David M Berman

Queen's University, Kingston, Ontario, Canada

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Publications (105)719.99 Total impact

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    ABSTRACT: The prognostic value of phosphatase and tensin homolog (PTEN) loss in prostate cancer has primarily been evaluated by either fluorescence in situ hybridization (FISH) or immunohistochemistry (IHC). Previously, we found that PTEN loss by IHC was associated with increased risk of upgrading from biopsy (Gleason 3 + 3) to prostatectomy (Gleason 7+). Now, using an evaluable subset of 111 patients with adjacent biopsy sections, we analyzed the association between PTEN deletion in cancer and the odds of upgrading by a highly sensitive and specific four-color FISH assay. We also compared the concordance of PTEN loss by IHC and PTEN deletion by FISH. PTEN deletion was found in 27 % (12/45) of upgraded cases compared with 11 % (7/66) of controls (P = 0.03). Cancers with PTEN deletions were more likely to be upgraded than those without deletions (adjusting for age odds ratio = 3.40, 95 % confidence interval 1.14-10.11). With respect to concordance, of 93 biopsies with PTEN protein detected by IHC, 89 (96 %) had no PTEN deletion by FISH, and of 18 biopsies without PTEN protein by IHC, 15 had homozygous or hemizygous PTEN deletion by FISH. Only 4 biopsies of the 93 (4 %) with PTEN protein intact had PTEN deletion by FISH. When the regions of uncertainty in these biopsies were systematically studied by FISH, intra-tumoral variation of PTEN deletion was found, which could account for variation in immunoreactivity. Thus, FISH provides a different approach to determining PTEN loss when IHC is uncertain. Both FISH and IHC are concordant, showing consistent positive associations between PTEN loss and upgrading.
    No preview · Article · Feb 2016 · Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin
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    ABSTRACT: Purpose: Prostate cancers incite tremendous morbidity upon metastatic growth. We previously identified Asporin (ASPN) as a potential mediator of metastatic progression found within the tumor microenvironment. ASPN contains an aspartic acid (D)-repeat domain and germline polymorphisms in D-repeat-length have been associated with degenerative diseases. Associations of germline ASPN D polymorphisms with risk of prostate cancer progression to metastatic disease have not been assessed. Experimental design: Germline ASPN D-repeat-length was retrospectively analyzed in 1600 men who underwent radical prostatectomy for clinically localized prostate cancer and in 548 non-cancer controls. Multivariable Cox proportional hazards models were used to test the associations of ASPN variations with risk of subsequent oncologic outcomes including metastasis. Orthotopic xenografts were used to establish allele- and stroma-specific roles for ASPN D variants in metastatic prostate cancer. Results: Variation at the ASPN D locus was differentially associated with poorer oncologic outcomes. ASPN D14 (HR=1.72, 95%CI=1.05-2.81, P=0.032) and heterozygosity for ASPN D13/14 (HR=1.86, 95%CI=1.03-3.35, P=0.040) were significantly associated with metastatic recurrence, while homozygosity for the ASPN D13 variant was significantly associated with a reduced risk of metastatic recurrence (HR=0.44, 95%CI=0.21-0.94, P=0.035) in multivariable analyses. Orthotopic xenografts established biologic roles for ASPN D14 and ASPN D13 variants in metastatic prostate cancer progression that were consistent with patient based data. Conclusions: We observed associations between ASPN D variants and oncologic outcomes including metastasis. Our data suggest that ASPN expressed in the tumor microenvironment is a heritable modulator of metastatic progression.
    No preview · Article · Oct 2015 · Clinical Cancer Research
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    ABSTRACT: Background: The 5-year cancer specific survival (CSS) for patients with muscle invasive urothelial carcinoma of the bladder (MIBC) treated with cystectomy alone is approximately 50%. Platinum based neoadjuvant chemotherapy (NAC) plus cystectomy results in a marginal 5-10% increase in 5-year CSS in MIBC. Interestingly, responders to NAC (<ypT2) have a 5-year CSS of 90% which is in stark contrast to the 30-40% CSS for those whose MIBC is resistance to NAC. While the implementation of NAC for MIBC is increasing, it is still not widely utilized due to concerns related to delay of cystectomy, potential side-effects, and inability to predict effectiveness. Recently suggested molecular signatures of chemoresponsiveness, which could prove useful in this setting, would be of considerable utility but are yet to be translated into clinical practice. Methods: mRNA expression data from a prior report on a NAC-treated MIBC cohort were re-analyzed in conjunction with the antibody database of the Human Protein Atlas (HPA) to identify candidate protein based biomarkers detectable by immunohistochemistry (IHC). These candidate biomarkers were subsequently tested in tissue microarrays derived from an independent cohort of NAC naive MIBC biopsy specimens from whom the patients were treated with neoadjuvant gemcitabine cisplatin NAC and subsequent cystectomy. The clinical parameters that have been previously associated with NAC response were also examined in our cohort. Results: Our analyses of the available mRNA gene expression data in a discovery cohort (n = 33) and the HPA resulted in 8 candidate protein biomarkers. The combination of GDPD3 and SPRED1 resulted in a multivariate classification tree that was significantly associated with NAC response status (Goodman-Kruskal γ = 0.85 p<0.0001) in our independent NAC treated MIBC cohort. This model was independent of the clinical factors of age and clinical tumor stage, which have been previously associated with NAC response by our group. The combination of both these protein biomarkers detected by IHC in biopsy specimens along with the relevant clinical parameters resulted in a prediction model able to significantly stratify the likelihood of NAC resistance in our cohort (n = 37) into two well separated halves: low-26% n = 19 and high-89% n = 18, Fisher's exact p = 0.0002). Conclusion: We illustrate the feasibility of translating a gene expression signature of NAC response from a discovery cohort into immunohistochemical markers readily applicable to MIBC biopsy specimens in our independent cohort. The results from this study are being characterized in additional validation cohorts. Additionally, we anticipate that emerging somatic mutations in MIBC will also be important for NAC response prediction. The relationship of the findings in this study to the current understanding of variant histologic subtypes of MIBC along with the evolving molecular subtypes of MIBC as it relates to NAC response remains to be fully characterized.
    Full-text · Article · Jul 2015 · PLoS ONE
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    ABSTRACT: Squamous cell carcinoma (SCC) of the bladder is an uncommon form of bladder cancer. Using a large population-based sample we sought to describe the outcomes of patients with squamous histology and to define the factors that influence prognosis in these patients. All incident cases of bladder cancer in Ontario undergoing cystectomy from 1994 to 2008 were identified. Electronic treatment records and detailed pathologic information were linked to the study data set. Patients were divided into 3 cohorts: pure SCC, urothelial carcinoma (UC) with squamous differentiation (UCSD), and pure UC. Cox modeling was performed to evaluate factors associated with overall survival (OS) and cancer-specific survival (CSS). There were identified 178, 325, and 2,884 cases of SCC, UCSD, and UC, respectively. The unadjusted 5-year OS for these groups were 33%, 28%, and 34%, respectively. Patients had higher rates of T3/4 disease with SCC (72%) and UCSD (73%) than those with UC (61%, P<0.001). There was no difference in node positivity among groups (20%, 27%, and 25%, P = 0.519). After adjusting for covariates, SCC did not portend a worse survival, at 5 years. However, SCC did result in a more rapid disease trajectory, with survival curves of SCC and UC crossing at the 5-year mark. Adjusted CSS/OS of UCSD was also not significantly different from UC. Among those patients with SCC, factors associated with CSS included age>70 (hazard ratio [HR] = 1.96, 95% CI: 1.16-3.30), T category≥3 (HR = 2.09, 95% CI: 1.24-3.50), N positive disease (HR = 2.59, 95% CI: 1.55-4.32), lymphovascular invasion (HR = 1.98, 95% CI: 1.13-3.47), and positive surgical margins (HR = 2.95, 95% CI: 1.47-5.93). After adjusting for patient and disease characteristics, we have found that SCC leads to a more rapid disease course with survival that is equivalent to UC by 5 years. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jul 2015 · Urologic Oncology
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    ABSTRACT: To describe lymph node counts in routine clinical practice and evaluate their association with outcomes to explore its utility as a quality indicator. Electronic records of treatment and surgical pathology reports were linked with the population-based Ontario Cancer Registry to identify all patients who underwent cystectomy between 1994 and 2008. Temporal trends were described over 3 periods: 1994 to 1998, 1999 to 2000, and 2004 to 2008. Multivariate generalized linear regression analysis was used to determine the factors associated with the use of pelvic lymph node dissection (PLND). A Cox proportional hazards regression model was used to explore the associations between PLND and survival. The study population included 2,802 patients. Use of PLND (50%, 62%, and 85%, correspondingly), median node yield (5, 6, and 9, correspondingly), and node density (56%, 50%, and 39%, correspondingly) all improved over the study periods, 1994 to 1998, 1999 to 2000, and 2004 to 2008 (P<0.001). In multivariate analysis, factors associated with not having PLND include advanced age, female sex, lower socioeconomic status, low surgeon volume, and partial cystectomy. In adjusted analyses, patients who did not receive a PLND had inferior overall (hazard ratio = 1.26, 95% CI: 1.15-1.38) and cancer-specific (hazard ratio = 1.23, 95% CI: 1.11-1.36) survival. Node yield, as well as density, was also associated with long-term survival. There is significant variation in use and quality of PLND at cystectomy in routine practice. Node counts are independently associated with long-term survival, and this association is persistent despite adjustment for provider-related variables. These results suggest that lymph node counts are a valid quality indicator of surgical care of muscle-invasive bladder cancer. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Jul 2015 · Urologic Oncology
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    Preview · Article · Apr 2015 · The Journal of Urology
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    ABSTRACT: To evaluate gemcitabine-cisplatin (GC) neoadjuvant cisplatin-based chemotherapy (NAC) for pathologic response (pR) and cancer-specific outcomes following radical cystectomy (RC) for muscle-invasive bladder cancer and identify clinical parameters associated with pR. We studied 150 consecutive cases of muscle-invasive bladder cancer that received GC NAC followed by open RC (2000-2013). A cohort of 121 patients treated by RC alone was used for comparison. Pathologic response and cancer-specific survival (CSS) were compared. We created the Johns Hopkins Hospital Dose Index to characterize chemotherapeutic dosing regimens and accurately assess sufficient neoadjuvant dosing regarding patient tolerance. No significant difference was noted in 5-year CSS between GC NAC (58%) and non-NAC cohorts (61%). The median follow-up was 19.6 months (GC NAC) and 106.5 months (non-NAC). Patients with residual non-muscle-invasive disease after GC NAC exhibit similar 5-year CSS relative to patients with no residual carcinoma (P = 0.99). NAC pR (≤pT1) demonstrated improved 5-year CSS rates (90.6% vs. 27.1%, P<0.01) and decreased nodal positivity rates (0% vs. 41.3%, P<0.01) when compared with nonresponders (≥pT2). Clinicopathologic outcomes were inferior in NAC pathologic nonresponders when compared with the entire RC-only-treated cohort. A lower pathologic nonresponder rate was seen in patients tolerating sufficient dosing of NAC as stratified by the Johns Hopkins Hospital Dose Index (P = 0.049), congruent with the National Comprehensive Cancer Network guidelines. A multivariate classification tree model demonstrated 60 years of age or younger and clinical stage cT2 as significant of NAC response (P< 0.05). Pathologic nonresponders fare worse than patients proceeding directly to RC alone do. Multiple predictive models incorporating clinical, histopathologic, and molecular features are currently being developed to identify patients who are most likely to benefit from GC NAC. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Mar 2015 · Urologic Oncology
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    ABSTRACT: Purpose Prostate cancer aggressiveness and appropriate therapy are routinely determined following biopsy sampling. Current clinical and pathologic parameters are insufficient for accurate risk prediction leading primarily to overtreatment but also missed opportunities for curative therapy. Experimental design An 8-biomarker proteomic assay for intact tissue biopsies predictive of prostate pathology was defined in a study of 381 patient biopsies with matched prostatectomy specimens. A second blinded study of 276 cases validated this assay's ability to distinguish 'favorable' versus 'non-favorable' pathology independently and relative to current risk classification systems (NCCN and D'Amico). Results A favorable biomarker risk score of ≤0.33, and a non-favorable risk score of >0.80 (possible range between 0 and 1) were defined on 'false negative' and 'false positive' rates of 10% and 5%, respectively. At a risk score ≤0.33, predictive values for favorable pathology in very low- and low-risk NCCN and low-risk D'Amico groups were 95%, 81.5%, and 87.2%, respectively, higher than for these current risk classification groups themselves (80.3%, 63.8%, and 70.6%, respectively). The predictive value for non-favorable pathology was 76.9% at biomarker risk scores >0.8 across all risk groups. Increased biomarker risk scores correlated with decreased frequency of favorable cases across all risk groups. The validation study met its two co-primary endpoints, separating favorable from non-favorable pathology (AUC, 0.68, P<0.0001, odds ratio=20.9) and GS-6 versus non-GS-6 pathology (AUC, 0.65, P<0.0001, OR=12.95). Conclusion The 8-biomarker assay provided individualized, independent prognostic information relative to current risk stratification systems, and may improve the precision of clinical decision-making following prostate biopsy. Copyright © 2015, American Association for Cancer Research.
    Full-text · Article · Mar 2015 · Clinical Cancer Research
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    ABSTRACT: We evaluated primary tumors from two cohorts, Spain (N = 111) and Greece (N = 102), for patients who were treated with platinum-based chemotherapy. Patients were tested for HER2 status (IHC score of 3+ or FISH ratio of ≥2.2) by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), DNA copy number, mRNA expression, and mutation status in patients with metastatic urothelial carcinoma (UC), and its impact on survival. ERBB2 mutation was determined by hotspot sequencing. mRNA expression was assessed using NanoString counting. Association of overall survival (OS) and HER2 status was assessed by a Cox regression model. NIH-3T3 cells containing HER2 V777L were assessed for growth, invasion, and HER2 kinase activation. In all, 22% of Spanish and 4% of Greek cohorts had 3+ HER2 staining by IHC. FISH amplification was identified in 20% of Spanish and 4% of Greek cohorts. Kappa coefficient between FISH and IHC was 0.47. HER2 status was not associated with OS in univariate (Spanish P = 0.34; Greek P = 0.11) or multivariate (Spanish P = 0.49; Greek P = 0.12) analysis. HER2-positive tumors expressed higher levels of HER2 mRNA than HER2-negative tumors (P < 0.001). HER2 mutations (V777L and L755S) were identified in two (2%) patients. In vitro analysis of V777L results in transformation of NIH-3T3 cells, leading to increased growth, invasion on soft agar, and HER2 kinase constitutive activation. In summary, HER2 overexpression or amplification in the primary tumor did not predict OS in patients with metastatic UC. HER2 positivity rates can differ between different populations. Further trials in genomically screened patients are needed to assess HER2-targeted therapies in UC. © 2015 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
    Full-text · Article · Feb 2015 · Cancer Medicine
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    ABSTRACT: To assess radical cystectomy (RC) outcomes and adjuvant chemotherapy (ACT) use in the elderly in routine practice. Bladder cancer occurs most commonly in the elderly. RC, standard treatment for muscle-invasive bladder cancer, presents challenges in older patients. Suboptimal evidence guides ACT use. All patients undergoing RC for urothelial cancer in Ontario from 1994 to 2008 were identified using the Ontario Cancer Registry. Pathology reports and treatment records were linked to the database. Patients were age stratified as <70, 70-74, 75-79 and ≥80 years. Logistic regression and Cox proportional hazards identified associations with and effectiveness of ACT use. We identified 3320 patients: 1362 (41%) aged <70 years; 674 (20%) aged 70-74 years; 674 (19%) aged 75-79 years, and 657 (20%) aged ≥80 years. Thirty-day (1%, 2%, 2%, 6%; P <.0001) and 90-day (5%, 8%, 9%, 15%; P <.0001) mortality increased with age. Age-stratified 5-year cancer-specific survival was 42%, 37%, 34%, and 32%, respectively (P <.001); 5-year overall survival was 40%, 34%, 28%, and 23%, respectively (P <.001). ACT decreased with age (27%, 16%, 12%, 5%; P <.0001). Among ACT patients, 87% aged <70 years received cisplatin vs 73% aged ≥70 years (P = .003). ACT was associated with improved cancer-specific survival (hazard ratio [HR] = 0.73 and 95% confidence interval [CI] = 0.59-0.89 for age <70 years and HR = 0.73 [95% CI = 0.59-0.89] for ≥70 years) and overall survival (HR = 0.70 [95% CI = 0.58-0.85] for age <70 years and HR = 0.70 [95% CI = 0.59-0.84] for ≥70 years) across all age groups. Cystectomy carries a higher risk of postoperative mortality in elderly patients in routine clinical practice. ACT is used infrequently in older patients despite a substantial survival benefit observed across all age groups. Copyright © 2015 Elsevier Inc. All rights reserved.
    No preview · Article · Feb 2015 · Urology
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    ABSTRACT: Prostate cancer is the most prevalently diagnosed and the second cause of cancer-related death in North American men. Several approaches have been proposed to augment detection of prostate cancer using different imaging modalities. Due to advantages of ultrasound imaging, these approaches have been the subject of several recent studies. This paper presents the results of a feasibility study on differentiating between lower and higher grade prostate cancer using ultrasound RF time series data. We also propose new spectral features of RF time series to highlight aggressive prostate cancer in small ROIs of size 1 mm × 1 mm in a cohort of 19 ex vivo specimens of human prostate tissue. In leave-one-patient-out cross-validation strategy, an area under accumulated ROC curve of 0.8 has been achieved with overall sensitivity and specificity of 81% and 80%, respectively. The current method shows promising results on differentiating between lower and higher grade of prostate cancer using ultrasound RF time series.
    Full-text · Conference Paper · Jan 2015
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    Full-text · Article · Nov 2014 · European Urology Supplements
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    ABSTRACT: To describe the relationships between procedure volume and late survival after cystectomy for muscle-invasive bladder cancer (MIBC) and explore variables explaining any effect. Electronic records of treatment and surgical pathology reports were linked to a population-based registry to identify patients who underwent cystectomy during 1994-2008 in Ontario, Canada. Explanatory variables included adjuvant chemotherapy, lymph node dissection (LND), and margin status. A Cox proportional hazards regression model was used to explore associations between volume and cancer-specific survival (CSS) as well as overall survival. The cohort included 2802 MIBC patients treated with cystectomy. High-volume hospitals were more likely to have used adjuvant chemotherapy (25% vs 18%; P <.001), more likely to have performed an LND (83% vs 53%; P <.001), and associated with a lower 90-day mortality (6% vs 10%; P = .032). Low-volume hospitals had a lower 5-year CSS rate of 32% (28%-36%) compared with those of high-volume centers at 38% (33%-42%). Individual surgeon volume was similarly associated with both early- and long-term outcomes. In multivariate analysis, both surgeon and hospital volumes were associated with CSS and overall survival. The surgeon volume effect on long-term outcomes was modestly modified by indicators of the quality of the LND, with little effect of the other explanatory variables. Higher provider volume is associated with higher CSS in patients with MIBC in the general population. The volume effect was modestly mediated by the quality of LND. Copyright © 2014 Elsevier Inc. All rights reserved.
    No preview · Article · Oct 2014 · Urology
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    ABSTRACT: Objectives To investigate reporting patterns and outcomes associated with lymphovascular invasion in a general population setting.Methods We identified all cystectomy patients with muscle-invasive urothelial cancer in Ontario, Canada, 1994–2008. Surgical pathology reports were analyzed for pathological variables including lymphovascular invasion. Lymphovascular invasion reporting patterns were described over time. A Cox proportional hazards model was used to evaluate the association of lymphovascular invasion with survival.ResultsOf the 2802 cases identified, lymphovascular invasion status was reported in 75%. Lymphovascular invasion reporting significantly improved over the study period and was correlated with poor prognostic pathological features (T stage and N stage). Comprehensive cancer center status was not consistently associated with lymphovascular invasion reporting. Patients with lymphovascular invasion had substantially lower survival than patients who were lymphovascular invasion-negative or whose lymphovascular invasion status was unstated (P < 0.001). Lymphovascular invasion was independently associated with survival in patients regardless of lymph node metastasis. After adjusting for age, stage, comorbidity, margin status and adjuvant chemotherapy, lymphovascular invasion remained strongly associated with reduced survival (hazard ratio 1.98, 95% confidence interval 1.71–2.29).Conclusions Although routine reporting of lymphovascular invasion has improved over the years, pathologists appear to be biased towards evaluating lymphovascular invasion in patients with high-stage disease. Despite this bias, lymphovascular invasion remains an important prognostic factor among patients treated by cystectomy. Pathologists in general practice should report lymphovascular invasion status more consistently and urologists should hold their pathology colleagues to a higher standard.
    No preview · Article · Oct 2014 · International Journal of Urology
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    ABSTRACT: Inflammation is associated with several diseases of the prostate including benign enlargement and cancer, but a causal relationship has not been established. Our objective was to characterize the prostate inflammatory microenvironment after infection with a human prostate derived bacterial strain and to determine the effect of inflammation on prostate cancer progression. To this end, we mimicked typical human prostate infection with retrograde urethral instillation of CP1, a human prostatic isolate of Escherichia coli. CP1 bacteria were tropic for the accessory sex glands and induced acute inflammation in the prostate and seminal vesicles with chronic inflammation lasting at least one year. Compared to controls, infection induced both acute and chronic inflammation with epithelial hyperplasia, stromal hyperplasia, and inflammatory cell infiltrates. In areas of inflammation, epithelial proliferation and hyperplasia often persist despite decreased expression of androgen receptor (AR). Inflammatory cells in the prostates of CP1 infected mice were characterized at 8 weeks post-infection by flow cytometry, which showed an increase in macrophages and lymphocytes, particularly Th17 cells. Inflammation was additionally assessed in the context of carcinogenesis. Multiplex cytokine profiles of inflamed prostates showed distinct inflammatory cytokines were expressed during prostate inflammation and cancer, with a subset of cytokines synergistically increased during concurrent inflammation and cancer. Furthermore, CP1 infection in the Hi-Myc mouse model of prostate cancer accelerated the development of invasive prostate adenocarcinoma with 70% more mice developing cancer by 4.5 months of age. This study provides direct evidence that prostate inflammation accelerates prostate cancer progression, and gives insight into the microenvironment changes induced by inflammation that may accelerate tumour initiation or progression.
    No preview · Article · Oct 2014 · The Journal of Pathology
  • W. MacKillop · R. Siemens · K. Zaza · W. Kong · P. Peng · D. Berman · C. Booth

    No preview · Article · Sep 2014 · International journal of radiation oncology, biology, physics

  • No preview · Article · Sep 2014 · International journal of radiation oncology, biology, physics
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    ABSTRACT: Background Anaplastic lymphoma kinase (ALK) genomic alterations have emerged as a potent predictor of benefit from treatment with ALK inhibitors in several cancers. Currently, there is no information about ALK gene alterations in urothelial carcinoma (UC) and its correlation with clinical or pathologic features and outcome. Methods Samples from patients with advanced UC and correlative clinical data were collected. Genomic imbalances were investigated by array comparative genomic hybridization (aCGH). ALK gene status was evaluated by fluorescence in situ hybridization (FISH). ALK expression was assessed by immunohistochemistry (IHC) and high-throughput mutation analysis with Oncomap 3 platform. Next generation sequencing was performed using Illumina Genome Analyzer IIx, and Illumina HiSeq 2000 in the FISH positive case. Results 70 of 96 patients had tissue available for all the tests performed. Arm level copy number gains at chromosome 2 were identified in 17 (24%) patients. Minor copy number alterations (CNAs) in the proximity of ALK locus were found in 3 patients by aCGH. By FISH analysis, one of these samples had a deletion of the 5′ALK. Whole genome next generation sequencing was inconclusive to confirm the deletion at the level of the ALK gene at the coverage level used. We did not observe an association between ALK CNA and overall survival, ECOG PS, or development of visceral disease. Conclusions ALK genomic alterations are rare and probably without prognostic implications in UC. The potential for testing ALK inhibitors in UC merits further investigation but might be restricted to the identification of an enriched population.
    Full-text · Article · Aug 2014 · PLoS ONE
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    ABSTRACT: Objective To evaluate whether pathologic factors are associated with differential effect of ACT.Patients and Methods In this population-based retrospective cohort study we linked electronic records of treatment and surgical pathology to the Ontario Cancer Registry. The study population included all patients with MIBC undergoing cystectomy in Ontario 1994-2008. Factors associated with overall (OS) and cancer-specific survival (CSS) were evaluated using Cox proportional hazards. We tested for interaction between the following variables and ACT effect-size: N stage, margin status, T stage, and lymphovascular invasion (LVI).ResultsThe study population included 2802 patients; 19% were treated with ACT. Interaction terms with ACT for OS/CSS are: N stage (p<0.001/p<0.001); margin status (p=0.054/p=0.048); T stage (p=0.509/p=0.286); and LVI (p=0.361/p=0.405). Magnitude of effect for ACT was greater for patients with node-positive disease (OS HR 0.56, [95%CI 0.47-0.67], CSS HR 0.60 [0.49-0.72]) than for patients with node-negative disease (OS HR 0.80 [0.61-1.03], CSS HR 0.79 [0.59-1.07]). ACT was also associated with greater effect among patients with involved margins (OS HR 0.45 [95%CI 0.33-0.62], CSS HR 0.40 [0.28-0.57]) compared to patients with negative margins (OS HR 0.75 [0.65-0.87], CSS HR 0.79 [0.67-0.93]).Conclusions In this population-based cohort study we observe evidence of interaction between ACT effect and nodal stage and surgical margin status. Our results suggest that patients at highest risk of disease recurrence may derive greatest benefit from ACT.
    No preview · Article · Aug 2014 · BJU International
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    ABSTRACT: Metaplasia can result when injury reactivates latent developmental signaling pathways that determine cell phenotype. Barrett's esophagus is a squamous-to-columnar epithelial metaplasia caused by reflux esophagitis. Hedgehog (Hh) signaling is active in columnar-lined, embryonic esophagus and inactive in squamous-lined, adult esophagus. We showed previously that Hh signaling is reactivated in Barrett's metaplasia and overexpression of Sonic hedgehog (SHH) in mouse esophageal squamous epithelium leads to a columnar phenotype. Here, our objective was to identify Hh target genes involved in Barrett's pathogenesis. By microarray analysis, we found that the transcription factor Foxa2 is more highly expressed in murine embryonic esophagus compared with postnatal esophagus. Conditional activation of Shh in mouse esophageal epithelium induced FOXA2, while FOXA2 expression was reduced in Shh knockout embryos, establishing Foxa2 as an esophageal Hh target gene. Evaluation of patient samples revealed FOXA2 expression in Barrett's metaplasia, dysplasia, and adenocarcinoma but not in esophageal squamous epithelium or squamous cell carcinoma. In esophageal squamous cell lines, Hh signaling upregulated FOXA2, which induced expression of MUC2, an intestinal mucin found in Barrett's esophagus, and the MUC2-processing protein AGR2. Together, these data indicate that Hh signaling induces expression of genes that determine an intestinal phenotype in esophageal squamous epithelial cells and may contribute to the development of Barrett's metaplasia.
    Full-text · Article · Aug 2014 · Journal of Clinical Investigation

Publication Stats

7k Citations
719.99 Total Impact Points


  • 2013-2015
    • Queen's University
      • Department of Pathology and Molecular Medicine
      Kingston, Ontario, Canada
    • Queens University of Charlotte
      New York, United States
  • 2004-2015
    • Johns Hopkins University
      • • Department of Pathology
      • • Department of Medicine
      Baltimore, Maryland, United States
    • University of Iowa
      Iowa City, Iowa, United States
  • 2009-2014
    • University of South Florida St. Petersburg
      St. Petersburg, Florida, United States
  • 2009-2012
    • Johns Hopkins Medicine
      • Department of Pathology
      Baltimore, Maryland, United States
  • 2006-2009
    • All Children's Hospital
      Florida City, Florida, United States
  • 2005-2007
    • Bristol-Myers Squibb
      New York, New York, United States
    • National Institutes of Health
      • Branch of Surgery
      Bethesda, MD, United States
  • 2004-2006
    • National Cancer Institute (USA)
      • Laboratory of Pathology
      Maryland, United States
  • 2003-2004
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
  • 2002
    • University of Washington Seattle
      Seattle, Washington, United States