Andrew J Evans

Publications (45)195.57 Total impact

• Article: Preneoplasia in the prostate gland with emphasis on high grade prostatic intraepithelial neoplasia.

  Jennifer L O Merrimen, Andrew J Evans, John R Srigley
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  ABSTRACT: There are a variety of morphological patterns and processes that have been implicated in the pathogenesis of prostate cancer. Prostatic intraepithelial neoplasia (PIN), inflammation with or without atrophy, and adenosis (atypical adenomatous hyperplasia) have all been given candidate status as precursor lesions of prostatic adenocarcinoma. Based on decades of research, high grade prostatic intraepithelial neoplasia (HPIN), a proliferative lesion of prostatic secretory cells, has emerged as the most likely morphological pre-invasive lesion involved in the evolution of many but not all prostatic adenocarcinomas. In this manuscript, we briefly discuss other proposed precursors of prostatic adenocarcinoma and then focus on the history, diagnostic criteria and morphology of HPIN. The incidence of HPIN and its relationship to prostate cancer is reviewed. The differential diagnosis of large glandular patterns in the prostate is discussed in depth. Finally, we summarise the recent clinicopathological studies evaluating the clinical significance of HPIN and discuss follow-up strategies in men diagnosed with HPIN.
  Pathology 03/2013; · 2.38 Impact Factor
• Article: Standardization of Gleason grading among 337 European pathologists.

  Lars Egevad, Amar S Ahmad, Ferran Algaba, Daniel M Berney, Liliane Boccon-Gibod, Eva Compérat, Andrew J Evans, David Griffiths, Rainer Grobholz, Glen Kristiansen, Cord Langner, Antonio Lopez-Beltran, Rodolfo Montironi, Sue Moss, Pedro Oliveira, Ben Vainer, Murali Varma, Philippe Camparo
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  ABSTRACT: Aims:  The 2005 International Society of Urological Pathology (ISUP) modification of Gleason grading recommended that the highest grade should always be included in the Gleason score (GS) in prostate biopsies. We analysed the impact of this recommendation on reporting of GS 6 versus 7. Methods and results:  Fifteen expert uropathologists reached two-thirds consensus on 15 prostate biopsies with GS 6-7 cancer. Eighty-five microphotographs were graded by 337 of 617 members of the European Network of Uropathology (ENUP), representing 19 countries. There was agreement between expert and majority member GS in 12 of 15 cases, while members upgraded in three cases. Among members and the expert consensus, a GS >6 was assigned by 64.5% and 60%, respectively. Mean member GS was higher than consensus GS in nine of 15 cases. A Gleason pattern (GP) 5 was reported by 0.3-5.6% in 10 cases. Agreement between consensus and member GS was 58.2-89.3% (mean 71.4%) in GS 6 cases and 46.3-63.8% (mean 56.4%) in GS 7 cases (P = 0.009). Conclusions:  While undergrading of prostate cancer used to be prevalent, some now tend to overgrade. Minimum diagnostic criteria for GP 4 and 5 in biopsies need to be better defined. Image libraries reviewed by experts may be useful for standardization.
  Histopathology 01/2013; 62(2):247-256. · 3.08 Impact Factor
• Article: PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade.

  Maisa Yoshimoto, Keyue Ding, Joan M Sweet, Olga Ludkovski, Greg Trottier, Kyu S Song, Anthony M Joshua, Neil E Fleshner, Jeremy A Squire, Andrew J Evans
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  ABSTRACT: Prostatic adenocarcinoma is an epithelial malignancy characterized by marked histological heterogeneity. It most often has a multifocal distribution within the gland, and different Gleason grades may be present within different foci. Data from our group and others have shown that the genomic deletion of the phosphatase and tensin homolog deleted on chromosome 10 (PTEN) tumor suppressor gene and the disruption of the ETS gene family have a central role in prostate cancer and are likely to be associated with Gleason grade. In this study, prostate cancer samples were systematically analyzed to determine whether there was concordance between PTEN losses and TMPRSS2-ERG fusion rearrangements, within or between foci in multifocal disease, using well-annotated tissue microarrays (TMAs) consisting of 724 cores derived from 142 radical prostatectomy specimens. Three-color fluorescence in situ hybridization analysis of both the PTEN deletion and the TMPRSS2-ERG fusion was used to precisely map genetic heterogeneity, both within and between tumor foci represented on the TMA. PTEN deletion was observed in 56 of 134 (42%) patients (hemizygous=42 and homozygous=14). TMPRSS2-ERG fusion was observed in 63 of 139 (45%) patients. When analyzed by Gleason pattern for a given TMA core, PTEN deletions were significantly associated with Gleason grades 4 or 5 over grade 3 (P<0.001). Although TMPRSS2-ERG fusions showed a strong relationship with PTEN deletions (P=0.007), TMPRSS2-ERG fusions did not show correlation with Gleason grade. The pattern of genetic heterogeneity of PTEN deletion was more diverse than that observed for TMPRSS2-ERG fusions in multifocal disease. However, the marked interfocal discordance for both TMPRSS2-ERG fusions and PTEN deletions was consistent with the concept that multiple foci of prostate cancer arise independently within the same prostate, and that individual tumor foci can have distinct patterns of genetic rearrangements.Modern Pathology advance online publication, 28 September 2012; doi:10.1038/modpathol.2012.162.
  Modern Pathology 09/2012; · 4.79 Impact Factor
• Article: Utility of whole slide imaging and virtual microscopy in prostate pathology.

  Philippe Camparo, Lars Egevad, Ferran Algaba, Daniel M Berney, Liliane Boccon-Gibod, Eva Compérat, Andrew J Evans, Rainer Grobholz, Glen Kristiansen, Cord Langner, Antonio Lopez-Beltran, Rodolfo Montironi, Pedro Oliveira, Ben Vainer, Murali Varma
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  ABSTRACT: Whole slide imaging (WSI) has been used in conjunction with virtual microscopy (VM) for training or proficiency testing purposes, multicentre research, remote frozen section diagnosis and to seek specialist second opinion in a number of organ systems. The feasibility of using WSI/VM for routine surgical pathology reporting has also been explored. In this review, we discuss the utility and limitations of WSI/VM technology in the histological assessment of specimens from the prostate. Features of WSI/VM that are particularly well suited to assessment of prostate pathology include the ability to examine images at different magnifications as well as to view histology and immunohistochemistry side-by-side on the screen. Use of WSI/VM would also solve the difficulty in obtaining multiple identical copies of small lesions in prostate biopsies for teaching and proficiency testing. It would also permit annotation of the virtual slides, and has been used in a study of inter-observer variation of Gleason grading to facilitate precise identification of the foci on which grading decisions had been based. However, the large number of sections examined from each set of prostate biopsies would greatly increase time required for scanning as well as the size of the digital file, and would also be an issue if digital archiving of prostate biopsies is contemplated. Z-scanning of glass slides, a process that increases scanning time and file size would be required to permit focusing a virtual slide up and down to assess subtle nuclear features such as nucleolar prominence. The common use of large blocks to process prostatectomy specimens would also be an issue, as few currently available scanners can scan such blocks. A major component of proficiency testing of prostate biopsy assessment involves screening of the cores to detect small atypical foci. However, screening virtual slides of wavy fragmented prostate cores using a computer mouse aided by an overview image is very different from screening glass slides using a microscope stage. Hence, it may be more appropriate in this setting to mark the lesional area and focus only on the interpretation component of competency testing. Other issues limiting the use of digital pathology in prostate pathology include the cost of high quality slide scanners for WSI and high resolution monitors for VM as well as the requirement for fast Internet connection as even a subtle delay in presentation of images on the screen may be very disturbing for a pathologist used to the rapid viewing of glass slides under a microscope. However, these problems are likely to be overcome by technological advances in the future.
  Apmis 04/2012; 120(4):298-304. · 1.99 Impact Factor
• Article: The value of triple antibody (34βE12 + p63 + AMACR) cocktail stain in radical prostatectomy specimens with crushed surgical margins.

  Najla Al Daoud, Gangyong Li, Andrew J Evans, Theodorus H van der Kwast
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  ABSTRACT: Triple antibody cocktail immunohistochemical staining is routinely used as an ancillary method to establish a diagnosis of prostate cancer in biopsies with small foci of atypical glands. Crush artefact can distort surgical margins in radical prostatectomy specimens, occasionally making it difficult to diagnose a positive margin. To investigate the ability of a cocktail stain to distinguish carcinoma from benign prostatic glands at the edge of crushed margins in prostatectomy specimens. 10 radical prostatectomy specimens with crushed benign glands at the surgical margins, and 20 with crushed margins positive for carcinoma were retrieved from the pathology archives. The latter included 16 (80%) with positive apical margins, 2 (10%) incised intraprostatic margins, and 1 (5%) soft tissue margin. Two-colour triple antibody stain using a cocktail of antibodies against α-methylacyl coenzyme A racemase (AMACR), high molecular weight keratin and p63 was performed on all the selected cases. In 10/10 specimens with crushed benign glands, basal cell staining continued to be detectable, while AMACR staining was negative in all cases (0/10). In the positive margin cases, none of the crushed glands expressed basal cell marker staining (0/20), whereas 14/20 (70%) of the cases showed variable levels of AMACR positivity at the inked margin. Two-colour triple antibody cocktail stain is useful in the assessment of most, but not all, surgical margins with crushed artefact in prostatectomy specimens by helping to establish whether glands are malignant or benign.
  Journal of clinical pathology 01/2012; 65(5):437-40. · 2.43 Impact Factor
• Article: Therapy-associated effects in the prostate gland.

  John R Srigley, Brett Delahunt, Andrew J Evans
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  ABSTRACT: Diverse therapies are used to treat both benign prostatic hyperplasia and adenocarcinoma. Transurethral resection, a common surgical procedure, may give rise to characteristic necrobiotic granulomas that manifest in subsequent pathology samples. Radiation and hormone therapy have traditionally been used in prostatic adenocarcinoma. Morphological effects are often identified in needle biopsy specimens, transurethral resectates, and radical prostatectomy specimens. A range of histological changes are noted in the non-neoplastic prostate tissue, as well as in the pre-neoplastic and carcinomatous areas. Other ablative therapies, such as cryotherapy, and emerging focal therapies, including high-intensity focused ultrasound, photodynamic therapy, and interstitial laser thermotherapy, may have morphological effects on prostate tissue. It is important for the pathologist to be aware of the spectrum of histological changes affecting the prostate gland post-therapy. The treatment effects may obscure residual carcinoma, and make measurements of tumour extent and stage difficult. Furthermore, some therapies can profoundly alter the neoplastic glands to such an extent that Gleason scoring is no longer valid. As new therapies are developed for prostate cancer, it is important to document their effects on benign and malignant prostate tissue and to understand possible implications for traditional prognostic factors, especially Gleason grade.
  Histopathology 01/2012; 60(1):153-65. · 3.08 Impact Factor
• Article: Gleason grading: past, present and future

  Brett Delahunt, Rose J Miller, John R Srigley, Andrew J Evans, Hemamali Samaratunga
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  ABSTRACT: Delahunt B, Miller R J, Srigley J R, Evans A J & Samaratunga H (2012) Histopathology60, 75–86 Gleason grading: past, present and futureIn 1966 Donald Gleason developed his grading and scoring system for prostatic adenocarcinoma. This classification was refined in 1974 and gained almost universal acceptance, being classified as a category 1 prognostic parameter by the College of American Pathologists. Modifications to the classification were recommended at a conference convened by the International Society of Urological Pathology (ISUP) in 2005. This modified classification has resulted in a significant upgrading of tumours, although some studies have shown a greater concordance between needle biopsy and radical prostatectomy scores when compared to classical Gleason (CG) grading. The ISUP consensus conference recommended that for needle biopsies higher tertiary patterns should be incorporated into the final Gleason score, and this has been correlated with biochemical failure, tumour volume and mortality. Recently the validity of including cribriform glands as a component of Gleason pattern 3 has been questioned and it has been recommended that all tumours showing cribriform architecture should be classified as Gleason pattern 4. The recommendations arising from the 2005 Consensus Conference were largely unsupported by validating data, yet this new grading system has achieved widespread usage. It is unfortunate that recent suggestions for further modification are similarly lacking in supporting evidence. In view of this it is recommended that the Modified Gleason Scoring Classification should continue to be utilized in its original (2005) format and that any future alterations should be implemented only when mandated by tumour-related outcome studies.
  Histopathology 12/2011; 60(1):75 - 86. · 3.08 Impact Factor
• Article: Active surveillance of small renal masses: progression patterns of early stage kidney cancer.

  Michael A S Jewett, Kamal Mattar, Joan Basiuk, Christopher G Morash, Stephen E Pautler, D Robert Siemens, Simon Tanguay, Ricardo A Rendon, Martin E Gleave, Darrel E Drachenberg, [......], Hannah Chung, Joseph L Chin, Neil E Fleshner, Andrew J Evans, Brenda L Gallie, Masoom A Haider, John R Kachura, Ghada Kurban, Kimberly Fernandes, Antonio Finelli
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  ABSTRACT: Most early stage kidney cancers are renal cell carcinomas (RCCs), and most are diagnosed incidentally by imaging as small renal masses (SRMs). Indirect evidence suggests that most small RCCs grow slowly and rarely metastasize. To determine the progression and growth rates for newly diagnosed SRMs stratified by needle core biopsy pathology. A multicenter prospective phase 2 clinical trial of active surveillance of 209 SRMs in 178 elderly and/or infirm patients was conducted from 2004 until 2009 with treatment delayed until progression. Patients underwent serial imaging and needle core biopsies. We measured rates of change in tumor diameter (growth measured by imaging) and progression to ≥ 4 cm, doubling of tumor volume, or metastasis with histology on biopsy. Local progression occurred in 25 patients (12%), plus 2 progressed with metastases (1.1%). Of the 178 subjects with 209 SRMs, 127 with 151 SRMs had>12 mo of follow-up with two or more images, with a mean follow-up of 28 mo. Their tumor diameters increased by an average of 0.13 cm/yr. Needle core biopsy in 101 SRMs demonstrated that the presence of RCC did not significantly change growth rate. Limitations included no central review of imaging and pathology and a short follow-up. This is the first SRM active surveillance study to correlate growth with histology prospectively. In the first 2 yr, the rate of local progression to higher stage is low, and metastases are rare. SRMs appear to grow very slowly, even if biopsy proven to be RCC. Many patients with SRMs can therefore be initially managed conservatively with serial imaging, avoiding the morbidity of surgical or ablative treatment.
  European urology 07/2011; 60(1):39-44. · 7.67 Impact Factor
• Article: Treatment effects in the prostate including those associated with traditional and emerging therapies.

  Andrew J Evans, Paul Ryan, Theodorus Van derKwast
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  ABSTRACT: Classic treatment options for prostate cancer consist of radical prostatectomy, antiandrogen (or hormonal) therapy, and radiation therapy. Hormonal and radiation therapy, in particular, have well known, often profound effects on the histologic appearance of benign prostate tissue and prostatic carcinoma. The tissue changes induced by these treatments have been comprehensively described in several sources. Novel therapies ranging from focal ablative treatments to highly targeted molecular therapies are beginning to emerge and pathologists will play a central role in documenting the effects of these treatments on normal and malignant prostate tissue. It is therefore important that pathologists have access to basic treatment information and a solid working knowledge of the morphologic changes induced by these therapies. This will ensure accurate interpretation and reporting of posttreatment prostate specimens. This review is based on a presentation given by Dr A. Evans at the International Society of Urological Pathology Companion Society Meeting (Hot Topics in Urological Pathology) at The United States Canadian Academy of Pathology Meeting in Washington DC on March 20, 2010. This review will cover the histopathologic features seen in benign prostate tissue and prostatic carcinoma seen following: hormonal therapy, radiation therapy, ablative therapies such as vascular-targeted photodynamic therapy, interstitial laser thermotherapy, and high-intensity focussed ultrasound. An emphasis is placed on these specific modalities as they are currently in use as primary, salvage, or investigational therapy in the treatment of prostate cancer.
  Advances in anatomic pathology 07/2011; 18(4):281-93. · 3.22 Impact Factor
• Source

  Available from: Antonio Lopez-Beltran

  Article: Interactive digital slides with heat maps: a novel method to improve the reproducibility of Gleason grading.

  Lars Egevad, Ferran Algaba, Daniel M Berney, Liliane Boccon-Gibod, Eva Compérat, Andrew J Evans, Rainer Grobholz, Glen Kristiansen, Cord Langner, Gina Lockwood, Antonio Lopez-Beltran, Rodolfo Montironi, Pedro Oliveira, Matthias Schwenkglenks, Ben Vainer, Murali Varma, Vincent Verger, Philippe Camparo
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  ABSTRACT: Our aims were to analyze reporting of Gleason pattern (GP) 3 and 4 prostate cancer with the ISUP 2005 Gleason grading and to collect consensus cases for standardization. We scanned 25 prostate biopsy cores diagnosed as Gleason score (GS) 6-7. Fifteen genitourinary pathologists graded the digital slides and circled GP 4 and 5 in a slide viewer. Grading difficulty was scored as 1-3. GP 4 components were classified as type 1 (cribriform), 2 (fused), or 3 (poorly formed glands). A GS of 5-6, 7 (3 + 4), 7 (4 + 3), and 8-9 was given in 29%, 41%, 19%, and 10% (mean GS 6.84, range 6.44-7.36). In 15 cases, at least 67% of observers agreed on GS groups (consensus cases). Mean interobserver weighted kappa for GS groups was 0.43. Mean difficulty scores in consensus and non-consensus cases were 1.44 and 1.66 (p = 0.003). Pattern 4 types 1, 2, and 3 were seen in 28%, 86%, and 67% of GP 4. All three coexisted in 16% (11% and 23% in consensus and non-consensus cases, p = 0.03). Average estimated and calculated %GP 4/5 were 29% and 16%. After individual review, the experts met to analyze diagnostic difficulties. Areas of GP 4 and 5 were displayed as heat maps, which were helpful for identifying contentious areas. A key problem was to agree on minimal criteria for small foci of GP 4. In summary, the detection threshold for GP 4 in NBX needs to be better defined. This set of consensus cases may be useful for standardization.
  Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 06/2011; 459(2):175-82. · 2.49 Impact Factor
• Article: Deregulation of E2-EPF ubiquitin carrier protein in papillary renal cell carcinoma.

  Frederik C Roos, Andrew J Evans, Walburgis Brenner, Bill Wondergem, Jeffery Klomp, Pardeep Heir, Olga Roche, Christian Thomas, Heiko Schimmel, Kyle A Furge, Bin T Teh, Joachim W Thüroff, Christian Hampel, Michael Ohh
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  ABSTRACT: Molecular pathways associated with pathogenesis of sporadic papillary renal cell carcinoma (PRCC), the second most common form of kidney cancer, are poorly understood. We analyzed primary tumor specimens from 35 PRCC patients treated by nephrectomy via gene expression analysis and tissue microarrays constructed from an additional 57 paraffin-embedded PRCC samples via immunohistochemistry. Gene products were validated and further studied by Western blot analyses using primary PRCC tumor samples and established renal cell carcinoma cell lines, and potential associations with pathologic variables and survival in 27 patients with follow-up information were determined. We show that the expression of E2-EPF ubiquitin carrier protein, which targets the principal negative regulator of hypoxia-inducible factor (HIF), von Hippel-Lindau protein, for proteasome-dependent degradation, is markedly elevated in the majority of PRCC tumors exhibiting increased HIF1α expression, and is associated with poor prognosis. In addition, we identified multiple hypoxia-responsive elements within the E2-EPF promoter, and for the first time we demonstrated that E2-EPF is a hypoxia-inducible gene directly regulated via HIF1. These findings reveal deregulation of the oxygen-sensing pathway impinging on the positive feedback mechanism of HIF1-mediated regulation of E2-EPF in PRCC.
  American Journal Of Pathology 02/2011; 178(2):853-60. · 4.89 Impact Factor
• Article: International Society of Urological Pathology (ISUP) Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens. Working group 3: extraprostatic extension, lymphovascular invasion and locally advanced disease.

  Cristina Magi-Galluzzi, Andrew J Evans, Brett Delahunt, Jonathan I Epstein, David F Griffiths, Theo H van der Kwast, Rodolfo Montironi, Thomas M Wheeler, John R Srigley, Lars L Egevad, Peter A Humphrey
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  ABSTRACT: The International Society of Urological Pathology Consensus Conference on Handling and Staging of Radical Prostatectomy Specimens in Boston made recommendations regarding the standardization of pathology reporting of radical prostatectomy specimens. Issues relating to extraprostatic extension (pT3a disease), bladder neck invasion, lymphovascular invasion and the definition of pT4 were coordinated by working group 3. It was agreed that prostate cancer can be categorized as pT3a in the absence of adipose tissue involvement when cancer bulges beyond the contour of the gland or beyond the condensed smooth muscle of the prostate at posterior and posterolateral sites. Extraprostatic extension can also be identified anteriorly. It was agreed that the location of extraprostatic extension should be reported. Although there was consensus that the amount of extraprostatic extension should be quantitated, there was no agreement as to which method of quantitation should be employed. There was overwhelming consensus that microscopic urinary bladder neck invasion by carcinoma should be reported as stage pT3a and that lymphovascular invasion by carcinoma should be reported. It is recommended that these elements are considered in the development of practice guidelines and in the daily practice of urological surgical pathology.
  Modern Pathology 01/2011; 24(1):26-38. · 4.79 Impact Factor
• Article: Re: Barriers and facilitators to adoption of soft copy interpretation from the user perspective: Lessons learned from filmless radiology for slideless pathology. J Pathol Inform, 2011;2:1, Patterson et al.

  Andrew J Evans
  Journal of pathology informatics. 01/2011; 2:8.
• Article: Prostate cancer localization with multispectral MRI using cost-sensitive support vector machines and conditional random fields.

  Yusuf Artan, Masoom A Haider, Deanna L Langer, Theodorus H van der Kwast, Andrew J Evans, Yongyi Yang, Miles N Wernick, John Trachtenberg, Imam Samil Yetik
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  ABSTRACT: Prostate cancer is a leading cause of cancer death for men in the United States. Fortunately, the survival rate for early diagnosed patients is relatively high. Therefore, in vivo imaging plays an important role for the detection and treatment of the disease. Accurate prostate cancer localization with noninvasive imaging can be used to guide biopsy, radiotherapy, and surgery as well as to monitor disease progression. Magnetic resonance imaging (MRI) performed with an endorectal coil provides higher prostate cancer localization accuracy, when compared to transrectal ultrasound (TRUS). However, in general, a single type of MRI is not sufficient for reliable tumor localization. As an alternative, multispectral MRI, i.e., the use of multiple MRI-derived datasets, has emerged as a promising noninvasive imaging technique for the localization of prostate cancer; however almost all studies are with human readers. There is a significant inter and intraobserver variability for human readers, and it is substantially difficult for humans to analyze the large dataset of multispectral MRI. To solve these problems, this study presents an automated localization method using cost-sensitive support vector machines (SVMs) and shows that this method results in improved localization accuracy than classical SVM. Additionally, we develop a new segmentation method by combining conditional random fields (CRF) with a cost-sensitive framework and show that our method further improves cost-sensitive SVM results by incorporating spatial information. We test SVM, cost-sensitive SVM, and the proposed cost-sensitive CRF on multispectral MRI datasets acquired from 21 biopsy-confirmed cancer patients. Our results show that multispectral MRI helps to increase the accuracy of prostate cancer localization when compared to single MR images; and that using advanced methods such as cost-sensitive SVM as well as the proposed cost-sensitive CRF can boost the performance significantly when compared to SVM.
  IEEE Transactions on Image Processing 09/2010; 19(9):2444-55. · 3.04 Impact Factor
• Article: Frequently asked questions concerning the use of whole-slide imaging telepathology for neuropathology frozen sections.

  Andrew J Evans, Tim-Rasmus Kiehl, Sidney Croul
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  ABSTRACT: TP involves the provision of pathology services over a distance using the Internet to link pathologists at the "viewing site" with diagnostic material in a "remote site." Robotic microscopes were a mainstay of TP; however, this is now changing with the development of whole-slide imaging (WSI) systems which enable rapid production of digital slides that can be reviewed over a complete range of magnifications with a viewing experience closely replicating that of light microscopy. As such, WSI will undoubtedly become a viable option for pathology departments considering TP for remote frozen section (FS) coverage, and in the future for rapid consultation on difficult cases. For reasons to be discussed below, it may be particularly attractive to use WSI TP for neuropathology frozen sections (NPFS). We have been using WSI TP for primary NPFS diagnoses since 2006. This brief review provides answers to questions that we have frequently been asked about our program. The answers reflect our experience, and it is important to note that our recommendations may not be applicable in all institutions. The reader is directed to the recent literature for more detailed information on WSI as well as a complete description of our TP program.
  Seminars in Diagnostic Pathology 08/2010; 27(3):160-6. · 1.26 Impact Factor
• Article: Oncolytic targeting of renal cell carcinoma via encephalomyocarditis virus.

  Frederik C Roos, Andrew M Roberts, Irene I L Hwang, Eduardo H Moriyama, Andrew J Evans, Stephanie Sybingco, Ian R Watson, Leticia A M Carneiro, Craig Gedye, Stephen E Girardin, Laurie E Ailles, Michael A S Jewett, Michael Milosevic, Brian C Wilson, John C Bell, Sandy D Der, Michael Ohh
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  ABSTRACT: Apoptosis is a fundamental host defence mechanism against invading microbes. Inactivation of NF-kappaB attenuates encephalomyocarditis virus (EMCV) virulence by triggering rapid apoptosis of infected cells, thereby pre-emptively limiting viral replication. Recent evidence has shown that hypoxia-inducible factor (HIF) increases NF-kappaB-mediated anti-apoptotic response in clear-cell renal cell carcinoma (CCRCC) that commonly exhibit hyperactivation of HIF due to the loss of its principal negative regulator, von Hippel-Lindau (VHL) tumour suppressor protein. Here, we show that EMCV challenge induces a strong NF-kappaB-dependent gene expression profile concomitant with a lack of interferon-mediated anti-viral response in VHL-null CCRCC, and that multiple established CCRCC cell lines, as well as early-passage primary CCRCC cultured cells, are acutely susceptible to EMCV replication and virulence. Functional restoration of VHL or molecular suppression of HIF or NF-kappaB dramatically reverses CCRCC cellular susceptibility to EMCV-induced killing. Notably, intratumoural EMCV treatment of CCRCC in a murine xenograft model rapidly regresses tumour growth. These findings provide compelling pre-clinical evidence for the usage of EMCV in the treatment of CCRCC and potentially other tumours with elevated HIF/NF-kappaB-survival signature.
  EMBO Molecular Medicine 07/2010; 2(7):275-88. · 10.33 Impact Factor
• Article: Prostate tissue composition and MR measurements: investigating the relationships between ADC, T2, K(trans), v(e), and corresponding histologic features.

  Deanna L Langer, Theodorus H van der Kwast, Andrew J Evans, Anna Plotkin, John Trachtenberg, Brian C Wilson, Masoom A Haider
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  ABSTRACT: To investigate relationships between magnetic resonance (MR) imaging measurements and the underlying composition of normal and malignant prostate tissue. Twenty-four patients (median age, 63 years; age range, 44-72 years) gave informed consent to be examined for this research ethics board-approved study. Before undergoing prostatectomy, patients were examined with T2-weighted, diffusion-weighted, T2 mapping, and dynamic contrast material-enhanced MR imaging at 1.5 T. Maps of apparent diffusion coefficient (ADC), T2, volume transfer constant (K(trans)), and extravascular extracellular space (v(e)) were calculated. Whole-mount hematoxylin-eosin-stained sections were generated and digitized at histologic resolution. Percentage areas of tissue components (nuclei, cytoplasm, stroma, luminal space) were measured by using image segmentation. Corresponding regions on MR images and histologic specimens were defined by using anatomically defined segments in peripheral zone (PZ) and central gland tissue. Cancer and normal PZ regions were identified at histopathologic analysis. Each MR parameter-histologic tissue component pair was assessed by using linear mixed-effects models, and cancer versus normal PZ values were compared by using nonparametric tests. ADC and T2 were inversely related to percentage area of nuclei and percentage area of cytoplasm and positively related to percentage area of luminal space (P < or = .01). These trends were reversed for K(trans) (P < .001). K(trans) had a significantly negative (P = .01) slope versus percentage area of stroma, and v(e) had a positive (P = .008) slope versus percentage area of stroma. The v(e) was inversely proportional to the percentage area of nuclei (P = .05). All MR imaging parameters (P < or = .05) and the percentage areas of all tissue components (P < or = .001) except stroma (P > .48) were significantly different between cancer and normal PZ tissue. MR imaging-derived parameters measured in the prostate were significantly related to the proportion of specific histologic components that differ between normal and malignant PZ tissue. These relationships may help define imaging-related histologic prognostic parameters for prostate cancer.
  Radiology 05/2010; 255(2):485-94. · 5.73 Impact Factor
• Article: Supervised and unsupervised methods for prostate cancer segmentation with multispectral MRI.

  Sedat Ozer, Deanna L Langer, Xin Liu, Masoom A Haider, Theodorus H van der Kwast, Andrew J Evans, Yongyi Yang, Miles N Wernick, Imam S Yetik
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  ABSTRACT: Magnetic resonance imaging (MRI) has been proposed as a promising alternative to transrectal ultrasound for the detection and localization of prostate cancer and fusing the information from multispectral MR images is currently an active research area. In this study, the goal is to develop automated methods that combine the pharmacokinetic parameters derived from dynamic contrast enhanced (DCE) MRI with quantitative T2 MRI and diffusion weighted imaging (DWI) in contrast to most of the studies which were performed with human readers. The main advantages of the automated methods are that the observer variability is removed and easily reproducible results can be efficiently obtained when the methods are applied to a test data. The goal is also to compare the performance of automated supervised and unsupervised methods for prostate cancer localization with multispectral MRI. The authors use multispectral MRI data from 20 patients with biopsy-confirmed prostate cancer patients, and the image set consists of parameters derived from T2, DWI, and DCE-MRI. The authors utilize large margin classifiers for prostate cancer segmentation and compare them to an unsupervised method the authors have previously developed. The authors also develop thresholding schemes to tune support vector machines (SVMs) and their probabilistic counterparts, relevance vector machines (RVMs), for an improved performance with respect to a selected criterion. Moreover, the authors apply a thresholding method to make the unsupervised fuzzy Markov random fields method fully automatic. The authors have developed a supervised machine learning method that performs better than the previously developed unsupervised method and, additionally, have found that there is no significant difference between the SVM and RVM segmentation results. The results also show that the proposed methods for threshold selection can be used to tune the automated segmentation methods to optimize results for certain criteria such as accuracy or sensitivity. The test results of the automated algorithms indicate that using multispectral MRI improves prostate cancer segmentation performance when compared to single MR images, a result similar to the human reader studies that were performed before. The automated methods presented here can help diagnose and detect prostate cancer, and improve segmentation results. For that purpose, multispectral MRI provides better information about cancer and normal regions in the prostate when compared to methods that use single MRI techniques; thus, the different MRI measurements provide complementary information in the automated methods. Moreover, the use of supervised algorithms in such automated methods remain a good alternative to the use of unsupervised algorithms.
  Medical Physics 04/2010; 37(4):1873-83. · 2.83 Impact Factor
• Source

  Available from: Sylvia L Asa

  Article: Primary frozen section diagnosis by robotic microscopy and virtual slide telepathology: the University Health Network experience.

  Andrew J Evans, Runjan Chetty, Blaise A Clarke, Sidney Croul, Danny M Ghazarian, Tim-Rasmus Kiehl, Bayardo Perez Ordonez, Suganthi Ilaalagan, Sylvia L Asa
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  ABSTRACT: Although telepathology (TP) has not been widely implemented for primary frozen section diagnoses, interest in its use is growing as we move into an age of increasing sub-specialization and centralization of pathology services. University Health Network (UHN) is a 3-site academic institution in downtown Toronto. The pathology department is consolidated at its Toronto General Hospital (TGH) site. The Toronto Western Hospital (TWH), located 1 mile to west of TGH, has no on-site pathologist and generates 5-10 frozen section cases per week. Over 95% of these frozen sections are submitted by neurosurgeons, in most cases to confirm the presence of lesional tissue and establish a tissue diagnosis. In 2004, we implemented a robotic microscopy (RM) TP system to cover these frozen sections. In 2006, we changed to a virtual slide (VS) TP system. Between November 2004 and September 2006, 350 primary frozen section diagnoses were made by RM. An additional 633 have been reported by VS TP since October 2006, giving a total of 983 frozen sections from 790 patients. Eighty-eight percent of these cases have been single specimens with total turnaround times averaging 19.98 and 15.68 minutes per case by RM and VS TP, respectively (P < 0.0001). Pathologists required an average of 9.65 minutes to review a slide by RM. This decreased 4 fold to 2.25 minutes following the change to VS TP (P < 0.00001). Diagnostic accuracy has been 98% with both modalities and our overall deferral rate has been 7.7%. Mid-case technical failure has occurred in 3 cases (0.3%) resulting in a delay where a pathologist went to TWH to report the frozen section. Discrepant cases have typically involved minor interpretive errors related to tumor type. None of our discrepant TP diagnoses have had clinical impact to date. We have found TP to be reliable and accurate for frozen section diagnoses. In addition to its superior speed and image quality, the VS approach readily facilitates consultation with colleagues on difficult cases. As a result, there has been greater overall pathologist satisfaction with VS TP.
  Seminars in Diagnostic Pathology 11/2009; 26(4):165-76. · 1.26 Impact Factor
• Article: Suppression of hypoxia-inducible factor 2alpha restores p53 activity via Hdm2 and reverses chemoresistance of renal carcinoma cells.

  Andrew M Roberts, Ian R Watson, Andrew J Evans, David A Foster, Meredith S Irwin, Michael Ohh
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  ABSTRACT: p53 mutations are rarely detected in clear cell renal cell carcinoma (CCRCC), but, paradoxically, these tumors remain highly resistant to chemotherapy and death receptor-induced death. Here, we show that the accumulation of hypoxia-inducible factor 2alpha (HIF2alpha), a critical oncogenic event in CCRCC following the loss of von Hippel-Lindau (VHL) tumor suppressor protein, leads to Hdm2-mediated suppression of p53. Primary CCRCC specimens exhibiting strong hypoxic signatures show increased levels of activated nuclear phospho-Hdm2(Ser(166)), which is concomitant with low p53 expression. The abrogation of Hdm2-p53 interaction using the small-molecule Hdm2 inhibitor nutlin-3 or the downregulation of HIF2alpha via HIF2alpha-specific short hairpin RNA or wild-type VHL reconstitution restores p53 function and reverses the resistance of CCRCC cells to Fas-mediated and chemotherapy-induced cell death. These findings unveil a mechanistic link between HIF2alpha and p53 and provide a rationale for combining Hdm2 antagonists with chemotherapy for the treatment of CCRCC.
  Cancer Research 11/2009; 69(23):9056-64. · 7.86 Impact Factor