Publications by authors named "Li Yan Khor"

33 Publications

Immunological Hallmarks for Clinical Response to BCG in Bladder Cancer.

Front Immunol 2020 29;11:615091. Epub 2021 Jan 29.

Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore.

Intravesical Bacillus Calmette-Guerin (BCG) is an effective immunotherapy for non-muscle invasive bladder cancer (NMIBC). However, recurrence and progression remain frequent warranting deeper insights into its mechanism. We herein comprehensively profiled blood and tissues obtained from NMIBC patients before, during and after BCG treatment using cytometry by time-of-flight (CyTOF) and RNA sequencing to identify the key immune subsets crucial for anti-tumor activity. We observed the temporal changes of peripheral immune subsets including NKT cells, central memory CD4 T cells, CD8 T cells and regulatory T cells (Treg) during the course of BCG. Gene expression analysis revealed enriched immune pathways involving in T cell activation and chemotaxis, as well as a more diversified T cell receptor repertoire in post-BCG tissues. Moreover, tissue multiplexed-immunofluorescence (mIF) showed baseline densities of non-Treg and CD8PD-1 T cells were predictive of response and better recurrence-free survival after BCG. Remarkably, post-BCG tissues from responders were found to be infiltrated with more active CD8PD-1 T cells and non-Treg CD4FOXP3 T cells; but increased exhausted CD8PD-1 T cells were found in non-responders. Taken together, we identified predictive biomarkers for response and uncovered the post-treatment expansion of exhausted PD-1CD8 T cells as key to BCG resistance, which could potentially be restored by combining with anti-PD-1 immunotherapy.
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http://dx.doi.org/10.3389/fimmu.2020.615091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879685PMC
January 2021

Biomarkers for Precision Urothelial Carcinoma Diagnosis: Current Approaches and the Application of Single-Cell Technologies.

Cancers (Basel) 2021 Jan 12;13(2). Epub 2021 Jan 12.

A. Menarini Biomarkers Singapore Pte Ltd., Singapore 117440, Singapore.

Urothelial carcinoma (UC) is the most frequent malignancy of the urinary system and is ranked the sixth most diagnosed cancer in men worldwide. Around 70-75% of newly diagnosed UC manifests as the non-muscle invasive bladder cancer (NMIBC) subtype, which can be treated by a transurethral resection of the tumor. However, patients require life-long monitoring due to its high rate of recurrence. The current gold standard for UC diagnosis, prognosis, and disease surveillance relies on a combination of cytology and cystoscopy, which is invasive, costly, and associated with comorbidities. Hence, there is considerable interest in the development of highly specific and sensitive urinary biomarkers for the non-invasive early detection of UC. In this review, we assess the performance of current diagnostic assays for UC and highlight some of the most promising biomarkers investigated to date. We also highlight some of the recent advances in single-cell technologies that may offer a paradigm shift in the field of UC biomarker discovery and precision diagnostics.
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http://dx.doi.org/10.3390/cancers13020260DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827267PMC
January 2021

PD-L1 expression is an unfavourable prognostic indicator in Asian renal cell carcinomas.

J Clin Pathol 2020 Aug 24;73(8):463-469. Epub 2020 Jan 24.

Anatomical Pathology, Singapore General Hospital, Singapore

Background/aims: The programmed cell death receptor 1 (PD-1) checkpoint inhibitor, nivolumab, has been approved for the treatment of metastatic renal cell carcinoma (RCC). However, the understanding of the expression and distribution of PD ligand 1 (PD-L1) in the tumour immune microenvironment and its prognostic role in an Asian cohort is limited. Our group investigated PD-L1 protein expression in a cohort of Asian patients with RCC of mixed ethnicity, using two commercially available antibody clones.

Methods: E1L3N and SP263 anti-PD-L1 clones were used to categorise RCCs of various histological subtypes, diagnosed at our institution between 1995 and 2008, into PD-L1-positive or PD-L1-negative groups, based on a 1% Tumour Proportion Score (TPS) cut-off.

Results: In total, 267 (83%) clear cell (cc)RCC and 55 (17%) non-ccRCC cases were studied. Overall PD-L1 protein expression rates for the entire cohort were 13% and 8% for the E1L3N and SP263 clones, respectively. Patients bearing PD-L1-positive tumours experienced significantly decreased disease-free survival (DFS; E1L3N: p=0.01; SP263: p=0.03) but not overall survival, compared with those with PD-L1-negative tumours. Multivariate survival analysis further confirmed the results of the E1L3N clone (HR 1.85, 95% CI 1.10 to 3.13, p=0.02), but not SP263, after adjusting for pathological stage, histological subtype and grade. The addition of PD-L1 (E1L3N) TPS to clinicopathological features significantly increased the prognostic value for DFS (∆LRχ=5.25; p=0.022), compared with clinicopathological features alone.

Conclusions: PD-L1 protein expression was associated with an unfavourable prognosis in our study cohort. PD-L1 (E1L3N) expression was an independent prognostic indicator of clinical outcome in all RCCs when using a 1% cut-off.
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http://dx.doi.org/10.1136/jclinpath-2019-206092DOI Listing
August 2020

Multiparametric MRI reporting using Prostate Imaging Reporting and Data System version 2.0 (PI-RADSv2) retains clinical efficacy in a predominantly post-biopsy patient population.

Asian J Urol 2019 Jul 1;6(3):256-263. Epub 2018 Jun 1.

Department of Urology, Singapore General Hospital, Singapore.

Objective: To evaluate the efficacy of multiparametric magnetic resonance imaging (mp-MRI) using Prostate Imaging Reporting and Data System version 2.0 (PI-RADSv2) definitions in detecting organ-confined prostate cancer.

Methods: All patients who underwent radical prostatectomy between January 1, 2014 and December 30, 2014 were identified. All underwent mp-MRI within 180 days before surgery. Those with prior pelvic irradiation or androgen deprivation therapy were excluded. Fully embedded, whole-mount histopathology was centrally reviewed and correlated with imaging for tumour location, Gleason score (GS) and stage.

Results: There were 39 patients included, of which 35 (90%) had mp-MRI done post-biopsy. A total of 93 cancer foci were identified on whole-mount pathology, of which mp-MRI detected 63 (68%). Of those detected by mp-MRI, 14 were PI-RADS 3 ( = 6 for GS 6,  = 8 for GS 7, no GS ≥ 8) and 49 were PI-RADS 4-5 ( = 7 for GS 6,  = 33 for GS 7, and  = 9 for GS ≥ 8). There were 30 (32%) cancer foci missed by mp-MRI ( = 15 for GS 6,  = 13 for GS 7 and  = 2 for GS ≥ 8). A lesion classified as PI-RADS 4-5 predicted a higher grade cancer on pathology as compared to PI-RADS 3 (for GS 7 lesions, odds ratio [OR] = 3.53, 95% CI: 0.93-13.45,  = 0.064). The mp-MRI size detection limit was 20 mm and 100 mm for 50% and 75% probability of cancer, respectively. In associating with radiological and pathologic stage, the weighted Kappa value was 0.69 ( < 0.0001). The sensitivity and positive predictive values for this study were 68% (95% CI: 57%-77%) and 78% (95% CI: 67%-86%), respectively.

Conclusion: In this predominantly post-biopsy cohort, mp-MRI using PI-RADSv2 reporting has a reasonably high diagnostic accuracy in detecting clinically significant prostate cancer.
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http://dx.doi.org/10.1016/j.ajur.2018.05.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6595160PMC
July 2019

IgG4-Related Disease of the Thyroid Gland Requiring Emergent Total Thyroidectomy: A Case Report.

Head Neck Pathol 2019 Sep 31;13(3):523-527. Epub 2018 May 31.

Division of Pathology, Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.

IgG4-related disease of the thyroid gland is a recently recognized subtype of thyroiditis, often with rapid progression requiring surgical treatment. It is considered as a spectrum of disease varying from early IgG4-related Hashimoto's thyroiditis (HT) pattern to late fibrosing HT or Riedel's thyroiditis patterns. Here, we report a 47-year-old Malay woman presenting with progressively painless neck swelling over 3 years and subclinical hypothyroidism. Computed tomography (CT) scan revealed diffuse thyroid enlargement (up to 13 cm) with retrosternal extension and without regional lymphadenopathy. Fine needle aspiration of the thyroid showed a limited number of follicular epithelial cell groups with widespread Hurthle cell change and scanty background colloid, but no evidence of lymphocytosis. The cytologic features fell into the category of 'atypia of undetermined significance'. Subsequently, the patient developed hypercapnic respiratory failure secondary to extrinsic upper airway compression by the thyroid mass and underwent emergent total thyroidectomy. Histology of the thyroid showed diffuse dense lymphoplasmacytic infiltrate and fibrosis. Follicular cells exhibited reactive nuclear features and some Hurthle cell change. IgG4+ plasma cells were over 40/high power field while overall IgG4/IgG ratio was above 50%. The overall features suggest the diagnosis of IgG4-related disease of the thyroid gland in the form of IgG4-related HT. Post-surgery, the patient was found to have markedly elevated serum IgG4 concentration but PET/CT did not show significant increased fludeoxyglucose uptake in other areas. Her recovery was complicated by a ventilator-associated pneumonia with empyema, limiting early use of corticosteroids for treatment of IgG4-related disease.
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http://dx.doi.org/10.1007/s12105-018-0940-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684687PMC
September 2019

TFE3-Expressing Epithelioid Rich Perivascular Epithelioid Cell Neoplasm (PEComa) of the Bladder with Unusual Benign Course.

Ann Clin Lab Sci 2018 Jan;48(1):110-115

Department of Pathology, Singapore General Hospital, Singapore.

Perivascular epithelioid cell tumor (PEComa) is an uncommon tumor which presents with epithelioid and spindled cell morphology and is immunoreactive for myogenic and melanocytic markers. Recently, a subset of PEComas has been reported to harbor gene rearrangement.In this case report, we describe a -expressing primary bladder PEComa in a 27-year-old male patient with acute myeloid leukaemia in remission. The tumor displayed epithelioid morphology with surrounding delicate blood vessels and was devoid of a prominent spindle cell component. Malignant features were not identified. The tumor expressed HMB45, CD117, and focal patchy positive expression for SMA. gene translocation was confirmed by Fluorescence in-situ hybridization. RT-PCR assay confirmed the presence of gene fusion.In contrast to previously reported aggressive gene-rearranged bladder PEComa cases, our case shows benign histologic and clinical features. Current clinical follow-up also shows a benign course.
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January 2018

Prospective Validation of Diagnostic Tumor Biomarkers in Men Treated With Radiotherapy for Prostate Cancer.

J Natl Cancer Inst 2017 02;109(2):1-8

Departments of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA.

Background: In prior retrospective studies, we assessed a number of prostate tumor tissue biomarkers that were associated independently with the clinical outcome of men treated with radiotherapy (RT) ± androgen deprivation therapy (ADT). In this report, the associations of selected biomarkers with biochemical or clinical disease failure (BCDF) were prospectively evaluated in men with T1-T3 prostate cancer on a randomized hypofractionation trial.

Methods: Biomarkers were analyzed in 263 of 303 men randomly assigned to standard vs moderate hypofractionation. Median follow-up was 65.9 months. Archival tissue was analyzed for Ki-67 (n = 231), MDM2 (n = 209), p16 (n = 195), Cox-2 (n = 126), p53 (n = 206), bcl2 (n = 223), bax (n = 210), and PKA (n = 160). The base model for multivariable Fine-Gray regression analysis included treatment assignment and risk groups. All statistical tests were two-sided.

Results: Each biomarker was tested one at a time relative to the base model and selected for inclusion in multivariable analysis. Ki-67 (hazard ratio [HR] = 2.31, 95% confidence interval [CI] = 1.19 to 4.48, P = .01) and bcl2&bax (HR = 2.19, 95% CI = 1.08 to 4.46, P = .03) were statistically significantly related to higher BCDF and were independently statistically significant when considered jointly (Ki-67: HR = 2.26, 95% CI = 1.12 to 4.58, P = .02; bcl2&bax: HR = 2.14, 95% CI = 1.03 to 4.41, P = .04). At 2.5 years postradiotherapy, the C-index of Ki-67 was 73.2%, while for the base model was only 46.2%; Ki-67 was the most statistically significant when tested without bcl2&bax.

Conclusions: In this prospective multiple biomarker analysis in men with prostate cancer treated with RT±ADT, both Ki-67 and bcl2&bax were independently related to early BCDF; however, Ki-67 alone is indicated to be the most clinically meaningful by C-index analysis and is universally available.
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http://dx.doi.org/10.1093/jnci/djw232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6075027PMC
February 2017

Gleason grade grouping of prostate cancer is of prognostic value in Asian men.

J Clin Pathol 2017 Sep 13;70(9):745-753. Epub 2017 Mar 13.

Department of Anatomical Pathology, Singapore General Hospital, Singapore, Singapore.

Aim: The International Society of Urological Pathology made recommendations for the use of Grade Groups (GG) originally described by Epstein and colleagues over Gleason score (GS) alone in 2014, which was subsequently adopted by the WHO classification in 2016. The majority of studies validating this revision have been in Caucasian populations. We therefore asked whether the new GG system was retrospectively associated with biochemical disease-free survival in a mixed-ethnicity cohort of Asian men.

Methods: A total of 680 radical prostatectomies (RPs) from 2005 to 2014 were included. GS from initial biopsy and RP were compared and used to allocate cases to GG, defined as: 1 (GS≤6); 2 (GS 3+4=7); 3 (GS 4+3=7); 4 (GS 4+4=8/5+3=8/3+5=8) and 5 (GS 9-10). Biochemical recurrence was defined as two consecutive post-RP prostate-specific antigen (PSA) levels of >0.2 ng/mL after post-RP PSA reaching the nadir of <0.1 ng/mL.

Results: Our data showed that Kaplan-Meier analysis revealed significant differences in biochemical recurrence within Gleason GG based on either biopsy or prostatectomy scoring. Multivariate analysis further confirmed that a higher GG was significantly associated with risk of biochemical recurrence. This GG system had a higher prognostic discrimination for both initial biopsy and RP than GS.

Conclusions: Our study validates the use of the revised and updated GG system in a mixed-ethnicity population of Asian men. Higher GG was significantly associated with increased risk of biochemical recurrence. We therefore recommend its use to inform clinical management for patients with prostate cancer.
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http://dx.doi.org/10.1136/jclinpath-2016-204276DOI Listing
September 2017

Tumor Necrosis Adds Prognostically Significant Information to Grade in Clear Cell Renal Cell Carcinoma: A Study of 842 Consecutive Cases From a Single Institution.

Am J Surg Pathol 2016 09;40(9):1224-31

*Cleveland Clinic, Robert J. Tomsich Pathology and Laboratory Medicine Institute †Cleveland Clinic, Quantitative Health Sciences, Lerner Research Institute ‡Department of Hematology and Oncology, Cleveland Clinic, Taussig Cancer Institute, Cleveland, OH.

Tumor necrosis has been shown to be an independent predictor of adverse outcome in renal cell carcinoma. A modification of the International Society of Urological Pathology (ISUP) grading system for renal cell carcinomas has recently been proposed, which incorporates the presence of tumor necrosis into grade. The investigators proposing this system found that necrosis added significant prognostic information to ISUP grade. We attempted to describe our experience with the effect of tumor necrosis in relationship to nuclear grade by reviewing the slides from a large consecutive series of localized clear cell renal cell carcinomas from our institution and obtaining long-term clinical follow-up information (overall survival). Of the 842 clear cell renal cell carcinomas reviewed, 265 (31.5%) were ISUP grade 1 or 2, 437 (51.9%) were ISUP grade 3, and 140 (16.6%) were ISUP grade 4. Tumor necrosis was present in 177 (21%) cases. Five hundred and forty-seven (64.9%) cases were stage pT1, 83 (9.9%) were stage pT2, 193 (22.9%) were stage pT3a, and 19 (2.3%) were pT3b or higher. Median follow-up was 73.2 months (range 0.12 to 273.6), and 310 (36.8%) patients died. On univariable analysis, there was no significant difference in outcome for tumors of ISUP grades 1 to 3. After adjustment for age, tumor stage, and tumor size, ISUP grade 4 and necrosis were significant predictors of overall survival on multivariable analysis. When the recently proposed modified grading system incorporating tumor necrosis was applied to our data, there was no significant difference in overall survival between patients with modified grade 1 tumors and those with modified grade 2 tumors (P=0.31); however, there was a statistically significant difference between patients with modified grade 1 or 2 tumors and those with modified grade 3 tumors (P=0.04),and a substantial difference in outcome between those with modified grade 3 and modified grade 4 tumors (P<0.001). When a recursive partitioning approach was applied to our data, patients of a given ISUP grade could be further prognostically separated according to the presence or absence of necrosis and could be divided into 3 statistically significant prognostic groups: (1) non-necrotic ISUP grade 1 to 3 tumors, (2) ISUP grade 1 to 3 tumors with necrosis and ISUP grade 4 tumors with <10% necrosis, and (3) ISUP grade 4 tumors with >10% necrosis. In conclusion, our study shows that tumor necrosis adds additional prognostic information to ISUP grade and that quantification of necrosis can further stratify patients with ISUP grade 4 tumors.
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http://dx.doi.org/10.1097/PAS.0000000000000690DOI Listing
September 2016

Plasma exchange in the treatment of thyroid storm secondary to type II amiodarone-induced thyrotoxicosis.

Endocrinol Diabetes Metab Case Rep 2016 6;2016:160039. Epub 2016 Jul 6.

Department of Endocrinology , Singapore General Hospital , Singapore.

Unlabelled: Type II amiodarone-induced thyrotoxicosis (AIT) is an uncommon cause of thyroid storm. Due to the rarity of the condition, little is known about the role of plasma exchange in the treatment of severe AIT. A 56-year-old male presented with thyroid storm 2months following cessation of amiodarone. Despite conventional treatment, his condition deteriorated. He underwent two cycles of plasma exchange, which successfully controlled the severe hyperthyroidism. The thyroid hormone levels continued to fall up to 10h following plasma exchange. He subsequently underwent emergency total thyroidectomy and the histology of thyroid gland confirmed type II AIT. Management of thyroid storm secondary to type II AIT can be challenging as patients may not respond to conventional treatments, and thyroid storm may be more harmful in AIT patients owing to the underlying cardiac disease. If used appropriately, plasma exchange can effectively reduce circulating hormones, to allow stabilisation of patients in preparation for emergency thyroidectomy.

Learning Points: Type II AIT is an uncommon cause of thyroid storm and may not respond well to conventional thyroid storm treatment.Prompt diagnosis and therapy are important, as patients may deteriorate rapidly.Plasma exchange can be used as an effective bridging therapy to emergency thyroidectomy.This case shows that in type II AIT, each cycle of plasma exchange can potentially lower free triiodothyronine levels for 10h.Important factors to consider when planning plasma exchange as a treatment for thyroid storm include timing of each session, type of exchange fluid to be used and timing of surgery.
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http://dx.doi.org/10.1530/EDM-16-0039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4933981PMC
July 2016

Renal Neoplasms With Overlapping Features of Clear Cell Renal Cell Carcinoma and Clear Cell Papillary Renal Cell Carcinoma: A Clinicopathologic Study of 37 Cases From a Single Institution.

Am J Surg Pathol 2016 Feb;40(2):141-54

Robert J Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, OH.

Clear cell papillary renal cell carcinoma (CCPRCC) was recently included in the International Society of Urological Pathology Vancouver Classification of Renal Neoplasia as a subtype of RCC that is morphologically, immunohistochemically, and genetically distinct from both clear cell renal cell carcinoma (CCRCC) and papillary renal cell carcinoma. In our clinical practice we have observed tumors with overlapping histologic features of CCPRCC and CCRCC; therefore, our aim was to describe the morphologic, immunohistochemical, and clinical characteristics of these tumors. We examined a large series of consecutive nephrectomies diagnosed as CCRCC and found 37 tumors with morphologic overlap between CCRCC and CCPRCC, identifying 2 patterns. Pattern 1 tumors (N=19) had areas diagnosable as CCRCC admixed with foci having a prominent linear arrangement of nuclei away from the basement membrane imparting a resemblance to CCPRCC; however, other morphologic features commonly seen in CCPRCC (such as branching acini and cystic spaces with papillary tufts) were not typical and, when present, were focal or poorly developed. Pattern 2 (N=18) tumors had 2 discrete areas, one area with an appearance strongly resembling CCPRCC and the other with higher grade nuclei and features diagnosable as CCRCC, sometimes including rhabdoid differentiation, sarcomatoid differentiation, necrosis, and high-stage disease. Four (21%) of the pattern 1 tumors had grade 3 nuclei in the CCRCC-like areas, and 4 were high stage (pT3a). Of the 16 immunostained pattern 1 tumors, all expressed cytokeratin 7 (CK7) at least focally in the CCPRCC-like areas, strongly and diffusely in 9 (56%) cases; 12 (75%) showed negative to focal and/or weak CK7 expression in the CCRCC-like areas. CD10, α-methylacyl-CoA-racemase, high-molecular-weight cytokeratin, and carbonic anhydrase IX (CA IX) had no significant differential expression between these foci. No cup-like staining pattern was seen with CA IX. Two (11%) patients with pattern 1 tumors developed metastases, and 1 (5%) subsequently died of disease. Eleven (61%) pattern 2 cases had the International Society of Urological Pathology grade 3 nuclei in the CCRCC-like areas, and 7 (39%) were grade 4 (4 of these cases had rhabdoid features; 1 was also sarcomatoid). Of the 16 immunostained pattern 2 tumors, 8 (50%) showed strong diffuse CK7 expression in the CCPRCC-like areas, and 9 (56%) showed complete lack of CK7 expression in the CCRCC-like areas. CD10, α-methylacyl-CoA-racemase, and high-molecular-weight cytokeratin did not have significant differential expression. Membranous expression of CA IX, typically strong and diffuse, was identified in both the CCPRCC-like and CCRCC-like areas in all cases tested (with a cup-like pattern at least focally in the CCPRCC-like areas of 10 [63%] pattern 2 cases). Five (28%) patients with pattern 2 tumors had distant metastases, 3 (17%) of whom subsequently died of disease. Renal cell carcinomas with areas resembling both CCRCC and CCPRCC occur. Some can have high-grade and high-stage foci, and aggressive clinical outcomes are seen. Given this malignant potential, we would presently diagnose such cases as CCRCC. These 2 patterns of renal neoplasia underscore the need for caution in diagnosing CCPRCC on limited sampling, reserving the diagnosis for those tumors that strictly fulfill both morphologic and immunohistochemical criteria.
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http://dx.doi.org/10.1097/PAS.0000000000000583DOI Listing
February 2016

Diagnostic Biomarkers in Eosinophilic Renal Neoplasms.

Urol Clin North Am 2016 Feb;43(1):87-94

Department of Pathology, Singapore General Hospital, 20 College Road, Academia, Level 7, Diagnostics Tower, Singapore 169856, Singapore; Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, MD10, 4 Medical Drive, Singapore 117594, Singapore; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, MD10, 4 Medical Drive, Singapore 117594, Singapore; Duke-NUS Graduate Medical School Singapore, 8 College Road, Singapore 169857, Singapore. Electronic address:

Incidental small renal masses identified on imaging are increasingly investigated via needle core or fine needle aspiration biopsies with limited material provided for rendering a diagnosis. Lesions with a prominent eosinophilic or oncocytic cell presence showing morphologic overlap between well-known eosinophilic neoplasms are challenging to diagnose. We review the range of known benign and malignant eosinophilic renal neoplasms and their immunoprofiles to elucidate a useful panel of stains that may assist the pathologist in making an accurate diagnosis.
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http://dx.doi.org/10.1016/j.ucl.2015.08.008DOI Listing
February 2016

Papanicolaou tests with coexisting squamous and glandular abnormalities.

Cancer Cytopathol 2014 Aug 17;122(8):620-6. Epub 2014 Jun 17.

Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio.

Background: Papanicolaou (Pap) test interpretations of atypical glandular cells are associated with subsequent detection of squamous and, less often, glandular malignancies. A Pap test with a combined interpretation of squamous and glandular atypia indicates concern for either 2 distinct lesions (both squamous and glandular) or involvement of cervical squamous and glandular epithelium by a single pathologic process. Dual interpretations can potentially guide patient management. This retrospective study describes an institutional experience with Pap test dual reporting of squamous and glandular atypia and patient follow-up in these cases.

Methods: Following institutional review board approval, a search of the anatomic pathology database for Pap tests with both atypical squamous and atypical glandular interpretations from January 2005 to December 2010 was performed. Other recorded data included: prior history, age, human papillomavirus (HPV) status, and most severe follow-up histologic diagnosis.

Results: Of 361,953 Pap tests interpreted in the laboratory during this period, a total of 230 (0.06%) patients with dual interpretation Pap tests and follow-up were identified. Follow-up pathology results on these patients were predominantly squamous lesions (51.7%). Glandular lesions only were detected in 14 cases (6.1%). Nine (3.9%) patients had both squamous and glandular pathology.

Conclusions: Over a 6-year period, dual Pap test interpretations with both squamous and glandular atypia were more often associated with squamous than glandular lesions. Dual interpretations did identify coexisting squamous and glandular lesions. However, the number of cases was small.
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http://dx.doi.org/10.1002/cncy.21448DOI Listing
August 2014

Lack of Association between COX-2 Staining Level and Biochemical Recurrence Following Salvage Radiation Therapy for Recurrent Prostate Cancer.

J Radiat Oncol 2013 Sep;2(3):309-314

Section of Biostatistics, Mayo Clinic Florida, Jacksonville, FL, USA.

Objective: The ability to predict which men will experience biochemical recurrence (BCR) after salvage radiation therapy (SRT) for recurrent prostate cancer following radical prostatectomy has potential for improvement. Cyclooxygenase-2 (COX-2) overexpression has previously correlated with poor clinical outcomes following primary treatment for prostate cancer, however its predictive ability in the specific setting of SRT has not been examined to date. This study evaluated the association between COX-2 staining intensity and BCR following SRT for recurrent prostate cancer.

Methods: We utilized a cohort of 151 patients who underwent SRT between July 1987 and July 2003. COX-2 staining intensity in primary tumor samples was detected using monoclonal antibodies and quantified using a computer-assisted method. The association between COX-2 staining intensity and BCR was evaluated using multivariable Cox regression models.

Results: When examining COX-2 staining level as three-level categorical variable (low, moderate, high) based on approximate sample tertiles, there was no evidence of an association with BCR (P=0.18). More specifically, in comparison to patients with low staining intensity, there was no significant difference in risk of BCR for moderate (Relative risk [RR]: 1.17, P=0.56) or high (RR: 0.72, P=0.22) COX-2 staining intensity patients. This lack of association was also observed when considering COX-2 staining intensity as a continuous variable (RR: 0.83, P=0.15).

Conclusion: Our results indicate that COX-2 staining intensity is likely of little use in discriminating prognosis of SRT. It appears that the search for prognostic factors associated with BCR should continue elsewhere in order to further enhance patient selection for SRT.
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http://dx.doi.org/10.1007/s13566-013-0099-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3780452PMC
September 2013

Ki-67 is an independent predictor of metastasis and cause-specific mortality for prostate cancer patients treated on Radiation Therapy Oncology Group (RTOG) 94-08.

Int J Radiat Oncol Biol Phys 2013 Jun 6;86(2):317-23. Epub 2013 Mar 6.

University of Wisconsin Carbone Cancer Center, Madison, Wisconsin, USA.

Purpose: The association of Ki-67 staining index (Ki67-SI) with overall survival (OS), disease-specific mortality (DSM), distant metastasis (DM), and biochemical failure (BF) was examined in men with favorable- to intermediate-risk prostate cancer receiving radiation therapy (RT) alone or with short-term androgen deprivation (ADT) in Radiation Therapy Oncology Group (RTOG) 94-08.

Methods And Materials: 468 patients (23.6%) on RTOG 94-08 had sufficient tissue for Ki67-SI analysis. The median follow-up time was 7.9 years. Ki67-SI was determined by immunohistochemistry and quantified manually and by image analysis. Correlative analysis versus clinical outcome was performed using the third quartile (≥Q3) cutpoint. A proportional hazards multivariable analysis (MVA) dichotomized covariates in accordance with trial stratification and randomization criteria.

Results: In MVAs adjusted for all treatment covariates, high Ki67-SI (≥Q3) was correlated with increased DSM (hazard ratio [HR] 2.48, P=.03), DM (HR 3.5, P=.002), and BF (HR 3.55, P<.0001). MVA revealed similar Ki67-associated hazard ratios in each separate treatment arm for DSM, DM, and BF; these reached significance only for DM in the RT-alone arm and for BF in both arms. Ki67-SI was not a significant predictor of intraprostatic recurrence assessed by repeated biopsy 2 years after treatment. Patients with a high or low Ki67-SI seemed to experience a similar relative benefit from the addition of ADT to radiation.

Conclusions: High Ki67-SI independently predicts for increased DSM, DM, and protocol BF in primarily intermediate-risk prostate cancer patients treated with RT with or without ADT on RTOG 94-08 but does not predict for local recurrence or for increased relative benefit from ADT. This and prior studies lend support for the use of Ki67-SI as a stratification factor in future trials.
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http://dx.doi.org/10.1016/j.ijrobp.2013.01.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646974PMC
June 2013

Evaluation of MDM2, p16, and p53 staining levels as biomarkers of biochemical recurrence following salvage radiation therapy for recurrent prostate cancer.

Prostate 2012 Dec 18;72(16):1757-66. Epub 2012 Apr 18.

Biostatistics Unit, Mayo Clinic Florida, Jacksonville, Florida 32224, USA.

Background And Purpose: The selection of appropriate candidates for salvage radiation therapy (SRT) to address a rising PSA following radical prostatectomy remains challenging. Herein, we provide the first evaluation of the ability of staining levels of the tumor based biomarkers MDM2, p16, and p53 to aid in prediction of biochemical recurrence (BCR) among men undergoing SRT for recurrent prostate cancer.

Material And Methods: We identified 152 patients who were treated with SRT between July 1987 and July 2003. Staining levels of MDM2, p16, and p53 in primary tumor samples removed during prostatectomy were detected using monoclonal antibodies and quantified by use of a computer-assisted method. Associations of staining levels with BCR were evaluated using Cox proportional hazards regression models; relative risks (RRs) and 95% confidence intervals (CIs) were estimated.

Results: Compared to patients with low staining (≤median) as measured by percentage of cells with nuclear staining, there was no significant difference in risk of BCR for patients with high MDM2 staining (RR: 0.90, 95% CI: 0.57-1.45, P = 0.67), high p16 staining (RR: 0.88, 95% CI: 0.54-1.44, P = 0.62), or high p53 staining (RR: 1.33, 95% CI: 0.84-2.11, P = 0.23) in multivariable analysis. These results were consistent when considering alternate percentile cutpoints and alternate quantifications of biomarker staining.

Conclusions: Our results provide evidence that MDM2, p16, and p53 staining levels are not useful in the prediction of BCR after SRT. As such, these biomarkers are of little clinical use in the selection of appropriate candidates for SRT.
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http://dx.doi.org/10.1002/pros.22528DOI Listing
December 2012

PKA knockdown enhances cell killing in response to radiation and androgen deprivation.

Int J Cancer 2011 Feb 19;128(4):962-73. Epub 2010 Oct 19.

Basic Science Division, Fox Chase Cancer Center, Philadelphia, PA, USA.

The therapeutic efficacy of Gem®231, a second generation antisense molecule targeted to the RIα subunit of PKA(RIα) (AS-PKA), administered in combination with androgen deprivation (AD) and radiation therapy (RT), was examined in androgen sensitive (LNCaP) and insensitive (PC3) cell lines. Apoptosis was assayed by Caspase 3 + 7 activity and Annexin V binding. AS-PKA significantly increased apoptosis in vitro from RT (both lines), with further increases in LNCaP cells grown in AD medium. In LNCaP cells, AD increased phosphorylated mitogen activated protein-kinase (pMAPK), which was reduced by AS-PKA relative to the mismatch (MM) controls. AS-PKA also reduced pMAPK levels in PC3 cells. Cell death was measured by clonogenic survival assays. In vivo, LNCaP cells were grown orthotopically in nude mice. Tumor kinetics were measured by magnetic resonance imaging and serum prostate-specific antigen. PC3 cells were grown subcutaneously and tumor volume assessed by caliper measurements. In PC3 xenografts, AS-PKA caused a significant increase in tumor doubling time relative to MM controls as a monotherapy or in combination with RT. In orthotopic LNCaP tumors, AS-PKA was ineffective as a monotherapy; however, it caused a statistically significant increase in tumor doubling time relative to MM controls when used in combination with AD, with or without RT. PKA(RIα) levels in tumors were quantified via immunohistochemical (IHC) staining and image analysis. IHC measurements in LNCaP cells exhibited that AS-PKA reduced PKA(RIα) levels in vivo. We demonstrate for the first time that AS-PKA enhances cell killing androgen sensitive prostate cancer cells to AD ± RT and androgen insensitive cells to RT.
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http://dx.doi.org/10.1002/ijc.25634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3391603PMC
February 2011

Survivin is a potential mediator of prostate cancer metastasis.

Int J Radiat Oncol Biol Phys 2010 Nov 16;78(4):1095-103. Epub 2010 Mar 16.

Arthur G. James Comprehensive Cancer Center, The Ohio State University Medical School, Columbus, OH 43210, USA.

Purpose: We examined whether Survivin expression is associated with an increased risk of metastasis in prostate cancer.

Methods And Materials: A total of 205 patients with T1 (23%) and T2 (77%) prostate cancer were treated with conventional external beam radiation therapy from 1991 to 1993 at the Massachusetts General Hospital. Of the patients, 62 had adequate and suitable-stained tumor material for Survivin analysis. Median follow-up was 102 months (range, 5-127 months). Distant failure was determined on the basis of clinical criteria. In preclinical studies, replication-deficient adenovirus encoding phosphorylation-defective Survivin Thr34→Ala dominant-negative mutant pAd-S(T34A) or short hairpin RNA (shRNA) was used to inhibit Survivin in prostate cancer models, and the cell motility, morphology, and metastasis were investigated.

Results: Our correlative data on men with early-stage (T1/T2) prostate cancers treated at Massachusetts General Hospital by definitive radiotherapy indicated that overexpression of Survivin (positive staining in ≥10% cells) was associated with a significantly increased risk for the subsequent development of distant metastasis (p = 0.016) in the univariate analysis. In the multivariate analysis, overexpression of Survivin remained an independent predictor of distant metastasis (p = 0.008). The inhibition of Survivin dramatically inhibited invasiveness of prostate cancer cells in the in vitro invasion assay and spontaneous metastasis in the Dunning prostate cancer in vivo model. Furthermore, attenuation of Survivin resulted in changes in the microtubule cytoskeleton, loss of cellular polarity, and loss of motility.

Conclusions: This study suggests that Survivin may be a potentially important prognostic marker and promising therapeutic target in metastatic prostate cancer.
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http://dx.doi.org/10.1016/j.ijrobp.2009.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4348096PMC
November 2010

Cytoskeleton alterations in melanoma: aberrant expression of cortactin, an actin-binding adapter protein, correlates with melanocytic tumor progression.

Mod Pathol 2010 Feb 6;23(2):187-96. Epub 2009 Nov 6.

Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.

Cortactin is a multidomain actin-binding protein important for the functions of cytoskeleton by regulating cortical actin dynamics. It is involved in a diverse array of basic cellular functions. Tumorigenesis and tumor progression involves alterations in actin cytoskeleton proteins. We sought to study the role of cortactin in melanocytic tumor progression using immunohistochemistry on human tissues. The results reveal quantitative differences between benign and malignant lesions. Significantly higher cortactin expression is found in melanomas than in nevi (P<0.0001), with levels greater in metastatic than in invasive melanomas (P<0.05). Qualitatively, tumor tissues often show aberrant cortactin localization at the cell periphery, corresponding to its colocalization with filamentous actin in cell cortex of cultured melanoma cells. This suggests an additional level of protein dysregulation. Furthermore, in patients with metastatic disease, high-level cortactin expression correlates with poor disease-specific survival. Our data, in conjunction with outcome data on several other types of human cancers and experimental data from melanoma cell lines, supports a potential role of aberrant cortactin expression in melanoma tumor progression and a rational for targeting key elements of actin-signaling pathway for developmental therapeutics in melanomas.
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http://dx.doi.org/10.1038/modpathol.2009.157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2827925PMC
February 2010

The importance of protein kinase A in prostate cancer: relationship to patient outcome in Radiation Therapy Oncology Group trial 92-02.

Clin Cancer Res 2009 Sep 25;15(17):5478-84. Epub 2009 Aug 25.

Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, Florida 33136, USA.

Purpose: We previously reported that protein kinase A type I (PKA(RIalpha)) overexpression was predictive of outcome in prostate cancer patients treated with radiotherapy (RT) +/- short-term androgen deprivation (STAD) on Radiation Therapy Oncology Group (RTOG) protocol 86-10. Here, we attempt to verify our prior findings and test the hypothesis that the relationship of the length of AD to patient outcome is affected by PKA(RIalpha) overexpression.

Experimental Design: There were 313 cases in the RTOG 92-02 study cohort with available tissue and suitable staining by immunohistochemistry. Median follow-up was 10.1 years. The intensity of PKA(RIalpha) staining intensity was quantified manually and by image analysis. Multivariate analyses were done for overall mortality using Cox proportional hazards models and for local failure, biochemical failure, distant metastasis, and cause-specific mortality using Fine and Gray's regression models.

Results: The expression levels of PKA(RIalpha), determined by manual and image analysis, were strongly correlated (P < 0.0001). In the multivariate analyses, manual-quantified and image analysis-quantified PKA(RIalpha) staining intensities were independent predictors of distant metastasis (P < 0.01), local failure (P < 0.05), and biochemical failure (P
Conclusions: PKA(RIalpha) overexpression has been shown in two RTOG trials to be associated with an increased risk of failure after AD + RT. In this series of contemporary high-risk patients, PKA(RIalpha) overexpression was associated with diminished response to LTAD + RT relative to STAD + RT, suggesting that such patients would be ideal for a PKA(RIalpha) knockdown strategy.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-2704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763098PMC
September 2009

MDM2 and Ki-67 predict for distant metastasis and mortality in men treated with radiotherapy and androgen deprivation for prostate cancer: RTOG 92-02.

J Clin Oncol 2009 Jul 26;27(19):3177-84. Epub 2009 May 26.

Department of Radiation Oncology, University of Miami, Sylvester Comprehensive Cancer Center, 1475 NW 12th Ave, Suite 1501, Miami, FL 33130, USA.

PURPOSE MDM2 regulates p53, which controls cell cycle arrest and apoptosis. Both proteins, along with Ki-67, which is an established strong determinant of metastasis, have shown promise in predicting the outcome of men treated with radiation therapy (RT) with or without short-term androgen deprivation (STAD). This report compares the utility of abnormal expression of these biomarkers in estimating progression in a cohort of men treated on RTOG 92-02. PATIENTS AND METHODS Adequate tissue for immunohistochemistry was available for p53, Ki-67, and MDM2 analyses in 478 patient cases. The percentage of tumor nuclei staining positive (PSP) was quantified manually or by image analysis, and the per-sample mean intensity score (MIS) was quantified by image analysis. Cox regression models were used to estimate overall mortality (OM), and Fine and Gray's regressions were applied to the end points of distant metastasis (DM) and cause-specific mortality (CSM). Results In multivariate analyses that adjusted for all markers and treatment covariates, MDM2 overexpression was significantly related to DM (P = .02) and OM (P = .003), and Ki-67 overexpression was significantly related to DM (P < .0001), CSM (P = .0007), and OM (P = .01). P53 overexpression was significantly related to OM (P = .02). When considered in combination, the overexpression of both Ki-67 and MDM2 at high levels was associated with significantly increased failure rates for all end points (P < .001 for DM, CSM, and OM). CONCLUSION Combined MDM2 and Ki-67 expression levels were independently related to distant metastasis and mortality and, if validated, could be considered for risk stratification of patients with prostate cancer in clinical trials.
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http://dx.doi.org/10.1200/JCO.2008.19.8267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716939PMC
July 2009

Evaluation of ki-67 staining levels as an independent biomarker of biochemical recurrence after salvage radiation therapy for prostate cancer.

Int J Radiat Oncol Biol Phys 2009 Dec 21;75(5):1364-70. Epub 2009 May 21.

College of Medicine, Mayo Clinic Florida, Jacksonville, FL 32224, USA.

Purpose: We recently published a scoring algorithm to predict biochemical recurrence (BCR) after salvage radiation therapy (SRT) for prostate cancer. Currently, this algorithm is based on clinicopathologic features and does not incorporate information from tumor-based biomarkers. Herein, we evaluate the ability of Ki-67 staining in primary prostate cancer to independently aid in the prediction of BCR among men undergoing SRT.

Methods And Materials: We identified 147 patients who were treated with SRT between July 1987 and July 2003 at Mayo Clinic (Rochester, MN; Jacksonville, FL; Scottsdale, AZ). Staining levels of Ki-67 in primary tumor samples were detected by use of a monoclonal antibody and quantified by use of a computer-assisted method. We used Cox proportional hazards models to examine the association of Ki-67 staining and BCR in single-variable models and after multivariable adjustment.

Results: The risk of BCR for men with tumors in the highest tertile of Ki-67 staining is approximately two times that for men with tumors in the lower two tertiles (relative risk, 2.02; 95% confidence interval, 1.23-3.32; p = 0.005) after adjustment for the features in our original scoring algorithm. Further adjustment for additional covariates did not attenuate this association. Evidence from concordance index values supports that Ki-67 staining adds to the predictive ability of our existing scoring algorithm.

Conclusions: Our data suggest that higher levels of Ki-67 staining are associated with increased risk of BCR after SRT, independent of existing clinicopathologic covariates. Future studies involving larger numbers of patients are required to validate these results and also explore possible means of combining this biomarker with existing prognostic tools.
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http://dx.doi.org/10.1016/j.ijrobp.2008.12.061DOI Listing
December 2009

Prognostic value of survivin in locally advanced prostate cancer: study based on RTOG 8610.

Int J Radiat Oncol Biol Phys 2009 Mar 30;73(4):1033-42. Epub 2008 Oct 30.

Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.

Purpose: To examine the prognostic value of nuclear and cytoplasmic survivin expression in men with locally advanced prostate cancer who were enrolled in Radiation Therapy Oncology Group (RTOG) protocol 8610.

Methods And Materials: RTOG 8610 was a Phase III randomized study comparing the effect of radiotherapy plus short-term androgen deprivation with radiotherapy alone. Of the 456 eligible patients, 68 patients had suitably stained tumor material for nuclear survivin analysis and 65 patients for cytoplasmic survivin.

Results: Compared with patients with nuclear survivin intensity scores of 191.2 had significantly improved prostate cancer survival (hazard ratio [HR], 0.45; 95% confidence interval [CI], 0.20-1.00, p = 0.0452). On multivariate analysis, nuclear survivin intensity scores >191.2 were significantly associated with improved overall survival (HR, 0.46; 95% CI, 0.25-0.86; p = 0.0156) and prostate cancer survival (HR, 0.36; 95% CI, 0.16-0.84; p = 0.0173). On univariate analysis, compared with patients with cytoplasmic survivin integrated optical density 82.7 showed a significantly increased risk of local progression (HR, 2.49; 95% CI, 1.03-6.01; p = 0.0421).

Conclusion: Nuclear overexpression of survivin was associated with improved overall and prostate cancer survival on multivariate analysis, and cytoplasmic overexpression of survivin was associated with increased rate of local progression on univariate analysis in patients with locally advanced prostate cancer treated on RTOG 8610. Our results might reflect the different functions of survivin and its splice variants, which are known to exist in distinct subcellular compartments.
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http://dx.doi.org/10.1016/j.ijrobp.2008.06.1489DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2678565PMC
March 2009

Protein kinase A RI-alpha predicts for prostate cancer outcome: analysis of radiation therapy oncology group trial 86-10.

Int J Radiat Oncol Biol Phys 2008 Aug 1;71(5):1309-15. Epub 2008 May 1.

Department of Radiation Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.

Purpose: The RI-alpha regulatory subunit of protein kinase A type 1 (PKA) is constitutively overexpressed in human cancer cell lines and is associated with active cell growth and neoplastic transformation. This report examined the association between PKA expression and the endpoints of biochemical failure (BF), local failure (LF), distant metastasis (DM), cause-specific mortality (CSM), and overall mortality in men treated with radiotherapy, with or without short-term androgen deprivation in Radiation Therapy Oncology Group trial 86-10.

Methods And Materials: Pretreatment archival diagnostic tissue samples from 80 patients were stained for PKA by immunohistochemical methods from a parent cohort of 456 cases. PKA intensity was scored manually and by image analysis. The Cox proportional hazards model for overall mortality and Fine and Gray's regression models for CSM, DM, LF and BF were then applied to determine the relationship of PKA expression to the endpoints.

Results: The pretreatment characteristics of the missing and determined PKA groups were not significantly different. On univariate analyses, a high PKA staining intensity was associated with BF (image analysis, continuous variable, p = 0.022), LF (image analysis, dichotomized variable, p = 0.011), CSM (manual analysis, p = 0.037; image analysis, continuous, p = 0.014), and DM (manual analysis, p = 0.029). On multivariate analyses, the relationships to BF (image analysis, continuous, p = 0.03), LF (image analysis, dichotomized, p = 0.002), and DM remained significant (manual analysis, p = 0.018). In terms of CSM, a trend toward an association was seen (manual analysis, p = 0.08; image analysis, continuous, p = 0.09).

Conclusion: PKA overexpression was significantly related to patient outcome and is a potentially useful biomarker for identifying high-risk prostate cancer patients who might benefit from a PKA knockdown strategy.
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http://dx.doi.org/10.1016/j.ijrobp.2007.12.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2756067PMC
August 2008

COX-2 expression predicts prostate-cancer outcome: analysis of data from the RTOG 92-02 trial.

Lancet Oncol 2007 Oct 18;8(10):912-20. Epub 2007 Sep 18.

Radiation Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA.

Background: COX-2 is overexpressed in some cancers, including prostate cancer; however, little is known about the effect of COX-2 overexpression on outcome in radiation-treated patients with prostate cancer. We aimed to study COX-2 overexpression and outcome in a well-defined cohort of men who received treatment with short-term androgen deprivation (STAD) plus radiotherapy or long-term androgen deprivation (LTAD) plus radiotherapy.

Methods: Men with prostate cancer who had participated in the Radiation Therapy Oncology Group (RTOG) 92-02 trial and for whom sufficient diagnostic tissue was available for immunohistochemical staining and image analysis of COX-2 expression were enrolled in this study. Patients in the 92-02 trial had been randomly assigned to treatment with STAD plus radiotherapy or LTAD plus radiotherapy. Multivariate analyses by Cox proportional hazards models were done to assess whether associations existed between COX-2 staining intensity and the RTOG 92-02 primary endpoints of biochemical failure (assessed by the American Society for Therapeutic Radiology and Oncology [ASTRO] and Phoenix criteria), local failure, distant metastasis, cause-specific mortality, overall mortality, and any failure.

Findings: 586 patients with sufficient diagnostic tissue for immunohistochemical staining and image analysis of COX-2 expression were included in this study. In the multivariate analyses, the intensity of COX-2 staining as a continuous covariate was an independent predictor of distant metastasis (hazard ratio [HR] 1.181 [95% CI 1.077-1.295], p=0.0004); biochemical failure by two definitions (ASTRO HR 1.073 [1.018-1.131], p=0.008; Phoenix HR 1.073 [1.014-1.134], p=0.014); and any failure (HR 1.068 [1.015-1.124], p=0.011). The higher the expression of COX-2, the greater the chance of failure. As a dichotomous covariate, COX-2 overexpression seemed to be most discriminating of outcome for those who received STAD compared with those who received LTAD.

Interpretation: To our knowledge, this is the first study to establish an association of COX-2 expression with outcome in patients with prostate cancer who have had radiotherapy. Increasing COX-2 expression was significantly associated with biochemical failure, distant metastasis, and any failure. COX-2 inhibitors might improve patient response to radiotherapy in those treated with or without androgen deprivation. Our findings suggest that LTAD might overcome the effects of COX-2 overexpression. Therefore, COX-2 expression might be useful in selecting patients who need LTAD.
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http://dx.doi.org/10.1016/S1470-2045(07)70280-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2080621PMC
October 2007

Antisense-MDM2 sensitizes LNCaP prostate cancer cells to androgen deprivation, radiation, and the combination in vivo.

Int J Radiat Oncol Biol Phys 2007 Jul;68(4):1151-60

Department of Radiation Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA.

Purpose: To test the effects of antisense (AS)-MDM2 alone and with androgen deprivation (AD), radiotherapy (RT), and AD + RT on wild-type LNCaP cells in an orthotopic in vivo model.

Methods: Androgen-sensitive LNCaP cells were grown in the prostates of nude mice. Magnetic resonance imaging-based tumor volume and serum prostate-specific antigen (PSA) measurements were used to assess effects on tumor response. Tumor response was measured by biochemical and tumor volume failure definitions and doubling time estimates from fitted PSA and tumor volume growth curves. Expression of MDM2, p53, p21, and Ki-67 was quantified using immunohistochemical staining and image analysis of formalin-fixed tissue, analogous to methods used clinically.

Results: Antisense-MDM2 significantly inhibited the growth of LNCaP tumors over the mismatch controls. The most significant increase in tumor growth delay and tumor doubling time was from AS-MDM2 + AD + RT, although the effect of AS-MDM2 + AD was substantial. Expression of MDM2 was significantly reduced by AS-MDM2 in the setting of RT.

Conclusions: This is the first in vivo investigation of the effects of AS-MDM2 in an orthotopic model and the first to demonstrate incremental sensitization when added to AD and AD + RT. The results with AD underscore the potential to affect micrometastatic disease, which is probably responsible for treatment failure in 30-40% of men with high-risk disease.
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http://dx.doi.org/10.1016/j.ijrobp.2007.03.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763094PMC
July 2007

Prognostic value of p16 in locally advanced prostate cancer: a study based on Radiation Therapy Oncology Group Protocol 9202.

J Clin Oncol 2007 Jul;25(21):3082-9

Massachusetts General Hospital/Harvard Medical School, Department of Radiation Oncology, Boston, MA 02114, USA.

Purpose: Deregulation of the retinoblastoma (RB) pathway is commonly found in virtually all known human tumors. p16, the upstream regulator of RB, is among the most commonly affected member of this pathway. In the present study, we examined the prognostic value of p16 expression in men with locally advanced prostate cancer who were enrolled on Radiation Therapy Oncology Group protocol 9202.

Patients And Methods: RTOG 9202 was a phase III randomized study comparing long-term (LT) versus short-term (ST) androgen-deprivation therapy (AD). Of the 1,514 eligible cases, 612 patients had adequate tumor material for p16 analysis. Expression levels of p16 were determined by immunohistochemistry (IHC). IHC staining was scored quantitatively using an image analysis system.

Results: On multivariate analysis, intact p16 expression was significantly associated with decreased rate of distant metastases (P = .0332) when both STAD and LTAD treatment arms were considered together. For patients with intact (high levels of immunostaining) p16 (mean p16 index > 81.3%), LTAD plus radiotherapy (RT) significantly improved prostate cancer survival (PCS) compared with STAD plus RT (P = .0008) and reduced the frequency of distant metastasis (P = .0069) compared with STAD plus RT. In contrast, for patients with tumors demonstrating p16 loss (low levels of immunostaining, mean p16 index < or = 81.3%), LTAD plus RT significantly improved biochemical no evidence of disease survival over STAD (P < .0001) primarily by decreasing the frequency of local progression (P = .02), as opposed to distant metastasis, which was the case in the high-p16 cohort.

Conclusion: Low levels of p16 on image analysis appear to be associated with a significantly higher risk of distant metastases among all study patients. p16 expression levels also appear to identify patients with locally advanced prostate cancer with distinct patterns of failure after LTAD.
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http://dx.doi.org/10.1200/JCO.2006.08.4152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2777649PMC
July 2007

Bcl-2 and Bax expression predict prostate cancer outcome in men treated with androgen deprivation and radiotherapy on radiation therapy oncology group protocol 92-02.

Clin Cancer Res 2007 Jun;13(12):3585-90

Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA.

Purpose: Bcl-2 is antiapoptotic, and its overexpression has been associated with resistance to androgen deprivation and poor outcome in some patients treated with radiotherapy. Bax is proapoptotic, regulating Bcl-2 through heterodimer formation. In a prior study, Bcl-2 and Bax were not related to outcome in locally advanced patients treated with radiotherapy or short-term androgen deprivation + radiotherapy (STAD+RT) on another Radiation Therapy Oncology Group trial (86-10). A follow-up investigation was carried out here in more contemporary high-risk men treated on Radiation Therapy Oncology Group 92-02 with STAD+RT or long-term AD+RT (LTAD+RT).

Experimental Design: Adequate tissue was available to be analyzed immunohistochemically in 502 patients for Bcl-2 and 343 patients for Bax. Univariate and multivariate analyses by Cox proportional hazards models were applied to end points of failure.

Results: Bcl-2 was positive in 45.6% cases, and Bax expression altered in 53.9% cases. Abnormal Bcl-2 was not related to any of the failure end points tested. Altered Bax expression was significantly associated with any failure (P = 0.023) and marginally with biochemical failure (P = 0.085). The combination of negative Bcl-2/normal Bax expression seemed more robust, being significantly related to reduced biochemical failure (P = 0.036) and any failure (P = 0.046). The predictive value of negative Bcl-2/normal Bax was most pronounced in those who received STAD+RT, as opposed to LTAD+RT.

Conclusions: Normal Bax expression was associated with significantly more favorable outcome. The combination of negative Bcl-2 and normal Bax was more consistently significant, particularly when STAD+RT was the treatment administered. These data suggest that LTAD+RT should be used when either Bcl-2 or Bax is abnormally expressed.
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http://dx.doi.org/10.1158/1078-0432.CCR-06-2972DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2763095PMC
June 2007

Activated STAT3 as a correlate of distant metastasis in prostate cancer: a secondary analysis of Radiation Therapy Oncology Group 86-10.

Urology 2007 Mar;69(3):505-9

Department of Interdisciplinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA.

Objective: STAT3 participates in the regulation of cellular growth, survival, and oncogenesis. We evaluated the association between activated STAT3 expression and overall survival, disease-specific survival, distant metastasis, and local progression in a cohort of patients treated with either radiotherapy alone or radiotherapy plus short-term androgen blockade.

Methods: A total of 456 assessable patients were included in the Radiation Therapy Oncology Group 86-10 trial. Of these, 62 patients had sufficient tissue for the analysis of STAT3 expression by immunohistochemistry. Nuclear staining was quantified by an image analysis system.

Results: No significant difference was found in the distribution of clinical characteristics and assigned treatment between the patients available for STAT3 analysis (STAT3 cohort) and the others in the Radiation Therapy Oncology Group 86-10 trial (n = 394). Activated STAT3 correlated inversely with the development of distant metastasis (risk ratio [RR] = 0.81, P = 0.04) but not with overall survival, cause-specific survival, or local progression. Similar results were obtained when the data were dichotomized (ACIS index greater than 29%, RR = 0.41, P = 0.07). On multivariate analysis, activated STAT3 (continuous variable) was an independent predictor of distant metastasis (RR = 0.79, P = 0.04).

Conclusions: Activated STAT3 was inversely related to the development of distant metastasis in prostate cancer. This marker should be evaluated further in a larger cohort of patients.
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http://dx.doi.org/10.1016/j.urology.2006.11.006DOI Listing
March 2007