bluuebunny/crossref_metadata_2025_split huggingface dataset:
An automated, sensitive, high-throughput biomarker protocol for tissue microarrays containing archival prostate specimens: The prognostic potential of an ERG EMT panel.
Authors: Brown Mick D. , Salman Ahmad , Hart Claire , Clarke Noel W. 
Published: February 2017

181 Background: Tissue microarrays (TMAs), linked to clinical databases containing clinical outcome data, offer a great potential for defining and validating new biomarkers in urological oncology. The long term follow up required for true clinical outcome prostate cancer results in the use of archival material for TMA construction. The use of such material has inherent problems which must be overcome to unlock the full potential of prostate TMAs. Methods: A prostate 2,450 core TMA containing normal, prostatic intraepithelial neoplasia and malignant prostate tissue from 524 archival patient specimens was constructed and analysed. Each core was independently verified histologically. An automated, high throughput fluorescent staining (Leica BOND-MAX), image capture (Carl Zeiss Microimaging Mirax scanner) and scoring (Definiens Tissue Studio) protocol was compared with standardised conventional staining and manual scoring techniques. Results: Image analysis showed excellent correlation (r=0.785) and absolute agreement between the automated and manual scoring protocols (ICC=0.769, 95% CI [0.629-0.877]). Replicate analysis demonstrated that the automated, high throughput protocol was more reliable and consistent than the standardised manual staining and scoring protocols. The increased sensitivity of fluorescent staining in the automated protocol highlighted significant (p>0.0001) antigen degradation (pan-cytokeratin), hence poorly persevered regions, in 50.7% of the archival TMA cores. Using well preserved cores the potential of combining Erg expression with EMT markers as a prognostic marker will be presented. Conclusions: This study shows that archival TMAs can be utilised for biomarker characterisation and validation. However there are caveats to their use, namely antigen preservation. The use of multicolour automated protocols, which utilise a house keeping antigen, circumvents these caveats and releases the full potential of TMAs in biomarker research.
The effect of selective JAK2 inhibitor SAR302503 on tumorigenic STAT3 signaling in human prostate cancer in vivo.
Authors: Moreira Dayson , Pal Sumanta Kumar , Sun Fangxian , Kortylewski Marcin 
Published: February 2017

192 Background: STAT3 transcription factor is a critical mediator of signaling by IL-6, a cytokine promoting aggressive, castration-resistant prostate cancers (CPRCs). Importantly, STAT3 activation propagates from cancer cells to the tumor-associated immune cells, thereby generating immunosuppressive and proangiogenic tumor microenvironment. Janus kinase inhibitors provide an attractive method for disrupting IL-6/Jak/STAT3 signaling in both cancer and immune cells to amplify therapeutic effects. Methods: We tested the effect of selective Jak2 inhibitor, SAR302503, in xenotransplanted DU145 CPRCs and the tumor-associated myeloid immune cells in NSG mice. Results: Our initial results confirmed verified that oral gavage of 75 to 100 mg/kg SAR302503 results in dose-dependent inhibition of Jak2 phosphorylation in lysates from whole s.c. growing DU145 tumors within 18 h after treatment. Repeated daily treatment using SAR302503 (75 mg/kg) reduced phosphorylation of both Jak2 and STAT3, induced cancer cell death and significantly reduced growth of aggressive DU145 tumors. More detailed flow cytometric analysis revealed confirmed STAT3 inhibition in cancer cells and even greater extent in tumor-associated myeloid cells. SAR302503 did not reduce the total percentage of tumor-infiltrating myeloid cells. However, it promoted maturation of myeloid-derived suppressor cells. Conclusions: Our findings indicate that SAR302503 can potentially induce both direct and immune-mediated effects on castration-resistant prostate tumors. These preliminary results merit further studies in syngeneic tumor models that will assess whether Jak2/STAT3 inhibition can disrupt immunosuppressive and/or angiogenic functions of prostate cancer-associated myeloid cells. Further, these results may support clinical examination of SAR302503 either alone or in combination with other immunomodulatory therapies for metastatic CPRC.
Clinical characteristics and management of late symptom flare following stereotactic body radiation therapy for clinically localized prostate cancer.
Authors: Woo Jennifer Ai-Lian , Chen Leonard N. , Oermann Eric , Chen Viola , Yung Thomas M. , Kim Joy S. , Collins Brian Timothy , Suy Simeng , Lynch John H. , Dritschilo Anatoly , Collins Sean P. 
Published: February 2017

194 Background: Stereotactic body radiation therapy (SBRT) is increasingly utilized as primary treatment for clinically localized prostate cancer. While acute urinary symptoms are well recognized, late toxicities of SBRT have not been fully described. Here, we characterize the clinical features of late symptom flare and describe symptom management approaches. Methods: Two hudred sixteen patients with clinically localized prostate cancer were treated with SBRT between February 2008 and January 2011 at Georgetown University Hospital. Twenty-nine patients who experienced late-symptom flare were included in this retrospective analysis. Treatment was delivered using the CyberKnife (35 Gy to 36.25 Gy in five fractions). Prevalence of urinary toxicities was determined using CTCAE v.4. Patient-reported urinary symptoms were assessed using the American Urological Association Symptom Score (AUA) and the Expanded Prostate Cancer Index Composite (EPIC) short form. Results: Median age was 66 with 55% being of African descent. Late grade 2 frequency/urgency peaked at 12 months (17.2%), then returned to baseline at 18 months. Late grade 2 retention peaked at 18 months (65.5%), then returned to baseline at 24 months. Late grade greater than or equal to 1 dysuria peaked at nine months (25.0%), then returned to baseline at 24 months. Alpha-antagonist usage peaked at 18 months (85%) then decreased at 24 months. At 12 months, 21% required anti-inflammatories and/or urethral analgesics. Median AUA score rose from a baseline of 6 to 15 at 12 months, then returned to baseline by 24 months. EPIC urinary function and bother scores dropped to a nadir at 9 to 12 months post-treatment, then returned to baseline at 24 months. Conclusions: Symptom flare is a late syndrome consisting of various degrees of urinary frequency/urgency, retention and dysuria. It occurs approximately one year following SBRT, resolves spontaneously, and urinary function returns to baseline by two years. Early identification and initiation of conservative symptomatic management may decrease the need for invasive interventions. Anticipatory counseling prior to treatment may limit bother due to these transient urinary symptoms.
Efficacy of combined androgen blockade with zoledronic acid treatment in prostate cancer with bone metastasis: The Zoledronic Acid/Androgen Blockade Trial on Prostate Cancer (Zabton-PC) study.
Authors: Ueno Satoru , Mizokami Atsushi , Fukagai Takashi , Fujimoto Naohiro , Ohoka Hitoshi , Kondo Yukihiro , Arai Gaku , Ide Hisamitsu , Namiki Mikio 
Published: February 2017

207 Background: Zoledronic acid (ZA) reduces the onset risk of skeletal-related events (SRE) caused by bone metastasis in prostate cancer (PCa) patients and improves the QOL. Therefore ZA has become a standard supportive therapy for PCa with bone metastasis. However, it remains unclear when the physicians should start ZA treatment. In the present study, we investigated whether combination of ZA could delay PSA relapse of PCa and prevent SREs. Methods: The patients were randomly classified in two groups (combined androgen blockade (CAB) alone group and CAB + ZA treatment group). In the CAB + ZA group, 4 mg ZA was intravenously administered every 4 weeks with the start of treatment. The first end point was a period to PSA relapse, and the secondary end point was SREs rate. Results: Untreated 60 PCa patients with bone metastasis were enrolled by 2011 from 2006. Thirty one patients were treated with CAB alone and 29 patients were treated with CAB + ZA. There were no significant differences in the baseline characteristics in the both groups, and the mean observation period was 27.4 months and 32.1 months, respectively. Although there was no significant difference in progression free survival (PFS) (p=0.073), tendency that CAB + ZA shows better PFS than CAB alone group was observed (time to 50% PFS was extended 11.6 months than CAB alone group). Moreover, the sub analysis using the patients with more than Gleason score 7, CAB +ZA group showed significantly longer PFS than the CAB group (p=0.021). And statistically significant difference was recognized in SRE rate between the two groups (p=0.019), ZA tended to delay the occurrence of SRE in PCa patients. Conclusions: This result indicates that the use of ZA at the beginning of hormonal therapy have not only a preventive effect on the occurrence of SREs but also a relapse-delaying effect, especially in the patients with high Gleason score and severe bone metastasis. Though careful observation is essential, since the long-term use of ZA may increase the incidence of adverse effects, CAB-ZA treatment may be recommended for the treatment of PCa patients with bone metastasis.
Bicalutamide (150 mg) monotherapy versus LHRHa as neoadjuvant treatment in intermediate- and high-risk prostate cancer: A case matched study.
Authors: Mitchell Darren M. , McDowell Cliona , McGivern Ursula , Corey Gemma , O'Hare Jolyne , O'Sullivan Joe M. 
Published: February 2017

226 Background: The role of neo-adjuvant Lutenising Hormone Releasing Hormone Agonist (LHRHa) therapy prior to radical radiotherapy of intermediate and high risk prostate cancer (PC) has been clearly defined. Anti-androgen (AA) monotherapy is often used as an alternative to castration therapy in this setting due to a more favorable toxicity profile, however the evidence base is weaker. We compared biochemical failure free survival (BFFS) and prostate-specific antigen (PSA) kinetics in men receiving radical radiotherapy for localised prostate cancer and neo-adjuvant hormones with either AA or LHRHa therapy. Methods: All men with intermediate and high risk PC treated with AA monotherapy prior to radical prostate radiotherapy between April 2004 and December 2008 were individually case matched for key prognostic factors with men treated with neoadjuvant LHRHa monotherapy at our institution. BFFS, PSA kinetics, and absolute pre-RT, post neo-adjuvant hormone PSA (PRPH-PSA) level were analyzed. Results: Sixty five men treated with AA monotherapy were matched to with 65 men treated with LHRHa. The median follow-up was 74 months and 67 months, respectively. Phoenix BFFS was seen in 14 (23.4%) and nine (13.8%) of AA and LHRHa patients respectively with the log rank test indicating no statistically significant difference between the groups. Statistically significant differences were seen between groups in the PRPH-PSA with a geometric mean of 2.0ng/ml (range 0.1 – 11.2) for AA patients and 1.0ng/ml (range 0.1 – 11.1) for LHRHa patients (p<0.001). There was no significant difference between groups in the geometric mean PSA halving time or velocity during the neo-adjuvant period. A PRPH-PSA of less than 1.0ng/ml and less than 0.1ng/ml was seen in 16 (24.6%) and two (3%) of the AA patients and 34 (52.3%) and three (4.6%) of LHRHa patients, respectively. Conclusions: Our case matched study demonstrates that there was no statistical difference in BFFS between patients receiving neo-adjuvant AA versus LHRHa at median follow-up of 72 months. AA monotherapy resulted in less PRPH-PSA suppression when compared to neo-adjuvant LHRHa alone. Longer follow-up is required to determine if the differences in PSA kinetics translate into clinically meaningful differences.
A predicitve algorithm for response to abiraterone in metastatic castration relapsed prostate cancer (CRPC).
Authors: Afshar Mehran , Al-Alloosh Fawaz , James Nicholas David , Clarke Helen , Pirrie Sarah , Porfiri Emilio 
Published: February 2017

238 Background: Numerous novel therapies for castration relapsed prostate cancer (CRPC) have led to a rapidly evolving approach to its management. Rationalisation of treatment combinations and sequencing of therapy requires identification of men who are more likely to benefit from a particular treatment. An unmet clinical need exists in this domain. We present the findings of a review of patients treated with abiraterone at our centre, and describe a novel predictive algorithm in this setting employing previously undefined pre-determinants of response. Methods: Patients with CRCP treated with abiraterone post-docetaxel at Queen Elizabeth Hospital between August 2010 and February 2012 were identified. Electronic patient records were utilised to extract variables including patient demographics, tumor characteristics, treatment history and other potential predictors of response such as prostate-specific antigen (PSA), hemoglobin (Hb), and alkaline phosphatase (ALP). Outcome measures included overall survival (OS), adverse events and PSA response rate. OS was estimated using the Kaplan-Meier method, and univariate and multivariate analyses were performed on potential prognosticators. Multivariate Beta coefficients were used to generate a predictive algorithm to identify two distinct risk groups. Results: Sixty one patients met the inclusion criteria. From starting abiraterone, the median OS was 12.6m, and median duration of follow-up was 11.5m. In univariate analysis seven factors impacted OS: age, response duration to androgen deprivation therapy (ADT), Hb, time from diagnosis to starting abiraterone, and ALP. Subsequent multivariate analysis identified three independent predictors of OS: duration of response to ADT (HR: 0.95, p=0.006), performance status (HR: 0.71, p=0.013), and baseline Hb (HR: 0.47, p=<0.001). A predictive algorithm dividing the cohort into high- and low-risk groups derived a diverging Kaplan-Meier curve without overlapping 95% CI’s. The low risk group did not reach median survival. Conclusions: This retrospective review has identified a predictive scoring algorithm for response to abiraterone in CRPC. We suggest that further analysis in the form of external validation is needed in order to justify its use in individualisation of patient management and stratification of patients for prospective clinical trials.
Surgical pathology and the patient: A systematic review evaluating the primary audience of pathology reports.
Authors: Mossanen Matthew , Wright Jonathan L. , True Lawrence D. , Vakar-Lopez Funda , Lavallee Danielle , Gore John L. 
Published: February 2017

261 Background: For patients with a diagnosis of cancer, the pathology reports represent a sentinel document that dictates prognosis and management. However, a substantial subset of patients may lack the ability to comprehend this complex document while making medical decisions. As a result, many cancer patients may stand to benefit from more patient-centered pathology reports. We sought to review the available literature in order to identify the primary audience of surgical pathology reports for the most common malignancies in men and women in the U.S. Methods: A systematic review was conducted using PubMed,MEDLINEdatabases, Cochrane Reviews,and Google Scholar. Data from the American Cancer Society were used to determine the most common cancers projected for 2013 for men and women in the U.S. (prostate and breast cancer, respectively, followed by lung and colorectal cancers). An expert panel developed a list of search criteria and an iterative search was performed and articles were screened for relevance. We summarize the results of the literature search with descriptive statistics. Results: No articles addressed the patient as the target audience of oncologic pathology reports. No articles evaluated the readability of pathology reports or literacy levels required to interpret pathology reports. We did not identify any articles that described standardized approaches for discussing the pathology of the most common cancers in men and women with patients or their caregivers. Twelve articles were devoted to renovation of pathology reports to promote the exchange of information between physicians, most of which (58%) addressed breast cancer pathology. Conclusions: Patient-centered cancer communication is a common theme in the care of oncology patients and represents an important metric in determining patient satisfaction. Yet, oncologic pathology reports do not include patients or their caregivers as target audiences. Limited resources are available to help patients comprehend their pathology reports. Efforts to improve patient centered communication, such as through the use of patient-centered pathology reports, may address this overlooked aspect of cancer care.
A phase I trial of muscadine grape skin in men with biochemically recurrent prostate cancer.
Authors: Paller Channing Judith , Rudek Michelle A. , Antonarakis Emmanuel S. , Eisenberger Mario A. , Hammers Hans J. , Zhou Xian Chong , Dowling Donna , King Serina , Hudock Susan , Denmeade Samuel R. , Wagner William D. , Rosner Gary L. , Hudson Tamaro , Carducci Michael Anthony 
Published: February 2017

263 Background: New therapies are being explored as an alternative to observation in men with biochemically recurrent prostate cancer (BRPC). Muscadine Grape Skin (MPX) is comprised of ellagic acid, quercetin, and resveratrol and demonstrates preclinical activity against prostate cancer cells in vitro. Here we summarize data from a phase I dose finding trial. Methods: This phase I study assigned non-metastatic BRPC patients to increasing doses of MPX (Muscadine Naturals) in cohorts of two patients, with six patients at the highest dose, using a modified continual reassessment method. Dose selection is based on preclinical data showing the equivalent of 500 to 4,000 mg of MPX to be safe in mouse models. Our primary end point was to determine the recommended phase II dosing. We calculated changes in prostate-specific antigen (PSA) doubling time (PSADT) from at least three measurements prior to trial initiation and PSA measurements on study. Results: The cohort (n=14, 71% white, 29% black) had a median follow-up of 14.7 (6.9 to 20.7) months, median age 61, median Gleason seven, and median PSA of 5.1 ng/mL (0.2 to 153.4). Four patients had possibly related gastrointestinal symptoms, including grade 1 flatulence, grade 1 soft stools, and grade 1 burping. No other related adverse events were reported and one patient reported improvement of chronic constipation. Two of 14 patients came off study for metastatic disease. Median within-patient PSADT increased from 9.4 to 12.3 months with a PSADT difference of 3.9 months. Conclusions: These data suggest that 4,000 mg of MPX is safe, and exploratory review of change in PSADT suggests there is enough data to proceed to a phase II trial. Both low dose (500 mg) and high dose (4,000 mg) MPX are being further investigated in a multicenter, placebo-controlled, dose evaluating phase II trial. Clinical trial information: NCT01317199.
Expression of prostate-specific membrane antigen (PSMA) on circulating tumor cells (CTCs) in castration-resistant prostate cancer.
Authors: Lee Florence , Yu Angela , Anderson Amanda , Marrinucci Dena , Magargal Wells W. , DiPippo Vincent A. , Olson William C. 
Published: February 2017

266 Background: Prostate-specific membrane antigen (PSMA) is expressed ubiquitously in prostate adenocarcinoma, and the intensity of expression increases with disease aggressiveness. Exploiting PSMA for therapy could potentially be aided by a minimally invasive means for measuring PSMA on tumor cells. Here we describe the development and characteristics of a novel assay for quantitating PSMA on canonical and non-canonical circulating tumor cells (CTCs). Methods: The PSMA CTC test was developed using LNCaP (high PSMA), 22Rv1 (low PSMA) and PC3 (no PSMA) cells spiked into normal blood. Nucleated blood cells were plated onto glass slides and subjected to immunofluorescent staining followed by CTC identification using the Pyxis Scanning Platform at Epic Sciences. The four-color assay evaluated PSMA expression on individual CTCs, identified as cells which are cytokeratin+, CD45-, and with an intact DAPI nucleus. Multiple antibody clones and assay conditions were evaluated, and the final PSMA CTC test has high specificity and sensitivity. Acceptance criteria included signal intensities in LNCaP versus PC3, subcellular localization of PSMA, and potential interference by a PSMA-targeted therapy. Clinical feasibility of the optimized assay was assessed on samples from CRPC patients. Results: The average PSMA signal intensity for LNCaP was 20-fold higher than that for PC3 and 10-fold higher than the minimum cutoff. PSMA displayed a predominantly membrane-localized pattern of staining that was distinct from cytokeratin. Assay performance was unaffected by the presence of PSMA ADC, a PSMA-targeted antibody-drug conjugate that is in phase II clinical testing. In feasibility tests on patient samples, the assay demonstrated utility in detecting and quantitating PSMA on individual and clustered CTCs as well as on apoptotic, cytokeratin-negative, and small cytokeratin-positive CTC candidates. Conclusions: PSMA expression was successfully detected and quantitated on diverse types of circulating cells present in the blood of patients with CRPC. Assay performance was unaffected by the presence of a PSMA-targeted therapeutic agent. PSMA CTC data are being collected in the ongoing phase II study of PSMA ADC for comparison with treatment outcomes.
Standardizing patient-centered outcomes measurement in prostate cancer: An international, cross-disciplinary effort.
Authors: Martin Neil E. , Massey Laura , Stowell Caleb , Graefen Markus , Huland Hartwig ,   ICHOM Prostate Cancer Working Group
Published: February 2017

271 Background: The prospective collection of standardized, patient-centered outcomes for men with prostate cancer will allow intra- and inter-institutional comparisons, patient education, self-assessment and dissemination of best practices. We lack recommended standardized sets of such outcomes. Methods: Through the International Consortium for Health Outcomes Measurement, a working group of urologists, radiation oncologists, registry representatives and patient advocates convened to develop a recommended minimum set of measures which institutions would collect on all prostate patients. Using a modified Delphi method over a series of in-person meetings and conference calls, a final set of recommendations was developed. Results: Approximately 30 experts in prostate cancer care from North America, Europe, Australia, and the Middle East participated in the process, representing academic centers, registries and patients. We defined the scope of this initial effort as outcomes related to the management of localized prostate cancer. The group recommended cross-disciplinary measures applicable to a variety of treatment approaches from surveillance to radiation and prostatectomy. Standards were identified for disease control definitions as well as baseline patient and disease-specific risk stratification factors. Domains of patient reported outcomes to be tracked in follow up were identified including urinary incontinence, urinary irritation, bowel irritation, sexual function, and symptoms related to hormonal therapy. Finally, specific tools to assess these domains and gaps in our current tools were identified. The final recommended set will be presented. Conclusions: Standardized outcome reporting is a necessary component in the movement towards high-value health care. Patient-centered outcomes related to toxicity and disease control can be identified and systemized by a multidisciplinary group of experts. The result of this project is an initial step in what will be an iterative process with the goal of improving the care of all men with prostate cancer. An international pilot project has been proposed based on implementing the final set of recommendations.