SciCombinator

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Concept: Prostate cancer

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Background Abiraterone acetate plus prednisolone improves survival in men with relapsed prostate cancer. We assessed the effect of this combination in men starting long-term androgen-deprivation therapy (ADT), using a multigroup, multistage trial design. Methods We randomly assigned patients in a 1:1 ratio to receive ADT alone or ADT plus abiraterone acetate (1000 mg daily) and prednisolone (5 mg daily) (combination therapy). Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or prostate-specific antigen (PSA) progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first. The primary outcome measure was overall survival. The intermediate primary outcome was failure-free survival (treatment failure was defined as radiologic, clinical, or PSA progression or death from prostate cancer). Results A total of 1917 patients underwent randomization from November 2011 through January 2014. The median age was 67 years, and the median PSA level was 53 ng per milliliter. A total of 52% of the patients had metastatic disease, 20% had node-positive or node-indeterminate nonmetastatic disease, and 28% had node-negative, nonmetastatic disease; 95% had newly diagnosed disease. The median follow-up was 40 months. There were 184 deaths in the combination group as compared with 262 in the ADT-alone group (hazard ratio, 0.63; 95% confidence interval [CI], 0.52 to 0.76; P<0.001); the hazard ratio was 0.75 in patients with nonmetastatic disease and 0.61 in those with metastatic disease. There were 248 treatment-failure events in the combination group as compared with 535 in the ADT-alone group (hazard ratio, 0.29; 95% CI, 0.25 to 0.34; P<0.001); the hazard ratio was 0.21 in patients with nonmetastatic disease and 0.31 in those with metastatic disease. Grade 3 to 5 adverse events occurred in 47% of the patients in the combination group (with nine grade 5 events) and in 33% of the patients in the ADT-alone group (with three grade 5 events). Conclusions Among men with locally advanced or metastatic prostate cancer, ADT plus abiraterone and prednisolone was associated with significantly higher rates of overall and failure-free survival than ADT alone. (Funded by Cancer Research U.K. and others; STAMPEDE ClinicalTrials.gov number, NCT00268476 , and Current Controlled Trials number, ISRCTN78818544 .).

Concepts: Epidemiology, Clinical trial, Cancer, Metastasis, Oncology, Prostate cancer, Radiation therapy, Prostate-specific antigen

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Discordant trends in the incidence of metastatic breast and prostate cancer since the widespread implementation of early-detection efforts may reflect distinct disease dynamics or may result from the different screening strategies used.

Concepts: Epidemiology, Cancer, Breast cancer, Metastasis, Prostate cancer, Radiation therapy, BRCA2, Screening

171

Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) induces apoptosis in a variety of cancer cell lines with little or no effect on normal cells. However, its effect is limited as some cancers including pancreatic cancer show de novo resistance to TRAIL induced apoptosis. In this study we report that GSK-3 inhibition using the pharmacologic agent AR-18, enhanced TRAIL sensitivity in a range of pancreatic and prostate cancer cell lines. This sensitization was found to be caspase-dependent, and both pharmacological and genetic knock-down of GSK-3 isoforms resulted in apoptotic features as shown by cleavage of PARP and caspase-3. Elevated levels of reactive oxygen intermediates and disturbance of mitochondrial membrane potential point to a mitochondrial amplification loop for TRAIL-induced apoptosis after GSK-3 inhibition. Consistent with this, overexpression of anti-apoptotic mitochondrial targets such as Bcl-XL, Mcl-1, and Bcl-2 rescued PANC-1 and PPC-1 cells from TRAIL sensitization. However, overexpression of the caspase-8 inhibitor CrmA also inhibited the sensitizing effects of GSK-3 inhibitor, suggesting an additional role for GSK-3 that inhibits death receptor signaling. Acute treatment of mice bearing PANC-1 xenografts with a combination of AR-18 and TRAIL also resulted in a significant increase in apoptosis, as measured by caspase-3 cleavage. Sensitization to TRAIL occurred despite an increase in β-catenin due to GSK-3 inhibition, suggesting that the approach might be effective even in cancers with dysregulated β-catenin. These results suggest that GSK-3 inhibitors might be effectively combined with TRAIL for the treatment of pancreatic cancer.

Concepts: Vitamin D, Gene expression, Cancer, Oncology, Apoptosis, Obesity, Prostate cancer, Enzyme inhibitor

169

To evaluate the incidence of leukoencephalopathy after whole-brain radiation therapy (WBRT) in patients with brain metastases.

Concepts: Medicine, Cancer, Oncology, Cervical cancer, Chemotherapy, Prostate cancer, Melanoma

168

Androgen deprivation (AD) is an effective method for initially suppressing prostate cancer (PC) progression. However, androgen-refractory PC cells inevitably emerge from the androgen-responsive tumor, leading to incurable disease. Recent studies have shown AD induces cellular senescence, a phenomenon that is cell-autonomously tumor-suppressive but which confers tumor-promoting adaptations that can facilitate the advent of senescence-resistant malignant cell populations. Because androgen-refractory PC cells emerge clonally from the originally androgen-responsive tumor, we sought to investigate whether AD-induced senescence (ADIS) affects acquisition of androgen-refractory behavior in androgen-responsive LNCaP and LAPC4 prostate cancer cells. We find that repeated exposure of these androgen-responsive cells to senescence-inducing stimuli via cyclic AD leads to the rapid emergence of ADIS-resistant, androgen-refractory cells from the bulk senescent cell population. Our results show that the ADIS phenotype is associated with tumor-promoting traits, notably chemoresistance and enhanced pro-survival mechanisms such as inhibition of p53-mediated cell death, which encourage persistence of the senescent cells. We further find that pharmacologic enforcement of p53/Bax activation via Nutlin-3 prior to establishment of ADIS is required to overcome the associated pro-survival response and preferentially trigger pervasive cell death instead of senescence during AD. Thus our study demonstrates that ADIS promotes outgrowth of androgen-refractory PC cells and is consequently a suboptimal tumor-suppressor response to AD.

Concepts: Cancer, Disease, Oncology, Death, Senescence, Organism, Cell division, Prostate cancer

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BACKGROUND: Cancer outlier profile analysis (COPA) has proven to be an effective approach to analyzing cancer expression data, leading to the discovery of the TMPRSS2 and ETS family gene fusion events in prostate cancer. However, the original COPA algorithm did not identify down-regulated outliers, and the currently available R package implementing the method is similarly restricted to the analysis of over-expressed outliers. Here we present a modified outlier detection method, mCOPA, which contains refinements to the outlier-detection algorithm, identifies both over- and under-expressed outliers, is freely available, and can be applied to any expression dataset. RESULTS: We compare our method to other feature-selection approaches, and demonstrate that mCOPA frequently selects more-informative features than do differential expression or variance-based feature selection approaches, and is able to recover observed clinical subtypes more consistently. We demonstrate the application of mCOPA to prostate cancer expression data, and explore the use of outliers in clustering, pathway analysis, and the identification of tumour suppressors. We analyse the under-expressed outliers to identify known and novel prostate cancer tumour suppressor genes, validating these against data in Oncomine and the Cancer Gene Index. We also demonstrate how a combination of outlier analysis and pathway analysis can identify molecular mechanisms disrupted in individual tumours. CONCLUSIONS: We demonstrate that mCOPA offers advantages, compared to differential expression or variance, in selecting outlier features, and that the features so selected are better able to assign samples to clinically annotated subtypes. Further, we show that the biology explored by outlier analysis differs from that uncovered in differential expression or variance analysis. mCOPA is an important new tool for the exploration of cancer datasets and the discovery of new cancer subtypes, and can be combined with pathway and functional analysis approaches to discover mechanisms underpinning heterogeneity in cancers.

Concepts: Gene expression, Cancer, Oncology, Prostate cancer, Tumor, Tumor suppressor gene, Normal distribution, Outlier

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Purpose: To flesh out the ESUR guidelines for the standardized interpretation of multiparametric magnetic resonance imaging (mMRI) for the detection of prostate cancer and to present a graphic reporting scheme for improved communication of findings to urologists. Materials and Methods: The ESUR has recently published a structured reporting system for mMRI of the prostate (PI-RADS). This system involves the use of 5-point Likert scales for grading the findings obtained with different MRI techniques. The mMRI includes T2-weighted MRI, diffusion-weighted imaging, dynamic contrast-enhanced MRI, and MR spectroscopy. In a first step, the fundamentals of technical implementation were determined by consensus, taking into account in particular the German-speaking community. Then, representative images were selected by consensus on the basis of examinations of the three institutions. In addition, scoring intervals for an aggregated PI-RADS score were determined in consensus. Results: The multiparametric methods were discussed critically with regard to implementation and the current status. Criteria used for grading mMRI findings with the PI-RADS classification were concretized by succinct examples. Using the consensus table for aggregated scoring in a clinical setting, a diagnosis of suspected prostate cancer should be made if the PI-RADS score is 4 or higher (≥ 10 points if 3 techniques are used or ≥ 13 points if 4 techniques are used). Finally, a graphic scheme was developed for communicating mMRI prostate findings. Conclusion: Structured reporting according to the ESUR guidelines contributes to quality assurance by standardizing prostate mMRI, and it facilities the communication of findings to urologists.

Concepts: Cancer, Medical imaging, Prostate cancer, Nuclear magnetic resonance, Magnetic resonance imaging, Radiology, Diffusion MRI, In vivo magnetic resonance spectroscopy

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BACKGROUND: A small pre-test study was conducted to ascertain potential harm and anxiety associated with distributing information about possible cancer treatment options at the time of biopsy, prior to knowledge about a definitive cancer diagnosis. Priming men about the availability of multiple options before they have a confirmed diagnosis may be an opportunity to engage patients in more informed decision-making. METHODS: Men with an elevated PSA test or suspicious Digital Rectal Examination (DRE) who were referred to a urology clinic for a biopsy were randomized to receive either the clinic’s usual care (UC) biopsy instruction sheet (n = 11) or a pre-biopsy educational (ED) packet containing the biopsy instruction sheet along with a booklet about the biopsy procedure and a prostate cancer treatment decision aid originally written for newly diagnosed men that described in detail possible treatment options (n = 18). RESULTS: A total of 62% of men who were approached agreed to be randomized, and 83% of the ED group confirmed they used the materials. Anxiety scores were similar for both groups while awaiting the biopsy procedure, with anxiety scores trending lower in the ED group: 41.2 on a prostate-specific anxiety instrument compared to 51.7 in the UC group (p = 0.13). ED participants reported better overall quality of life while awaiting biopsy compared to the UC group (76.4 vs. 48.5, p = 0.01). The small number of men in the ED group who went on to be diagnosed with cancer reported being better informed about the risks and side effects of each option compared to men diagnosed with cancer in the UC group (p = 0.07). In qualitative discussions, men generally reported they found the pre-biopsy materials to be helpful and indicated having information about possible treatment options reduced their anxiety. However, 2 of 18 men reported they did not want to think about treatment options until after they knew their biopsy results. CONCLUSIONS: In this small sample offering pre-biopsy education about potential treatment options was generally well received by patients, appeared to be beneficial to men who went on to be diagnosed, and did not appear to increase anxiety unnecessarily among those who had a negative biopsy.

Concepts: Cancer, Metastasis, Biopsy, Prostate cancer, Screening, Benign prostatic hyperplasia, Rectal examination, Prostate-specific antigen

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Prostate cancer screening depends on a careful balance of benefits, in terms of reduced prostate cancer mortality, and harms, in terms of overdiagnosis and overtreatment. We aimed to estimate the effect on overdiagnosis of restricting prostate specific antigen (PSA) testing by age and baseline PSA.

Concepts: Cancer, Prostate cancer, Urology, Screening, Prostate, Overdiagnosis, Prostate-specific antigen, Prostate cancer screening

166

Patients with advanced prostate cancer almost invariably develop osseous metastasis. Although many studies indicate that the activation of NF-κB signaling appears to be correlated with advanced cancer and promotes tumor metastasis by influencing tumor cell migration and angiogenesis, the influence of altered NF-κB signaling in prostate cancer cells within boney metastatic lesions is not clearly understood. While C4-2B and PC3 prostate cancer cells grow well in the bone, LNCaP cells are difficult to grow in murine bone following intraskeletal injection. Our studies show that when compared to LNCaP, NF-κB activity is significantly higher in C4-2B and PC3, and that the activation of NF-κB signaling in prostate cancer cells resulted in the increased expression of the osteoclast inducing genes PTHrP and RANKL. Further, conditioned medium derived from NF-κB activated LNCaP cells induce osteoclast differentiation. In addition, inactivation of NF-κB signaling in prostate cancer cells inhibited tumor formation in the bone, both in the osteolytic PC3 and osteoblastic/osteoclastic mixed C4-2B cells; while the activation of NF-κB signaling in LNCaP cells promoted tumor establishment and proliferation in the bone. The activation of NF-κB in LNCaP cells resulted in the formation of an osteoblastic/osteoclastic mixed tumor with increased osteoclasts surrounding the new formed bone, similar to metastases commonly seen in patients with prostate cancer. These results indicate that osteoclastic reaction is required even in the osteoblastic cancer cells and the activation of NF-κB signaling in prostate cancer cells increases osteoclastogenesis by up-regulating osteoclastogenic genes, thereby contributing to bone metastatic formation.

Concepts: Cancer, Breast cancer, Metastasis, Oncology, Lung cancer, Prostate cancer, Osteoclast, Tumor