Daniel M Berney

Barts Cancer Institute, Londinium, England, United Kingdom

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Publications (122)497.61 Total impact

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    ABSTRACT: Active surveillance (AS) is an important management option for men with low-risk, clinically localized prostate cancer. The clinical parameters for patient selection and definition of progression for AS protocols are evolving as data from several large cohorts matures. Vital to this process is the critical role pathologic parameters play in identifying appropriate candidates for AS. These findings need to be reproducible and consistently reported by surgical pathologists. This report highlights the importance of accurate pathology reporting as a critical component of these protocols.
    Virchows Archiv : an international journal of pathology. 10/2014;
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    ABSTRACT: Prostate cancer has a variable clinical behaviour with frequently unpredictable outcome. DNA methylation plays an important role in determining the biology of cancer but prognostic information is scanty. We assessed the potential of gene-specific DNA methylation changes to predict death from prostate cancer in a cohort of untreated men in the UK.
    BMC Cancer 09/2014; 14(1):655. · 3.33 Impact Factor
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    ABSTRACT: Abstract Chromosomal rearrangements and fusion genes play important roles in tumor development and progression. Four high-frequency prostate cancer-specific fusion genes were recently reported in Chinese cases. We attempted to confirm one of the fusion genes, USP9Y-TTTY15, by reverse transcription PCR, but detected the presence of the USP9Y-TTTY15 fusion transcript in cancer samples, nonmalignant prostate tissues, and normal tissues from other organs, demonstrating that it is a transcription-induced chimeric RNA, which is commonly produced in normal tissues. In 105 prostate cancer samples and case-matched adjacent nonmalignant tissues, we determined the expression level of USP9Y-TTTY15 and a previously reported transcription-induced chimeric RNA, SLC45A3-ELK4. The expression levels of both chimeric RNAs vary greatly in cancer and normal cells. USP9Y-TTTY15 expression is neither higher in cancer than adjacent normal tissues, nor correlated with features of advanced prostate cancer. Although the expression level of SLC45A3-ELK4 is higher in cancer than normal cells, and a dramatic increase in its expression from normal to cancer cells is correlated with advanced disease, its expression level in cancer samples alone is not correlated with any clinical parameters. These data show that both chimeric RNAs contribute less to prostate carcinogenesis than previously reported.
    Omics : a journal of integrative biology. 09/2014;
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    ABSTRACT: Members of the International Society of Urological Pathology (ISUP) participated in a half-day consensus conference to discuss guidelines and recommendations regarding best practice approaches to use of immunohistochemistry (IHC) in differential diagnostic situations in urologic pathology, including bladder, prostate, testis and, kidney lesions. Four working groups, selected by the ISUP leadership, identified several high-interest topics based on common or relevant challenging diagnostic situations and proposed best practice recommendations, which were discussed by the membership. The overall summary of the discussions and the consensus opinion forms the basis of a series of articles, one for each organ site. This Special Article summarizes the overall recommendations made by the four working groups. It is anticipated that this ISUP effort will be valuable to the entire practicing community in the appropriate use of IHC in diagnostic urologic pathology.
    The American journal of surgical pathology. 08/2014; 38(8):1017-1022.
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    ABSTRACT: The judicious use of immunostains can be of significant diagnostic assistance in the interpretation of testicular neoplasms when the light microscopic features are ambiguous. A limited differential diagnosis by traditional morphology is required for the effective use of immunohistochemistry (IHC); otherwise, the inevitable occurrence of exceptions to anticipated patterns will lead to "immunoconfusion." The diagnosis of tumors in the germ cell lineage, the great majority of primary tumors of the testis, has been considerably facilitated over the past decade by IHC directed at developmentally important nuclear transcription factors, including OCT4, SALL4, SOX2, and SOX17, that are mostly restricted to certain tumor histotypes. In conjunction with other markers, a specific diagnosis can be achieved in most instances through a panel of 3 or 4 immunostains and often fewer. IHC among tumors in the sex cord-stromal group may produce a significant proportion of false-negative cases until more sensitive and equally specific markers are validated. The negativity of these tumors for the IHC stains used for germ cell tumors is key in the important distinction of neoplasms in these 2 general categories. In this review, the International Society of Urological Pathologists (ISUP) provides diagnostic guidelines in the form of algorithms to assist practicing pathologists confronting a differential diagnostic question concerning a testicular neoplasm. The goal of ISUP is to anticipate commonly encountered differential diagnoses and recommend an efficient and limited pattern of IHC stains to resolve the question.
    The American journal of surgical pathology 05/2014; · 4.06 Impact Factor
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    ABSTRACT: There is a lack of biomarkers to predict outcome with targeted therapy in metastatic clear cell renal cancer (mccRCC). This may be because dynamic molecular changes occur with therapy. To explore if dynamic, targeted-therapy-driven molecular changes correlate with mccRCC outcome. Multiple frozen samples from primary tumours were taken from sunitinib-naïve (n=22) and sunitinib-treated mccRCC patients (n=23) for protein analysis. A cohort (n=86) of paired, untreated and sunitinib/pazopanib-treated mccRCC samples was used for validation. Array comparative genomic hybridisation (CGH) analysis and RNA interference (RNAi) was used to support the findings. Three cycles of sunitinib 50mg (4 wk on, 2 wk off). Reverse phase protein arrays (training set) and immunofluorescence automated quantitative analysis (validation set) assessed protein expression. Differential expression between sunitinib-naïve and treated samples was seen in 30 of 55 proteins (p<0.05 for each). The proteins B-cell CLL/lymphoma 2 (BCL2), mutL homolog 1 (MLH1), carbonic anhydrase 9 (CA9), and mechanistic target of rapamycin (mTOR) (serine/threonine kinase) had both increased intratumoural variance and significant differential expression with therapy. The validation cohort confirmed increased CA9 expression with therapy. Multivariate analysis showed high CA9 expression after treatment was associated with longer survival (hazard ratio: 0.48; 95% confidence interval, 0.26-0.87; p=0.02). Array CGH profiles revealed sunitinib was associated with significant CA9 region loss. RNAi CA9 silencing in two cell lines inhibited the antiproliferative effects of sunitinib. Shortcomings of the study include selection of a specific protein for analysis, and the specific time points at which the treated tissue was analysed. CA9 levels increase with targeted therapy in mccRCC. Lower CA9 levels are associated with a poor prognosis and possible resistance, as indicated by the validation cohort. Drug treatment of advanced kidney cancer alters molecular markers of treatment resistance. Measuring carbonic anhydrase 9 levels may be helpful in determining which patients benefit from therapy.
    European Urology 05/2014; · 10.48 Impact Factor
  • European Urology 03/2014; · 10.48 Impact Factor
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    ABSTRACT: It is not known how uropathologists currently report histopathological features of prostate biopsies such as core length, tumor extent, perineural invasion, and non-tumor-associated features such as inflammation and hyperplasia in needle biopsies. A web-based survey was distributed among 661 members of the European Network of Uropathology. Complete replies were received from 266 pathologists in 22 European countries. Total core lengths were reported by 64 %. The numbers of cores positive for cancer was given by 79 %. Linear cancer extent was reported by 81 %, most often given in millimeters for each core (53 %) followed by the estimation of percentage of cancer in each core (40 %). A gap of benign tissue between separate cancer foci in a single core would always be subtracted by 48 % and by 63 % if cancer foci were minute and widely separated. Perineural invasion was reported by 97 %. Fat invasion by tumor was interpreted as extraprostatic extension by 81 %. Chronic and active/acute inflammation was always reported by 32 and 56 % but only if pronounced by 54 and 39 %, respectively. While most (79 %) would never diagnose benign prostatic hyperplasia on needle biopsy, 21 % would attempt to make this diagnosis. Reporting practices for prostate biopsies are variable among European pathologists. The great variation in some methodologies used suggests a need for further international consensus, in order for retrospective data to be comparable between different institutions.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 03/2014; · 2.68 Impact Factor
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    ABSTRACT: Background:Androgen receptor (AR)-gene amplification, found in 20-30% of castration-resistant prostate cancer (CRPCa) is proposed to develop as a consequence of hormone-deprivation therapy and be a prime cause of treatment failure. Here we investigate AR-gene amplification in cancers before hormone deprivation therapy.Methods:A tissue microarray (TMA) series of 596 hormone-naive prostate cancers (HNPCas) was screened for chromosome X and AR-gene locus-specific copy number alterations using four-colour fluorescence in situ hybridisation.Results:Both high level gain in chromosome X (4 fold; n=4, 0.7%) and locus-specific amplification of the AR-gene (n=6, 1%) were detected at low frequencies in HNPCa TMAs. Fluorescence in situ hybridisation mapping whole sections taken from the original HNPCa specimen blocks demonstrated that AR-gene amplifications exist in small foci of cells (600 nm, 1% of tumour volume). Patients with AR gene-locus-specific copy number gains had poorer prostate cancer-specific survival.Conclusion:Small clonal foci of cancer containing high level gain of the androgen receptor (AR)-gene develop before hormone deprivation therapy. Their small size makes detection by TMA inefficient and suggests a higher prevalence than that reported herein. It is hypothesised that a large proportion of AR-amplified CRPCa could pre-date hormone deprivation therapy and that these patients would potentially benefit from early total androgen ablation.British Journal of Cancer advance online publication, 30 January 2014; doi:10.1038/bjc.2014.13 www.bjcancer.com.
    British Journal of Cancer 01/2014; · 5.08 Impact Factor
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    ABSTRACT: Ductal adenocarcinoma of the prostate (DAC) is clinically important as its behaviour may differ from that of acinar adenocarcinoma. Our aim was to investigate the interobserver variability of this diagnosis among experts in uropathology and define diagnostic criteria. Photomicrographs of 21 carcinomas with ductal features were distributed among 20 genitourinary pathologists from 8 countries. DAC was diagnosed by 18 observers (mean 13.2 cases, range 6-19). In 11 (52%) cases a 2/3 consensus was reached for a diagnosis of DAC and in 5 (24%) there was consensus against. In DAC the respondents reported papillary architecture (86%), stratification of nuclei (82%), high-grade nuclear features (54%), tall columnar epithelium (53%), elongated nuclei (52%), cribriform architecture (40%) and necrosis (7%). The most important diagnostic feature reported for DAC was papillary architecture (59%), while nuclear and cellular features were considered most important in only 2% to 11% of cases. The most common differential diagnoses were intraductal prostate cancer (52%), high-grade PIN (37%) and acinar adenocarcinoma (17%). The most common reason for not diagnosing DAC was lack of typical architecture (33%). Papillary architecture was the most useful diagnostic feature of DAC, while nuclear and cellular features were considered less important. This article is protected by copyright. All rights reserved.
    Histopathology 01/2014; · 2.86 Impact Factor
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    ABSTRACT: Genomic changes affecting tumour suppressor genes are fundamental to cancer. We applied SNP array analysis to a panel of testicular germ cell tumours to search for novel tumour suppressor genes and identified a frequent small deletion on 6q25.3 affecting just one gene; ZDHHC14. The expression of ZDHHC14, a putative protein palmitoyltransferase with unknown cellular function, was decreased both at RNA and protein levels in testicular germ cell tumours. ZDHHC14 expression was also significantly decreased in a panel of prostate cancer samples and cell lines. Through next generation sequencing of the ZDHHC14 genomic locus we discovered several mutations in both cancer types. Inducible overexpression of ZDHHC14 led to reduced cell viability and increased apoptosis through the classic caspase-dependent pathway. Finally, we confirmed our in vitro findings of the tumour suppressor role of ZDHHC14 in a mouse xenograft model, showing that overexpression of ZDHHC14 inhibits tumourigenesis. Thus we have identified a novel tumour suppressor gene that is commonly downregulated in testicular germ cell tumours and prostate cancer, as well as given insight into the cellular functional role of ZDHHC14, a potential protein palmitoyltransferase that may play a key protective role in cancer.
    The Journal of Pathology 01/2014; · 7.59 Impact Factor
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    ABSTRACT: Background:Current imaging criteria for categorising disease response in metastatic renal cell carcinoma (mRCC) correlate poorly with overall survival (OS) in patients on anti-angiogenic therapies. We prospectively assess diffusion-weighted and multiphase contrast-enhanced (MCE) MR imaging (MRI) as markers of outcome.Methods:Treatment-naive mRCC patients on a phase II trial using sunitinib completed an MRI substudy. Whole-tumour apparent diffusion coefficient (ADC) maps and histograms were generated, and mean ADC and AUClow (proportion of the tumour with ADC values lying below the 25th percentile of the ADC histogram) recorded. On MCE-MRI, regions of interest were drawn around the most avidly enhancing components to analyse enhancement parameters. Baseline (n=26) and treatment-related changes in surviving patients (n=20) were correlated with OS. Imaged metastases were also analysed.Results:Forty-seven per cent of the patients showed significant changes in whole-tumour mean ADC following therapy, but there was no correlation with outcome. Patients with a high baseline AUClow and greater-than-median AUClow increase had reduced OS (HR=3.67 (95% confidence interval (CI)=1.23-10.9), P=0.012 and HR=3.72 (95% CI=0.98-14.21), P=0.038, respectively). There was no correlation between MCE-MRI parameters and OS. Twenty-eight metastases were analysed and showed positive correlation with primary tumour mean ADC for individual patients (r=0.607; P<0.001).Conclusion:Primary RCC ADC histogram analysis shows dynamic changes with sunitinib. Patients in whom the tumour ADC histogram demonstrated high baseline AUClow or a greater-than-median increase in AUClow with treatment had reduced OS.British Journal of Cancer advance online publication, 24 December 2013; doi:10.1038/bjc.2013.790 www.bjcancer.com.
    British Journal of Cancer 12/2013; · 5.08 Impact Factor
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    ABSTRACT: To investigate how biologically relevant markers change in response to anti-angiogenic therapy in metastatic renal cell carcinoma (mRCC) and correlate these changes with outcome. The study utilised sequential tumor tissue and functional imaging (taken at baseline and 12-16 weeks) obtained from 3 similar phase II studies. All three studies investigated the role of VEGF tyrosine kinase inhibitors (TKIs) prior to planned nephrectomy in untreated mRCC (n=85). The effect of targeted therapy on 10 biomarkers was measured from sequential tissue. CGH array and DNA methylation profiling (MethylCap-seq) was performed in matched frozen pairs. Biomarker expression was correlated with early progression (progression as best response) and delayed progression (between 12-16 weeks). VEGF TKI treatment caused a significant reduction in vessel density [CD31], phospho-S6K expression, PDL-1 expression and FOXP3 expression (p<0•05 for each). It also caused a significant increase in cytoplasmic FGF-2, MET receptor expression in vessels, Fuhrman tumor grade and Ki67 (p<0•05 for each). Higher levels of Ki67 and CD31 were associated with delayed progression (p<0•05). Multiple samples (n=5) from the same tumor showed marked heterogeneity of tumor grade, which increased significantly with treatment. Array CGH showed extensive intra-patient variability, which did not occur in DNA methylation analysis. TKI treatment is associated with dynamic changes relevant biomarkers, despite significant heterogeneity in chromosomal and protein, but not epigenetic expression. Changes to Ki67 and grade indicate that treatment is associated with an increase in the aggressive phenotype of the tumor.
    Clinical Cancer Research 10/2013; · 7.84 Impact Factor
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    ABSTRACT: The 2009 International Society of Urological Pathology (ISUP) consensus conference on handling and staging of radical prostatectomy specimens issued recommendations for standardization of pathology reporting of radical prostatectomy specimens. The conference addressed specimen handling, T2 substaging, prostate cancer volume, extraprostatic extension, lymphovascular invasion, seminal vesicle invasion, lymph node metastases and surgical margins. This review summarizes the conclusions and recommendations resulting from the consensus process.
    Annales de Pathologie 06/2013; 33(3):155–161. · 0.24 Impact Factor
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    ABSTRACT: Background:The natural history of prostate cancer is highly variable and difficult to predict. We report on the prognostic value of phosphatase and tensin homologue (PTEN) loss in a cohort of 675 men with conservatively managed prostate cancer diagnosed by transurethral resection of the prostate.Methods:The PTEN status was assayed by immunohistochemistry (PTEN IHC) and fluorescent in situ hybridisation (PTEN FISH). The primary end point was death from prostate cancer.Results:The PTEN IHC loss was observed in 18% cases. This was significantly associated with prostate cancer death in univariate analysis (hazard ratio (HR)=3.51; 95% CI 2.60-4.73; P=3.1 × 10(-14)). It was highly predictive of prostate cancer death in the 50% of patients with a low risk score based on Gleason score, PSA, Ki-67 and extent of disease (HR=7.4; 95% CI 2.2-24.6; P=0.012) ), but had no prognostic value in the higher risk patients. The PTEN FISH loss was only weakly associated with PTEN IHC loss (κ=0.5). Both PTEN FISH loss and amplification were univariately predictive of death from prostate cancer, but this was not maintained in the multivariate analyses.Conclusion:In low-risk patients, PTEN IHC loss adds prognostic value to Gleason score, PSA, Ki-67 and extent of disease.British Journal of Cancer advance online publication, 21 May 2013; doi:10.1038/bjc.2013.248 www.bjcancer.com.
    British Journal of Cancer 05/2013; · 5.08 Impact Factor
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    ABSTRACT: The existence of a benign form of postpubertal testicular teratoma, apart from the rare dermoid cyst, is not widely recognized. This study reports 25 apparently benign postpubertal testicular teratomas, including 10 cases of dermoid cyst and 15 of nondermoid teratomas, which occurred in 25 patients, 12 to 59 years of age (mean, 24 y). Postpubertal status was based on active spermatogenesis in the testis. On gross examination 15 of 16 tumors with available information had a variably prominent cystic component filled with keratinous or mucoid material. On microscopic examination, the 10 dermoid cysts were lined by keratinizing, stratified squamous epithelium with associated pilosebaceous units and sweat glands in an organoid arrangement. Squamous cysts also occurred in 10 of 15 nondermoid teratomas, which by definition lacked adnexal structures. Apart from 2 dermoid cysts additional elements occurred in all cases, most commonly ciliated or respiratory-type epithelium (64%) and smooth muscle (68%). Organoid arrangements were also present in 5 of the nondermoid teratomas. No case showed cytologic atypia nor did the parenchyma adjacent to the teratomas of either type show intratubular germ cell neoplasia, unclassified type, microlithiasis, scarred zones, or more than focal perilesional tubular atrophy/sclerosis. Spermatogenesis was intact in all cases. FISH study for chromosome 12p was performed in 18 cases, and none displayed an abnormal 12p chromosome. All 17 patients that had follow-up information were alive at postoperative intervals of 5 to 168 months, although physician-confirmed disease-free status was unfortunately not available in 6 of these. This study supports the recognition and separate classification of not only dermoid cysts but also a small subset of apparently benign testicular teratomas in postpubertal patients that share many features with dermoid cysts but lack cutaneous-type adnexal structures. Features important in the recognition of both forms of these specialized teratomas of the postpubertal testis include absence of all of the following: cytologic atypia, intratubular germ cell neoplasia, unclassified type, significant tubular atrophy/tubular sclerosis, scarred zones, impaired spermatogenesis, microlithiasis, and evidence of chromosome 12p amplification. Other features include frequent organoid morphology and prominent components of ciliated epithelium and smooth muscle. It is important to distinguish these teratomas from the usual ones seen in postpuberal patients because of the malignant potential of the latter.
    The American journal of surgical pathology 04/2013; · 4.06 Impact Factor
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    ABSTRACT: Background Vascular endothelial growth factor (VEGF)-targeted therapy is administered continuously until progression in metastatic clear cell renal cancer (mRCC). The role of intermittent therapy is under investigation. Preclinical data raise concerns about this approach.Materials and methodsThis study combined the data from three similar phase II studies investigating VEGF-targeted therapy prior to planned nephrectomy for untreated mRCC (European Union Drug Regulating Authorities Clinical Trials 2006-004511-21, 2006-006491-38 and 2009-016675-29). The significance of progression during the planned treatment break (median 4.3 weeks) was assessed.ResultsSixty-two patients had a structured treatment interruption for nephrectomy after achieving clinical benefit from treatment and restarted therapy. Twenty-three of these patients (37%) progressed (Response Evaluation Criteria In Solid Tumors v1.1) on the first scan after the treatment break. Subsequent stabilisation of disease occurred in 16 of the 23 (70%) progressing patients when the same VEGF tyrosine kinase inhibitor (TKI) was reintroduced. Baseline characteristics, such as the Memorial Sloan Kettering Cancer Centre prognostic score, did not predispose to the development of this progression. Progression during the treatment break was associated with an increased risk of death on multivariate analysis {hazard ratio (HR) 5.56; [95% confidence interval 2.29-13.5], P < 0.01}. Sequential fluorodeoxyglucose positron emission tomography showed a rebound in metabolic activity during the treatment break.Conclusions Progression during planned VEGF TKI treatment interruptions is frequent and associated with a poor prognosis. Treatment cessation should be pursued with caution.
    Annals of Oncology 04/2013; · 7.38 Impact Factor

Publication Stats

2k Citations
497.61 Total Impact Points


  • 2011–2014
    • Barts Cancer Institute
      Londinium, England, United Kingdom
    • Università Politecnica delle Marche
      • Institute of Pathological Anatomy
      Ancona, The Marches, Italy
    • University of Cordoba (Spain)
      Cordoue, Andalusia, Spain
    • Skåne University Hospital
      Malmö, Skåne, Sweden
    • Autonomous University of Barcelona
      Cerdanyola del Vallès, Catalonia, Spain
  • 2002–2014
    • Queen Mary, University of London
      • • Centre for Cancer Prevention
      • • Centre for Molecular Oncology
      • • Barts and The London School of Medicine and Dentistry
      Londinium, England, United Kingdom
  • 2012
    • University of Wales
      Cardiff, Wales, United Kingdom
    • Indiana University-Purdue University Indianapolis
      • Department of Pathology and Laboratory Medicine
      Indianapolis, IN, United States
  • 2001–2011
    • Nottinghamshire Healthcare NHS Trust
      Nottigham, England, United Kingdom
  • 2010
    • Ontario Institute for Cancer Research
      Toronto, Ontario, Canada
  • 2008–2010
    • University of London
      • • The Institute of Cancer Research
      • • The London School of Medicine and Dentistry
      Londinium, England, United Kingdom
    • Institute of Cancer Research
      Londinium, England, United Kingdom
    • St. Michael's Hospital
      Toronto, Ontario, Canada