatures (P = 0.03 and 0.08, respectively). This study is a first characterization of these signatures in DCIS. These signatures have significant clinicopathologic associations and tend to be conserved as the tumor progresses from DCIS to invasive breast cancer.

    View details for DOI 10.1007/s10549-009-0654-0

    View details for Web of Science ID 000280807900008

    View details for PubMedID 19949854

  • New cutpoints to identify increased HER2 copy number: analysis of a large, population-based cohort with long-term follow-up BREAST CANCER RESEARCH AND TREATMENT Jensen, K. C., Turbin, D. A., Leung, S., Miller, M. A., Johnson, K., Norris, B., Hastie, T., McKinney, S., Nielsen, T. O., Huntsman, D. G., Gilks, C. B., West, R. B. 2008; 112 (3): 453-459

    Abstract

    HER2 gene amplification and/or protein overexpression in breast cancer is associated with a poor prognosis and predicts response to anti-HER2 therapy. We examine the natural history of breast cancers in relationship to increased HER2 copy numbers in a large population-based study.HER2 status was measured by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) in approximately 1,400 breast cancer cases with greater than 15 years of follow-up. Protein expression was evaluated with two different commercially-available antibodies.We looked for subgroups of breast cancer with different clinical outcomes, based on HER2 FISH amplification ratio. The current HER2 ratio cut point for classifying HER2 positive and negative cases is 2.2. However, we found an increased risk of disease-specific death associated with FISH ratios of >1.5. An 'intermediate' group of cases with HER2 ratios between 1.5 and 2.2 was found to have a significantly better outcome than the conventional 'amplified' group (HER2 ratio >2.2) but a significantly worse outcome than groups with FISH ratios less than 1.5.Breast cancers with increased HER2 copy numbers (low level HER2 amplification), below the currently accepted positive threshold ratio of 2.2, showed a distinct, intermediate outcome when compared to HER2 unamplified tumors and tumors with HER2 ratios greater than 2.2. These findings suggest that a new cut point to determine HER2 positivity, at a ratio of 1.5 (well below the current recommended cut point of 2.2), should be evaluated.

    View details for DOI 10.1007/s10549-007-9887-y

    View details for Web of Science ID 000261951000007

    View details for PubMedID 18193353

  • Characterization of a novel anti-fatty acid synthase (FASN) antiserum in breast tissue MODERN PATHOLOGY Jensen, K. C., Schaeffer, D. F., Cheang, M., Montgomery, K., West, R. B., Gilks, C. B., Ross, D., Turashvili, G., Schnitt, S., van de Rijn, M. 2008; 21 (12): 1413-1420

    Abstract

    Fatty acid synthase (FASN) expression has been reported in many different tumors, including breast cancer. In gene microarray studies, the fatty acid synthase gene co-clustered with cytokeratins 5 and 17 and other genes that defined the basal-like subset of breast cancers. To define the use of this marker in breast pathology, a rabbit polyclonal antiserum (S143) to a peptide fragment of this gene was produced and compared with a commercially available monoclonal antibody by immunohistochemistry on various tissue microarrays and whole tissue sections. The tissue microarrays included 1090 breast cancers and 244 normal breast tissues. Whole tissue sections consisted of benign and malignant tissues from breast resection specimens. In contrast to other 'basal' markers identified by gene expression profiling data, the fatty acid synthase (FASN) expression pattern in normal breast was notable for its expression in only a small subset of basal and suprabasal cells. Dual staining experiments revealed that the subpopulation of cells labeling with FASN did not coexpress myoepithelial markers CK5/6 or p63, but did coexpress e-cadherin. In addition to staining a subset of basal and suprabasal cells, the antiserum highlighted apocrine differentiation, and stained 106/144 (74%) cases of columnar cell lesions and five of five cases of flat epithelial atypia. Despite its association with basal keratins in gene array studies, FASN expression did not correlate significantly with the outcome in breast cancer. We describe an expression pattern that highlights only a subset of basal and suprabasal cells in normal breast ducts and we show by dual expression studies that this subset of cells is different from myoepithelial and basal cytokeratin-positive cells. In addition, FASN expression is described in apocrine metaplasia, columnar cell lesions, and flat epithelial atypia.

    View details for DOI 10.1038/modpathol.2008.163

    View details for Web of Science ID 000261109000001

    View details for PubMedID 18820672

  • Microsatellite instability and mismatch repair protein defects in ovarian epithelial neoplasms in patients 50 years of age and younger AMERICAN JOURNAL OF SURGICAL PATHOLOGY Jensen, K. C., Mariappan, M. R., Putcha, G. V., Husain, A., Chun, N., Ford, J. M., Schrijver, I., Longacre, T. A. 2008; 32 (7): 1029-1037

    Abstract

    Ovarian malignancies occurring in the setting of hereditary nonpolyposis colorectal carcinoma syndrome typically present in young women, often as the first or "sentinel" cancer, but the frequency of microsatellite instability (MSI) and mismatch repair (MMR) defects in ovarian surface epithelial malignancies in women

    View details for Web of Science ID 000257298000010

    View details for PubMedID 18469706

  • The utility of PAX5 immunohistochemistry in the diagnosis of undifferentiated malignant neoplasms MODERN PATHOLOGY Jensen, K. C., Higgins, J. P., Montgomery, K., Kaygusuz, G., van de Rijn, M., Natkunam, Y. 2007; 20 (8): 871-877

    Abstract

    PAX5 is a B-cell transcription factor whose expression at the protein level is reliably detected by immunohistochemistry in routine biopsies. The purpose of this study was to investigate whether PAX5 immunohistochemistry has diagnostic benefit as a B-cell marker in the work-up of undifferentiated malignant neoplasms. Twenty-five cases previously diagnosed as undifferentiated malignant neoplasms were selected. In addition, 59 hematolymphoid and 884 non-hematolymphoid malignancies were studied such that the specificity of PAX5 immunohistochemistry could be addressed. Two of the 25 (8%) undifferentiated neoplasms showed diffuse staining for PAX5, which indicated a B-cell derivation for these neoplasms that was not appreciated at the time of initial diagnosis. PAX5 staining was detected in the vast majority of hematolymphoid tumors of B-cell derivation but only in 5 of 884 (less than 1%) non-hematolymphoid tumors. Our results further show that PAX5 may be the only detectable marker of B lineage in lymphomas that lack or show equivocal CD45RB and CD20 expression. We conclude that the addition of PAX5 to a panel of immunohistologic markers used in the interrogation of undifferentiated neoplasms is of diagnostic benefit. Its expression can also facilitate the diagnosis of classical and nodular lymphocyte-predominant Hodgkin lymphoma with atypical morphologic and immunohistologic features. Lastly, we have shown that the lack of its expression at the protein level in many epithelial and mesenchymal neoplasms renders PAX5 expression an extremely specific marker of the B lineage.

    View details for Web of Science ID 000248219700008

    View details for PubMedID 17529924

  • Cytologic diagnosis of columnar-cell lesions of the breast DIAGNOSTIC CYTOPATHOLOGY Jensen, K. C., Kong, C. S. 2007; 35 (2): 73-79

    Abstract

    This study describes the cytologic features of breast columnar-cell lesions (CCLs) and determines whether these lesions can be diagnosed by fine-needle aspiration. We present ten cases of biopsy-proven CCL with prior fine-needle aspiration material and discuss the spectrum of changes, as well as features important in the cytologic distinction of CCL from diagnostic mimics. CCLs were characterized by flat sheets of cells with enlarged nuclei, distinct cell borders, and finely granular cytoplasm. Cytologic atypia ranged from minimal to severe, and many cases (8/10) exhibited a paucity of myoepithelial cells. CCL showed significant cytologic overlap with papillary neoplasms and well-differentiated adenocarcinomas. The prospective diagnosis of CCL cannot reliably be made by fine-needle aspiration. However, it is important to recognize the range of cytologic atypia that can be seen with CCL to avoid an overdiagnosis of malignancy.

    View details for DOI 10.1002/dc.20601

    View details for Web of Science ID 000243827100001

    View details for PubMedID 17230565

  • Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma Clin Cancer Res Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, Hernandez-Boussard T, Livasy C, Cowan D, Dressler L, Akslen LA, Ragaz J, Gown AM, Gilks CB, van de Rijn M, Perou CM 2004; 10 (16): 5367-5374
  • Targeting a Glioblastoma Cancer Stem-Cell Population Defined by EGF Receptor Variant III. Cancer research Emlet, D. R., Gupta, P., Holgado-Madruga, M., Del Vecchio, C. A., Mitra, S. S., Han, S., Li, G., Jensen, K. C., Vogel, H., Xu, L. W., Skirboll, S. S., Wong, A. J. 2014; 74 (4): 1238-1249

    Abstract

    The relationship between mutated proteins and the cancer stem cell population is unclear. Glioblastoma tumors frequently express EGFRvIII, an EGFR variant that arises via gene rearrangement and amplification. However, expression of EGFRvIII is restricted despite the prevalence of the alteration. Here we show that EGFRvIII is highly co-expressed with CD133 and that EGFRvIII+/CD133+ defines the population of cancer stem cells with the highest degree of self-renewal and tumor initiating ability. EGFRvIII+ cells are associated with other stem/progenitor markers while markers of differentiation are found in EGFRvIII- cells. EGFRvIII expression is lost in standard cell culture but its expression is maintained in tumor sphere culture, and cultured cells also retain the EGFRvIII+/CD133+ co-expression and self-renewal and tumor initiating abilities. Elimination of the EGFRvIII+/CD133+ population using a bispecific antibody reduced tumorigenicity of implanted tumor cells better than any reagent directed against a single epitope. This work demonstrates that a mutated oncogene can have CSC specific expression and be used to specifically target this population.

    View details for DOI 10.1158/0008-5472.CAN-13-1407

    View details for PubMedID 24366881

  • A clinical trial of lovastatin for modification of biomarkers associated with breast cancer risk. Breast cancer research and treatment Vinayak, S., Schwartz, E. J., Jensen, K., Lipson, J., Alli, E., McPherson, L., Fernandez, A. M., Sharma, V. B., Staton, A., Mills, M. A., Schackmann, E. A., Telli, M. L., Kardashian, A., Ford, J. M., Kurian, A. W. 2013; 142 (2): 389-398

    Abstract

    Pre-clinical and epidemiologic studies provide rationale for evaluating lipophilic statins for breast cancer prevention. We conducted a single-arm, biomarker modulation trial of lovastatin among women with increased risk of breast cancer. Eligibility criteria included a deleterious germline mutation in BRCA1, BRCA2, CDH1, or TP53; lifetime breast cancer risk of ≥20 % as estimated by the Claus model; or personal history of estrogen receptor and progesterone receptor-negative breast cancer. Participants received 40 mg of lovastatin orally twice daily for 6 months. We evaluated the following biomarkers before and after lovastatin use: breast duct cytology (primary endpoint), serum lipids, C-reactive protein, insulin-like growth factor-1, IGF binding protein-3, lipid peroxidation, oxidative DNA damage, 3-hydroxy-3-methylglutaryl CoA reductase genotype, and mammographic density. Thirty women were enrolled, and 26 (86.7 %) completed the study. For the primary endpoint of changes in breast duct cytology sampled by random periareolar fine needle aspiration, most participants [57.7 %, 95 % confidence interval (CI) 38.9-74.5 %] showed no change after lovastatin; 19.2 % (CI 8.1-38.3 %) had a favorable change in cytology, 7.7 % (95 % CI 1.0-25.3 %) had an unfavorable change, and 15.4 % (95 % CI 5.5-34.2 %) had equivocal results due to acellular specimens, usually after lovastatin. No significant changes were observed in secondary biomarker endpoints. The study was generally well-tolerated: 4 (13.3 %) participants did not complete the study, and one (3.8 %) required a dose reduction. This trial was technically feasible, but demonstrated no significant biomarker modulation; contributing factors may include insufficient sample size, drug dose and/or duration. The results are inconclusive and do not exclude a favorable effect on breast cancer risk.

    View details for DOI 10.1007/s10549-013-2739-z

    View details for PubMedID 24166281

  • Radio logic assessment of retropharyngeal node involvement in oropharyngeal carcinomas stratified by HPV status RADIOTHERAPY AND ONCOLOGY Tang, C., Komakula, S., Chan, C., Murphy, J. D., Jiang, W., Kong, C., Lee-Enriquez, N., Jensen, K. C., Fischbein, N. J., Quynh-Thu Le, Q. T. 2013; 109 (2): 293-296
  • EGFRvIII gene rearrangement is an early event in glioblastoma tumorigenesis and expression defines a hierarchy modulated by epigenetic mechanisms. Oncogene Del Vecchio, C. A., Giacomini, C. P., Vogel, H., Jensen, K. C., Florio, T., Merlo, A., Pollack, J. R., Wong, A. J. 2013; 32 (21): 2670-2681

    Abstract

    Amplification and rearrangements of the epidermal growth factor receptor (EGFR) gene are frequently found in glioblastoma multiforme (GBM). The most common variant is EGFR variant III (EGFRvIII). Research suggests that EGFRvIII could be a marker for a cancer stem cell or tumor-initiating population. If amplification and rearrangement are early events in tumorigenesis, this implies that they should be preserved throughout the tumor. However, in primary GBM, EGFRvIII expression is focal and sporadic. Unexpectedly, we found EGFR amplification and rearrangement throughout the tumor, including regions with no EGFRvIII expression, suggesting that mechanisms exist to modulate EGFRvIII expression even in the presence of high gene amplification. To study this phenomenon, we characterized three GBM cell lines with endogenous EGFRvIII. EGFRvIII expression was heterogeneous, with both positive and negative populations maintaining the genetic alterations, akin to primary tumors. Furthermore, EGFRvIII defined a hierarchy where EGFRvIII-positive cells gave rise to additional positive and negative cells. Only cells that had recently lost EGFRvIII expression could re-express EGFRvIII, providing an important buffer for maintaining EGFRvIII-positive cell numbers. Epigenetic mechanisms had a role in maintaining heterogeneous EGFRvIII expression. Demethylation induced a 20-60% increase in the percentage of EGFRvIII-positive cells, indicating that some cells could re-express EGFRvIII. Surprisingly, inhibition of histone deacetylation resulted in a 50-80% reduction in EGFRvIII expression. Collectively, this data demonstrates that EGFR amplification and rearrangement are early events in tumorigenesis and EGFRvIII follows a model of hierarchical expression. Furthermore, EGFRvIII expression is restricted by epigenetic mechanisms, suggesting that drugs that modulate the epigenome might be used successfully in glioblastoma tumors.

    View details for DOI 10.1038/onc.2012.280

    View details for PubMedID 22797070

  • Earlier Detection of Breast Cancer with Ultrasound Molecular Imaging in a Transgenic Mouse Model CANCER RESEARCH Bachawal, S. V., Jensen, K. C., Lutz, A. M., Gambhir, S. S., Tranquart, F., Tian, L., Willmann, J. K. 2013; 73 (6): 1689-1698

    Abstract

    While there is an increasing role of ultrasound for breast cancer screening in patients with dense breast, conventional anatomical ultrasound lacks sensitivity and specificity for early breast cancer detection. In this study, we assessed the potential of ultrasound molecular imaging using clinically translatable vascular endothelial growth factor receptor type 2 (VEGFR2)-targeted microbubbles (MB(VEGFR2)) to improve the diagnostic accuracy of ultrasound in earlier detection of breast cancer and ductal carcinoma in situ (DCIS) in a transgenic mouse model [FVB/N-Tg(MMTV-PyMT)634Mul]. In vivo binding specificity studies (n = 26 tumors) showed that ultrasound imaging signal was significantly higher (P < 0.001) using MB(VEGFR2) than nontargeted microbubbles and imaging signal significantly decreased (P < 0.001) by blocking antibodies. Ultrasound molecular imaging signal significantly increased (P < 0.001) when breast tissue (n = 315 glands) progressed from normal [1.65 ± 0.17 arbitrary units (a.u.)] to hyperplasia (4.21 ± 1.16), DCIS (15.95 ± 1.31), and invasive cancer (78.1 ± 6.31) and highly correlated with ex vivo VEGFR2 expression [R(2) = 0.84; 95% confidence interval (CI), 0.72-0.91; P < 0.001]. At an imaging signal threshold of 4.6 a.u., ultrasound molecular imaging differentiated benign from malignant entities with a sensitivity of 84% (95% CI, 78-88) and specificity of 89% (95% CI, 81-94). In a prospective screening trail (n = 63 glands), diagnostic performance of detecting DCIS and breast cancer was assessed and two independent readers correctly diagnosed malignant disease in more than 95% of cases and highly agreed between each other [intraclass correlation coefficient (ICC) = 0.98; 95% CI, 97-99]. These results suggest that VEGFR2-targeted ultrasound molecular imaging allows highly accurate detection of DCIS and breast cancer in transgenic mice and may be a promising approach for early breast cancer detection in women.

    View details for DOI 10.1158/0008-5472.CAN-12-3391

    View details for Web of Science ID 000316187500006

    View details for PubMedID 23328585

  • Identification of Sox9-Dependent Acinar-to-Ductal Reprogramming as the Principal Mechanism for Initiation of Pancreatic Ductal Adenocarcinoma CANCER CELL Kopp, J. L., von Figura, G., Mayes, E., Liu, F., Dubois, C. L., Morris, J. P., Pan, F. C., Akiyama, H., Wright, C. V., Jensen, K., Hebrok, M., Sander, M. 2012; 22 (6): 737-750

    Abstract

    Tumors are largely classified by histologic appearance, yet morphologic features do not necessarily predict cellular origin. To determine the origin of pancreatic ductal adenocarcinoma (PDA), we labeled and traced pancreatic cell populations after induction of a PDA-initiating Kras mutation. Our studies reveal that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features. We show that formation of acinar-derived premalignant lesions depends on ectopic induction of the ductal gene Sox9. Moreover, when concomitantly expressed with oncogenic Kras, Sox9 accelerates formation of premalignant lesions. These results provide insight into the cellular origin of PDA and suggest that its precursors arise via induction of a duct-like state in acinar cells.

    View details for DOI 10.1016/j.ccr.2012.10.025

    View details for Web of Science ID 000312467000007

    View details for PubMedID 23201164

  • Chest Wall Leiomyosarcoma After Breast-Conservative Therapy for Early-Stage Breast Cancer in a Young Woman With Li-Fraumeni Syndrome JOURNAL OF THE NATIONAL COMPREHENSIVE CANCER NETWORK Henry, E., Villalobos, V., Million, L., Jensen, K. C., West, R., Ganjoo, K., Lebensohn, A., Ford, J. M., Telli, M. L. 2012; 10 (8): 939-942

    Abstract

    Li-Fraumeni syndrome (LFS) is one of the most penetrant forms of familial cancer susceptibility syndromes, characterized by early age at tumor onset and a wide spectrum of malignant tumors. Identifying LFS in patients with cancer is clinically imperative because they have an increased sensitivity to ionizing radiation and are more likely to develop radiation-induced secondary malignancies. This case report describes a young woman whose initial presentation of LFS was early-onset breast cancer and whose treatment of this primary malignancy with breast conservation likely resulted in a secondary malignancy arising in her radiation field. As seen in this case, most breast cancers in patients with LFS exhibit a triple-positive phenotype (estrogen receptor-positive/progesterone receptor-positive/HER2-positive). Although this patient met classic LFS criteria based on age and personal and family history of cancer, the NCCN Clinical Practice Guidelines in Oncology for Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancer endorse genetic screening for TP53 mutations in a subset of patients with early-onset breast cancer, even in the absence of a suggestive family history, because of the potential for de novo TP53 mutations.

    View details for Web of Science ID 000307494000004

    View details for PubMedID 22878818

  • Methods for registration of magnetic resonance images of ex vivo prostate specimens with histology JOURNAL OF MAGNETIC RESONANCE IMAGING Kimm, S. Y., Tarin, T. V., Lee, J. H., Hu, B., Jensen, K., Nishimura, D., Brooks, J. D. 2012; 36 (1): 206-212

    Abstract

    To evaluate two methods of scanning and tissue processing to achieve accurate magnetic resonance (MR)-histologic correlation in human prostate specimens.Two prostates had acrylic paint markers injected to define the plane of imaging and serve as internal fiducials. Each was placed on a polycarbonate plane-finder device (PFD), which was adjusted to align the imaging and cutting planes. Three prostates were aligned by use of a plane finder key (PFK), a polycarbonate plate that locks the specimen in a cylindrical carrier. Markers were injected for registration analysis. Prostates were imaged, then sectioned. Imaging software was used to create registration maps of the MR and histology images. Measurements between control points were made and compared.Accurate correlation was achieved between MR and histologic images. The mean displacement (MD) between the corresponding registration points using the PFD technique ranged from 1.11-1.38 mm for each section. The MD for all sections was 1.24 mm. The MD using the PFK technique ranged from 0.79-1.01 mm for each section, and the MD across all sections for the PFK was 0.92 mm.We describe two methods that can achieve accurate, reproducible correlation between MR imaging and histologic sections in human prostatectomy specimens.

    View details for DOI 10.1002/jmri.23614

    View details for Web of Science ID 000305185700021

    View details for PubMedID 22359365

  • Dietary Vitamin D-3 and 1,25-Dihydroxyvitamin D-3 (Calcitriol) Exhibit Equivalent Anticancer Activity in Mouse Xenograft Models of Breast and Prostate Cancer ENDOCRINOLOGY Swami, S., Krishnan, A. V., Wang, J. Y., Jensen, K., Horst, R., Albertelli, M. A., Feldman, D. 2012; 153 (6): 2576-2587

    Abstract

    1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3) or calcitriol], the hormonally active vitamin D metabolite, exhibits anticancer actions in models of breast cancer and prostate cancer. Because CYP27B1 (1?-hydroxylase), the enzyme catalyzing 1,25(OH)(2)D(3) formation in the kidney, is also expressed in extrarenal tissues, we hypothesize that dietary vitamin D(3) will be converted to 25(OH)D(3) in the body and then to 1,25(OH)(2)D(3) locally in the cancer microenvironment in which it will exert autocrine/paracrine anticancer actions. Immunocompromised mice bearing MCF-7 breast cancer xenografts showed significant tumor shrinkage (>50%) after ingestion of a vitamin D(3)-supplemented diet (5000 IU/kg) compared with a control diet (1000 IU/kg). Dietary vitamin D(3) inhibition of tumor growth was equivalent to administered calcitriol (0.025, 0.05, or 0.1 ?g/mouse, three times a week). Both treatments equivalently inhibited PC-3 prostate cancer xenograft growth but to a lesser extent than the MCF-7 tumors. Calcitriol at 0.05 ?g and 0.1 ?g caused modest but statistically significant increases in serum calcium levels indicating that the dietary vitamin D(3) comparison was to a maximally safe calcitriol dose. Dietary vitamin D(3) did not increase serum calcium, demonstrating its safety at the concentration tested. The vitamin D(3) diet raised circulating 1,25 dihydroxyvitamin D levels and did not alter CYP27B1 mRNA in the kidney but increased it in the tumors, suggesting that extrarenal sources including the tumors contributed to the elevated circulating 1,25 dihydroxyvitamin D(3). Both calcitriol and dietary vitamin D(3) were equipotent in suppressing estrogen synthesis and signaling and other proinflammatory and growth signaling pathways. These preclinical data demonstrate the potential utility of dietary vitamin D(3) supplementation in cancer prevention and therapy.

    View details for DOI 10.1210/en.2011-1600

    View details for Web of Science ID 000304370700010

    View details for PubMedID 22454149

  • Epidermal Growth Factor Receptor Variant III Contributes to Cancer Stem Cell Phenotypes in Invasive Breast Carcinoma CANCER RESEARCH Del Vecchio, C. A., Jensen, K. C., Nitta, R. T., Shain, A. H., Giacomini, C. P., Wong, A. J. 2012; 72 (10): 2657-2671

    Abstract

    EGFRvIII is a tumor-specific variant of the epidermal growth factor receptor (EGFR). Although EGFRvIII is most commonly found in glioblastoma, its expression in other tumor types remains controversial. In this study, we investigated EGFRvIII expression and amplification in primary breast carcinoma. Our analyses confirmed the presence of EGFRvIII, but in the absence of amplification or rearrangement of the EGFR locus. Nested reverse transcriptase PCR and flow cytometry were used to detect a higher percentage of positive cases. EGFRvIII-positive cells showed increased expression of genes associated with self-renewal and epithelial-mesenchymal transition along with a higher percentage of stem-like cells. EGFRvIII also increased in vitro sphere formation and in vivo tumor formation. Mechanistically, EGFRvIII mediated its effects through the Wnt/?-catenin pathway, leading to increased ?-catenin target gene expression. Inhibition of this pathway reversed the observed effects on cancer stem cell (CSC) phenotypes. Together, our findings show that EGFRvIII is expressed in primary breast tumors and contributes to CSC phenotypes in breast cancer cell lines through the Wnt pathway. These data suggest a novel function for EGFRvIII in breast tumorigenesis.

    View details for DOI 10.1158/0008-5472.CAN-11-2656

    View details for Web of Science ID 000307346800020

    View details for PubMedID 22419663

  • Next generation of optical diagnostics for bladder cancer using probe-based confocal laser endomicroscopy PHOTONIC THERAPEUTICS AND DIAGNOSTICS VIII, PTS 1 AND 2 Liu, J., Chang, T. C., Pan, Y., Hsiao, S. T., Mach, K. E., Jensen, K. C., Liao, J. C. 2012; 8207

    View details for DOI 10.1117/12.907623

    View details for Web of Science ID 000302580900030

  • A Novel Aldehyde Dehydrogenase-3 Activator Leads to Adult Salivary Stem Cell Enrichment In Vivo CLINICAL CANCER RESEARCH Banh, A., Xiao, N., Cao, H., Chen, C., Kuo, P., Krakow, T., Bavan, B., Khong, B., Yao, M., Ha, C., Kaplan, M. J., Sirjani, D., Jensen, K., Kong, C. S., Mochly-Rosen, D., Koong, A. C., Quynh-Thu Le, Q. T. 2011; 17 (23): 7265-7272

    Abstract

    To assess aldehyde dehydrogenase (ALDH) expression in adult human and murine submandibular gland (SMG) stem cells and to determine the effect of ALDH3 activation in SMG stem cell enrichment.Adult human and murine SMG stem cells were selected by cell surface markers (CD34 for human and c-Kit for mouse) and characterized for various other stem cell surface markers by flow cytometry and ALDH isozymes expression by quantitative reverse transcriptase PCR. Sphere formation and bromodeoxyuridine (BrdUrd) incorporation assays were used on selected cells to confirm their renewal capacity and three-dimensional (3D) collagen matrix culture was applied to observe differentiation. To determine whether ALDH3 activation would increase stem cell yield, adult mice were infused with a novel ALDH3 activator (Alda-89) or with vehicle followed by quantification of c-Kit(+)/CD90(+) SMG stem cells and BrdUrd(+) salispheres.More than 99% of CD34(+) huSMG stem cells stained positive for c-Kit, CD90 and 70% colocalized with CD44, Nestin. Similarly, 73.8% c-Kit(+) mSMG stem cells colocalized with Sca-1, whereas 80.7% with CD90. Functionally, these cells formed BrdUrd(+) salispheres, which differentiated into acinar- and ductal-like structures when cultured in 3D collagen. Both adult human and murine SMG stem cells showed higher expression of ALDH3 than in their non-stem cells and 84% of these cells have measurable ALDH1 activity. Alda-89 infusion in adult mice significantly increased c-Kit(+)/CD90(+) SMG population and BrdUrd(+) sphere formation compared with control.This is the first study to characterize expression of different ALDH isozymes in SMG stem cells. In vivo activation of ALDH3 can increase SMG stem cell yield, thus providing a novel means for SMG stem cell enrichment for future stem cell therapy.

    View details for DOI 10.1158/1078-0432.CCR-11-0179

    View details for Web of Science ID 000298133600009

    View details for PubMedID 21998334

  • Dynamic Real-time Microscopy of the Urinary Tract Using Confocal Laser Endomicroscopy UROLOGY Wu, K., Liu, J., Adams, W., Sonn, G. A., Mach, K. E., Pan, Y., Beck, A. H., Jensen, K. C., Liao, J. C. 2011; 78 (1): 225-231

    Abstract

    To develop the diagnostic criteria for benign and neoplastic conditions of the urinary tract using probe-based confocal laser endomicroscopy (pCLE), a new technology for dynamic, in vivo imaging with micron-scale resolution. The suggested diagnostic criteria will formulate a guide for pCLE image interpretation in urology.Patients scheduled for transurethral resection of bladder tumor (TURBT) or nephrectomy were recruited. After white-light cystoscopy (WLC), fluorescein was administered as contrast. Different areas of the urinary tract were imaged with pCLE via direct contact between the confocal probe and the area of interest. Confocal images were subsequently compared with standard hematoxylin and eosin analysis.pCLE images were collected from 66 participants, including 2 patients who underwent nephrectomy. We identified key features associated with different anatomic landmarks of the urinary tract, including the kidney, ureter, bladder, prostate, and urethra. In vivo pCLE of the bladder demonstrated distinct differences between normal mucosa and neoplastic tissue. Using mosaicing, a post hoc image-processing algorithm, individual image frames were juxtaposed to form wide-angle views to better evaluate tissue microarchitecture.In contrast to standard pathologic analysis of fixed tissue with hematoxylin and eosin, pCLE provides real time microscopy of the urinary tract to enable dynamic interrogation of benign and neoplastic tissues in vivo. The diagnostic criteria developed in this study will facilitate adaptation of pCLE for use in conjunction with WLC to expedite diagnosis of urinary tract pathology, particularly bladder cancer.

    View details for DOI 10.1016/j.urology.2011.02.057

    View details for Web of Science ID 000292080300062

    View details for PubMedID 21601243

  • Comparison of 2.6-and 1.4-mm Imaging Probes for Confocal Laser Endomicroscopy of the Urinary Tract JOURNAL OF ENDOUROLOGY Adams, W., Wu, K., Liu, J., Hsiao, S. T., Jensen, K. C., Liao, J. C. 2011; 25 (6): 917-921

    Abstract

    Probe-based confocal laser endomicroscopy (pCLE) is an emerging technology for dynamic, in vivo imaging of the urinary tract with micron-scale resolution. We conducted a comparative analysis of pCLE with a 2.6-mm probe and a 1.4-mm probe that is compatible with flexible endoscopes.Sixty-seven patients scheduled for bladder tumor resection were recruited. pCLE imaging was performed using 2.6- and 1.4-mm probes. Image quality with the different probes was examined and further compared with standard histopathology.Images with the 2.6-mm probe have better resolution of cell morphology. The 1.4-mm probe has a wider field of view and better view of microarchitecture. While image quality with the 2.6-mm probe is superior, the 1.4-mm probe is compatible with flexible cystoscopy and maneuverability is maintained, enabling imaging of areas of the bladder that were previously challenging to access with the larger probe.The optical specifications of the 2.6-mm probe are more suitable for distinguishing urinary tract histopathology. Further design optimization to improve resolution and additional validation of the diagnostic accuracy of the smaller probe are needed to help extend application of pCLE for optical biopsy of the upper and lower urinary tract.

    View details for DOI 10.1089/end.2010.0686

    View details for Web of Science ID 000291553500004

    View details for PubMedID 21568756

  • Real Time Diagnosis of Bladder Cancer with Probe-Based Confocal Laser Endomicroscopy IMAGING, MANIPULATION, AND ANALYSIS OF BIOMOLECULES, CELLS, AND TISSUES IX Liu, J., Wu, K., Adams, W., Hsiao, S. T., Mach, K. E., Beck, A. H., Jensen, K. C., Liao, J. C. 2011; 7902

    View details for DOI 10.1117/12.874243

    View details for Web of Science ID 000297677500045

  • HER2 Intermediate Breast Cancers AMERICAN JOURNAL OF SURGICAL PATHOLOGY Jensen, K. C., Nielsen, T. O., Gilks, C. B., West, R. B. 2009; 33 (11): 1739-1739

    View details for Web of Science ID 000271795800022

    View details for PubMedID 19745698

  • Modulation of Vitamin D Receptor Activity by the Corepressor Hairless: Differential Effects of Hairless Isoforms ENDOCRINOLOGY Malloy, P. J., Wang, J., Jensen, K., Feldman, D. 2009; 150 (11): 4950-4957

    Abstract

    The vitamin D receptor (VDR) and its corepressor Hairless (HR) are thought to regulate key steps in the hair cycle because mutations in VDR or HR cause alopecia in humans and mice. Many mammalian cells express two major HR isoforms due to alternative splicing of exon 17. HR isoform-a encodes an 1189-amino acid protein (full-length HR), and isoform-b encodes an 1134-amino acid protein (HRDelta1072-1126). We demonstrated that both HR isoforms are expressed in primary human keratinocytes and in the human keratinocyte cell line HaCaT. In transfected COS-7 cells, the full-length HR repressed VDR-mediated transactivation. In contrast, HRDelta1072-1126 failed to suppress and even stimulated VDR-mediated transactivation. In coimmunoprecipitation, both HR isoforms interacted with the VDR, but only the full-length HR interacted with histone deacetylase 1 (HDAC1). Alanine mutagenesis of two conserved glutamic acids residues (E1100A/E1101A) encoded by exon 17 completely eliminated HR corepressor activity and interactions with HDAC1. When the two HR isoforms were coexpressed in COS-7 cells, the corepressor activity of the full-length HR was not antagonized by the HRDelta1072-1126 isoform. When transfected into HaCaT cells, the full-length HR inhibited endogenous CYP24A1 basal gene expression as well as 1,25-dihydroxyvitamin D3-stimulated CYP24A1 expression. HRDelta1072-1126 failed to suppress basal or 1,25-dihydroxyvitamin D3-stimulated CYP24A1 gene expression. In conclusion, we have demonstrated that both HR isoforms are expressed in keratinocytes and that the HRDelta1072-1126 isoform lacks corepressor activity and is unable to bind HDACs. HRDelta1072-1126 may function as a coactivator in some settings by inhibiting HDAC recruitment to the VDR transcriptional complex.

    View details for DOI 10.1210/en.2009-0358

    View details for Web of Science ID 000271007700015

    View details for PubMedID 19819974

  • Optical Biopsy of Human Bladder Neoplasia With In Vivo Confocal Laser Endomicroscopy JOURNAL OF UROLOGY Sonn, G. A., Jones, S. E., Tarin, T. V., Du, C. B., Mach, K. E., Jensen, K. C., Liao, J. C. 2009; 182 (4): 1299-1305

    Abstract

    Confocal laser endomicroscopy is a new endoscopic imaging technology that could complement white light cystoscopy by providing in vivo bladder histopathology. We evaluated confocal laser endomicroscopy by imaging normal, malignant appearing and indeterminate bladder mucosa in a pilot study.Patients scheduled to undergo transurethral resection of bladder tumors were recruited during a 3-month period. After standard cystoscopy fluorescein was administered intravesically and/or intravenously as a contrast dye. A 2.6 mm probe based confocal laser endomicroscope was passed through a 26 Fr resectoscope to image normal and abnormal appearing areas. The images were collected with 488 nm excitation at 8 to 12 frames per second. The endomicroscopic images were compared with standard hematoxylin and eosin analysis of transurethral resection of bladder tumor specimens.Of the 27 recruited patients 8 had no cancer, 9 had low grade tumors, 9 had high grade tumors and 1 had a low grade tumor with a high grade focus. Endomicroscopic images demonstrated clear differences between normal mucosa, and low and high grade tumors. In normal urothelium larger umbrella cells are seen most superficially followed by smaller intermediate cells and the less cellular lamina propria. In contrast, low grade papillary tumors demonstrate densely arranged but normal-shaped small cells extending outward from fibrovascular cores. High grade tumors show markedly irregular architecture and cellular pleomorphism.We report the first study to our knowledge of in vivo confocal laser endomicroscopy in the urinary tract. Marked differences among normal urothelium, low grade tumors and high grade tumors were visualized. Pending further clinical investigation and technological improvement, confocal laser endomicroscopy may become a useful adjunct to conventional cystoscopy.

    View details for DOI 10.1016/j.juro.2009.06.039

    View details for Web of Science ID 000269764100016

    View details for PubMedID 19683270

  • Fibered Confocal Microscopy of Bladder Tumors: An ex Vivo Study JOURNAL OF ENDOUROLOGY Sonn, G. A., Mach, K. E., Jensen, K., Hsiung, P., Jones, S., Contag, C. H., Wang, T. D., Liao, J. C. 2009; 23 (2): 197-201

    Abstract

    The inadequacy of white-light cystoscopy to detect flat bladder tumors is well recognized. Great interest exists in developing other imaging technologies to augment or supplant conventional cystoscopy. Fibered confocal microscopy offers the promise of providing in vivo histopathologic information to help distinguish malignant from benign bladder lesions. We report the initial use of this technology to visualize tumors in the human bladder.We performed ex vivo fibered confocal imaging of fresh radical cystectomy specimens using the Mauna Kea Technologies Cellvizio system. The findings were compared with results from standard histopathology.The bladders of four patients were imaged using the fibered confocal microscope. Normal and neoplastic urothelium manifested differences in cellular and vascular density.This study demonstrates the feasibility of using fibered confocal microscopy to detect histologic differences between normal and neoplastic urothelium, and establishes a foundation for the use of fiber-based confocal microscopy in clinical studies.

    View details for DOI 10.1089/end.2008.0524

    View details for Web of Science ID 000263355500005

    View details for PubMedID 19196063

  • Gene expression profiling identifies p63 as a diagnostic marker for giant cell tumor of the bone MODERN PATHOLOGY Lee, C., Espinosa, I., Jensen, K. C., Subramanian, S., Zhu, S. X., Varma, S., Montgomery, K. D., Nielsen, T. O., van de Rijn, M., West, R. B. 2008; 21 (5): 531-539

    Abstract

    Giant cell tumor of the bone (GCTOB) is a primary bone tumor that occurs mainly in young adults and is capable of locally aggressive growth. Its histologic appearance can resemble a number of benign and malignant tumors but no useful diagnostic marker is known currently. To identify diagnostic markers for this tumor, global gene expression profiling using cDNA microarray was performed on 6 fresh-frozen GCTOB, 3 aneurysmal bone cysts, 4 fibrous dysplasias and 12 giant cell tumors of tendon sheath/diffuse-type giant cell tumors. Unsupervised hierarchical clustering separated the tumors based on their histopathologic types, and significance analysis of microarray identified several genes including TP73L (encoding the p63 protein) that are significantly highly expressed in GCTOB relative to these other tumors. The diagnostic utility of p63 was subsequently confirmed using anti-p63 antibody on a series of 26 GCTOB, 25 aneurysmal bone cysts, 15 chondroblastomas, 13 giant cell reparative granulomas, 13 chondromyxoid fibromas, 4 brown tumors, 4 fibrous dysplasias, 53 giant cell tumors of tendon sheath/diffuse-type giant cell tumors and 385 additional mesenchymal tumors in tissue microarrays. Strong p63 nuclear staining was present in 18 of 26 (69%) GCTOB, 3 of 15 (20%) chondroblastomas and in 1 of 25 (4%) aneurysmal bone cysts while none of the other tumors commonly considered in the differential diagnosis of GCTOB showed any detectable p63 staining. Strong p63 staining is rare in bone and soft-tissue tumors in general. In contrast to the pattern of p63 staining, the majority of the chondroblastomas (70%) demonstrated S-100 immunoreactivity while only a minority of the GCTOB (8%) was immunoreactive for S-100. These findings altogether show that p63 can be used as a diagnostic marker to aid the clinical diagnosis of GCTOB.

    View details for DOI 10.1038/modpathol.3801023

    View details for Web of Science ID 000255256600004

    View details for PubMedID 18192965

  • A case of prostatic adenocarcinoma recurrence presenting as ductal carcinoma of the prostate NATURE CLINICAL PRACTICE UROLOGY Tu, W. H., Jensen, K., Freiha, F., Liao, J. C. 2008; 5 (1): 55-58

    Abstract

    A 61-year-old man with a history of recurrent prostate cancer presented with obstructive urinary symptoms. He had been diagnosed with locally invasive adenocarcinoma of the prostate 10 years previously and treated with neoadjuvant hormonal and external beam radiation therapies. Because of the patient's rising PSA level, he had been started on goserelin 6 years after this diagnosis and bicalutamide 6 months before the current presentation. The patient presented to the urology clinic with worsening lower urinary tract symptoms consisting of nocturia, urgency, and weak stream.Physical examination revealed a largely normal digital rectal examination, although there was slight asymmetry. The post-void residual urine volume was approximately 200 ml. Laboratory tests showed no evidence of urinary tract infection, but confirmed a rising PSA level despite low serum testosterone levels. Cystoscopic examination revealed hypervascular, large lateral prostatic lobes obstructing the bladder neck. The bladder was normal.The patient underwent transurethral resection of the prostate. Soon after the resection started, bilateral papillary tumors arising from the stroma of both prostatic lobes were uncovered. Owing to the diffuse nature of the papillary tumors, complete resection was not possible. Pathologic analysis confirmed the presence of ductal carcinoma of the prostate.The patient had an uneventful postoperative course and reported improvement of voiding symptoms. Staging with bone scan and CT of the abdomen and pelvis demonstrated multi-focal bony metastasis. The patient was started on docetaxel-based chemotherapy for hormone refractory recurrence of prostate cancer as ductal carcinoma of the prostate. He remains under close surveillance for clinical response and progression of disease.

    View details for DOI 10.1038/ncpuro0994

    View details for Web of Science ID 000252111100013

    View details for PubMedID 18185514

  • Nonfunctioning parathyroid carcinoma: case report and review of literature. Endocrine practice Fernandez-Ranvier, G. G., Jensen, K., Khanafshar, E., Quivey, J. M., Glastonbury, C., Kebebew, E., Duh, Q., Clark, O. H. 2007; 13 (7): 750-757

    Abstract

    To report a case of nonfunctioning parathyroid carcinoma that was incidentally found during a thyroidectomy for multinodular goiter.We present a case report, detailing the clinical course and histologic findings in a patient with a nonfunctional parathyroid carcinoma. The related literature is also reviewed.A 67-year-old woman presented with a 30-year history of a multinodular goiter that was symptomatic. A total thyroidectomy was performed. Histologic examination revealed not only a multinodular thyroid but also a mass in the left lobe, which was diagnostic of a parathyroid carcinoma. Serum calcium and parathyroid hormone levels were normal postoperatively. Eleven months after the initial operation, a suprasternal mass developed, and she underwent neck reexploration and subtotal resection of an invasive recurrent nonfunctioning parathyroid carcinoma. The serum parathyroid hormone and calcium levels were normal before and after the operation. Postoperatively, the patient underwent radiation therapy. Twenty-three months after the initial operation, a computed tomographic scan of the chest revealed an interval increase in size of a nodule in the left lower lobe of the lung, and 30 months after her initial operation, she underwent resection of an isolated, 1-cm (greatest diameter), metastatic parathyroid carcinoma in the left lower lobe of the lung. The patient is currently doing well without evidence of recurrent disease.Nonfunctioning parathyroid carcinomas are difficult to diagnose and to treat. Recurrent disease after operation is common, and radiation therapy may help stabilize tumor growth. Patients with nonfunctioning parathyroid carcinomas appear to have a poorer prognosis than do those with functioning parathyroid cancers.

    View details for PubMedID 18194932

  • Parathyroid carcinoma, atypical parathyroid adenoma, or parathyromatosis? CANCER Fernandez-Ranvier, G. G., Khanafshar, E., Jensen, K., Zarnegar, R., Lee, J., Kebebew, E., Duh, Q., Clark, O. H. 2007; 110 (2): 255-264

    Abstract

    Parathyroid carcinoma, atypical parathyroid adenoma, and parathyromatosis can be differentiated relatively easily from typical parathyroid adenomas, but distinguishing them from each other is more difficult.A retrospective study of 28 consecutive patients with parathyroid carcinoma, 7 patients with atypical parathyroid adenoma, and 13 patients with parathyromatosis who were treated at the University of California at San Francisco Medical Center between 1966 and 2005 was performed. Patient demographics and clinical characteristics, indication for surgery, intraoperative findings, histopathologic characteristics, disease recurrence or persistence, site of invasion/metastases, and survival were compared in the 3 groups.Parathyroid carcinoma (19 of 28 patients) and atypical adenoma (4 of 7 patients) were significantly more common in men, whereas parathyromatosis was more common in women (10 of 13 patients) (P = .02). A palpable neck mass and hoarseness were almost exclusively present in patients with parathyroid carcinoma. Prior to the first parathyroid surgery, patients with parathyroid carcinoma were found to have higher blood calcium levels (>/=14 mg/dL in 16 of 26 patients [62%]), whereas only 1 of 6 patients with atypical adenoma (17%) and no patients with parathyromatosis were found to have profound hypercalcemia (P < .01). Intraoperatively, patients with parathyroid carcinoma and atypical adenoma presented with single lesions, whereas patients with parathyromatosis had multiple small lesions. Histopathologic findings were well defined in parathyroid carcinoma, but some findings overlapped in the 3 tumors studied.Patients with parathyroid carcinoma often differ from those with atypical parathyroid adenoma or parathyromatosis at the time of presentation because patients with parathyroid carcinoma have more profound hypercalcemia as well as invasive tumors. However, at times it is difficult to distinguish between these conditions both clinically and by final histologic examination.

    View details for DOI 10.1002/cncr.22790

    View details for Web of Science ID 000247985600004

    View details for PubMedID 17559137

  • Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma CLINICAL CANCER RESEARCH Nielsen, T. O., Hsu, F. D., Jensen, K., Cheang, M., Karaca, G., Hu, Z. Y., Hernandez-Boussard, T., Livasy, C., Cowan, D., Dressler, L., Akslen, L. A., Ragaz, J., GOWN, A. M., Gilks, C. B., van de Rijn, M. V., Perou, C. M. 2004; 10 (16): 5367-5374

    Abstract

    Expression profiling studies classified breast carcinomas into estrogen receptor (ER)+/luminal, normal breast-like, HER2 overexpressing, and basal-like groups, with the latter two associated with poor outcomes. Currently, there exist clinical assays that identify ER+/luminal and HER2-overexpressing tumors, and we sought to develop a clinical assay for breast basal-like tumors.To identify an immunohistochemical profile for breast basal-like tumors, we collected a series of known basal-like tumors and tested them for protein patterns that are characteristic of this subtype. Next, we examined the significance of these protein patterns using tissue microarrays and evaluated the prognostic significance of these findings.Using a panel of 21 basal-like tumors, which was determined using gene expression profiles, we saw that this subtype was typically immunohistochemically negative for estrogen receptor and HER2 but positive for basal cytokeratins, HER1, and/or c-KIT. Using breast carcinoma tissue microarrays representing 930 patients with 17.4-year mean follow-up, basal cytokeratin expression was associated with low disease-specific survival. HER1 expression was observed in 54% of cases positive for basal cytokeratins (versus 11% of negative cases) and was associated with poor survival independent of nodal status and size. c-KIT expression was more common in basal-like tumors than in other breast cancers but did not influence prognosis.A panel of four antibodies (ER, HER1, HER2, and cytokeratin 5/6) can accurately identify basal-like tumors using standard available clinical tools and shows high specificity. These studies show that many basal-like tumors express HER1, which suggests candidate drugs for evaluation in these patients.

    View details for Web of Science ID 000223454600011

    View details for PubMedID 15328174

  • Detection of pelvic lymph node micrometastasis in stage IA2-IB2 cervical cancer by immunohistochemical analysis GYNECOLOGIC ONCOLOGY Juretzka, M. M., Jensen, K. C., Longacre, T. A., Teng, N. N., Husain, A. 2004; 93 (1): 107-111

    Abstract

    The objectives of this study were to (1) determine the incidence of lymph node micrometastasis in cervical cancer by immunohistochemical analysis and (2) determine if the presence of micrometastasis is a poor prognostic feature in early cervical cancer.We retrospectively reviewed the medical records of 62 patients who underwent radical hysterectomy and lymphadenectomy for FIGO stage IA2-IB2 cervical cancer at Stanford University Hospital from 1990 to 2000. Forty-nine patients with negative lymph nodes were identified. A total of 976 formalin-fixed paraffin-embedded pelvic lymphadenectomy specimens were serially sectioned and stained with anti-cytokeratin antibodies AE1 and AE1/CAM5.2.Six patients had stage IA2 disease, 37 had stage IB1, and 6 had IB2. The mean age of the patients was 44 years (range, 24-76). Seventy-one percent had squamous cell carcinomas, 22% had adenocarcinomas, and 6% had other types. Lymph node micrometastases were immunohistochemically detected in 4 of the 49 (8.1%) patients, comprising 4 of 976 (0.41%) pelvic lymph nodes examined. Twelve of 45 (15.6%) patients with negative nodes had lymph-vascular space invasion (LVSI) whereas 3 of 4 (75%) patients with micrometastases had LVSI. At a mean follow-up time of 39.4 months, 2 of 4 (50%) patients with micrometastasis had recurrent disease, while 3 of 45 (6.7%) patients without micrometastasis developed recurrent disease.These preliminary data suggest that immunohistochemical detection of pelvic lymph nodes is more frequent in patients with LVSI and may identify patients needing adjuvant chemoradiation.

    View details for DOI 10.1016/j.ygyno.2003.11.033

    View details for Web of Science ID 000220850800016

    View details for PubMedID 15047221

  • Procollagen 1 expression in atypical fibroxanthoma and other tumors JOURNAL OF CUTANEOUS PATHOLOGY Jensen, K., Wilkinson, B., Wines, N., Kossard, S. 2004; 31 (1): 57-61

    Abstract

    Procollagen (PC) is secreted by fibroblasts into the extracellular matrix, where it is cleaved to form collagen. The rat anti-human PC-1 monoclonal antibody has been reported to react with atypical fibroxanthoma (AFX), a poorly differentiated but usually benign skin lesion common in elderly patients. We have studied PC-1 staining in 50 tumors with AFX histological features (four of which were subsequently reclassified as non-AFX tumors) to confirm this prior observation. In addition, we have investigated PC-1 in other skin tumors, particularly those with spindled cell or sclerosing/desmoplastic morphologies.Archival material was retrieved and sections were prepared and immunostained with PC-1 as well as a panel of antibodies, including S-100 and MNF-116 (cytokeratins 5, 6, 7, 8, 17, and 19).PC-1 staining was strongly positive in 40 of 46 (87%) AFXs. Three AFXs displayed weak staining with PC-1 even after repeat staining of 10 tumors that were initially weak. Three additional tumors stained with both PC-1 and MNF-116 and were classified as AFX-like squamous cell carcinoma (SCC). One tumor with AFX-like histology was PC-1 negative and S-100 positive and was classified as an AFX-like melanoma. Positive staining in tumor cells was observed in three of nine (33%) desmoplastic malignant melanomas, three of eight (38%) desmoplastic SCCs, zero of 10 (0%) desmoplastic trichoepitheliomas, zero of 10 (0%) morpheic basal cell carcinomas, and zero of 10 (0%) sclerosing sweat duct carcinomas.PC-1 is a useful antibody in a diagnostic immunohistochemical panel when investigating AFX and AFX-like tumors; however, good technical quality and careful interpretation are necessary when using a panel of antibodies, particularly to keratin and S-100 protein, for optimal accuracy.

    View details for Web of Science ID 000187275100009

    View details for PubMedID 14675286

  • Cytokeratin staining in Merkel cell carcinoma: An immunohistochemical study of cytokeratins 5/6, 7, 17, and 20 APPLIED IMMUNOHISTOCHEMISTRY & MOLECULAR MORPHOLOGY Jensen, K., Kohler, S., Rouse, R. V. 2000; 8 (4): 310-315

    Abstract

    Merkel cell carcinoma is an aggressive cutaneous neoplasm with neuroendocrine differentiation that carries a poor prognosis. Its homogeneous morphology is easily confused with lymphoma, leukemia, metastatic small cell carcinoma, and poorly differentiated cutaneous malignancies. Histopathologic diagnosis frequently requires support by immunohistochemistry. The authors investigated cytokeratins (CKs) 5/6, 7, 17, and 20 staining in paraffin sections of 26 Merkel cell carcinomas to expand the knowledge of the CK staining profile of this entity. Reactivity with anti-CK 20 was demonstrated in 23 of 26 Merkel cell carcinomas (88%). All three CK 20-negative tumors showed punctate staining with anti-keratin CAM5.2. Six of 26 tumors (23%) were positive for CK 7, a finding not previously reported. The staining patterns for both CKs 20 and 7 ranged from punctate (perinuclear) to localized (confined to half of the cytoplasm) to diffuse. Punctate CK 20 staining was seen in 17 of 26 cases but was the predominant pattern in only 10 cases. Antibodies to CKs 5/6 and 17 were each negative in the 13 cases for which these stains were performed. Both the positive and negative elements of the CK profile of this distinctive neoplasm provide additional useful diagnostic information for the differential diagnosis between Merkel cell carcinoma and other carcinomas that may simulate it. The authors note that the classically described perinuclear dotlike keratin staining pattern is not universally seen with CK 20 and that CK 7 staining may be seen in a subset of Merkel cell carcinomas.

    View details for Web of Science ID 000165547800008

    View details for PubMedID 11127923

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