Publications by authors named "Sheila F Faraj"

35 Publications

Extended Versus Limited Pelvic Lymph Node Dissection During Radical Prostatectomy for Intermediate- and High-risk Prostate Cancer: Early Oncological Outcomes from a Randomized Phase 3 Trial.

Eur Urol 2021 May 5;79(5):595-604. Epub 2020 Dec 5.

Instituto do Cancer do Estado de Sao Paulo, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil.

Background: The role of extended pelvic lymph node dissection (EPLND) in the surgical management of prostate cancer (PCa) patients remains controversial, mainly because of a lack of randomized controlled trials (RCTs).

Objective: To determine whether EPLND has better oncological outcomes than limited PLND (LPLND.

Design, Setting And Participants: This was a prospective, single-center phase 3 trial in patients with intermediate- or high-risk clinically localized PCa.

Intervention: Randomization (1:1) to LPLND (obturator nodes) or EPLND (obturator, external iliac, internal iliac, common iliac, and presacral nodes) bilaterally.

Outcome Measurements And Statistical Analysis: The primary endpoint was biochemical recurrence-free survival (BRFS). Secondary outcomes were metastasis-free survival (MFS), cancer-specific survival (CSS), and histopathological findings. The trial was designed to show a minimal 15% advantage in 5-yr BRFS by EPLND.

Results And Limitations: In total, 300 patients were randomized from May 2012 to December 2016 (150 LPLND and 150 EPLND). The median BRFS was 61.4 mo in the LPLND group and not reached in the EPLND group (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.63-1.32; p =  0.6). Median MFS was not reached in either group (HR 0.57, 95% CI 0.17-1.8; p =  0.3). CSS data were not available because no patient died from PCa before the cutoff date. In exploratory subgroup analysis, patients with preoperative biopsy International Society of Urological Pathology (ISUP) grade groups 3-5 who were allocated to EPLND had better BRFS (HR 0.33, 95% CI 0.14-0.74, interaction p =  0.007). The short follow-up and surgeon heterogeneity are limitations to this study.

Conclusion: This RCT confirms that EPLND provides better pathological staging, while differences in early oncological outcomes were not demonstrated. Our subgroup analysis suggests a potential BCRFS benefit in patients diagnosed with ISUP grade groups 3-5; however, these findings should be considered hypothesis-generating and further RCTs with larger cohorts and longer follow up are necessary to better define the role of EPLND during RP.

Patient Summary: In this study, we investigated early outcomes in prostate cancer patients undergoing prostatectomy according to the anatomic extent of lymph node resection. We found that extended removal of lymph nodes did not reduce biochemical recurrence of prostate cancer in the expected range.
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http://dx.doi.org/10.1016/j.eururo.2020.11.040DOI Listing
May 2021

Prognostic Value of Systemic Inflammatory Biomarkers in Patients with Metastatic Renal Cell Carcinoma.

Pathol Oncol Res 2020 Oct 24;26(4):2489-2497. Epub 2020 Jun 24.

Instituto do Cancer do Estado de Sao Paulo, Av. Dr. Arnaldo, 251, Sao Paulo, SP, 01246-000, Brazil.

Metastatic renal cell carcinoma (mRCC) encompasses a heterogeneous group of neoplasms with distinct clinical behavior and prognoses. As a result of the increasing number of therapeutic options in the metastatic setting, it is crucial to improve prognostic stratification ability. We aimed to evaluate the prognostic value of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and combination platelet count and neutrophil lymphocyte ratio (COP-NLR) in patients with mRCC. We evaluated a cohort of mRCC patients treated with first-line pazopanib or sunitinib. Levels of NLR, PLR and COP-NLR were measured prior to systemic treatment and evaluated as prognostic predictors. Primary endpoint was overall survival (OS). Data from 276 patients were included, of which 54.7% received first-line pazopanib and 45.3%, sunitinib. Memorial Sloan-Kettering Cancer Center risk classification was intermediate and poor in 50% and 42.6% of patients, respectively. High NLR (> 3.5) was associated with inferior OS (median 9.6 vs 17.8 months, P < 0.001). A high PLR (> 200) was associated with inferior OS (median 10.3 vs 17 months, P = 0.002). The median OS in the COP-NLR 1, 2 and 3 groups were 19.0 months (95% CI 15.3-26.0), 13.1 months (95% CI 9.8-17.0) and 7.4 months (95% CI 3.6-11.9), respectively (P < 0.001). In the multivariate analysis, high NLR and high COP-NLR were associated with inferior OS. Both high NLR and high COP-NLR were associated with poorer OS in our cohort of patients with mRCC treated with first-line pazopanib or sunitinib.
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http://dx.doi.org/10.1007/s12253-020-00840-0DOI Listing
October 2020

Real-world evidence on first-line treatment for metastatic renal cell carcinoma with non-clear cell and sarcomatoid histologies: are sunitinib and pazopanib interchangeable?

Ecancermedicalscience 2019 4;13:973. Epub 2019 Nov 4.

Instituto do Cancer do Estado de São Paulo, Faculdade de Medicina da Universidade de São Paulo, Av Dr Arnaldo 251, São Paulo 01246-000, Brazil.

Introduction: Non-clear cell renal cell carcinoma (nccRCC) and sarcomatoid renal cell carcinoma (sRCC) are underrepresented in clinical trials. Treatment approaches are frequently extrapolated from data of clear cell renal cell carcinoma, in which pazopanib is non-inferior to sunitinib. We aim to compare the effectiveness of first-line sunitinib and pazopanib for nccRCC and sRCC.

Methods: We evaluated a retrospective cohort of patients with metastatic nccRCC and sRCC treated with first-line sunitinib or pazopanib at an academic cancer centre. Overall survival (OS), progression-free survival (PFS) and response rate were measured. Kaplan-Meier and log-rank analyses were used for time-to-event data. Cox regression was used for prognostic factors.

Results: Fifty-three patients were included; 16 (30.1%) treated with sunitinib and 37 (69.9%) with pazopanib. Forty-six (86.8%) patients had nccRCC and 7 (13.2%) had sRCC. The majority had intermediate or poor International Metastatic Renal-Cell Carcinoma Database Consortium risk (93%).Median PFS was 6.6 months with sunitinib and 4.9 months with pazopanib (HR 1.75; = 0.078). Treatment with pazopanib was associated with inferior OS in comparison with sunitinib (median OS: 30.4 months versus 8.7 months; HR 2.71, 95% CI 1.31-5.58, = 0.007). These results were confirmed in subgroup analysis of patients with papillary, chromophobe and MiT family translocation histologies (median OS: 38.7 months versus 14.7 months; HR 3.16, 95% CI 1.20-8.29, = 0.019). Unclassified and sarcomatoid histologies had inferior OS (median: 6.9 and 1.1 months, respectively) regardless of the treatment used.

Conclusion: In this patient cohort, pazopanib was associated with inferior OS in comparison with sunitinib for metastatic nccRCC. Larger trials are ideally warranted to confirm these results.
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http://dx.doi.org/10.3332/ecancer.2019.973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6946421PMC
November 2019

Gastric cancer molecular classification and adjuvant therapy: Is there a different benefit according to the subtype?

J Surg Oncol 2020 Apr 3;121(5):804-813. Epub 2019 Dec 3.

Department of Radiology and Oncology, Faculdade de Medicina, Hospital das Clinicas HCFMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil.

Background: Gastric cancer (GC) has been defined in distinct molecular subtypes with different therapeutic implications. However, its clinical significance and prognosis regarding standard chemotherapy (CMT) remains unclear. This study aimed to analyze the impact of perioperative or adjuvant treatment among subtypes of GC.

Methods: We retrospectively evaluated all stage II/III patients with GC who underwent a curative gastrectomy. Based on immunohistochemistry and in situ hybridization techniques, GC was classified into five subtypes: Epstein-Barr virus (EBV) positive, microsatellite instability (MSI), e-cadherin aberrant, p53-aberrant, and p53-normal.

Results: Among the 178 CG included, 111 patients received CMT and 67 were treated with surgery alone. Survival analysis showed that p53-aberrant GC treated with CMT had better disease-free survival (DFS) compared with surgery alone (P = .001).There was no significant difference in DFS between patients who received CMT and those with surgery alone for EBV, MSI, E-cadherin, and p53-normal GC. An improvement in overall survival was observed only for E-cadherin (P = .001) and p53-aberrant (P < .001) patients who received CMT.

Conclusions: CMT showed different impact on the survival of CG according to the molecular subtype. No survival benefit was observed for EBV and MSI groups who received CMT. GC with p53-aberrant had a significant benefit in survival with standard therapy.
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http://dx.doi.org/10.1002/jso.25792DOI Listing
April 2020

NKX3.1 and Prostein Expression in Testicular Tissue and Sex Cord-stromal Tumors.

Am J Surg Pathol 2020 01;44(1):61-67

Departments of Pathology.

Prostate cancer is well known to metastasize to the testis and is not an uncommon finding on castration performed for advanced disease. Although germ cell tumors make up the majority of testis neoplasms, there are more rare tumors, such as rete testis adenocarcinoma, that can mimic metastatic disease. NKX3.1 and prostein (P501S) are antibodies highly specific for prostate origin. Relatively little is known of the expression of these markers in testicular tissue. We investigated the expression of NKX3.1 and P501S in testicular tissues, sex cord-stromal tumors, germ cell tumors, and rete testis adenocarcinoma. We found strong diffuse nuclear staining for NKX3.1 in Sertoli cells of the testis. Expression of NKX3.1 was seen in 0/3 ovarian Sertoli cell tumors, 1/4 testicular Sertoli cell tumors, and in the Sertoli cell component of 1/12 ovarian Sertoli-Leydig cell tumors. We found moderate, diffuse cytoplasmic positivity for P501S in rete testis epithelium and in testicular Leydig cells. P501S also highlighted Leydig cells in 9/12 Sertoli-Leydig cell tumors of the ovary. Two of 3 Leydig cell tumors of the testis showed weak to moderate, diffuse cytoplasmic staining for P501S. All cases of embryonal carcinoma and pure seminoma were negative for both NKX3.1 and P501S. One case of rete testis adenocarcinoma showed patchy positivity for both NKX3.1 and P501S. In conclusion, NKX3.1 shows routine expression in Sertoli cells and P501S shows routine expression in Leydig cells and rete testis epithelium. In addition, these markers can be positive in sex cord-stromal tumors and rete testis adenocarcinoma.
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http://dx.doi.org/10.1097/PAS.0000000000001367DOI Listing
January 2020

Insulin-like growth factor-1 receptor expression in upper tract urothelial carcinoma.

Virchows Arch 2019 Jan 18;474(1):21-27. Epub 2018 Oct 18.

Department of Pathology, The University of Alabama at Birmingham, WP Building, Suite P230 l 619 19th Street, South, Birmingham, AL, 35249-7331, USA.

Insulin-like growth factor-1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor that plays a crucial role in cell proliferation, growth, differentiation, and apoptosis. IGF1R overexpression has been observed in several cancers, including invasive bladder carcinomas, as a potential prognostic factor. Given known biologic differences between upper and lower urinary tract urothelial carcinoma, we assessed the expression status and prognostic significance of IGF1R in upper tract urothelial carcinoma (UTUC). Two tissue microarrays (TMAs) were built from 99 Japanese patients with non-metastatic UTUC submitted to radical nephroureterectomy between 1997 and 2011. TMAs were constructed with triplicate tumor and paired benign urothelium. Membranous IGF1R staining was evaluated using immunohistochemistry. Two scoring methods were applied (Her2-score and H-score). The highest score was assigned to each tumor. IGF1R positivity was defined as Her2-score ≥ 1+. Association with clinicopathologic parameters and outcome was assessed using hazard ratios (HR) with 95% confidence intervals (CI) and adjusted P values. We found positive IGF1R expression in 70% of UTUC. Outcomes were as follows: tumor recurrence, 33%; tumor progression, 59%; overall mortality, 33%; and cancer-specific mortality, 30%. IGF1R was not associated with any clinicopathologic features. In addition, IGF1R expression was not associated with tumor recurrence (HR = 0.54, CI = 0.25-1.1, P = 0.11), tumor progression (HR = 1.6, CI = 0.8-3.1, P = 0.19), overall mortality (HR = 1.5, CI = 0.68-3.4, P = 0.31), or cancer-specific mortality (HR = 1.6, CI = 0.68-3.8, P = 0.27). Positive IGF1R expression was found in more than two thirds of UTUC. This finding provides a rationale to investigate IGF1R as a potential therapeutic target in UTUC. In contrast to bladder cancer, IGF1R expression in UTUC did not correlate with outcome, further pointing to biologic differences between UTUC and bladder cancer.
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http://dx.doi.org/10.1007/s00428-018-2468-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6730551PMC
January 2019

Reply to "Poorly differentiated clusters in colorectal liver metastases: Prognostic significance in synchronous and metachronous metastases".

J Surg Oncol 2018 06 3;117(8):1858-1859. Epub 2018 May 3.

Digestive Surgery Division, Liver Surgery Unit, Department of Gastroenterology, University of Sao Paulo Medical School, Sao Paulo, Brazil.

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http://dx.doi.org/10.1002/jso.25079DOI Listing
June 2018

Clinicopathological and prognostic features of Epstein-Barr virus infection, microsatellite instability, and PD-L1 expression in gastric cancer.

J Surg Oncol 2018 Apr 13;117(5):829-839. Epub 2018 Mar 13.

Cancer Institute, University of Sao Paulo, Sao Paulo, Brazil.

Background And Objectives: Gastric cancer (GC) has recently been categorized in molecular subtypes, which include Epstein-Barr (EBV)-positive and microsatellite instability (MSI) tumors. This distinction may provide prognostic information and identifies therapeutic targets. The aim of this study was to evaluate EBV, MSI, and PD-L1 immunoexpression in GC and its relationship with clinicopathological characteristics and patient's prognosis.

Methods: We evaluated 287 GC patients who underwent D2-gastrectomy through immunohistochemistry for DNA mismatch repair proteins and PD-L1, and in situ hybridization for EBV detection utilizing tissue microarray.

Results: EBV-positive and MSI were identified in 10.5% and 27% of the GCs, respectively. EBV positivity was associated to male gender (P = 0.032), proximal location (P < 0.001), undetermined Lauren type (P < 0.001), poorly differentiated histology (P = 0.043) and severe inflammatory infiltrate (P < 0.001). MSI-tumors were associated to older age (P = 0.002), subtotal gastrectomy (P = 0.004), pN0 (P = 0.024) and earlier TNM stage (P = 0.020). PD-L1-positive was seen in 8.8% of cases, with predominant expression in EBV-positive GC (P < 0.001). MSI was associated to better survival outcomes.

Conclusion: EBV-positive GCs had increased PD-L1 expression, while MSI GC had better survival outcome. EBV and MSI subgroups are distinct GC entities, their recognition is feasible by conventional techniques, and it may help individualize follow-up and guide adjuvant therapy.
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http://dx.doi.org/10.1002/jso.25022DOI Listing
April 2018

Prognostic significance of poorly differentiated clusters and tumor budding in colorectal liver metastases.

J Surg Oncol 2018 Jun 15;117(7):1364-1375. Epub 2018 Feb 15.

Digestive Surgery Division, Liver Surgery Unit, Department of Gastroenterology, University of Sao Paulo Medical School, São Paulo, Brazil.

Background: Histomorphological features have been described as prognostic factors after resection of colorectal liver metastases (CLM). The objectives of this study were to assess the prognostic significance of tumor budding (TB) and poorly differentiated clusters (PDC) among CLM, and their association with other prognostic factors.

Methods: We evaluated 229 patients who underwent a first resection of CLM. Slides stained by HE were assessed for TB, PDC, tumor border pattern, peritumoral pseudocapsule, peritumoral, and intratumoral inflammatory infiltrate. Lymphatic and portal invasion were evaluated through D2-40 and CD34 antibody.

Results: Factors independently associated with poor overall survival were nodules>4 (P = 0.002), presence of PDC G3 (P = 0.007), portal invasion (P = 0.005), and absence of tumor pseudocapsule (P = 0.006). Factors independently associated with disease-free survival included number of nodules>4 (P < 0.001), presence of PDC G3 (P = 0.005), infiltrative border (P = 0.031), portal invasion (P = 0.006), and absent/mild peritumoral inflammatory infiltrate (P = 0.002). PDC and TB were also associated with histological factors, as portal invasion (TB), peritumoral inflammatory infiltration (PDC), infiltrative border, and absence of tumor pseudocapsule (TB and PDC).

Conclusions: This is the first study demonstrating PDC as a prognostic factor in CLM. TB was also a prognostic factor, but it was not an independent predictor of survival.
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http://dx.doi.org/10.1002/jso.25017DOI Listing
June 2018

Pathological factors and prognosis of resected liver metastases of colorectal carcinoma: implications and proposal for a pathological reporting protocol.

Histopathology 2018 Feb 11;72(3):377-390. Epub 2017 Oct 11.

Department of Pathology, São Paulo State Cancer Institute, University of São Paulo Medical School, São Paulo, Brazil.

Colorectal cancer is a leading cause of death worldwide. The liver is the most common site of distant metastases, and surgery is the only potentially curative treatment, although the recurrence rate following surgery is high. In order to define prognosis after surgery, many histopathological features have been identified in the primary tumour. In turn, pathologists routinely report specific findings to guide oncologists on the decision to recommend adjuvant therapy. In general, the pathological report of resected colorectal liver metastases is limited to confirmation of the malignancy and details regarding the margin status. Most pathological reports of a liver resection for colorectal liver metastasis lack information on other important features that have been reported to be independent prognostic factors. We herein review the evidence to support a more detailed pathological report of the resected liver specimen, with attention to: the number and size of liver metastases; margin size; the presence of lymphatic, vascular, perineural and biliary invasion; mucinous pattern; tumour growth pattern; the presence of a tumour pseudocapsule; and the pathological response to neoadjuvant chemotherapy. In addition, we propose a new protocol for the evaluation of colorectal liver metastasis resection specimens.
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http://dx.doi.org/10.1111/his.13378DOI Listing
February 2018

Strong association of insulin-like growth factor 1 receptor expression with histologic grade, subtype, and HPV status in penile squamous cell carcinomas: a tissue microarray study of 112 cases.

Virchows Arch 2017 Jun 27;470(6):695-701. Epub 2017 Mar 27.

Centro para el Desarrollo de la Investigación Científica (CEDIC), Asunción, Paraguay.

Insulin-like growth factor-1 receptor (IGF1R) plays a key role in cell growth and transformation. It is overexpressed in several solid tumors. This study evaluates IGF1R immunoexpression in penile squamous cell carcinoma (SCC). Four tissue microarrays were built from formalin-fixed, paraffin-embedded blocks of 112 penile SCC from Paraguay. Membranous IGF1R expression was evaluated by immunohistochemistry using two different approaches. An H-score was calculated in each spot (stain intensity by extent), and a median score per tumor was obtained. The second approach consisted of a score similar to the scoring system that was used for evaluating HER2 immunoexpression. For each case, the highest category obtained at any spot was used for statistical analyses. IGF1R expression was compared by histologic subtype, grade, and human papillomavirus (HPV) status. Median H-score was 22.5. The distribution of IGF1R expression by HER2 approach was as follows: 0 in 33.0% cases, 1+ in 46.4%, 2+ in 14.3%, and 3+ in 6.2%. IGF1R H-scores were associated with basaloid and warty/basaloid subtypes (p = 0.0026) and higher grade (p = 0.00052). Although weaker when using the HER2 approach, the association of IGF1R expression with subtype (p = 0.015) and grade (p = 0.015) remained significant. Furthermore, there was an association between IGF1R expression by HER2 approach and HPV status (p = 0.012). IGF1R was expressed in about two thirds of penile SCC cases, showing a strong positive association with histologic grade, subtype, and HPV status. Considering that grade is a predictor of outcome IGF1R expression may have prognostic relevance and could point to a potential role for IGF1R inhibitors in treating penile SCC.
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http://dx.doi.org/10.1007/s00428-017-2110-6DOI Listing
June 2017

Comprehensive Determination of Prostate Tumor ETS Gene Status in Clinical Samples Using the CLIA Decipher Assay.

J Mol Diagn 2017 05 21;19(3):475-484. Epub 2017 Mar 21.

Department of Pathology, Johns Hopkins School of Medicine, Baltimore, Maryland; Department of Oncology, Johns Hopkins School of Medicine, Baltimore, Maryland. Electronic address:

ETS family gene fusions are common in prostate cancer and molecularly define a tumor subset. ERG is the most commonly rearranged, leading to its overexpression, followed by ETV1, ETV4, and ETV5, and these alterations are generally mutually exclusive. We validated the Decipher prostate cancer assay to detect ETS alterations in a Clinical Laboratory Improvement Amendments-accredited laboratory. Benchmarking against ERG immunohistochemistry and ETV1/4/5 RNA in situ hybridization, we examined the accuracy, precision, and reproducibility of gene expression ETS models using formalin-fixed, paraffin-embedded samples. The m-ERG model achieved an area under curve of 95%, with 93% sensitivity and 98% specificity to predict ERG immunohistochemistry status. The m-ETV1, -ETV4, and -ETV5 models achieved areas under curve of 98%, 88%, and 99%, respectively. The models had 100% robustness for ETS status, and scores were highly correlated across sample replicates. Models predicted 41.5% of a prospective radical prostatectomy cohort (n = 4036) to be ERG, 6.3% ETV1, 1% ETV4, and 0.4% ETV5. Of prostate tumor biopsy samples (n = 509), 41.2% were ERG, 8.6% ETV1, 0.4% ETV4, and none ETV5. Higher Decipher risk status tumors were more likely to be ETS (ERG or ETV1/4/5) in the radical prostatectomy and the biopsy cohorts (P < 0.05). These results support the utility of microarray-based ETS status prediction models for molecular classification of prostate tumors.
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http://dx.doi.org/10.1016/j.jmoldx.2017.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417038PMC
May 2017

SPINK1 Defines a Molecular Subtype of Prostate Cancer in Men with More Rapid Progression in an at Risk, Natural History Radical Prostatectomy Cohort.

J Urol 2016 11 27;196(5):1436-1444. Epub 2016 May 27.

Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address:

Purpose: Prostate cancer is clinically and molecularly heterogeneous. We determined the prognosis of men with ERG-ETS fusions and SPINK1 over expression.

Materials And Methods: Men were identified with intermediate or high risk localized prostate cancer treated with radical prostatectomy and no therapy before metastasis. A case-cohort design sampled a cohort (262) enriched with metastasis from the entire cohort and a cohort (213) enriched with metastasis from patients with biochemical recurrence. We analyzed transcriptomic profiles and subtyped tumors as m-ERG, m-ETS, m-SPINK1 or Triple Negative (m-ERG/m-ETS/m-SPINK1), and multivariable logistic regression analyses, Kaplan-Meier and multivariable Cox models were used to evaluate subtypes as predictors of clinical outcomes.

Results: Overall 36%, 13%, 11% and 40% of prostate cancer was classified as m-ERG, m-ETS, m-SPINK1 and Triple Negative, respectively. Univariable analysis demonstrated that m-SPINK1 tumors were more common in African-American men (OR 5, 95% CI 1.6-16) but less commonly associated with positive surgical margins (OR 0.16, 95% CI 0.03-0.69) compared to the m-ERG group. Compared to the Triple Negative group, m-SPINK1 showed similar associations with race and surgical margins in univariable and multivariable analyses across the entire cohort. Survival analyses did not show significant differences among m-ERG, m-ETS and Triple Negative cases. m-SPINK1 independently predicted prostate cancer specific mortality after metastasis (HR 2.48, 95% CI 0.96-6.4) and biochemical recurrence (HR 3, 95% CI 1.1-8).

Conclusions: SPINK1 over expression is associated with prostate cancer specific mortality in at risk men with biochemical and clinical recurrence after prostatectomy. ERG-ETS alterations are not prognostic for outcome.
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http://dx.doi.org/10.1016/j.juro.2016.05.092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6615051PMC
November 2016

Prevalence of human papillomavirus types and variants and p16(INK4a) expression in head and neck squamous cells carcinomas in São Paulo, Brazil.

Infect Agent Cancer 2016 4;11:20. Epub 2016 May 4.

Molecular Biology Laboratory, Center of Translational Research in Oncology, Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil (ICESP), São Paulo, Brazil.

Background: Human papillomavirus (HPV) prevalence in head and neck squamous cell carcinomas (HNSCC) diverges geographically. The reliability of using p16(INK4a) expression as a marker of viral infection is controversial in HNSCC. We evaluated HPV types and HPV-16 variants prevalence, and p16(INK4a) expression in HNSCC specimens provided by two different Institutions in São Paulo.

Methods: HPV DNA from formalin-fixed specimens was accessed by Inno-LiPA, HPV-16 variants by PCR-sequencing, and p16(INK4a) protein levels by immunohistochemistry.

Results: Overall, HPV DNA was detected among 19.4 % of the specimens (36/186). Viral prevalence was higher in the oral cavity (25.0 %, 23/92) then in other anatomical sites (oropharynx 14,3 %, larynx 13.7 %) when samples from both Institutions were analyzed together. HPV prevalence was also higher in the oral cavity when samples from both Institutions were analyzed separately. HPV-16 was the most prevalent type identified in 69.5 % of the HPV positive smaples and specimens were assigned into Asian-American (57.2 %) or European (42.8 %) phylogenetic branches. High expression of p16(INK4a) was more common among HPV positive tumors.

Conclusion: Our results support a role for HPV-16 in a subset of HNSCC.
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http://dx.doi.org/10.1186/s13027-016-0067-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855326PMC
May 2016

Overexpression of Insulin-like Growth Factor-1 Receptor Is Associated With Penile Cancer Progression.

Urology 2016 Jun 18;92:51-6. Epub 2016 Feb 18.

The James Buchanan Brady Urological Institute & Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD.

Objective: To evaluate insulin-like growth factor-1 receptor (IGF1R) expression in penile cancer and its association with oncologic outcomes.

Methods: Tissue microarrays were constructed from 53 patients treated at our institution. Expression of IGF1R was evaluated using a Her2-like scoring system. Overexpression was defined as 1+ or greater membranous staining. Association of IGF1R expression with pathologic features was assessed with comparative statistics, and association with local recurrence, progression to nodal or distance metastases, or death was assessed with Kaplan-Meier survival analysis and Cox proportional hazard regression models.

Results: Overall, IGF1R overexpression was seen in 33 (62%) cases. With a median follow-up of 27.8 months, IGF1R overexpression was associated with inferior progression-free survival (PFS) (P  =  .003). In a multivariable model controlling for grade, T stage, perineural invasion, and lymphovascular invasion, IGF1R expression was independently associated with disease progression (hazard ratio 2.3, 95% confidence interval 1.1-5.1, P  =  .03. Comparing patients without IGF1R overexpression to those with overexpression, 5-year PFS was 94.1% vs 45.8%.

Conclusion: IGF1R overexpression was associated with inferior PFS in penile cancer. Drugs that target IGF1R and downstream messengers may have a therapeutic benefit in patients that exhibit IGF1R overexpression.
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http://dx.doi.org/10.1016/j.urology.2016.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4874837PMC
June 2016

Clinical Validation of the 2005 ISUP Gleason Grading System in a Cohort of Intermediate and High Risk Men Undergoing Radical Prostatectomy.

PLoS One 2016 5;11(1):e0146189. Epub 2016 Jan 5.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland, United States of America.

In 2005, the International Society of Urological Pathology (ISUP) introduced several modifications to the original Gleason system that were intended to enhance the prognostic power of Gleason score (GS). The objective of this study was to clinically validate the 2005 ISUP Gleason grading system for its ability to detect metastasis. We queried our institutional RP database for men with NCCN clinically localized intermediate to high-risk disease undergoing radical prostatectomy (RP) between 1992 and 2010 with no additional treatment until the time of metastatic progression. A case-cohort design was utilized. A total of 333 available RP samples were re-reviewed and GS was reassigned per the 2005 ISUP Gleason system. Cumulative incidence of metastasis was 0%, 8.4%, 24.5% and 44.4% among specimens that were downgraded, unchanged, had one point GS increase and two point GS increase, respectively. The hazard ratio for metastasis raised in GS 8 and 9 compared to GS 7 from 2.77 and 5.91 to 3.49 and 9.31, respectively. The survival c-index of GS increased from 0.70 to 0.80 when samples were re-graded at 5 years post RP. The c-index of the reassigned GS was higher than the original GS (0.77 vs 0.64) for predicting PCSM at 10 years post RP. The regraded GS improved the prediction of metastasis and PCSM. This validates the updated Gleason grading system using an unambiguous clinical endpoint and highlights the need for reassignment of Gleason grading according to 2005 ISUP system when considering comparisons of novel biomarkers to clinicopathological variables in archival cohorts.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0146189PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712132PMC
June 2016

Germline Variants in Asporin Vary by Race, Modulate the Tumor Microenvironment, and Are Differentially Associated with Metastatic Prostate Cancer.

Clin Cancer Res 2016 Jan 7;22(2):448-58. Epub 2015 Oct 7.

Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland. Department of Oncology, Johns Hopkins University, Baltimore, Maryland. Sidney Kimmel Comprehensive Cancer Institute, Johns Hopkins University, Baltimore, Maryland.

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 1,600 men who underwent radical prostatectomy for clinically localized prostate cancer and in 548 noncancer 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% confidence interval (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.
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http://dx.doi.org/10.1158/1078-0432.CCR-15-0256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715968PMC
January 2016

Prognostic role and implications of mutation status of tumor suppressor gene ARID1A in cancer: a systematic review and meta-analysis.

Oncotarget 2015 Nov;6(36):39088-97

The Zucker Hillside Hospital, Psychiatry Research, North Shore - Long Island Jewish Health System, Glen Oaks, New York, USA.

Loss of the tumor suppressor gene AT-rich interactive domain-containing protein 1A (ARID1A) has been demonstrated in several cancers, but its prognostic role is unknown. We aimed to investigate the risk associated with loss of ARID1A (ARID1A-) for all-cause mortality, cancer-specific mortality and recurrence of disease in subjects with cancer. PubMed and SCOPUS search from database inception until 01/31/2015 without language restriction was conducted, contacting authors for unpublished data. Eligible were prospective studies reporting data on prognostic parameters in subjects with cancer, comparing participants with presence of ARID1A (ARID1A+) vs. ARID1A-, assessed either via immunohistochemistry (loss of expression) or with genetic testing (presence of mutation). Data were summarized using risk ratios (RR) for number of deaths/recurrences and hazard ratios (HR) for time-dependent risk related to ARID1A- adjusted for potential confounders. Of 136 hits, 25 studies with 5,651 participants (28 cohorts; ARID1A-: n = 1,701; ARID1A+: n = 3,950), with a mean follow-up period of 4.7 ± 1.8 years, were meta-analyzed. Compared to ARID1A+, ARID1A- significantly increased cancer-specific mortality (studies = 3; RR = 1.55, 95% confidence interval (CI) = 1.19-2.00, I(2) = 31%). Using HRs adjusted for potential confounders, ARID1A- was associated with a greater risk of cancer-specific mortality (studies = 2; HR = 2.55, 95%CI = 1.19-5.45, I(2) = 19%) and cancer recurrence (studies = 10; HR = 1.93, 95%CI = 1.22-3.05, I(2) = 76%). On the basis of these results, we have demonstrated that loss of ARID1A shortened time to cancer-specific mortality, and to recurrence of cancer when adjusting for potential confounders. For its role, this gene should be considered as an important potential target for personalized medicine in cancer treatment.
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http://dx.doi.org/10.18632/oncotarget.5142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4770758PMC
November 2015

Androgen-Regulated SPARCL1 in the Tumor Microenvironment Inhibits Metastatic Progression.

Cancer Res 2015 Oct 20;75(20):4322-34. Epub 2015 Aug 20.

The James Buchanan Brady Urological Institute, Department of Urology, Johns Hopkins University, Baltimore, Maryland. The Department of Oncology, Johns Hopkins University, Baltimore, Maryland. The Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, Maryland.

Prostate cancer is a leading cause of cancer death in men due to the subset of cancers that progress to metastasis. Prostate cancers are thought to be hardwired to androgen receptor (AR) signaling, but AR-regulated changes in the prostate that facilitate metastasis remain poorly understood. We previously noted a marked reduction in secreted protein, acidic and rich in cysteine-like 1 (SPARCL1) expression during invasive phases of androgen-induced prostate growth, suggesting that this may be a novel invasive program governed by AR. Herein, we show that SPARCL1 loss occurs concurrently with AR amplification or overexpression in patient-based data. Mechanistically, we demonstrate that SPARCL1 expression is directly suppressed by androgen-induced AR activation and binding at the SPARCL1 locus via an epigenetic mechanism, and these events can be pharmacologically attenuated with either AR antagonists or HDAC inhibitors. We establish using the Hi-Myc model of prostate cancer that in Hi-Myc/Sparcl1(-/-) mice, SPARCL1 functions to suppress cancer formation. Moreover, metastatic progression of Myc-CaP orthotopic allografts is restricted by SPARCL1 in the tumor microenvironment. Specifically, we show that SPARCL1 both tethers to collagen in the extracellular matrix (ECM) and binds to the cell's cytoskeleton. SPARCL1 directly inhibits the assembly of focal adhesions, thereby constraining the transmission of cell traction forces. Our findings establish a new insight into AR-regulated prostate epithelial movement and provide a novel framework whereby SPARCL1 in the ECM microenvironment restricts tumor progression by regulating the initiation of the network of physical forces that may be required for metastatic invasion of prostate cancer.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-0024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4609262PMC
October 2015

¹⁸F-DCFBC PET/CT for PSMA-Based Detection and Characterization of Primary Prostate Cancer.

J Nucl Med 2015 Jul 11;56(7):1003-1010. Epub 2015 Jun 11.

The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins Medical Institutions, Baltimore, Maryland.

Unlabelled: We previously demonstrated the ability to detect metastatic prostate cancer using N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-(18)F-fluorobenzyl-L-cysteine ((18)F-DCFBC), a low-molecular-weight radiotracer that targets the prostate-specific membrane antigen (PSMA). PSMA has been shown to be associated with higher Gleason grade and more aggressive disease. An imaging biomarker able to detect clinically significant high-grade primary prostate cancer reliably would address an unmet clinical need by allowing for risk-adapted patient management.

Methods: We enrolled 13 patients with primary prostate cancer who were imaged with (18)F-DCFBC PET before scheduled prostatectomy, with 12 of these patients also undergoing pelvic prostate MR imaging. Prostate (18)F-DCFBC PET was correlated with MR imaging and histologic and immunohistochemical analysis on a prostate-segment (12 regions) and dominant-lesion basis. There were no incidental extraprostatic findings on PET suggestive of metastatic disease.

Results: MR imaging was more sensitive than (18)F-DCFBC PET for detection of primary prostate cancer on a per-segment (sensitivities of up to 0.17 and 0.39 for PET and MR imaging, respectively) and per-dominant-lesion analysis (sensitivities of 0.46 and 0.92 for PET and MR imaging, respectively). However, (18)F-DCFBC PET was more specific than MR imaging by per-segment analysis (specificities of 0.96 and 0.89 for PET and MR imaging for corresponding sensitivity, respectively) and specific for detection of high-grade lesions (Gleason 8 and 9) greater than 1.0 mL in size (4/4 of these patients positive by PET). (18)F-DCFBC uptake in tumors was positively correlated with Gleason score (ρ = 0.64; PSMA expression, ρ = 0.47; and prostate-specific antigen, ρ = 0.52). There was significantly lower (18)F-DCFBC uptake in benign prostatic hypertrophy than primary tumors (median maximum standardized uptake value, 2.2 vs. 3.5; P = 0.004).

Conclusion: Although the sensitivity of (18)F-DCFBC for primary prostate cancer was less than MR imaging, (18)F-DCFBC PET was able to detect the more clinically significant high-grade and larger-volume tumors (Gleason score 8 and 9) with higher specificity than MR imaging. In particular, there was relatively low (18)F-DCFBC PET uptake in benign prostatic hypertrophy lesions, compared with cancer in the prostate, which may allow for more specific detection of primary prostate cancer by (18)F-DCFBC PET. This study demonstrates the utility of PSMA-based PET, which may be used in conjunction with MR imaging to identify clinically significant prostate cancer.
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http://dx.doi.org/10.2967/jnumed.115.154336DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4659400PMC
July 2015

Immunohistochemical expression of ARID1A in penile squamous cell carcinomas: a tissue microarray study of 112 cases.

Hum Pathol 2015 May 12;46(5):761-6. Epub 2015 Feb 12.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 31231; Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD 31231; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD 31231.

ARID1A, a member of the chromatin remodeling genes family, has been suggested as a novel tumor suppressor gene in gynecologic malignancies. However, its role in penile cancer has yet to be determined. This study assesses the immunohistochemical expression of ARID1A in penile squamous cell carcinoma (SCC) and its association with pathologic features, human papillomavirus (HPV) status, and previously reported mammalian target of rapamycin pathway markers in the same cohort. Four tissue microarrays were constructed from 112 cases of formalin-fixed, paraffin-embedded penile SCC from Paraguay. Each tumor was sampled 3 to 12 times. ARID1A expression was evaluated by immunohistochemistry using a polyclonal rabbit anti-ARID1A (BAF250A) antibody. An H score was calculated in each spot as the sum of expression intensity (0-3+) by extent (0%-100%). Median H score per case was used for statistical analysis. ARID1A expression was observed in all cases, ranging from 3% to 100% of tumor cells (median, 95%). In 96 cases (86%), ARID1A expression was observed in 90% or more tumor cells. HPV DNA was detected in 20 (38%) of 52 analyzed samples. There was a significant trend of association between ARID1A and histologic grade. ARID1A expression was not associated with histologic subtype (P = .61) or HPV status (P = .18). ARID1A expression decreased with decreasing levels of PTEN expression (P = .01). ARID1A was expressed in penile SCC, in most cases at high levels. A significant trend of association was found between histologic grade and ARID1A expression, with lower ARID1A expression, lower histologic grades, and decreased PTEN expression.
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http://dx.doi.org/10.1016/j.humpath.2015.01.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4696050PMC
May 2015

Assessment of tumoral PD-L1 expression and intratumoral CD8+ T cells in urothelial carcinoma.

Urology 2015 Mar;85(3):703.e1-6

Department of Pathology, Johns Hopkins University, Baltimore, MD; Department of Urology, Johns Hopkins University, Baltimore, MD; Department of Oncology, Johns Hopkins University, Baltimore, MD. Electronic address:

Objective: To evaluate programmed death ligand 1 (PD-L1) expression in urothelial carcinoma of the bladder in relationship with tumor-infiltrating CD8+ T cells.

Materials And Methods: Tissue microarrays were prepared from 56 cystectomy specimens performed at our hospital (1994-2002). PD-L1 immunoexpression was assessed using the murine antihuman PD-L1 monoclonal antibody 5H1. Extent of membranous PD-L1 expression was assigned in each spot. Spots showing ≥5% expression were considered positive. Average PD-L1 expression per tumor was also calculated (5% positivity cutoff). "High CD8 density" was defined as the presence of ≥60 CD8+ intraepithelial lymphocytes per high power field in a given spot. A tumor was considered high density if ≥50% of its spots were of high density.

Results: PD-L1 expression was positive in approximately 20% of tumors. None of the benign urothelium spots expressed PD-L1. High CD8 density was observed in approximately 20% of cases. CD8 density did not correlate with PD-L1 expression. Overall survival (OS) and disease-specific survival (DSS) rates were 14% and 28%, respectively (median follow-up, 31.5 months). PD-L1 expression was associated with age at cystectomy (P = .01). Remaining clinicopathologic parameters were not associated with PD-L1 expression or CD8 density. High CD8 density was associated with favorable OS (P = .02) and DSS (P = .02). The same was true when CD8 density was adjusted for demographic and clinicopathologic parameters. There was no correlation between PD-L1 expression and outcome.

Conclusion: High intratumoral CD8+ T cell density is associated with better OS and DSS in invasive urothelial carcinoma of the bladder. We found no correlation between PD-L1 expression and outcome.
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http://dx.doi.org/10.1016/j.urology.2014.10.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695997PMC
March 2015

Human papillomavirus infection and immunohistochemical p16(INK4a) expression as predictors of outcome in penile squamous cell carcinomas.

Hum Pathol 2015 Apr 31;46(4):532-40. Epub 2014 Dec 31.

Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231; Department of Urology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231; Department of Oncology, The Johns Hopkins Medical Institutions, Baltimore, MD 21231. Electronic address:

Approximately 50% of penile squamous cell carcinomas (SCC) are associated with high-risk human papillomavirus (HR-HPV) infection. We evaluated the correlation of p16(INK4a) expression and HR-HPV with clinicopathological features and outcome in a cohort of patients with penile SCC. Two tissue microarrays were constructed from 53 invasive penile SCC at our hospital. p16(INK4a) expression was assessed by immunohistochemistry (CINtec Kit). High-risk human papillomavirus status was assessed by in situ hybridization (INFORM HPV III family 16 probe B cocktail). High-risk human papillomavirus was detected in 8 cases (15%), and p16(INK4a) overexpression was found in 23 cases (44%). Both markers showed a significant association with histologic subtype (P = .017 and P = .01, respectively) and lymphovascular invasion (P = .015 and P = .015, respectively). Regarding outcome analyses, neither HPV infection nor p16(INK4a) overexpression significantly predicted overall survival or cancer-specific survival using Cox proportional hazards regression model. High-risk human papillomavirus positivity and p16(INK4a) overexpression were significantly associated with histologic subtype and presence of lymphovascular invasion. Human papillomavirus status was not predictive of outcome in our cohort.
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http://dx.doi.org/10.1016/j.humpath.2014.12.004DOI Listing
April 2015

Carnoy's solution is an adequate tissue fixative for routine surgical pathology, preserving cell morphology and molecular integrity.

Histopathology 2015 Feb 10;66(3):388-97. Epub 2014 Nov 10.

Cancer Institute(ICESP), University of Sao Paulo School of Medicine, Sao Paulo, Brazil.

Aims: To compare Carnoy's solution (CS) and 10% neutral buffered formalin solution (NBF) as tissue fixatives in colorectal cancer specimens.

Methods And Results: Surgical specimens from patients with colorectal cancer were analysed. Three groups were studied, as follows: group 1 consisted of 16 paired samples fixed in CS and NBF; and groups 2 and 3 consisted of 14 prospective and 80 retrospective samples, respectively, both randomized for fixation in CS or NBF. Groups 1 and 2 were analysed for amount, quality and integrity of DNA. Morphological analysis, including some of the usual special stains and polymerase chain reaction (PCR), were also performed for group 1, and Sanger sequencing for group 2. Immunohistochemical (IHC) reactions for mismatch repair proteins were studied in groups 1 and 3. Fixative performances were similar for morphology, special stains, and IHC reactions, as well as for the amount, quality and integrity of extracted DNA. PCR amplification was not possible in two cases from CS group 1. Sanger sequencing gave conclusive results for the CS samples tested.

Conclusions: Carnoy's solution and NBF are equivalent fixatives for colorectal cancer specimens and are adequate for routine utilization in surgical and molecular pathology.
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http://dx.doi.org/10.1111/his.12532DOI Listing
February 2015

ARID1A immunohistochemistry improves outcome prediction in invasive urothelial carcinoma of urinary bladder.

Hum Pathol 2014 Nov 23;45(11):2233-9. Epub 2014 Jul 23.

Department of Pathology, Johns Hopkins University, Baltimore 21231, MD; Department of Oncology, Johns Hopkins University, Baltimore 21231, MD; Department of Urology, Johns Hopkins University, Baltimore 21231, MD. Electronic address:

AT-rich interactive domain 1A (ARID1A) is tumor suppressor gene that interacts with BRG1 adenosine triphosphatase to form a SWI/SNF chromatin remodeling protein complex. Inactivation of ARID1A has been described in several neoplasms, including epithelial ovarian and endometrial carcinomas, and has been correlated with prognosis. In the current study, ARID1A expression in urothelial carcinoma (UC) of the bladder and its association with clinicopathological parameters and outcome are addressed. Five tissue microarrays were constructed from 136 cystectomy specimens performed for UC at our institution. Nuclear ARID1A staining was evaluated using immunohistochemistry. An H-score was calculated as the sum of the products of intensity (0-3) multiplied by extent of expression (0%-100%). Average H-score per case was used for statistical analysis. ARID1A expression was categorized in low and high using Youden index to define the cut point. ARID1A expression significantly increased from normal to noninvasive UC to invasive UC. For both tumor progression and cancer death, Youden index yielded an H-score of 288 as the optimal cut point for ARID1A expression. Low ARID1A expression showed a tendency for lower risk of tumor progression and cancer mortality. Adding ARID1A expression to pathologic features offers a better model for predicting outcome than pathologic features alone. Low ARID1A expression was more frequently seen in earlier stage disease. There was a tendency for low ARID1A expression to predict better outcome. More importantly, the findings indicate that adding ARID1A expression to pathologic features increases the goodness of fit of the predictive model.
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http://dx.doi.org/10.1016/j.humpath.2014.07.003DOI Listing
November 2014

High frequency of TERT promoter mutation in small cell carcinoma of bladder, but not in small cell carcinoma of other origins.

J Hematol Oncol 2014 Jul 20;7:47. Epub 2014 Jul 20.

TERT promoter mutations were recently discovered in melanoma by next generation sequencing. Subsequently, several malignancies including urothelial carcinoma were also found to be associated with the same TERT promoter mutations. Small cell carcinoma (SCC) of the urinary bladder is a rare subtype with an aggressive clinical course. Despite the frequent occurrence of TERT promoter mutations in urothelial carcinoma, the incidence of the mutations in SCC of the urinary bladder is unknown. In addition, as a potential molecular marker to distinguish SCC of the urinary bladder from SCC of the prostate, lung (SCLC) and other origins, this information may be clinically useful. We collected a total of 11 cases of SCC of the urinary bladder (10 cases are primary SCC of the urinary bladder; 1 case has primary SCC of the urinary bladder and liver metastasis). We also included 20 cases of SCLC, 2 cases of SCC of the prostate, 5 cases of Merkel cell carcinoma, and 6 cases of SCC from other sites (cervical, GE junction, breast, and soft tissue). In addition, 3 cases of non-neoplastic tissue from the matched SCC of bladder patient and 14 cases of benign urinary bladder were also included. All tumor sections have been examined to confirm the diagnosis and to make sure more than 20% are of tumor content. Genomic DNA was isolated from FFPE tissue and a fragment of the TERT promoter (145 bp) was amplified by PCR. The TERT promoter mutations are determined by bi-directional Sanger sequencing. All (11/11) SCC of the urinary bladder bear TERT promoter mutation C228T. Neither of SCC from all other origins nor matched non-neoplastic tissue contains the TERT promoter mutations. We demonstrated a high frequency TERT promoter mutation in SCC of the urinary bladder, but not in SCC of other origin, such as the prostate. The findings further illustrate molecular differences between SCC of the urinary bladder and SCC of other origins, despite their shared morphologic and immunophenotypic similarities. The TERT promoter mutation may be a biomarker differentiating SCC of the urinary bladder from SCC of other origins.
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http://dx.doi.org/10.1186/s13045-014-0047-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223615PMC
July 2014

Insulin-like growth factor-1 receptor overexpression is associated with outcome in invasive urothelial carcinoma of urinary bladder: a retrospective study of patients treated using radical cystectomy.

Urology 2014 Jun 6;83(6):1444.e1-6. Epub 2014 Apr 6.

Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD; Department of Urology, Johns Hopkins Medical Institutions, Baltimore, MD; Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD. Electronic address:

Objective: To assess the insulin-like growth factor-1 receptor (IGF1R) expression in urothelial carcinoma (UC) and its prognostic role in relation to clinicopathologic parameters.

Methods: A total of 100 cases of invasive UC were evaluated using tissue microarrays. Membranous IGF1R staining was evaluated using immunohistochemistry. A scoring method analogous to that of HER2 expression in breast carcinoma was used, and the highest score was assigned in each tumor. IGF1R was considered overexpressed in cases with score≥1.

Results: We found IGF1R overexpression in 62% of invasive UC. IGF1R overexpression was associated with race (P=.04) and pT category (P=.03). Median follow-up was 29 months (range, 0.5-212). Progression rate was 60%, and overall mortality and cancer-specific mortality rates were 69% and 51%, respectively. In invasive UC, IGF1R overexpression was significantly associated with overall mortality and cancer-specific mortality (Mantel Cox P=.0002 and P=.006, respectively). IGF1R overexpression was associated with increased hazard ratios (HRs) for overall mortality (HR=2.63, P=.001) and cancer-specific mortality (HR=2.45, P=.01), independently and after adjusting for clinicopathologic features and treatment modalities.

Conclusion: We found IGF1R overexpression in 62% of bladder UC. More importantly, IGF1R overexpression was a significant predictor of overall mortality and cancer-specific mortality, suggesting its potential role as a prognosticator in UC of bladder.
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http://dx.doi.org/10.1016/j.urology.2014.01.028DOI Listing
June 2014

Comprehensive profile of GATA binding protein 3 immunohistochemical expression in primary and metastatic renal neoplasms.

Hum Pathol 2014 Feb 4;45(2):244-8. Epub 2013 Dec 4.

Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21231; Department of Urology, Johns Hopkins University School of Medicine, Baltimore, MD 21231; Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21231. Electronic address:

Transcription factor GATA binding protein 3 (GATA3) has been suggested as a marker of urothelial carcinoma of the bladder and upper urinary tract. Its expression in primary and metastatic renal tumors has not been fully determined. We evaluated GATA3 expression in 47 oncocytomas, 196 primary renal cell carcinomas (RCCs) (71 clear cell, 53 papillary, 21 Xp11.2, 33 chromophobe RCCs, and 18 collecting duct carcinomas [CDC]), and 43 unrelated metastatic RCCs (41 clear cell and 2 Xp11.2 RCC). GATA3 nuclear expression was evaluated in tissue microarrays built from archival tissues using immunohistochemistry. Intensity (0 to 3+) and extent (percentage) of expression were assessed. Several cutoff values (>0%, >5%, and >10%) were evaluated to indicate GATA3 positivity. Among oncocytomas, 9 (19%) of 47 had some degree of nuclear GATA3 expression with median extent of 0% (0%-100%). When using either 5% or 10% cutoff values, 5 (11%) of 47 oncocytomas were positive. In primary RCCs, 6 (3%) of 196 had some degree of nuclear expression with a median extent of 0% (0%-100%). When using either 5% or 10% cutoff values, 2 cases remained positive (1%) (Xp11.2 and CDC). All metastatic RCCs were negative. We found an overall lack of GATA3 expression in primary and metastatic RCCs. GATA3 is expressed in a minority of oncocytomas, Xp11.2-RCC, and CDC. Given GATA3 positivity in upper urinary tract urothelial carcinoma, our findings support a role for GATA3 in the differential diagnosis of primary renal masses and a utility in the interrogation of metastatic tumors of unknown primary in the presence of a renal mass.
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http://dx.doi.org/10.1016/j.humpath.2013.08.020DOI Listing
February 2014