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Sample records for drives metastatic prostate

  1. Vaccine Therapy and Pembrolizumab in Treating Patients With Hormone-Resistant, Metastatic Prostate Cancer

    Science.gov (United States)

    2016-06-22

    Hormone-Resistant Prostate Cancer; Metastatic Malignant Neoplasm in the Bone; Metastatic Malignant Neoplasm in the Soft Tissues; Metastatic Prostate Carcinoma; Prostate Adenocarcinoma; Recurrent Prostate Carcinoma; Stage IV Prostate Cancer

  2. Enzalutamide in metastatic prostate cancer before chemotherapy

    DEFF Research Database (Denmark)

    Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana E

    2014-01-01

    BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not rece......BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have...... not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression...... at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; Pchemotherapy (hazard ratio, 0.35), the time until the first...

  3. Multiple urinary bladder masses from metastatic prostate adenocarcinoma

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    Richard Choo

    2010-12-01

    Full Text Available We present an unusual case of metastatic prostate adenocarcinoma that manifested with multiple exophytic intravesical masses, mimicking a multifocal primary bladder tumor. Biopsy with immunohistochemical analysis confirmed metastatic prostate adenocarcinoma. The patient was treated palliatively with external beam radiotherapy to prevent possible symptoms from local tumor progression. This case illustrates that when a patient with known prostate cancer presents with multifocal bladder tumors, the possibility of metastatic prostate cancer should be considered.

  4. Immunotherapy in metastatic prostate cancer

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    Slovin, Susan F.

    2016-01-01

    Introduction: Prostate cancer remains a challenge as a target for immunological approaches. The approval of the first cell-based immune therapy, Sipuleucel-T for prostate cancer introduced prostate cancer as a solid tumor with the potential to be influenced by the immune system. Methods: We reviewed articles on immunological management of prostate cancer and challenges that lie ahead for such strategies. Results: Treatments have focused on the identification of novel cell surface antigens thought to be unique to prostate cancer. These include vaccines against carbohydrate and blood group antigens, xenogeneic and naked DNA vaccines, and pox viruses used as prime-boost or checkpoint inhibitors. No single vaccine construct to date has resulted in a dramatic antitumor effect. The checkpoint inhibitor, anti-CTLA-4 has resulted in several long-term remissions, but phase III trials have not demonstrated an antitumor effect or survival benefit. Conclusions: Multiple clinical trials suggest that prostate cancer may not be optimally treated by single agent immune therapies and that combination with biologic agents, chemotherapies, or radiation may offer some enhancement of benefit. PMID:27843208

  5. Immunotherapy in metastatic prostate cancer

    Directory of Open Access Journals (Sweden)

    Susan F Slovin

    2016-01-01

    Full Text Available Introduction: Prostate cancer remains a challenge as a target for immunological approaches. The approval of the first cell-based immune therapy, Sipuleucel-T for prostate cancer introduced prostate cancer as a solid tumor with the potential to be influenced by the immune system. Methods: We reviewed articles on immunological management of prostate cancer and challenges that lie ahead for such strategies. Results: Treatments have focused on the identification of novel cell surface antigens thought to be unique to prostate cancer. These include vaccines against carbohydrate and blood group antigens, xenogeneic and naked DNA vaccines, and pox viruses used as prime-boost or checkpoint inhibitors. No single vaccine construct to date has resulted in a dramatic antitumor effect. The checkpoint inhibitor, anti-CTLA-4 has resulted in several long-term remissions, but phase III trials have not demonstrated an antitumor effect or survival benefit. Conclusions: Multiple clinical trials suggest that prostate cancer may not be optimally treated by single agent immune therapies and that combination with biologic agents, chemotherapies, or radiation may offer some enhancement of benefit.

  6. Metastatic prostate adenocarcinoma penis: Case report

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    Pablo Santiago Caicedo

    2014-08-01

    Full Text Available Objective: Describe a case report of a patient with prostatic adenocarcinoma metastatic to penis due to shortage reports of similar cases to perform a literature review. Methods: We identified a case of a patient with prostatic adenocarcinoma, who during de the course of a cystoscopy at Hospital Universitario San Jose (Third-level Public Hospital in Popayan, Colombia a suspicious nodule of malignancy was observed in the penis. We described the clinical case in order to proceed to a literature search for the discussion. Results: 72-year-old patient diagnosed with prostatic adenocarcinoma Gleason Score 4+5=9, treated with bilateral orchiectomy and a suspicious nodule of malignancy incidentally observed in the penis, currently undergoing palliative care with Karnofsky score of 30 points. Conclusion: cutaneous metastases are rare; indicate longstanding disease and poor prognosis.

  7. MOLECULAR MARKERS FOR METASTATIC PROSTATE ADENOCARCINOMA

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    I. S. Kunin

    2012-01-01

    Full Text Available The search of molecular markers of metastasing and prognosis in prostate cancer remains an urgent task. In this study, we investigated the relationship of gene expression heparanase-1 (HPSE1 and D-glucuronil C5-epimerase (GLCE with early disease relapse and metastasis of a 2,5−3 years after diagnosis. It was shown that the ratio of the expression levels of genes HPSE1/GLCE > 1 may serve as a prognostic relapse marker and trends of the tumour to metastasis. The data obtained suggest to use this option as a molecular marker for the diagnostics of metastatic process and the disease prognosis.

  8. Carcinoma of the prostate metastatic to the maxillary antrum.

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    Har-El, G; Avidor, I; Weisbord, A; Sidi, J

    1987-01-01

    Metastatic carcinoma of the maxillary antrum is an extreme rarity. Until 1980, less than 100 cases with distant primaries metastatic to the entire sinonasal tract had been reported. In a review of these cases, we found no mention of primary prostate cancer metastatic to the antrum. The purpose of this paper is to document the first case of this entity.

  9. Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer

    Science.gov (United States)

    2016-10-01

    AWARD NUMBER: W81XWH-14-1-0551 TITLE: Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer PRINCIPAL INVESTIGATOR: Ze’ev Ronai...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer 5b. GRANT NUMBER W81XWH-14-1-0551 5c...project is to develop a novel means to inhibit prostate cancer development and progression. The development of Siah1/2 inhibitors to the ubiquitin

  10. Molecular Subgroup of Primary Prostate Cancer Presenting with Metastatic Biology.

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    Walker, Steven M; Knight, Laura A; McCavigan, Andrena M; Logan, Gemma E; Berge, Viktor; Sherif, Amir; Pandha, Hardev; Warren, Anne Y; Davidson, Catherine; Uprichard, Adam; Blayney, Jaine K; Price, Bethanie; Jellema, Gera L; Steele, Christopher J; Svindland, Aud; McDade, Simon S; Eden, Christopher G; Foster, Chris; Mills, Ian G; Neal, David E; Mason, Malcolm D; Kay, Elaine W; Waugh, David J; Harkin, D Paul; Watson, R William; Clarke, Noel W; Kennedy, Richard D

    2017-10-01

    Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy. To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy. Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes, and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months. Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analysed using multivariable Cox regression and log-rank analysis. A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (metastatic assay) was developed and independently validated in the radical prostatectomy samples. Metastatic assay positive patients had increased risk of biochemical recurrence (multivariable hazard ratio [HR] 1.62 [1.13-2.33]; p=0.0092) and metastatic recurrence (multivariable HR=3.20 [1.76-5.80]; p=0.0001). A combined model with Cancer of the Prostate Risk Assessment post surgical (CAPRA-S) identified patients at an increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90-3.75]; p<0.0001 and HR=7.53 [4.13-13.73]; p<0.0001, respectively). The retrospective nature of the study is acknowledged as a potential limitation. The metastatic assay may identify a molecular subgroup of primary prostate cancers with metastatic potential. The metastatic assay may improve the ability to detect patients at risk of metastatic recurrence following radical prostatectomy. The impact of adjuvant therapies should be assessed in

  11. New drug development in metastatic prostate cancer.

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    Armstrong, Andrew J; George, Daniel J

    2008-01-01

    In 2007, drug development in castration-resistant metastatic prostate cancer (CRPC) remains challenging, due to the number of potentially viable molecular targets and clinical trials available, the lack of established surrogates for overall survival, and competing causes of mortality. This review will highlight the highest impact phase II and phase III trials of novel agents in the current CRPC landscape, and focus on both molecular targets and clinical trial designs that are more likely to demonstrate clinical benefit. The need for tissue correlative studies for target evaluation and drug mechanism is stressed to continue to advance the field and to define biomarkers that may identify patient populations that may derive a greater benefit from these molecular agents.

  12. Metastatic Prostate Adenocarcinoma Presenting Central Diabetes Insipidus

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    Hakkı Yılmaz

    2012-01-01

    Full Text Available The pituitary gland and infundibulum can be involved in a variety of medical conditions, including infiltrative diseases, fungal infections, tuberculosis, and primary and metastatic tumors. Metastases to the pituitary gland are absolutely rare, and they are generally secondary to pulmonary carcinoma in men and breast carcinoma in women. Pituitary metastases more commonly affect the posterior lobe and the infundibulum than the anterior lobe. The posterior lobe involvement may explain why patients with pituitary metastases frequently present with diabetes insipidus. We are presenting a case report of a 78-year-old male patient who had metastatic prostate with sudden onset of polyuria and persistent thirst. He had no electrolyte imbalance except mild hypernatremia. The MRI scan of the brain yielded a suspicious area in pituitary gland. A pituitary stalk metastasis was found on magnetic resonance imaging (MRI of pituitary. Water deprivation test was compatible with DI. A clinical response to nasal vasopressin was achieved and laboratory results revealed central diabetes insipidus. As a result, the intrasellar and suprasellar masses decreased in size, and urinary output accordingly decreased.

  13. Hyaluronan-Based Therapy for Metastatic Prostate Cancer

    Science.gov (United States)

    2015-07-01

    interplay between the extrinsic and intrinsic apoptotic pathways would be an effective rationale for cancer therapy . In reality , however, dulanermin...AWARD NUMBER: W81XWH-14-1-0184 TITLE: Hyaluronan-Based Therapy for Metastatic Prostate Cancer PRINCIPAL INVESTIGATOR: Dr. Magdelena...5a. CONTRACT NUMBER W81XWH-14-1-0184 Hyaluronan-Based Therapy for Metastatic Prostate Cancer 5b. GRANT NUMBER W81XWH-14-1-0184 5c. PROGRAM

  14. Microenvironment -Programmed Metastatic Prostate Cancer Stem Cells (mPCSCs)

    Science.gov (United States)

    2016-10-01

    AWARD NUMBER: W81XWH-13-1-0352 TITLE: Microenvironment-Programmed Metastatic Prostate Cancer Stem Cells (mPCSCs) PRINCIPAL INVESTIGATOR: Dean...G. Tang, M.D., Ph.D. CONTRACTING ORGANIZATION: University of Texas MD Anderson Cancer Center Houston, TX 77030 REPORT DATE: October 2016 TYPE OF...Sep 2016 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Microenvironment-Programmed Metastatic Prostate Cancer Stem Cells (mPCSCs) 5b. GRANT NUMBER 5c

  15. Supraclavicular lymph node: incidence of unsuspected metastatic prostate cancer.

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    Hematpour, Khashayar; Bennett, Carol J; Rogers, David; Head, Christian S

    2006-09-01

    An uncommon presentation of prostate carcinoma to the supraclavicular lymph nodes is herein reviewed. With prompt diagnosis and treatment, patient survival can be extended. A high index of suspicion is necessary to make the diagnosis. The clinical features of four cases involving metastatic prostate carcinoma will be discussed.

  16. MicroRNAs associated with metastatic prostate cancer.

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    Akira Watahiki

    Full Text Available OBJECTIVE: Metastasis is the most common cause of death of prostate cancer patients. Identification of specific metastasis biomarkers and novel therapeutic targets is considered essential for improved prognosis and management of the disease. MicroRNAs (miRNAs form a class of non-coding small RNA molecules considered to be key regulators of gene expression. Their dysregulation has been shown to play a role in cancer onset, progression and metastasis, and miRNAs represent a promising new class of cancer biomarkers. The objective of this study was to identify down- and up-regulated miRNAs in prostate cancer that could provide potential biomarkers and/or therapeutic targets for prostate cancer metastasis. METHODS: Next generation sequencing technology was applied to identify differentially expressed miRNAs in a transplantable metastatic versus a non-metastatic prostate cancer xenograft line, both derived from one patient's primary cancer. The xenografts were developed via subrenal capsule grafting of cancer tissue into NOD/SCID mice, a methodology that tends to preserve properties of the original cancers (e.g., tumor heterogeneity, genetic profiles. RESULTS: Differentially expressed known miRNAs, isomiRs and 36 novel miRNAs were identified. A number of these miRNAs (21/104 have previously been reported to show similar down- or up-regulation in prostate cancers relative to normal prostate tissue, and some of them (e.g., miR-16, miR-34a, miR-126*, miR-145, miR-205 have been linked to prostate cancer metastasis, supporting the validity of the analytical approach. CONCLUSIONS: The use of metastatic and non-metastatic prostate cancer subrenal capsule xenografts derived from one patient's cancer makes it likely that the differentially expressed miRNAs identified in this study include potential biomarkers and/or therapeutic targets for human prostate cancer metastasis.

  17. Metastatic Prostate Cancer to the Urethra Masquerading as Urothelial Carcinoma

    OpenAIRE

    Zardawi, Ibrahim; Chong, Peter

    2016-01-01

    Tumors of the urethra, whether primary or metastatic, are very rare. The true nature of urethral neoplasm is not always obvious clinically nor in routine histological sections. Immunostains should be performed on such lesions because of management implications. We present a case of multiple metastases to the urethra from a prostatic carcinoma, masquerading as multiple urothelial carcinomas. Pathologists and urologists should be aware of the possibility of metastasis from the prostate.

  18. Metastatic Prostate Cancer to the Urethra Masquerading as Urothelial Carcinoma.

    Science.gov (United States)

    Zardawi, Ibrahim; Chong, Peter

    2016-07-01

    Tumors of the urethra, whether primary or metastatic, are very rare. The true nature of urethral neoplasm is not always obvious clinically nor in routine histological sections. Immunostains should be performed on such lesions because of management implications. We present a case of multiple metastases to the urethra from a prostatic carcinoma, masquerading as multiple urothelial carcinomas. Pathologists and urologists should be aware of the possibility of metastasis from the prostate.

  19. Metastatic Prostate Cancer to the Urethra Masquerading as Urothelial Carcinoma

    Directory of Open Access Journals (Sweden)

    Ibrahim Zardawi

    2016-07-01

    Full Text Available Tumors of the urethra, whether primary or metastatic, are very rare. The true nature of urethral neoplasm is not always obvious clinically nor in routine histological sections. Immunostains should be performed on such lesions because of management implications. We present a case of multiple metastases to the urethra from a prostatic carcinoma, masquerading as multiple urothelial carcinomas. Pathologists and urologists should be aware of the possibility of metastasis from the prostate.

  20. Non-invasive actionable biomarkers for metastatic prostate cancer

    Directory of Open Access Journals (Sweden)

    Jun Luo

    2016-10-01

    Full Text Available In the current clinical setting, many disease management options are available for men diagnosed with prostate cancer. For metastatic prostate cancer, first-line therapies almost always involve agents designed to inhibit androgen receptor (AR signaling. Castration-resistant prostate cancers (CRPCs that arise following first-line androgen deprivation therapies (ADT may continue to respond to additional lines of AR-targeting therapies (abiraterone and enzalutamide, chemotherapies (docetaxel and cabazitaxel, bone-targeting Radium-223 therapy, and immunotherapy sipuleucel-T. The rapidly expanding therapies for CRPC is expected to transform this lethal disease into one that can be managed for prolonged period of time. In the past 3 years, a number of promising biomarkers that may help to guide treatment decisions have been proposed and evaluated, including androgen receptor splice variant-7 (AR-V7, a truncated AR lacking the ligand-binding domain (LBD and mediate constitutively-active AR signaling. Putative treatment selection markers such as AR-V7 may further improve survival benefit of existing therapies and help to accelerate development of new agents for metastatic prostate cancer. In the metastatic setting, it is important to consider compatibility between the putative biomarker with non-invasive sampling. In this review, biomarkers relevant to the setting of metastatic prostate cancer are discussed with respect to a number of key attributes critical for clinical development of non-invasive, actionable markers. It is envisioned that biomarkers for metastatic prostate cancer will continue to be discovered, developed, and refined to meet the unmet needs in both standard-of-care and clinical trial settings.

  1. Targeting bone physiology for the treatment of metastatic prostate cancer.

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    Autio, Karen A; Morris, Michael J

    2013-03-01

    Metastatic prostate cancer has a unique predilection for bone that can lead to significant clinical sequelae, such as fracture and cord compression. This tropism for bone yields not only clinical challenges, but also opportunities to understand the tumor biology in bone and to develop relevant therapeutic strategies. The process by which tumor cells migrate to bone, remain dormant, and then colonize and expand is based on complex interactions between prostate cancer tumor cells and the host microenvironment. This review will provide an overview of these interactions as well as therapies targeting osseous metastases in castration-resistant prostate cancer.

  2. Abiraterone in metastatic prostate cancer without previous chemotherapy

    NARCIS (Netherlands)

    Ryan, C.J.; Smith, M.R.; Bono, J. De; Molina, A.; Logothetis, C.J.; Souza, P. de; Fizazi, K.; Mainwaring, P.; Piulats, J.M.; Ng, S.; Carles, J.; Mulders, P.F.A.; Basch, E.; Small, E.J.; Saad, F.; Schrijvers, D.; Poppel, H. van; Mukherjee, S.D.; Suttmann, H.; Gerritsen, W.R.; Flaig, T.W.; George, D.J.; Yu, E.Y.; Efstathiou, E.; Pantuck, A.; Winquist, E.; Higano, C.S.; Taplin, M.E.; Park, Y.; Kheoh, T.; Griffin, T.; Scher, H.I.; Rathkopf, D.E.

    2013-01-01

    BACKGROUND: Abiraterone acetate, an androgen biosynthesis inhibitor, improves overall survival in patients with metastatic castration-resistant prostate cancer after chemotherapy. We evaluated this agent in patients who had not received previous chemotherapy. METHODS: In this double-blind study, we

  3. Metastatic Breast Carcinoma to the Prostate Gland.

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    Kapp, Meghan E; Giannico, Giovanna A; Desouki, Mohamed Mokhtar

    2016-01-01

    Cancer of the male breast is an uncommon event with metastases to the breast occurring even less frequently. Prostate carcinoma has been reported as the most frequent primary to metastasize to the breast; however, the reverse has not been previously reported. Herein, we present, for the first time, a case of breast carcinoma metastasizing to the prostate gland. Prostate needle core biopsy revealed infiltrative nests of neoplastic epithelioid cells, demonstrated by immunohistochemistry (IHC) to be positive for GATA3 and ER and negative for PSA and P501S. A prostate cocktail by IHC study demonstrated lack of basal cells (p63 and CK903) and no expression of P501S. The patient's previous breast needle core biopsy showed strong ER positivity and negative staining for PR and HER2. Similar to the prostate, the breast was negative for CK5/6, p63, and p40. This case demonstrates the importance of considering a broad differential diagnosis and comparing histology and IHC to prior known malignancies in the setting of atypical presentation or rare tumors.

  4. Metastatic Breast Carcinoma to the Prostate Gland

    Directory of Open Access Journals (Sweden)

    Meghan E. Kapp

    2016-01-01

    Full Text Available Cancer of the male breast is an uncommon event with metastases to the breast occurring even less frequently. Prostate carcinoma has been reported as the most frequent primary to metastasize to the breast; however, the reverse has not been previously reported. Herein, we present, for the first time, a case of breast carcinoma metastasizing to the prostate gland. Prostate needle core biopsy revealed infiltrative nests of neoplastic epithelioid cells, demonstrated by immunohistochemistry (IHC to be positive for GATA3 and ER and negative for PSA and P501S. A prostate cocktail by IHC study demonstrated lack of basal cells (p63 and CK903 and no expression of P501S. The patient’s previous breast needle core biopsy showed strong ER positivity and negative staining for PR and HER2. Similar to the prostate, the breast was negative for CK5/6, p63, and p40. This case demonstrates the importance of considering a broad differential diagnosis and comparing histology and IHC to prior known malignancies in the setting of atypical presentation or rare tumors.

  5. Stromal targeted therapy in bone metastatic prostate cancer: promise delivered

    Institute of Scientific and Technical Information of China (English)

    Oliver Sartor; William Goeckeler; Oyvind Bruland

    2011-01-01

    The ability of epithelial neoplasms to evade both hormonal and cytotoxic therapies is self-evident as the common carcinomas (lung,stomach,breast,colon and prostate) at their metastatic stage are rarely curable with current therapies.Though the precise reasons for incurability are debated,virtually all agree that tumor genetic heterogeneity makes eradication of the tumor difficult given ‘Darwinian' selection processes that are associated with the emergence of drug-resistant cellular clones.

  6. Evolving treatment paradigms for locally advanced and metastatic prostate cancer.

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    Dorff, Tanya B; Quek, Marcus L; Daneshmand, Siamak; Pinski, Jacek

    2006-11-01

    While men with early stage prostate cancer typically enjoy long-term survival after definitive management, for those who present with locally advanced or metastatic disease, survival is compromised. Multimodality therapy can prolong survival in these patients, with state-of-the-art options including intensity-modulated radiation or brachytherapy in conjunction with androgen ablation, adjuvant androgen ablation and/or chemotherapy with radical retropubic prostatectomy. In addition, novel biological therapies are being explored to target the unique molecular changes in prostate cancer cells and their interactions with the microenvironment. With these advances the outlook will undoubtedly improve, even for patients presenting with advanced disease. Careful application of these emerging therapies to a select group of prostate cancer patients most likely to obtain benefit from them is the challenge for urologists, medical oncologists and radiation oncologists for the future.

  7. Evaluation of metastatic potential of prostate cancer

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    Yoshitomo Chihara

    2011-06-01

    Full Text Available We aimed to establish a method for evaluating malignant potential of prostate cancer using prostatic core needle biopsy (PCNB before prostatectomy. If we can know the final pathological stage before treatment, we can select the most suitable therapeutic tactics. We then examined the expression of E-cadherin and type IV collagenase (MMP-9/-2, which play essential role in cancer cell invasion and metastasis. The expression ratio of MMP-9/-2 to E-cadherin (MER is revealed as the relevant marker correlated with the final pathological stage and Gleason score by prostatectomy specimens. We next confirmed the significance of MER in PCNB, which means PCNB MER enables the prediction of the final pathologic stage at the cancer diagnosis. However, the methodology measuring MER is complicated to produce an observer-to-observer deviation. We then establish a bicolor fluorescent ISH (bicolor FISH with a computerized fluorescence detector- based system. By this method, we can reduce an observer-to-observer deviation and a slide-to-slide deviation. The bicolor FISH-based MER is a useful tool for the preoperative evaluation of the final pathologic stage, by which we can assure a decision of prostatectomy indication.

  8. Prostate radiation in non-metastatic castrate refractory prostate cancer provides an interesting insight into biology of prostate cancer

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    Pascoe Abigail C

    2012-03-01

    Full Text Available Abstract Background The natural history of non-metastatic castrate refractory prostate cancer is unknown and treatment options are limited. We present a retrospective review of 13 patients with locally advanced or high risk prostate cancer, initially treated with hormone monotherapy and then treated with prostate radiation after becoming castration refractory. Findings Median PSA response following prostate radiation was 67.4%. Median time to biochemical progression following radiotherapy was 15 months and to detection of metastatic disease was 18.5 months. Median survival from castration resistance (to date of death or November 2011 was 60 months, with median survival from RT 42 months. Conclusion Prostate radiation appears to be beneficial even in patients with potential micrometastatic disease, which supports the hypothesis that the primary tumour is important in the progression of prostate cancer. These results are an interesting addition to the literature on the biology of prostate cancer especially as this data is unlikely to be available in the future due to combined prostate radiation and androgen deprivation therapy now being the standard of care.

  9. Targeted treatment of metastatic castration-resistant prostate cancer with sipuleucel-T immunotherapy

    NARCIS (Netherlands)

    Mulders, P.F.; Santis, M. de; Powles, T.; Fizazi, K.

    2015-01-01

    CONTEXT: Prostate cancer remains highly prevalent and has a poor clinical outcome once metastatic. Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T treatment extends survival but is independent of

  10. ERBB2 increases metastatic potentials specifically in androgen-insensitive prostate cancer cells.

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    Jessica Tome-Garcia

    Full Text Available Despite all the blood-based biomarkers used to monitor prostate cancer patients, prostate cancer remains as the second common cause of cancer mortality in men in the United States. This is largely due to a lack of understanding of the molecular pathways that are responsible for the aggressive forms of prostate cancers, the castrate-resistant prostate cancer and the metastatic prostate cancer. Cell signaling pathways activated by the ERBB2 oncogene or the RAS oncogene are frequently found to be altered in metastatic prostate cancers. To evaluate and define the role of the ERBB2/RAS pathway in prostate cancer metastasis, we have evaluated the impact of ERBB2- or RAS-overexpression on the metastatic potentials for four prostate cancer cell lines derived from tumors with different androgen sensitivities. To do so, we transfected the human DU145, LnCaP, and PC3 prostate cancer cells and the murine Myc-CaP prostate cancer cells with the activated form of ERBB2 or H-RAS and assessed their metastatic potentials by three complementary assays, a wound healing assay, a transwell motility assay, and a transwell invasion assay. We showed that while overexpression of ERBB2 increased the metastatic potential of the androgen-insensitive prostate cancer cells (i.e. PC3 and DU145, it did not affect metastatic potentials of the androgen-sensitive prostate cancer cells (i.e. LnCaP and Myc-CaP. In contrast, overexpression of H-RAS only increased the cell motility of Myc-CaP cells, which overexpress the human c-MYC oncogene. Our data suggest that ERBB2 collaborates with androgen signaling to promote prostate cancer metastasis, and that although RAS is one of the critical downstream effectors of ERBB2, it does not phenocopy ERBB2 for its impact on the metastatic potentials of prostate cancer cell lines.

  11. High Throughput Sequencing of Germline and Tumor from Men With Early-Onset Metastatic Prostate Cancer

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    2014-10-01

    challenge, Dr. Tomlins has continued to develop state of the art technologies to use formalin-fixed paraffin-embedded (FFPE) prostate cancer specimens...men with early-onset, metastatic prostate cancer PRINCIPAL INVESTIGATOR: Kathleen A. Cooney, M.D. CONTRACTING ORGANIZATION...High-Throughput Sequencing of Germline and Tumor From Men with Early-Onset Metastatic Prostate Cancer 5b. GRANT NUMBER W81XWH-13-1-0371 5c

  12. The oncologic role of local treatment in primary metastatic prostate cancer

    NARCIS (Netherlands)

    Ghadjar, P.; Briganti, A.; Visschere, P.J. De; Futterer, J.J.; Giannarini, G.; Isbarn, H.; Ost, P.; Sooriakumaran, P.; Surcel, C.I.; Bergh, R.C. van den; Oort, I.M. van; Yossepowitch, O.; Ploussard, G.

    2015-01-01

    PURPOSE: To determine the oncologic benefit or otherwise of local treatment of the prostate in patients with primary metastatic prostate cancer. METHODS: A review of the literature was performed in April 2014 using the Medline/PubMed database. Studies were identified using the search terms "prostate

  13. Increased survival in men with metastatic prostate cancer receiving chemo and hormone therapy

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    Men with hormone-sensitive metastatic prostate cancer who received the chemotherapy drug docetaxel given at the start of standard hormone therapy lived longer than patients who received hormone therapy alone, according to early results from a NIH-supporte

  14. Estramustine phosphate versus placebo as second line treatment after orchiectomy in patients with metastatic prostate cancer

    DEFF Research Database (Denmark)

    Iversen, P; Rasmussen, F; Asmussen, C

    1997-01-01

    We compared the effect of 560 mg. estramustine phosphate daily to placebo as a supplement to standard palliative therapy in patients with progressive disease after bilateral orchiectomy as first line therapy for metastatic prostate cancer.......We compared the effect of 560 mg. estramustine phosphate daily to placebo as a supplement to standard palliative therapy in patients with progressive disease after bilateral orchiectomy as first line therapy for metastatic prostate cancer....

  15. Targeted treatment of metastatic castration-resistant prostate cancer with sipuleucel-T immunotherapy

    OpenAIRE

    Mulders, Peter F.; Santis, Maria; Powles, Thomas; Fizazi, Karim

    2015-01-01

    Context Prostate cancer remains highly prevalent and has a poor clinical outcome once metastatic. Sipuleucel-T is an autologous cellular immunotherapy approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Sipuleucel-T treatment extends survival but is independent of traditional short-term markers of treatment response observed with chemotherapy and contemporary hormonal treatments. Therefore, it is essential that clinicians understand the mechanism of action o...

  16. Sleeping Beauty screen reveals Pparg activation in metastatic prostate cancer.

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    Ahmad, Imran; Mui, Ernest; Galbraith, Laura; Patel, Rachana; Tan, Ee Hong; Salji, Mark; Rust, Alistair G; Repiscak, Peter; Hedley, Ann; Markert, Elke; Loveridge, Carolyn; van der Weyden, Louise; Edwards, Joanne; Sansom, Owen J; Adams, David J; Leung, Hing Y

    2016-07-19

    Prostate cancer (CaP) is the most common adult male cancer in the developed world. The paucity of biomarkers to predict prostate tumor biology makes it important to identify key pathways that confer poor prognosis and guide potential targeted therapy. Using a murine forward mutagenesis screen in a Pten-null background, we identified peroxisome proliferator-activated receptor gamma (Pparg), encoding a ligand-activated transcription factor, as a promoter of metastatic CaP through activation of lipid signaling pathways, including up-regulation of lipid synthesis enzymes [fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), ATP citrate lyase (ACLY)]. Importantly, inhibition of PPARG suppressed tumor growth in vivo, with down-regulation of the lipid synthesis program. We show that elevated levels of PPARG strongly correlate with elevation of FASN in human CaP and that high levels of PPARG/FASN and PI3K/pAKT pathway activation confer a poor prognosis. These data suggest that CaP patients could be stratified in terms of PPARG/FASN and PTEN levels to identify patients with aggressive CaP who may respond favorably to PPARG/FASN inhibition.

  17. Radium-223 in metastatic castration resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Winston Vuong; Oliver Sartor; Sumanta K Pal

    2014-01-01

    In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC). For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival beneift in phase III studies. These agents include sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and (most recently) radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer (e.g. samarium-153 and strontium-89), radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors inlfuencing clinical implementation.

  18. Radium-223 in metastatic castration resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Winston Vuong

    2014-06-01

    Full Text Available In 2004, docetaxel was approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC. For the next several years, there was a lull in drug approvals. However, from 2010 onwards, 5 additional therapies have been approved on the basis of showing a survival benefit in phase III studies. These agents include sipuleucel-T, cabazitaxel, abiraterone, enzalutamide and (most recently radium-223. Amongst radiopharmaceuticals currently used for advanced prostate cancer (e.g. samarium-153 and strontium-89, radium-223 possesses several unique properties. As an alpha-emitting compound, the agent produces a high-energy output over a short range, facilitating selective destruction of tissue within the bone in the region of osteoblastic lesions while sparing surrounding normal tissue. The current review will outline biological rationale for radium-223 and also provide an overview of preclinical and clinical development of the agent. Rational sequencing of radium-223 and combinations, in the increasingly complex landscape of mCRPC will be discussed, along with factors influencing clinical implementation.

  19. Challenges in the sequencing of therapies for the management of metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Parente, Phillip; Parnis, Francis; Gurney, Howard

    2014-09-01

    Prior to 2010, docetaxel was the standard option for chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel-T) and radium-233 (for symptomatic bone metastases). With several other agents in the pipeline for late-stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient-focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices.

  20. Urothelial-Type adenocarcinoma of the prostate mimicking metastatic colorectal adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Brian P. Adley

    2006-12-01

    Full Text Available Adenocarcinoma arising in urinary bladder or prostatic urethra is uncommon. When they occur, the tumor can be mistaken for metastatic lesions, especially from the colon. Here we report the fifth case of a primary urothelial-type adenocarcinoma arising in the prostate which showed enteric differentiation. The patient was a 55 year-old male whose prostatic needle core biopsy showed a high grade adenocarcinoma which was initially thought to be metastatic colon cancer. A follow-up colonoscopy was unremarkable. Subsequent prostatectomy revealed a high grade adenocarcinoma which was positive for cytokeratins 7 and 20, carcinoembryonic antigen, CDX2, and high molecular weight cytokeratin, and negative for prostate specific antigen, prostate specific acid phosphatase and AMACR. A diagnosis of urothelial-type adenocarcinoma of the prostate was rendered. We review the literature regarding this entity, and discuss the differential diagnosis, emphasizing utility of immunohistochemistry in making the diagnosis. Finally, we speculate on the behavior of these rare tumors.

  1. CURRENT POSSIBILITIES OF TREATMENT FOR VISCERAL METASTASES IN PATIENTS WITH METASTATIC CASTRATION-REFRACTORY PROSTATE CANCER

    Directory of Open Access Journals (Sweden)

    A. V. Govorov

    2014-07-01

    Full Text Available Medications increasing the survival of patients with metastatic castration-refractory prostate cancer (CRPC are lacking today. In the past 3 years, in the pharmaceutical market there have been a few novel drugs to treat progressive prostate cancer. Abiraterone acetate is an androgen synthesis inhibitor, which is also used to increase the survival of patients with metastatic CRPC that progresses after chemotherapy. The results of treatment for metastatic CRPC depend on a number of factors. Visceral metastases are poor predictors of the course of the disease. The results of abiraterone acetate treatment were analyzed in CRPC patients with visceral metastases.

  2. Benzimidazole as Novel Therapy for Hormone-Refractory Metastatic Prostate Cancer

    Science.gov (United States)

    2011-05-01

    the growth of prostate cancer cells growing in the bone microenvironment . More strikingly, these anti-tumor effects remain active against prostate...and in the bone microenvironment , two clinical conditions of men with advanced prostate cancer. Conclusion: Metastatic tumor cells differ in their...Identification of these drugs resulted from a phenotypic (metastasis)-based in vitro screening of a library of marketed drugs. “Hits” from this screen

  3. Successful treatment of metastatic androgen-independent prostate carcinoma in a transsexual patient.

    Science.gov (United States)

    Dorff, Tanya B; Shazer, Ronald L; Nepomuceno, Edward M; Tucker, Steven J

    2007-06-01

    The occurrence of prostate carcinoma in transsexual patients has rarely been reported. These cases present a unique challenge in that such patients are effectively receiving androgen deprivation therapy. By definition, their disease is androgen-independent prostate cancer, and the role of local therapy is undefined. We report on a male-to-female transsexual patient with metastatic prostate cancer treated successfully with combination chemotherapy after previous standard therapy failed.

  4. The truth is in the water: metastatic prostate cancer presenting as an intermittent facial nerve palsy.

    Science.gov (United States)

    Wooles, N; Gupta, S; Wilkin-Crowe, H; Juratli, A

    2015-04-24

    An elderly man presented to the acute ear, nose and throat (ENT) services with a history of intermittent, self-limiting facial nerve palsy. Full ENT examination was normal, with all cranial nerves and peripheral neurology intact. Multiple imaging modalities suggested an aggressive bony lesion, secondary to locally advanced prostate malignancy with extensive metastatic infiltration. Prostate cancer is known to preferentially metastasise to bone and has been known to cause multiple cranial nerve palsies and ophthalmoplegia. This is the first case described in the literature of metastatic prostate cancer presenting with intermittent facial nerve palsy.

  5. Sipuleucel-T: in metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Plosker, Greg L

    2011-01-01

    Sipuleucel-T is an autologous active cellular immunotherapy used in the treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (CRPC). It is the first therapeutic cancer vaccine to receive US FDA approval. Approximately 3 days prior to each infusion of sipuleucel-T, patients undergo a leukapheresis procedure for collection of autologous peripheral blood mononuclear cells. Preparation of sipuleucel-T involves enrichment for antigen-presenting cells from the leukapheresis product and activation ex vivo with a recombinant fusion protein (PA2024). In the randomized, double-blind, placebo-controlled IMPACT study in patients with metastatic CRPC, sipuleucel-T was associated with a 22% relative reduction in the risk of death (hazard ratio 0.78; p = 0.03), which was the primary endpoint of the trial. After a median follow-up period of 34.1 months, median survival was 4.1 months longer with sipuleucel-T than placebo (25.8 vs 21.7 months). There was no significant between-group difference for the median time to objective disease progression (a secondary endpoint). Almost all patients treated with sipuleucel-T in clinical trials reported an adverse event, although these were mild or moderate in severity (grade 1 or 2) in most patients. The most common adverse events (e.g. infusion-related events, such as chills and fever) generally occurred within the first day after administration of sipuleucel-T and resolved within 2 days.

  6. Potential synergistic implications for stromal-targeted radiopharmaceuticals in bone-metastatic prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Oliver Sartor

    2011-01-01

    Genetic heterogeneity and chemotherapy-resistant 'stem cells' represent two of the most pressing issues in devising new strategies for the treatment of advanced prostate cancer. Though curative strategies have long been present for men with localized disease, metastatic prostate cancer is currently incurable. Though substantial improvements in outcomes are now possible through the utilization of newly approved therapies, novel combinations are clearly needed. Herein we describe potentially synergistic interactions between bone stromal-targeted radiopharmaceuticals and other therapies for treatment of bone-metastatic prostate cancer. Radiation has long been known to synergize with cytotoxic chemotherapies and recent data also suggest the possibility of synergy when combining radiation and immune-based strategies. Combination therapies will be required to substantially improve survival for men with castrate-resistant metastatic prostate cancer and we hypothesize that bone-targeted radiopharmaceuticals will play an important role in this process.

  7. Treatment sequencing in metastatic castrate-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Oliver Sartor

    2014-06-01

    Full Text Available Six different treatments have demonstrated improved survival in phase III trials targeted to patients with metastatic castration-resistant prostate cancer (mCRPC. Front-line therapeutic options for mCRPC include docetaxel, sipuleucel-T, abiraterone and radium-223. Post-docetaxel options include cabazitaxel, abiraterone, enzalutamide and radium-223. Despite much progress in recent years, much is yet unknown and debates occur over optimal treatment choices and sequences. None of the new agents have been compared to one another, thus physicians in practice today must make choices based on non-randomized comparisons, toxicity considerations and various assumptions. Abiraterone is now moving into the front line mCRPC space given recent regulatory approvals and enzalutamide will follow soon. Both of the hormonal agents have less toxicity when compared to chemotherapeutic options and both of these hormonal agents are expected to be used in a considerable number of mCRPC patients in the years ahead. Little data are available for the post-abiraterone or post-enzalutamide setting. In this review the currently available sequencing data are summarized and interpreted. It is now clear that cross resistance is a potential issue between various treatments, especially those agents that target the androgen axis. This review highlights the need for additional studies to optimize the current treatments for these patients.

  8. Treatment sequencing in metastatic castrate-resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Oliver Sartor; Silke Gillessen

    2014-01-01

    Six different treatments have demonstrated improved survival in phase III trials targeted to patients with metastatic castration-resistant prostate cancer (mCRPC). Front-line therapeutic options for mCRPC include docetaxel, sipuleucel-T, abiraterone and radium-223. Post-docetaxel options include cabazitaxel, abiraterone, enzalutamide and radium-223. Despite much progress in recent years, much is yet unknown and debates occur over optimal treatment choices and sequences. None of the new agents have been compared to one another, thus physicians in practice today must make choices based on non-randomized comparisons, toxicity considerations and various assumptions. Abiraterone is now moving into the front line mCRPC space given recent regulatory approvals and enzalutamide will follow soon. Both of the hormonal agents have less toxicity when compared to chemotherapeutic options and both of these hormonal agents are expected to be used in a considerable number of mCRPC patients in the years ahead. Little data are available for the post-abiraterone or post-enzalutamide setting. In this review the currently available sequencing data are summarized and interpreted. It is now clear that cross resistance is a potential issue between various treatments, especially those agents that target the androgen axis. This review highlights the need for additional studies to optimize the current treatments for these patients.

  9. Severe Hypocalcemia due to Denosumab in Metastatic Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Mohammed Muqeet Adnan

    2014-01-01

    Full Text Available Denosumab is a monoclonal antibody used for prevention of skeletal-related events (SREs in patients with bone metastases from solid tumors. Hypocalcemia is a rare and dangerous side effect of the drug Denosumab. We present a case of a patient with metastatic prostate cancer who developed severe hypocalcemia after the administration of the drug. The patient’s vitamin D levels were low when checked after administration of the drug, which likely predisposed him to the development of hypocalcemia. He was placed on high doses of oral and intravenous (IV calcium and vitamin D without any appreciable response in the serum calcium level. His ionized calcium remained below 0.71 mmol/L despite very high doses of oral and IV calcium supplements. During the hospital course, he developed hydronephrosis from the spread of a tumor and did not want to undergo percutaneous nephrostomy tube placement; therefore, it was decided to dialyse him for acute renal failure and to correct his hypocalcemia. Checking calcium and vitamin D levels prior to the administration of Denosumab is vital in preventing hypocalcemia. If hypocalcemia is severe and not responsive to high doses of vitamin D, oral and IV calcium, then hemodialysis with a high calcium bath can correct this electrolyte abnormality.

  10. Severe Hypocalcemia due to Denosumab in Metastatic Prostate Cancer.

    Science.gov (United States)

    Muqeet Adnan, Mohammed; Bhutta, Usman; Iqbal, Tanzeel; AbdulMujeeb, Sufyan; Haragsim, Lukas; Amer, Syed

    2014-01-01

    Denosumab is a monoclonal antibody used for prevention of skeletal-related events (SREs) in patients with bone metastases from solid tumors. Hypocalcemia is a rare and dangerous side effect of the drug Denosumab. We present a case of a patient with metastatic prostate cancer who developed severe hypocalcemia after the administration of the drug. The patient's vitamin D levels were low when checked after administration of the drug, which likely predisposed him to the development of hypocalcemia. He was placed on high doses of oral and intravenous (IV) calcium and vitamin D without any appreciable response in the serum calcium level. His ionized calcium remained below 0.71 mmol/L despite very high doses of oral and IV calcium supplements. During the hospital course, he developed hydronephrosis from the spread of a tumor and did not want to undergo percutaneous nephrostomy tube placement; therefore, it was decided to dialyse him for acute renal failure and to correct his hypocalcemia. Checking calcium and vitamin D levels prior to the administration of Denosumab is vital in preventing hypocalcemia. If hypocalcemia is severe and not responsive to high doses of vitamin D, oral and IV calcium, then hemodialysis with a high calcium bath can correct this electrolyte abnormality.

  11. Prostatic adenocarcinoma with mandibular metastatic lesion: case report.

    Science.gov (United States)

    Reyes Court, Daniel; Encina, Susana; Levy, Irene

    2007-10-01

    Metastatic lesions of primary tumors, which originate in different parts of the body, comprise almost 1 % of different types of oral cancers. These lesions can affect either bones or soft tissues in the maxillofacial region. Whenever the maxillofacial area is affected, the most common location is in the molar region of the mandible. The clinical presentation of mandibular metastasis follows a clinical pattern characterized by irradiated dental pain in the third molar region. The most frequent sign is parethesia of the area innervated by the mandibular alveolar dental nerve. Differential diagnosis and treatment of these patients can be extremely difficult because there a number of pathologic conditions with similar symptoms and because diagnostic examination can be highly confusing. The aim of this article is to present a case of prostatic adenocarcinoma where the only metastasis was found in the jaw. A literature review will be presented, hoping to contribute to the scarce information regarding this lesion, due to its low frequency and atypical expression of this type of metastasis in terms of etiology, biological behavior and treatment.

  12. A randomised comparison of 'Casodex' (bicalutamide) 150 mg monotherapy versus castration in the treatment of metastatic and locally advanced prostate cancer

    DEFF Research Database (Denmark)

    Tyrrell, C J; Kaisary, A V; Iversen, P;

    1998-01-01

    To evaluate the efficacy and tolerability of 'Casodex' monotherapy (150 mg daily) for metastatic and locally advanced prostate cancer.......To evaluate the efficacy and tolerability of 'Casodex' monotherapy (150 mg daily) for metastatic and locally advanced prostate cancer....

  13. Is there a role for antiandrogen monotherapy in patients with metastatic prostate cancer?

    DEFF Research Database (Denmark)

    Kaisary, A V; Iversen, P; Tyrrell, C J;

    2001-01-01

    with a prostate specific antigen (PSA) level 400 ng/ml) may decide that quality of life and symptomatic benefits outweigh the slight survival disadvantage seen in clinical trials and opt for bicalutamide monotherapy as an alternative to castration.Prostate Cancer and Prostatic Diseases (2001) 4, 196-203.......Castration is the most widely used form of androgen ablation employed in the treatment of metastatic (M1) prostate cancer. Non-steroidal antiandrogen monotherapy is a potential alternative treatment option for men for whom castration is unacceptable or not indicated. Of the three non...

  14. Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma

    DEFF Research Database (Denmark)

    Brasso, Klaus; Christensen, Ib Jarle; Johansen, Julia S;

    2006-01-01

    To examine the prognostic value of markers of bone metabolism (serum PINP, BAP, and CTX-I) and serum YKL-40 in metastatic prostate carcinoma (PC).......To examine the prognostic value of markers of bone metabolism (serum PINP, BAP, and CTX-I) and serum YKL-40 in metastatic prostate carcinoma (PC)....

  15. Abiraterone acetate for patients with metastatic castration-resistant prostate cancer progressing after chemotherapy

    DEFF Research Database (Denmark)

    Sternberg, Cora N; Castellano, Daniel; Daugaard, Gedske

    2014-01-01

    BACKGROUND: In the final analysis of the phase 3 COU-AA-301 study, abiraterone acetate plus prednisone significantly prolonged overall survival compared with prednisone alone in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. Here, we present the final...... analysis of an early-access protocol trial that was initiated after completion of COU-AA-301 to enable worldwide preapproval access to abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after chemotherapy. METHODS: We did a multicentre, open-label, early......-access protocol trial in 23 countries. We enrolled patients who had metastatic castration-resistant prostate cancer progressing after taxane chemotherapy. Participants received oral doses of abiraterone acetate (1000 mg daily) and prednisone (5 mg twice a day) in 28-day cycles until disease progression...

  16. Metastatic prostate mass to the intradural foramen magnum region: a case report.

    Science.gov (United States)

    Quillin, Joseph; Chittiboina, Prashant; Haydel, Justin; Nanda, Anil

    2012-10-01

    Intradural metastatic tumors of the foramen magnum region are extremely rare tumors. We report a 73-year-old patient that presented with right hemiparesis and a recent history of prostate biopsy for an enlarged prostate. Imaging revealed an anterolateral intradural foramen magnum mass with compression of the medulla. A right far lateral approach with condyle preservation was used to resect the mass. Pathological examination revealed the tumor as a metastatic prostate mass. The patient had a significant recovery of motor function and was given adjuvant external beam radiation. At the time of last follow-up, the patient had good clinical relief from the preoperative symptoms. To our knowledge, this is the first reported case of an intradural foramen magnum prostate tumor metastasis. We report on multimodal management of this rare, yet morbid presentation of a common tumor.

  17. Clinical use of abiraterone in the treatment of metastatic castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Zobniw CM

    2014-08-01

    Full Text Available Chrystia M Zobniw,1 Alanna Causebrook,2 Mei Ka Fong1 1Department of Pharmacy, Roswell Park Cancer Institute, Buffalo, NY, USA; 2School of Pharmacy, Lake Erie College of Osteopathic Medicine, Erie, PA, USA Abstract: Prostate cancer remains the most common type of cancer among men in the United States. Treatment for metastatic prostate cancer has improved significantly over the years with more and more agents improving overall survival. This review will address the pathophysiology of prostate cancer followed by the mechanism of action and the pharmacokinetic properties of abiraterone. The review will also discuss the role of abiraterone in the treatment of metastatic castrate-resistant prostate cancer. Keywords: glucocorticoid receptor, CYP17, pipeline, enzalutamide, sipuleucel-T, drug resistance, radium-223 dichloride

  18. LIGHT: A Novel Immunotherapy for Primary and Metastatic Prostate Cancer

    Science.gov (United States)

    2014-09-01

    effects due to the loss of testosterone (including fatigue, decreased sexual desire, weight gain, loss of muscle mass and osteoporosis ) and the well...beyond the prostate, immunotherapy may be the only way to treat it [6, 7]. A majority of clinical trials for the immunotherapy of prostate cancer...Localized Prostate Cancer. J Sex Med, 2012. 5. Fitzpatrick, J.M., Management of localized prostate cancer in senior adults : the crucial role of comorbidity

  19. Abiraterone plus prednisone improves survival in metastatic castration-resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Scott T Tagawa; Himisha Beltran

    2011-01-01

    In essentially just 1 year's time,we have seen science translated into exciting new therapeutic agents for men with metastatic castration-resistant prostate cancer (CRPC),1 most recently with the United States Food and Drug Administration (FDA) approval of abiraterone acetate in combination with prednisone.2 While prostate cancer has been known to be highly responsive to surgical or medical castration for well over half a century,3 what was once termed 'hormone refractory' prostate cancer inevitably developed,leading to cancerrelated death.Many consider the introduction of chemotherapy for CRPC initially for symptomatic benefit,then with improvements in survival,a substantial step forward.

  20. Prostate carcinoma metastatic to the skin as an extrammamary Paget’s disease

    Directory of Open Access Journals (Sweden)

    Petcu Eugen

    2012-08-01

    Full Text Available Abstract Aim The current paper describes a case of prostatic adenocarcinoma metastatic to the skin presenting as an extrammamary Paget's disease, a very rare and poorly characterised morphological entity. We report a case of prostatic carcinoma metastatic to skin showing a pattern of extramammary Paget's disease which has not been clearly illustrated in the literature Case presentation: A 63 year-old man with prostatic adenocarcinoma developed cutaneous metastases after 16 years. The inguinal metastases were sessile and 'keratotic.' The tumour displayed solid, glandular areas as well as a polypoid region suggestive of extramammary Paget's disease were identified. Discussion and conclusions We review the diagnostic criteria that have led to the correct histopathological diagnosis in this case. A differential diagnosis of the pagetoid spread in the skin and various forms of cutaneous metastases determined by a prostatic adenocarcinoma as well as the role of immunohistochemistry in establishing the prostatic origin are presented in the context of this case. Although, morphologically the cells presented in the skin deposits were not characteristic for adenocarcinoma of prostate, immunohistochemistry for PSA and PSAP suggested a prostatic origin. Virtual Slides The virtual slide(s for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1395450057455276

  1. Molecular Heterogeneity in Primary and Metastatic Prostate Tumor Tissue

    Science.gov (United States)

    2014-10-01

    her expertise in prostate cancer epidemiology, has coordinated meetings to discuss the study progress with collaborators, and has begun specimen and...Development of a tissue resource that combines within-person primary and lymph node-positive prostate cancer specimens. This resource is coordinated in...melatonin levels, sleep disruption, and risk of prostate cancer in elderly men. European Urology 2014 Advance online publication. doi: 10.1016/j.eururo

  2. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana

    2017-01-01

    Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated th...

  3. Docetaxel rechallenge after an initial good response in patients with metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Oudard, Stéphane; Kramer, Gero; Caffo, Orazio

    2015-01-01

    OBJECTIVE: To evaluate the benefit of docetaxel rechallenge in patients with metastatic castration-resistant prostate cancer (mCRPC) relapsing after an initial good response to first-line docetaxel. PATIENTS AND METHODS: We retrospectively reviewed the records of consecutive patients with mCRPC w...

  4. Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Heidenreich, Axel; Bracarda, Sergio; Mason, Malcolm;

    2014-01-01

    BACKGROUND: Cabazitaxel/prednisone has been shown to prolong survival versus mitoxantrone/prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or after docetaxel. Subsequently, compassionate-use programmes (CUPs) and expanded-access progra...

  5. Liver protects metastatic prostate cancer from induced death by activating E-cadherin signaling.

    Science.gov (United States)

    Ma, Bo; Wheeler, Sarah E; Clark, Amanda M; Whaley, Diana L; Yang, Min; Wells, Alan

    2016-11-01

    Liver is one of the most common sites of cancer metastasis. Once disseminated, the prognosis is poor as these tumors often display generalized chemoresistance, particularly for carcinomas that derive not from the aerodigestive tract. When these cancers seed the liver, the aggressive cells usually undergo a mesenchymal to epithelial reverting transition that both aids colonization and renders the tumor cells chemoresistant. In vitro studies demonstrate that hepatocytes drive this phenotypic shift. However, the in vivo evidence and the molecular signals that protect these cells from induced death are yet to be defined. Herein, we report that membrane surface E-cadherin-expressing prostate cancer cells were resistant to cell death by chemotherapeutic drugs but E-cadherin null cells or those expressing E-cadherin only in the cytoplasm were sensitive to death signals and chemotherapies both in vitro and in vivo. While cell-cell E-cadherin ligandation reduced mitogenesis, this chemoprotection was proliferation-independent as killing of both 5-ethynyl-2'-deoxyuridine-positive (or Ki67(+) ) and 5-ethynyl-2'-deoxyuridine-negative (Ki67(-) ) cells was inversely related to membrane-bound E-cadherin. Inhibiting the canonical survival kinases extracellular signal-regulated protein kinases, protein kinase B, and Janus kinase, which are activated by chemotherapeutics in epithelial cell-transitioned prostate cancer, abrogated the chemoresistance both in cell culture and in animal models of metastatic cancer. For disseminated tumors, protein kinase B disruption in itself had no effect on tumor survival but was synergistic with chemotherapy, leading to increased killing.

  6. Cyclin-dependent kinase 5 activity controls cell motility and metastatic potential of prostate cancer cells.

    Science.gov (United States)

    Strock, Christopher J; Park, Jong-In; Nakakura, Eric K; Bova, G Steven; Isaacs, John T; Ball, Douglas W; Nelkin, Barry D

    2006-08-01

    We show here that cyclin-dependent kinase 5 (CDK5), a known regulator of migration in neuronal development, plays an important role in prostate cancer motility and metastasis. P35, an activator of CDK5 that is indicative of its activity, is expressed in a panel of human and rat prostate cancer cell lines, and is also expressed in 87.5% of the human metastatic prostate cancers we examined. Blocking of CDK5 activity with a dominant-negative CDK5 construct, small interfering RNA, or roscovitine resulted in changes in the microtubule cytoskeleton, loss of cellular polarity, and loss of motility. Expression of a dominant-negative CDK5 in the highly metastatic Dunning AT6.3 prostate cancer cell line also greatly impaired invasive capacity. CDK5 activity was important for spontaneous metastasis in vivo; xenografts of AT6.3 cells expressing dominant-negative CDK5 had less than one-fourth the number of lung metastases exhibited by AT6.3 cells expressing the empty vector. These results show that CDK5 activity controls cell motility and metastatic potential in prostate cancer.

  7. Analysis of autophagic flux in response to sulforaphane in metastatic prostate cancer cells

    Science.gov (United States)

    Watson, Gregory W; Wickramasekara, Samanthi; Fang, Yufeng; Palomera-Sanchez, Zoraya; Maier, Claudia S; Williams, David E; Dashwood, Roderick H; Perez, Viviana I; Ho, Emily

    2015-01-01

    Scope The phytochemical sulforaphane has been shown to decrease prostate cancer metastases in a genetic mouse model of prostate carcinogenesis, though the mechanism of action is not fully known. Sulforaphane has been reported to stimulate autophagy, and modulation of autophagy has been proposed to influence sulforaphane cytotoxicity; however, no conclusions about autophagy can be drawn without assessing autophagic flux, which has not been characterized in prostate cancer cells following sulforaphane treatment. Methods and Results We conducted an investigation to assess the impact of sulforaphane on autophagic flux in two metastatic prostate cancer cell lines at a concentration shown to decrease metastasis in vivo. Autophagic flux was assessed by multiple autophagy related proteins and substrates. We found that sulforaphane can stimulate autophagic flux and cell death only at high concentrations, above what has been observed in vivo. Conclusion These results suggest that sulforaphane does not directly stimulate autophagy or cell death in metastatic prostate cancer cells under physiologically relevant conditions, but instead supports the involvement of in vivo factors as important effectors of sulforaphane- mediated prostate cancer suppression. PMID:26108801

  8. Novel tracers and their development for the imaging of metastatic prostate cancer.

    Science.gov (United States)

    Apolo, Andrea B; Pandit-Taskar, Neeta; Morris, Michael J

    2008-12-01

    There are presently no accurate methods of imaging prostate cancer metastases to bone. An unprecedented number of novel imaging agents, based on the biology of the disease, are now available for testing. We reviewed contemporary molecular imaging modalities that have been tested in humans with metastatic prostate cancer, with consideration of the studies' adherence to current prostate cancer clinical trial designs. Articles from the years 2002 to 2008 on PET using (18)F-FDG, (11)C-choline, (18)F-choline, (18)F-flouride, (11)C-acetate, (11)C-methionine, and (18)F-fluoro-5alpha-dihydrotestosterone in patients with metastatic prostate cancer were reviewed. Although these studies are encouraging, most focus on the rising population with prostate-specific antigen, and many involve small numbers of patients and do not adhere to consensus criteria for clinical trial designs in prostate cancer. Hence, although many promising agents are available for testing, such studies would benefit from closer collaboration between those in the fields of medical oncology and nuclear medicine.

  9. Immunohistochemical profiles of claudin-3 in primary and metastatic prostatic adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Becich Michael J

    2011-01-01

    Full Text Available Abstract Background Claudins are integral membrane proteins that are involved in forming cellular tight junctions. One member of the claudin family, claudin-3, has been shown to be overexpressed in breast, ovarian, and pancreatic cancer. Here we use immunohistochemistry to evaluate its expression in benign prostatic hyperplasia (BPH, prostatic intraepithelial neoplasia (PIN, normal tissue adjacent to prostatic adenocarcinoma (NAC, primary prostatic adenocarcinoma (PCa, and metastatic prostatic adenocarcinoma (Mets. Methods Tissue microarrays were immunohistochemically stained for claudin-3, with the staining intensities subsequently quantified and statistically analyzed using a one-way ANOVA with subsequent Tukey tests for multiple comparisons or a nonparametric equivalent. Fifty-three cases of NAC, 17 cases of BPH, 35 cases of PIN, 107 cases of PCa, and 55 cases of Mets were analyzed in the microarrays. Results PCa and Mets had the highest absolute staining for claudin-3. Both had significantly higher staining than BPH (p Conclusions To our knowledge, this represents one of the first studies comparing the immunohistochemical profiles of claudin-3 in PCa and NAC to specimens of PIN, BPH, and Mets. These findings provide further evidence that claudin-3 may serve as an important biomarker for prostate cancer, both primary and metastatic, but does not provide evidence that claudin-3 can be used to predict risk of metastasis.

  10. Integrated multimodal imaging of dynamic bone-tumor alterations associated with metastatic prostate cancer.

    Directory of Open Access Journals (Sweden)

    Jean-Christophe Brisset

    Full Text Available Bone metastasis occurs for men with advanced prostate cancer which promotes osseous growth and destruction driven by alterations in osteoblast and osteoclast homeostasis. Patients can experience pain, spontaneous fractures and morbidity eroding overall quality of life. The complex and dynamic cellular interactions within the bone microenvironment limit current treatment options thus prostate to bone metastases remains incurable. This study uses voxel-based analysis of diffusion-weighted MRI and CT scans to simultaneously evaluate temporal changes in normal bone homeostasis along with prostate bone metatastsis to deliver an improved understanding of the spatiotemporal local microenvironment. Dynamic tumor-stromal interactions were assessed during treatment in mouse models along with a pilot prospective clinical trial with metastatic hormone sensitive and castration resistant prostate cancer patients with bone metastases. Longitudinal changes in tumor and bone imaging metrics during delivery of therapy were quantified. Studies revealed that voxel-based parametric response maps (PRM of DW-MRI and CT scans could be used to quantify and spatially visualize dynamic changes during prostate tumor growth and in response to treatment thereby distinguishing patients with stable disease from those with progressive disease (p<0.05. These studies suggest that PRM imaging biomarkers are useful for detection of the impact of prostate tumor-stromal responses to therapies thus demonstrating the potential of multi-modal PRM image-based biomarkers as a novel means for assessing dynamic alterations associated with metastatic prostate cancer. These results establish an integrated and clinically translatable approach which can be readily implemented for improving the clinical management of patients with metastatic bone disease.

  11. Cancer of the prostate presenting with diffuse osteolytic metastatic bone lesions: a case report

    Directory of Open Access Journals (Sweden)

    Segamwenge Innocent Lule

    2012-12-01

    Full Text Available Abstract Introduction Prostate cancer is the second most common cancer in men and the fifth most common cancer worldwide. In the USA it is more common in African-American men than in Caucasian men. Prostate cancer frequently metastasizes to bone and the lesions appear osteoblastic on radiographs. Presentation with diffuse osteolytic bone lesions is rare. We describe an unusual presentation of metastatic prostate cancer with diffuse osteolytic bone lesions. Case presentation A 65-year-old Namibian man presented with anemia, thrombocytopenia and worsening back pains. In addition he had complaints of effort intolerance, palpitations, dysuria and mild symptoms of bladder outlet obstruction. On examination he was found to be anemic, had a swollen tender right shoulder joint and spine tenderness to percussion. On digital rectal examination he had asymmetrical enlargement of the prostate which felt nodular and hard with diffuse firmness in some parts. His prostate-specific antigen was greater than 100ng/mL and he had diffuse osteolytic lesions involving the right humerus, and all vertebral, femur and pelvic bones. His screen for multiple myeloma was negative and the prostate biopsy confirmed prostate cancer. Conclusion Prostate cancer rarely presents with diffuse osteolytic bone lesions and should be considered in the differential diagnosis when evaluating male patients with osteolytic bone lesions.

  12. Metastatic prostatic adenocarcinoma diagnosed in a bronchoalveolar lavage specimen: An unusual presentation of a common tumor

    Directory of Open Access Journals (Sweden)

    Adrienne E Moul

    2016-01-01

    Full Text Available Metastatic prostatic adenocarcinoma presenting as a primary lung disease is rare. We present a 52-year-old male with a 3-month history of cough, shortness of breath, and weight loss with clinical and radiological findings suggestive of a primary lung disease: Bilateral interstitial and alveolar opacities with blunting of the costophrenic angles, multiple diffuse foci of consolidations and nodules, predominantly subpleural and located in the lower lobes, and diffuse interlobular septal thickening and peribronchial thickening. The patient underwent bronchoscopy and bronchoalveolar lavage (BAL was obtained. Cytospin smears were diagnostic for a low-grade adenocarcinoma. Clinically, the patient had elevated serum prostate-specific antigen (PSA levels greater than 5,000 ng/mL. Because of this, immunocytochemistry for PSA was performed which was positive, confirming the diagnosis of metastatic prostatic adenocarcinoma. This unusual case of metastatic adenocarcinoma of the prostate first diagnosed by BAL highlights the significance of available clinical information and the use of immunocytochemistry for proper diagnosis.

  13. Sipuleucel-T for the treatment of metastatic prostate cancer: promise and challenges.

    Science.gov (United States)

    Paller, Channing J; Antonarakis, Emmanuel S

    2012-04-01

    In the past 18 mo, three new life-prolonging therapies have been approved by the US. Food and Drug Administration for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC), including sipuleucel-T, the first therapeutic vaccine approved for this disease. With very low toxicity and a demonstrable overall survival benefit, sipuleucel-T offers a promising new therapy and validates further investigation into other immunotherapy approaches for prostate cancer patients. However, questions about its mechanism of action, concerns about its cost, and its optimal sequencing in the prostate cancer treatment landscape may be limiting the adoption of sipuleucel-T. This review summarizes the state-of-the-science with respect to immunotherapy approaches for men with prostate cancer, provides information about the clinical development as well as the strengths and concerns associated with sipuleucel-T, and offers initial insights about where this promising treatment may best fit in the therapeutic landscape.

  14. Is there a role for antiandrogen monotherapy in patients with metastatic prostate cancer?

    DEFF Research Database (Denmark)

    Kaisary, A V; Iversen, P; Tyrrell, C J

    2001-01-01

    with a prostate specific antigen (PSA) level 400 ng/ml) may decide that quality of life and symptomatic benefits outweigh the slight survival disadvantage seen in clinical trials and opt for bicalutamide monotherapy as an alternative to castration.Prostate Cancer and Prostatic Diseases (2001) 4, 196-203.......Castration is the most widely used form of androgen ablation employed in the treatment of metastatic (M1) prostate cancer. Non-steroidal antiandrogen monotherapy is a potential alternative treatment option for men for whom castration is unacceptable or not indicated. Of the three non......-steroidal antiandrogens, bicalutamide ('Casodex'), flutamide and nilutamide, only bicalutamide has been compared with castration in large, controlled, randomised, Phase III trials in M1 patients. A post-hoc analysis of these studies indicated that bicalutamide 150 mg/day monotherapy may be of benefit to M1 patients...

  15. Is it Time to Change the Control Placebo Arms in Phase III Trials of Metastatic Castration Resistant Prostate Cancer?

    Science.gov (United States)

    Dogan, Mutlu; Erdem, Gokmen Umut; Zengin, Nurullah

    2015-01-01

    Prostate cancer is common all around the world. Hormonal therapy is the mainstay of therapy, however castration-resistant prostate cancer (CRPC) becomes a serious problem and needs further clinical trials with novel agents. Novel agents like cabazitaxel, abireterone acetate or enzalutamide are encouraging but we do not know which one is the best in metastatic CRPC. In here, treatment modalities for metastatic CRPC are discussed witha mini-review of the literature.

  16. Critical questions in metastatic castration-resistant prostate cancer: Integrating emerging clinical evidence and guideline recommendations

    Directory of Open Access Journals (Sweden)

    Mohamed Ali

    2016-01-01

    Full Text Available Metastatic castration-resistant prostate cancer (CRPC typically confers a poor prognosis, however, novel advances in treatment options, as well as biomarkers for monitoring disease response and progression, have recently helped improve survival rates. Additionally, new guidelines provide some direction on incorporating these new treatments but some confusion still exists among clinicians about best methods for initiating treatment and the optimal sequencing of agents to prolong survival. In this article, we review the literature and answer some frequently asked questions about treating men with metastatic CRPC, including choosing a first-line treatment, monitoring treatment response, and proceeding to additional lines of therapy.

  17. Role of Chemotherapy and Mechanisms of Resistance to Chemotherapy in Metastatic Castration-Resistant Prostate Cancer

    Science.gov (United States)

    Lohiya, Vipin; Aragon-Ching, Jeanny B.; Sonpavde, Guru

    2016-01-01

    Chemotherapy using the taxanes, docetaxel and cabazitaxel, remains an important therapeutic option in metastatic castration-resistant prostate cancer (CRPC). However, despite the survival benefits afforded by these agents, the survival increments are modest and resistance occurs universally. Efforts to overcome resistance to docetaxel by combining with biologic agents have heretofore been unsuccessful. Indeed, resistance to these taxanes is also associated with cross-resistance to the antiandrogen drugs, abiraterone and enzalutamide. Here, we discuss the various mechanisms of resistance to chemotherapy in metastatic CRPC and the potential role of emerging regimens and agents in varying clinical phases of development.

  18. Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma

    DEFF Research Database (Denmark)

    Brasso, Klaus; Christensen, Ib Jarle; Johansen, Julia S.;

    2006-01-01

    BACKGROUND: To examine the prognostic value of markers of bone metabolism (serum PINP, BAP, and CTX-I) and serum YKL-40 in metastatic prostate carcinoma (PC). METHODS: The biomarkers were determined by ELISAs in 153 metastatic PC patients before treatment with parenteral estrogen or total androgen...

  19. SOX9 drives WNT pathway activation in prostate cancer.

    Science.gov (United States)

    Ma, Fen; Ye, Huihui; He, Housheng Hansen; Gerrin, Sean J; Chen, Sen; Tanenbaum, Benjamin A; Cai, Changmeng; Sowalsky, Adam G; He, Lingfeng; Wang, Hongyun; Balk, Steven P; Yuan, Xin

    2016-05-02

    The transcription factor SOX9 is critical for prostate development, and dysregulation of SOX9 is implicated in prostate cancer (PCa). However, the SOX9-dependent genes and pathways involved in both normal and neoplastic prostate epithelium are largely unknown. Here, we performed SOX9 ChIP sequencing analysis and transcriptome profiling of PCa cells and determined that SOX9 positively regulates multiple WNT pathway genes, including those encoding WNT receptors (frizzled [FZD] and lipoprotein receptor-related protein [LRP] family members) and the downstream β-catenin effector TCF4. Analyses of PCa xenografts and clinical samples both revealed an association between the expression of SOX9 and WNT pathway components in PCa. Finally, treatment of SOX9-expressing PCa cells with a WNT synthesis inhibitor (LGK974) reduced WNT pathway signaling in vitro and tumor growth in murine xenograft models. Together, our data indicate that SOX9 expression drives PCa by reactivating the WNT/β-catenin signaling that mediates ductal morphogenesis in fetal prostate and define a subgroup of patients who would benefit from WNT-targeted therapy.

  20. Diagnostic utility of p501s (prostein in comparison to prostate specific antigen (PSA for the detection of metastatic prostatic adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Parwani Anil V

    2007-10-01

    Full Text Available Abstract Background Immunohistochemical detection of prostate specific antigen (PSA is widely used to identify metastatic prostatic adenocarcinoma. However, PSA may not be expressed in some poorly differentiated prostatic carcinomas and its immunoreactivity has been found in some non-prostatic tissues. P501s (prostein is a prostate-specific marker that is expressed in the cytoplasm of benign and malignant prostatic glandular cells. It has not been detected in any other normal or malignant tissues. The purpose of this study was to evaluate the expression of P501s in metastatic prostatic adenocarcinoma and compare its expression with PSA. Methods Immunohistochemical stains with anti-P501s antibodies were performed on 5-micron sections of tissue microarray (TMA specimens. The TMA is constructed with normal donor prostates (NDP, prostatic adenocarcinoma (PRCA, non-neoplastic prostatic tissues adjacent to malignant glands (NAT, benign prostatic hyperplasia (BPH, high-grade prostatic neoplasia (PIN, metastatic adenocarcinoma to lymph nodes (MLN, metastatic adenocarcinoma to other sites (MC, and samples of benign testis, colon, adrenal and kidney. The two groups of metastatic lesions were also subjected to stains with antibodies to PSA. A composite score (ranging from 0 to 3 was assigned to score intensity of staining. Results Granular staining pattern of p501s was seen in all benign glands (score = 1.77 – 2.1 and malignant acini (score = 1.52 at the apical aspect of cytoplasm, predominantly adjacent to the nuclei. No staining was observed in controls including testis, colon, adrenal and kidney. The MLN group received a score of 1.0, with 10% of cases negative for p501s. The MC cases had a score of 0.64, with 16.7% of case showing loss of p501s expression. Although the metastatic lesions demonstrated similar rate of negative expression with PSA antibody, only 2 MC cases (3.3% showed simultaneous negative stains for both P501S and PSA. Conclusion P501

  1. Molecular Heterogeneity in Primary and Metastatic Prostate Tumor Tissue

    Science.gov (United States)

    2015-06-01

    91), thyroid (94), cervical (95), brain (47), skin (87), prostate (63, 71, 72, 96), and colorectal cancer (92). In hepatocellular carcinoma, protein...Foxo3a, forkhead box O3; AR, androgen receptor; FAO, fatty acid oxidation; ACC2, acetyl-CoA carboxylases 2; NADPH, reduced form of nicotinamide

  2. Targeting Siah2 as Novel Therapy for Metastatic Prostate Cancer

    Science.gov (United States)

    2016-10-01

    Siah1/2 activity, which was found to effectively attenuate the growth of prostate cancer tumors in vivo when transplanted subcutaneously or...2015, and a ubiquitin workshop in China in June this year. Patent applications are expected upon further refining the Siah1/2 inhibitory peptide and

  3. Cabazitaxel:a new drug for metastatic prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Marijo Bilusic; William L Dahut

    2011-01-01

    @@ In Western countries, prostate cancer is the most common malignancy in men and ranks third in mortality.In 2010, an esti-mated 217 730 new cases are anticipated in the United States, and about 32 050 men are expected to die from the disease.

  4. LIGHT: A Novel Immunotherapy for Primary and Metastatic Prostate Cancer

    Science.gov (United States)

    2013-09-01

    overcome the suppressive activity of regulatory T cells while simultaneously inducing prostate cancer-specific immunity. LIGHT, a ligand for Herpes ...altering the tumor microenvironment by increasing NOS expression and compromising tumor immunosuppression via Tregs. REPORTABLE OUTCOMES 1. Oral ...13 APPENDICES Yan, Lisa Southern California Clinical and Translational Science Institute Oral Presentation- May 6, 2013 Forced LIGHT

  5. Critical questions in metastatic castration-resistant prostate cancer: Integrating emerging clinical evidence and guideline recommendations

    OpenAIRE

    2016-01-01

    Metastatic castration-resistant prostate cancer (CRPC) typically confers a poor prognosis, however, novel advances in treatment options, as well as biomarkers for monitoring disease response and progression, have recently helped improve survival rates. Additionally, new guidelines provide some direction on incorporating these new treatments but some confusion still exists among clinicians about best methods for initiating treatment and the optimal sequencing of agents to prolong survival. In ...

  6. EAU-ESTRO-SIOG Guidelines on Prostate Cancer. Part II: Treatment of Relapsing, Metastatic, and Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Cornford, Philip; Bellmunt, Joaquim; Bolla, Michel; Briers, Erik; De Santis, Maria; Gross, Tobias; Henry, Ann M; Joniau, Steven; Lam, Thomas B; Mason, Malcolm D; van der Poel, Henk G; van der Kwast, Theo H; Rouvière, Olivier; Wiegel, Thomas; Mottet, Nicolas

    2017-04-01

    To present a summary of the 2016 version of the European Association of Urology (EAU) - European Society for Radiotherapy & Oncology (ESTRO) - International Society of Geriatric Oncology (SIOG) Guidelines on the treatment of relapsing, metastatic, and castration-resistant prostate cancer (CRPC). The working panel performed a literature review of the new data (2013-2015). The guidelines were updated, and the levels of evidence and/or grades of recommendation were added based on a systematic review of the literature. Relapse after local therapy is defined by a rising prostate-specific antigen (PSA) level >0.2ng/ml following radical prostatectomy (RP) and >2ng/ml above the nadir after radiation therapy (RT). (11)C-choline positron emission tomography/computed tomography is of limited importance if PSA is 10ng/ml. Multiparametric magnetic resonance imaging and biopsy are important to assess biochemical failure following RT. Therapy for PSA relapse after RP includes salvage RT at PSA levels EAU-ESTRO-SIOG Guidelines on PCa summarise the most recent findings and advice for use in clinical practice. These PCa guidelines are the first endorsed by the European Society for Therapeutic Radiology and Oncology and the International Society of Geriatric Oncology and reflect the multidisciplinary nature of PCa management. A full version is available from the EAU office or online (http://uroweb.org/guideline/prostate-cancer/). In men with a rise in their PSA levels after prior local treatment for prostate cancer only, it is important to balance overtreatment against further progression of the disease since survival and quality of life may never be affected in many of these patients. For patients diagnosed with metastatic castrate-resistant prostate cancer, several new drugs have become available which may provide a clear survival benefit but the optimal choice will have to be made on an individual basis. Copyright © 2016 European Association of Urology. Published by Elsevier B

  7. How MMPs Impact Bone Responses to Metastatic Prostate Cancer

    Science.gov (United States)

    2011-04-30

    metastatic bone cancer: consensus recommendations from the Second Cambridge Conference. Clin Cancer Res 2008; 14: 6387-95. 10. Cackowski FC, Roodman GD...2005;184:1266–73. 20. Cackowski FC, Roodman GD. Perspective on the osteoclast: an an- giogenic cell? Ann N Y Acad Sci 2007;1117:12–25. 21. Bergers G...We are grateful to Kevin P. Weller and David K. Flaherty for their assistance with flow cytometry. Flow cytometry experiments were performed in the

  8. Acute Respiratory Distress Syndrome after Treatment of Metastatic Prostate Cancer with Taxotere: A Case Report and Literature Review

    Directory of Open Access Journals (Sweden)

    Ali Raufi

    2015-01-01

    Full Text Available Prostate cancer is the most common cancer in men. Docetaxel is a common chemotherapeutic agent that has proven its efficacy in the treatment of patients with both castration sensitive and resistant metastatic prostate cancer. We report a case of acute respiratory distress syndrome (ARDS in a patient with metastatic prostate cancer treated with docetaxel (Taxotere. ARDS is very rare but life threatening complication of docetaxel which requires aggressive supportive care and close monitoring. Better awareness and prompt diagnosis of this treatment related ARDS will improve the effectiveness and outcome of its management.

  9. Cabazitaxel as second-line or third-line therapy in patients with metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Kongsted, Per; Svane, Inge M; Lindberg, Henriette

    2016-01-01

    To compare treatment outcomes in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel (CA) as second-line or third-line therapy in the everyday clinical setting. Charts from 94 patients treated with CA as second-line (n=28) or third-line therapy (n=66) were...... evaluated. Common Terminology Criteria for Adverse Events were used to register grade 3-4 nonhematological toxicity during treatment with CA. Baseline metastatic castration-resistant prostate cancer-related prognostic factors, duration of therapy, and maximum prostate-specific antigen (PSA) percentage...

  10. Trends and Racial Differences in the Use of Androgen Deprivation Therapy for Metastatic Prostate Cancer

    Science.gov (United States)

    Carson, April P.; Howard, Daniel L.; Carpenter, William R.; Taylor, Yhenneko J.; Peacock, Sharon; Schenck, Anna P.; Godley, Paul A.

    2013-01-01

    Context Androgen deprivation therapy (ADT) is widely used to manage the symptoms of advanced prostate cancer and has been shown to slow the progression of the disease. Previous research investigating racial differences in the use of ADT has reported inconsistent findings. Objectives The purpose of this study was to assess use trends for ADT overall and by type (orchiectomy and luteinizing hormone-releasing hormone [LHRH] agonists) and the factors associated with time to receipt for metastatic prostate cancer. Methods Data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry and Medicare claims database were obtained for 5,273 men, aged 65 years and older and diagnosed with Stage IV prostate cancer during 1991–1999 from seven SEER regions. An accelerated failure time regression model with lognormal distribution was used to examine factors associated with mean time to receipt of ADT. Results African-American men were less likely than white men to receive any ADT after diagnosis (P management of metastatic prostate cancer. PMID:20471547

  11. LIGHT: A Novel Immunotherapy for Primary and Metastatic Prostate Cancer

    Science.gov (United States)

    2012-09-01

    Membrane bound LIGHT was detected via flow cytometry with LTR-Fc antibody . Expression of LIGHT correlates with the mRNA expression level, where 24 hours...prostate cancer but their regulatory T cells may be depleted via administration of diphtheria toxin. The advantage of using this transgenic mouse...Tumors were homogenized and supernatant was collected for a multiplex ELISA , Bioplex Assay (Figure 4). The following cytokines/chemokines were analyzed

  12. LIGHT: A Novel Immunotherapy for Primary and Metastatic Prostate Cancer

    Science.gov (United States)

    2015-11-01

    mitigat instrument LIGHT dra ls. TRAMP-C t were either u ere analyzed ulations. Tum ith the Gent a Lympholyt low cytometry er forced ex 1.3 require...microenvironment. In an HPV induced cervical cancer model, forced LIGHT expression induced naïve T cells recruitment into the tumor microenvironment... HPV -specific immunity and increased overall mice survival. Forced LIGHT expression has not been studied in a prostate cancer setting where tolerance

  13. Influence of BMPs on the formation of osteoblastic lesions in metastatic prostate cancer.

    Science.gov (United States)

    Feeley, Brian T; Gamradt, Seth C; Hsu, Wellington K; Liu, Nancy; Krenek, Lucie; Robbins, Paul; Huard, Johnny; Lieberman, Jay R

    2005-12-01

    The purpose of this study was to evaluate the role of BMPs on the formation of metastatic prostate cancer lesions to bone. Our results show that BMPs influence the development and progression of osteoblastic lesions and suggest that therapies that inhibit BMP activity may reduce the formation and progression of osteoblastic lesions. Prostate adenocarcinoma is the leading cause of cancer in North American men. The formation of skeletal metastases affects approximately 70% of patients with advanced disease, and a majority of these patients have osteoblastic lesions. Although BMPs have been found to be expressed in multiple oncogenic cell lines, their role in the formation of metastatic osteoblastic lesions remains uncharacterized. We hypothesized that BMPs influence the development of metastatic osteoblastic lesions associated with prostate cancer. Western blot analysis and RT-PCR was used to determine BMP receptor expression on osteoblastic prostate cancer cell lines LAPC-4 and LAPC-9. Migration, invasion, and cellular proliferation assays were used to quantify the effects of BMP-2, -4, and -7 on LAPC-4 cells in vitro. LAPC-9 cells alone or transfected with a retrovirus overexpressing noggin were injected into the tibias of SCID mice, and the animals were followed for 8 weeks. Tumor size was determined by radiographs and direct measurement. Histology was performed at the time of death. We determined that BMP receptor mRNA and protein was expressed on osteoblastic prostate cancer cell lines LAPC-4 and LAPC-9. In vitro studies showed that BMP-2 and -7 stimulated cellular migration and invasion of prostate cancer cells in a dose-dependent fashion, although BMP-4 had no effect. Noggin inhibited cellular migration and invasion of BMP-2- and -7-stimulated LAPC-4 cells. LAPC-9 cells implanted into immunodeficient mouse tibias formed an osteoblastic lesion with sclerotic bone at 8 weeks. Formation of osteoblastic lesions was inhibited by overexpression of noggin by prostate

  14. PrognosticValue of PINP,BoneAlkaline Phosphatase, CTX-I, andYKL-40 in Patients With Metastatic Prostate Carcinoma

    DEFF Research Database (Denmark)

    Brasso, Klaus; Christensen, Ib Jarle; Johansen, Julia S

    2006-01-01

    Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma. Prostate. 2006 Apr 1;66(5):503-13. PMID: 16372331 [PubMed - indexed for MEDLINE]......Prognostic value of PINP, bone alkaline phosphatase, CTX-I, and YKL-40 in patients with metastatic prostate carcinoma. Prostate. 2006 Apr 1;66(5):503-13. PMID: 16372331 [PubMed - indexed for MEDLINE]...

  15. Targeting Met and VEGFR Axis in Metastatic Castration-Resistant Prostate Cancer: 'Game Over'?

    Science.gov (United States)

    Modena, Alessandra; Massari, Francesco; Ciccarese, Chiara; Brunelli, Matteo; Santoni, Matteo; Montironi, Rodolfo; Martignoni, Guido; Tortora, Giampaolo

    2016-08-01

    Despite recent advances that have been made in the therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC), effective management of bone metastases remains a key goal not yet reached. The receptor tyrosine kinase MET and the vascular endothelial growth factor receptor (VEGFR) seem to play an important role in prostate cancer progression and pathological bone turnover, representing potential targets for improving clinical outcomes in mCRPC. Studies evaluating agents that target one or both these pathways have demonstrated modest activity but no improvement in overall survival. Nevertheless, this therapeutic strategy seems to still be a promising and engaging area of prostate cancer research and the interest in better understanding the MET/VEGFR axis and the mechanism of action of these inhibitors is growing. This review describes the rationale for targeting MET and VEGFR pathway in mCRPC and provides the clinical data available to date and an update on ongoing trials.

  16. Sarcosine Up-Regulates Expression of Genes Involved in Cell Cycle Progression of Metastatic Models of Prostate Cancer

    Science.gov (United States)

    Heger, Zbynek; Merlos Rodrigo, Miguel Angel; Michalek, Petr; Polanska, Hana; Masarik, Michal; Vit, Vitezslav; Plevova, Mariana; Pacik, Dalibor; Eckschlager, Tomas; Stiborova, Marie

    2016-01-01

    The effects of sarcosine on the processes driving prostate cancer (PCa) development remain still unclear. Herein, we show that a supplementation of metastatic PCa cells (androgen independent PC-3 and androgen dependent LNCaP) with sarcosine stimulates cells proliferation in vitro. Similar stimulatory effects were observed also in PCa murine xenografts, in which sarcosine treatment induced a tumor growth and significantly reduced weight of treated mice (p < 0.05). Determination of sarcosine metabolism-related amino acids and enzymes within tumor mass revealed significantly increased glycine, serine and sarcosine concentrations after treatment accompanied with the increased amount of sarcosine dehydrogenase. In both tumor types, dimethylglycine and glycine-N-methyltransferase were affected slightly, only. To identify the effects of sarcosine treatment on the expression of genes involved in any aspect of cancer development, we further investigated expression profiles of excised tumors using cDNA electrochemical microarray followed by validation using the semi-quantitative PCR. We found 25 differentially expressed genes in PC-3, 32 in LNCaP tumors and 18 overlapping genes. Bioinformatical processing revealed strong sarcosine-related induction of genes involved particularly in a cell cycle progression. Our exploratory study demonstrates that sarcosine stimulates PCa metastatic cells irrespectively of androgen dependence. Overall, the obtained data provides valuable information towards understanding the role of sarcosine in PCa progression and adds another piece of puzzle into a picture of sarcosine oncometabolic potential. PMID:27824899

  17. Fluid biopsy in patients with metastatic prostate, pancreatic and breast cancers

    Science.gov (United States)

    Marrinucci, Dena; Bethel, Kelly; Kolatkar, Anand; Luttgen, Madelyn S.; Malchiodi, Michael; Baehring, Franziska; Voigt, Katharina; Lazar, Daniel; Nieva, Jorge; Bazhenova, Lyudmila; Ko, Andrew H.; Korn, W. Michael; Schram, Ethan; Coward, Michael; Yang, Xing; Metzner, Thomas; Lamy, Rachelle; Honnatti, Meghana; Yoshioka, Craig; Kunken, Joshua; Petrova, Yelena; Sok, Devin; Nelson, David; Kuhn, Peter

    2012-02-01

    Hematologic spread of carcinoma results in incurable metastasis; yet, the basic characteristics and travel mechanisms of cancer cells in the bloodstream are unknown. We have established a fluid phase biopsy approach that identifies circulating tumor cells (CTCs) without using surface protein-based enrichment and presents them in sufficiently high definition (HD) to satisfy diagnostic pathology image quality requirements. This 'HD-CTC' assay finds >5 HD-CTCs mL-1 of blood in 80% of patients with metastatic prostate cancer (n = 20), in 70% of patients with metastatic breast cancer (n = 30), in 50% of patients with metastatic pancreatic cancer (n = 18), and in 0% of normal controls (n = 15). Additionally, it finds HD-CTC clusters ranging from 2 HD-CTCs to greater than 30 HD-CTCs in the majority of these cancer patients. This initial validation of an enrichment-free assay demonstrates our ability to identify significant numbers of HD-CTCs in a majority of patients with prostate, breast and pancreatic cancers.

  18. Vascular Differences Detected by MRI for Metastatic Versus Nonmetastatic Breast and Prostate Cancer Xenografts

    Directory of Open Access Journals (Sweden)

    Zaver M. Bhujwalla

    2001-01-01

    Full Text Available Several studies have linked vascular density, identified in histologic sections, to “metastatic risk.” Functional information of the vasculature, not readily available from histologic sections, can be obtained with contrast-enhanced MRI to exploit for therapy or metastasis prevention. Our aims were to determine if human breast and prostate cancer xenograffs preselected for differences in invasive and metastatic characteristics established correspondingly different vascular volume and permeability, quantified here with noninvasive MRI of the intravascular contrast agent albumin-GdDTPA. Tumor vascular volume and permeability of human breast and prostate cancer xenografts were characterized using MRI. Parallel studies confirmed the invasive behavior of these cell lines. Vascular endothelial growth factor (VEGF expression in the cell lines was measured using ELISA and Western blots. Metastasis to the lungs was evaluated with spontaneous as well as experimental assay. Metastatic tumors formed vasculature with significantly higher permeability or vascular volume (P < .05, two-sided unpaired t test. The permeability profile matched VEGF expression. Within tumors, regions of high vascular volume usually exhibited low permeability whereas regions of low vascular volume exhibited high permeability. We observed that although invasion was necessary, without adequate vascularization it was not sufficient for metastasis to occur.

  19. Disseminated intravascular coagulation in a patient with metastatic prostate cancer: Fatal outcome following strontium-89 therapy

    Energy Technology Data Exchange (ETDEWEB)

    Leong, C.; McKenzie, R.; Coupland, D.B. [Univ. of British Columbia, (Canada)] [and others

    1994-10-01

    A patient with metastatic prostate cancer was found to have low-grade disseminated intravascular coagulation (DIC). He had significant bone pain despite external-beam radiotherapy and was given {sup 89}Sr with subsequent thrombocytopenia and epistaxis. The patient died from generalized hemorrhage 36 days postinjection. Although it is not possible to establish a causal relationship between {sup 89}Sr and DIC, practitioners should be alert to complications associated with the primary disorder which might occur at a time to raise concern about the intervention. 8 refs., 1 tab.

  20. Enzalutamide Antitumour Activity Against Metastatic Castration-resistant Prostate Cancer Previously Treated with Docetaxel and Abiraterone

    DEFF Research Database (Denmark)

    Brasso, Klaus; Thomsen, Frederik B; Schrader, Andres J

    2015-01-01

    , AND PARTICIPANTS: Metastatic castration-resistant prostate cancer patients entering one of four European compassionate use programmes of enzalutamide. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was overall survival (OS). Secondary end points were association between OS and posttreatment...... prostate-specific antigen (PSA) kinetics, patient characteristics, and progression-free survival, respectively. Kaplan-Meier survival analysis and Cox proportional hazard analysis were performed. RESULTS AND LIMITATIONS: We identified 137 patients who prior to enzalutamide had progressed following a median....... Patients who had more than 30% or 50% falls in PSA had improved survival compared with patients who had no such PSA fall (11.4 mo vs 7.1 mo; p=0.001 and 12.6 vs 7.4 mo; p=0.007, respectively). Poor performance status and low haemoglobin was negatively associated with OS. CONCLUSIONS: Median OS...

  1. Complete Response to Bicalutamide Withdrawal Prolonged for Almost 2 Years in Patients With Metastatic Prostate Cancer.

    Science.gov (United States)

    Hongo, Hiroshi; Kosaka, Takeo; Oya, Mototsugu

    2014-09-01

    This is the first case report describing a complete response to bicalutamide withdrawal that lasted for almost 2 years in a patient with metastatic prostate cancer. An 80-year-old man who had prostate-specific antigen (PSA) level elevation (168.1 ng/mL) visited our hospital in February 2010. Bone scintigraphy showed pelvic metastases. We started hormonal therapy with leuprorelin and bicalutamide. The PSA concentration decreased to <0.1 ng/mL but started increasing again and reached 1.64 ng/mL in October 2012, at which time bicalutamide administration was discontinued. The PSA concentration decreased again and has remained below the limit of sensitivity for almost 2 years.

  2. miR-129-3p controls centrosome number in metastatic prostate cancer cells by repressing CP110.

    Science.gov (United States)

    Bijnsdorp, Irene V; Hodzic, Jasmina; Lagerweij, Tonny; Westerman, Bart; Krijgsman, Oscar; Broeke, Jurjen; Verweij, Frederik; Nilsson, R Jonas A; Rozendaal, Lawrence; van Beusechem, Victor W; van Moorselaar, Jeroen A; Wurdinger, Thomas; Geldof, Albert A

    2016-03-29

    The centrosome plays a key role in cancer invasion and metastasis. However, it is unclear how abnormal centrosome numbers are regulated when prostate cancer (PCa) cells become metastatic. CP110 was previously described for its contribution of centrosome amplification (CA) and early development of aggressive cell behaviour. However its regulation in metastatic cells remains unclear. Here we identified miR-129-3p as a novel metastatic microRNA. CP110 was identified as its target protein. In PCa cells that have metastatic capacity, CP110 expression was repressed by miR-129-3p. High miR-129-3p expression levels increased cell invasion, while increasing CP110 levels decreased cell invasion. Overexpression of CP110 in metastatic PCa cells resulted in a decrease in the number of metastasis. In tissues of PCa patients, low CP110 and high miR-129-3p expression levels correlated with metastasis, but not with the expression of genes related to EMT. Furthermore, overexpression of CP110 in metastatic PCa cells resulted in excessive-CA (E-CA), and a change in F-actin distribution which is in agreement with their reduced metastatic capacity. Our data demonstrate that miR-129-3p functions as a CA gatekeeper in metastatic PCa cells by maintaining pro-metastatic centrosome amplification (CA) and preventing anti-metastatic E-CA.

  3. The Effect of Multiplicity of Metastatic Sites on Hormone Refractory Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Amal Halim

    2012-10-01

    Full Text Available Background: This study retrospectively evaluated the prognostic factors and treatment outcome of patients with hormone-refractory prostate cancer who received chemotherapy.Methods: We reviewed records of hormone-refractory prostate cancer patients who received chemotherapy between December 2004 and May 2011 at the Clinical Oncology and Nuclear Medicine Department, Mansoura University and the Oncology Outpatient Clinic of East Delta Insurance Institute, Egypt with regards to patient characteristics, response to chemotherapy, toxicity, survival and prognostic factors.Results: A total of 37 records were analyzed. Patients' median age was 66 years. The majority (70% had bone metastases. One patient received single agent prednisolone and 2 received single agent vinorelbine. There were 34 (92% who received a docetaxel based chemotherapy regimen for whom we determined the treatment outcome andprognostic factors. Patients underwent a median of six cycles of treatment (range: 4–11. Fourteen of 34 patients (%41 had ≥50% decrease in serum prostatic-surface antigen. Among 16 patients who had measurable disease at the baseline, 8 (50% achieved a partial response according to radiographic criteria. Of the 25 patients who experienced cancer pain before treatment initiation, 15 (60% reduced their analgesic drug intake. Grades 3-4 neutropenia occurred in 13 (38% patients. The median follow-up period was 13 months and the median event-free survival was 7 months (range: 4-31. The median overall survival period was 12 months (range: 4.5-37. According to multivariate regression analysis, multiplicity of metastatic sites was the only independent prognostic factor (P=0.005.Conclusions: Hormone-refractory prostate cancer is not considered totally resistant to chemotherapy. In this study, multiplicity of metastatic sites is the only independent prognostic factor. Survival figures are not satisfactory, therefore additional research is needed for achieving a better

  4. The CT flare response of metastatic bone disease in prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Messiou, Christina; deSouza, Nandita M. (Cancer Research UK Clinical Magnetic Resonance Research Group, Inst. of Cancer Research and Royal Marsden NHS Foundation Trust, Surrey (United Kingdom)), email: Christina.Messiou@icr.ac.uk; Cook, Gary (Dept. of Nuclear Medicine, Royal Marsden NHS Foundation Trust, Surrey (United Kingdom)); Reid, Alison H.M.; Attard, Gerhardt; Dearnaley, David; deBono, Johann S. (Inst. of Cancer Research and Royal Marsden NHS Foundation Trust, Surrey (United Kingdom))

    2011-06-15

    Background New or worsening bone lesions in patients responding to treatment, known as the flare phenomenon is well described on 99mTc-MDP bone scintigraphy, but to our knowledge has not previously been described on CT. The appearance of new or worsening bone sclerosis on CT in patients with prostate cancer may therefore be erroneously classified as disease progression. Purpose To assess the incidence of osteoblastic healing flare response at 3-month CT assessment in patients with castrate-resistant prostate cancer and to identify associated features that enable differentiation from progressive metastatic bone disease at 3 months. Material and Methods CT scans of 67 patients with castrate-resistant prostate cancer undergoing treatment were reviewed by a radiologist blinded to clinical outcome. Changes in number, size, and density of metastatic bone lesions were documented and Response Evaluation Criteria in Solid Tumours (RECIST) in soft tissue lesions, alkaline phosphatase, prostate specific antigen, and 99mTc-MDP bone scans were used for correlation. Results Of the 39 patients who had 3- and 6-month follow-up, eight patients (21%) demonstrated an increase in number, size, or density of sclerotic lesions on the 3-month CT scan despite improvement in PSA and soft tissue lesions. Three out of eight patients (8%) maintained partial response/remained stable at follow-up and were defined as showing a flare response: in this group bone metastases evident on CT showed a qualitative and quantitative increase in density and no lesions faded at 3 months. In contrast, in all patients who progressed at 3 months by PSA/RECIST criteria (n = 8) bone lesions showed a mixed pattern with some lesions increasing and others decreasing in density. Conclusion The incidence of flare response of metastatic bone disease evident at 3-month post-treatment CT in patients with prostate cancer undergoing systemic treatment is 8%. In patients with falling PSA and stable/responding soft tissue

  5. Treatment Outcomes in Non-Metastatic Prostate Cancer Patients With Ultra-High Prostate-Specific Antigen

    Energy Technology Data Exchange (ETDEWEB)

    Tai, Patricia, E-mail: ptai2@yahoo.com [Saskatchewan Cancer Agency, Regina, SK (Canada); Tonita, Jon; Woitas, Carla; Zhu Tong [Saskatchewan Cancer Agency, Regina, SK (Canada); Joseph, Kurian [Department of Oncology, Cross Cancer Institute, University of Alberta, Calgary, AB (Canada); Skarsgard, David [Department of Oncology, Tom Baker Cancer Center, University of Alberta, Calgary, AB (Canada)

    2012-07-15

    Purpose: It is commonly believed that prostate cancer patients with very high prostate-specific antigen (PSA) levels are unlikely to benefit from definitive local treatment, and patients with very high PSA are often underrepresented in, or excluded from, randomized clinical trials. Consequently, little is known about their optimal treatment or prognosis. We performed a registry-based analysis of management and outcome in this population of patients. Methods and Materials: Our provincial Cancer Registry was used to identify all men who were diagnosed with prostate cancer from 1990 to 2001. A retrospective chart review provided information on stage, Gleason score, PSA at diagnosis, and treatment. In this study, ultra-high PSA was defined as PSA of {>=}50 ng/ml. For a more complete perspective, treatment outcomes of patients with PSA of 20 to 49.9 ng/ml were also studied. Results: Of the 8378 men diagnosed with prostate cancer during this period, 6,449 had no known nodal or distant metastatic disease. The median follow-up of this group was 67.2 months (range, 0-192 months). A total of 1534 patients had PSA of {>=}20 ng/ml. Among the 995 patients with PSA 20 to 49.9 ng/ml, 85 had radical prostatectomy (RP), and their 5- and 10-year cause-specific survivals (CSS) were 95% and 84%, respectively. The 497 patients treated with radiotherapy (RT) had 5- and 10-year CSS of 92% and 71%. For the 332 patients with PSA 50-99.9 ng/ml, RT was associated with 5- and 10-year CSS of 81% and 55%. For the 207 patients with PSA of {>=}100 ng/ml, RT was associated with 5- and 10-year CSS of 80% and 54%. Conclusions: This is the largest series in the world on non metastatic cancer patients with ultra-high PSA at diagnosis. Even in the setting of a very high presenting PSA level, prostatectomy and radiotherapy are often associated with prolonged survival.

  6. Optimal Sequencing of New Drugs in Metastatic Castration-Resistant Prostate Cancer: Dream or Reality?

    Science.gov (United States)

    Caffo, Orazio; Lunardi, Andrea; Trentin, Chiara; Maines, Francesca; Veccia, Antonello; Galligioni, Enzo

    2016-01-01

    The availability of new drugs capable of improving the overall survival of patients with metastatic castration-resistant prostate cancer has led to the possibility of using them sequentially in the hope of obtaining a cumulative survival benefit. The new agents have already been administered as third-line treatments in patients who have previously received them as second line in everyday clinical practice, but the efficacy of this practice is not yet supported by clinical trial data, and evidence of possible cross-resistance has reinforced the debate concerning the best sequence to use in order to maximise the benefit. Furthermore, the situation is further complicated by the possibility of administering new hormonal agents to chemotherapy-naïve patients, and novel chemotherapeutic agents to hormone-sensitive patients. This article critically reviews the available data concerning the sequential use of new drugs, and discusses the real evidence concerning their optimal positioning in the therapeutic strategy of metastatic castration-resistant prostate cancer.

  7. Chimeric antigen receptor-engineered T cells for the treatment of metastatic prostate cancer.

    Science.gov (United States)

    Hillerdal, Victoria; Essand, Magnus

    2015-04-01

    Cancer immunotherapy was selected as the Breakthrough of the Year 2013 by the editors of Science, in part because of the successful treatment of refractory hematological malignancies with adoptive transfer of chimeric antigen receptor (CAR)-engineered T cells. Effective treatment of B cell leukemia may pave the road to future treatment of solid tumors, using similar approaches. The prostate expresses many unique proteins and, since the prostate gland is a dispensable organ, CAR T cells can potentially be used to target these tissue-specific antigens. However, the location and composition of prostate cancer metastases complicate the task of treating these tumors. It is therefore likely that more sophisticated CAR T cell approaches are going to be required for prostate metastasis than for B cell malignancies. Two main challenges that need to be resolved are how to increase the migration and infiltration of CAR T cells into prostate cancer bone metastases and how to counteract the immunosuppressive microenvironment found in bone lesions. Inclusion of homing (chemokine) receptors in CAR T cells may improve their recruitment to bone metastases, as may antibody-based combination therapies to normalize the tumor vasculature. Optimal activation of CAR T cells through the introduction of multiple costimulatory domains would help to overcome inhibitory signals from the tumor microenvironment. Likewise, combination therapy with checkpoint inhibitors that can reduce tumor immunosuppression may help improve efficacy. Other elegant approaches such as induced expression of immune stimulatory cytokines upon target recognition may also help to recruit other effector immune cells to metastatic sites. Although toxicities are difficult to predict in prostate cancer, severe on-target/off-tumor toxicities have been observed in clinical trials with use of CAR T cells against hematological malignancies; therefore, the choice of the target antigen is going to be crucial. This review

  8. TH-E-BRF-08: Subpopulations of Similarly-Responding Lesions in Metastatic Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Lin, C; Harmon, S; Perk, T; Jeraj, R [University of Wisconsin - Madison, Madison, WI (United States)

    2014-06-15

    Purpose: In patients with multiple lesions, resistance to cancer treatments and subsequent disease recurrence may be due to heterogeneity of response across lesions. This study aims to identify subpopulations of similarly-responding metastatic prostate cancer lesions in bone using quantitative PET metrics. Methods: Seven metastatic prostate cancer patients treated with AR-directed therapy received pre-treatment and mid-treatment [F-18]NaF PET/CT scans. Images were registered using an articulated CT registration algorithm and transformations were applied to PET segmentations. Midtreatment response was calculated on PET-based texture features. Hierarchical agglomerative clustering was used to form groups of similarly-responding lesions, with the number of natural clusters (K) determined by the inconsistency coefficient. Lesion clustering was performed within each patient, and for the pooled population. The cophenetic coefficient (C) quantified how well the data was clustered. The Jaccard Index (JI) assessed similarity of cluster assignments from patient clustering and from population clustering. Results: 188 lesions in seven patients were identified for analysis (between 6 to 53 lesions per patient). Lesion response was defined as percent change relative to pre-treatment for 23 uncorrelated PET-based feature identifiers. . High response heterogeneity was found across all lesions (i.e. range ΔSUVmax =−95.98% to 775.00%). For intra-patient clustering, K ranged from 1–20. Population-based clustering resulted in 75 clusters, of 1-6 lesions each. Intra-patient clustering resulted in higher quality clusters than population clustering (mean C=0.95, range=0.89 to 1.00). For all patients, cluster assignments from population clustering showed good agreement to intra-patient clustering (mean JI=0.87, range=0.68 to 1.00). Conclusion: Subpopulations of similarly-responding lesions were identified in patients with multiple metastatic lesions. Good agreement was found between

  9. Locoregional symptoms in patients with de novo metastatic prostate cancer: Morbidity, management, and disease outcome.

    Science.gov (United States)

    Patrikidou, Anna; Brureau, Laurent; Casenave, Julien; Albiges, Laurence; Di Palma, Mario; Patard, Jean-Jacques; Baumert, Hervé; Blanchard, Pierre; Bossi, Alberto; Kitikidou, Kyriaki; Massard, Christophe; Fizazi, Karim; Blanchet, Pascal; Loriot, Yohann

    2015-05-01

    The paradigm change observed over the last few years in several solid tumors emphasizes the value of locoregional treatment in the presence of metastatic disease, currently ignored in de novo prostate cancer (CaP). We investigated the effect of the primary tumor that is left untreated on prostate cancer-specific morbidity and mortality, time to castration resistance, and overall survival (OS). We performed a bicentric cohort study. The overall population included de novo metastatic CaP managed at the Genito-Urinary Oncology Unit of the Gustave Roussy Institute and the Urology Clinic of the University Hospital of Pointe-à-Pitre, France. Descriptive statistical and outcome analyses were performed in the overall cohort and also separately in the N+M0 and M+subgroups. The overall cohort included 263 patients. Approximately two-thirds of patients (64%) presented with locoregional symptoms at diagnosis, and 78% throughout the disease. Of the symptomatic patients, 59% required a locoregional procedure. Median OS of patients with locoregional symptoms at diagnosis was shorter than in those who were asymptomatic (47 vs. 86 mo, P = 0.0007); this difference was maintained in the N+M0 and M+subgroups. Median OS and time to castration resistance showed a nonsignificant trend in favor of patients undergoing a locoregional treatment at diagnosis. The presence of symptoms due to locoregional disease in de novo metastatic CaP entails significant morbidity and even mortality and requires active management. Randomized prospective trials are needed to evaluate the role of initial definite locoregional treatment in these patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  10. Association of body composition with outcome of docetaxel chemotherapy in metastatic prostate cancer: a retrospective review.

    Directory of Open Access Journals (Sweden)

    Weixin Wu

    Full Text Available Docetaxel, a lipophilic drug, is indicated for castration-resistant metastatic prostate cancer. Most men with such disease would have had androgen-deprivation therapy, which decreases muscle and increases body fat. Obesity and body composition changes may influence the outcomes of docetaxel therapy.We conducted a retrospective review of 333 patients with metastatic prostate cancer treated with docetaxel at a comprehensive cancer center between October 7, 2004 and December 31, 2012. Body composition parameters were measured based on the areas of muscle and adipose tissues in the visceral and subcutaneous compartments on CT images at L3-4 levels. Dose calculations, toxicity and adverse reaction profiles, and overall survival were analyzed.Obese patients were younger at the diagnosis of prostate cancer and had a shorter duration from diagnosis to docetaxel therapy. Analysis of body composition found that a high visceral fat-to-subcutaneous fat area ratio (VSR was associated with poor prognosis but a high visceral fat-to-muscle area ratio (VMR and high body mass index were associated with increased duration from starting docetaxel to death, allowing such men to catch up with patients with normal body mass index in overall survival from cancer diagnosis to death. Cox proportional hazard regression showed that age ≥65 years, high VSR, abnormal serum alkaline phosphatase, and >10% reduction of initial dosage were significant predictors of shorter time between starting docetaxel and death, and that high VMR, obesity, and weekly regimens were significant predictors of longer survival after docetaxel.Obese and overweight patients may benefit more from weekly docetaxel regimens using the reference dosage of 35 mg/m2 without empirical dosage reduction.

  11. Positron emission tomography (PET) with 11C-5-hydroxytryptophan (5-HTP) in patients with metastatic hormone-refractory prostatic adenocarcinoma.

    Science.gov (United States)

    Kälkner, K M; Ginman, C; Nilsson, S; Bergström, M; Antoni, G; Ahlström, H; Långström, B; Westlin, J E

    1997-05-01

    The discovery of neuroendocrine differentiation in hormone-refractory prostatic adenocarcinoma has opened a potentially new therapeutic approach in this group of patients with a poor prognosis and few effective therapy modalities. Based on previous findings of increased uptake of 11C-5-hydroxytryptophan (11C-5-HTP) in neuroendocrine tumours using the PET technique, this tracer was applied in the study of 10 patients with metastatic hormone-refractory prostatic adenocarcinoma. In three patients, the study was repeated after treatment. An increased uptake of 11C-5-HTP was observed in all investigated skeletal lesions, although the magnitude of the uptake was moderate. The difference between the standard uptake values (SUV) in normal bone and metastatic lesions was significant (p HTP demonstrates an increase during the first minutes followed by a wash-out and a stabilization of the tissue/blood ratio at about 2. The Patlak plots demonstrated a gradual increase in the transport rate during the first 20 to 30 min, after which a constant level was observed. The SUV varied between patients and between lesions over time and treatment. The uptake of 11C-5-HTP discriminates metastatic lesions from normal bone and may thus aid in the diagnosis and, potentially, in treatment monitoring of metastatic hormone-refractory prostatic adenocarcinoma. Uptake kinetics are characterized by a wash-out and cannot alone be used as proof of neuroendocrine differentiation in hormone-refractory prostatic adenocarcinoma.

  12. Sipuleucel-T: Autologous Cellular Immunotherapy for Men with Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Robert B. Sims

    2011-01-01

    Full Text Available Sipuleucel T is an autologous cellular immunotherapy designed to stimulate an immune response in men diagnosed with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory prostate cancer. Sipuleucel T improves overall survival and provides an additional treatment option for this patient population.

  13. Sipuleucel-T: autologous cellular immunotherapy for men with asymptomatic or minimally symptomatic metastatic castrate resistant prostate cancer.

    Science.gov (United States)

    Sims, Robert B

    2011-01-01

    Sipuleucel T is an autologous cellular immunotherapy designed to stimulate an immune response in men diagnosed with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Sipuleucel T improves overall survival and provides an additional treatment option for this patient population.

  14. Sipuleucel-T: Autologous Cellular Immunotherapy for Men with Asymptomatic or Minimally Symptomatic Metastatic Castrate Resistant Prostate Cancer

    OpenAIRE

    Sims, Robert B.

    2011-01-01

    Sipuleucel T is an autologous cellular immunotherapy designed to stimulate an immune response in men diagnosed with asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer. Sipuleucel T improves overall survival and provides an additional treatment option for this patient population.

  15. Yes-mediated phosphorylation of focal adhesion kinase at tyrosine 861 increases metastatic potential of prostate cancer cells

    NARCIS (Netherlands)

    Chatterji, T.; Varkaris, A.S.; Parikh, N.U.; Song, J.H.; Cheng, C.J.; Schweppe, R.E.; Alexander, S.; Davis, J.W.; Troncoso, P.; Friedl, P.H.; Kuang, J.; Lin, S.H.; Gallick, G.E.

    2015-01-01

    To study the role of FAK signaling complexes in promoting metastatic properties of prostate cancer (PCa) cells, we selected stable, highly migratory variants, termed PC3 Mig-3 and DU145 Mig-3, from two well-characterized PCa cell lines, PC3 and DU145. These variants were not only increased migration

  16. Cabazitaxel in patients with metastatic castration-resistant prostate cancer: results of a compassionate use program in the Netherlands

    NARCIS (Netherlands)

    Wissing, M.D.; Oort, I.M. van; Gerritsen, W.R.; Eertwegh, A.J. van den; Coenen, J.L.; Bergman, A.M.; Gelderblom, H.

    2013-01-01

    BACKGROUND: Cabazitaxel has been reimbursed as a second-line therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC) in the Netherlands since 2011. Before reimbursement was available, cabazitaxel was provided through a Compassionate Use Program (CUP). We report the results of

  17. Supraclavicular lymphadenopathy as the initial presentation of metastatic prostate cancer: A case report and review of literature

    Science.gov (United States)

    Chan, Garson; Domes, Trustin

    2013-01-01

    Prostate cancer usually metastasizes to the regional lymph nodes, and distal metastases to supraclavicular lymph nodes are rarely reported, especially as an initial presentation. Limited case reports describe cervical lymphadenopathy as the initial presentation of metastatic prostate cancer, and often with widely disseminated disease. Patients with this initial presentation rarely undergo digital rectal examination or serum prostate-specific antigen (PSA) level measurement as part of their initial investigations. A high index of suspicion is necessary to make the diagnosis of prostate cancer in this clinical setting. We present a rare case of prostate carcinoma presenting with supraclavicular lymph node enlargement at the initial diagnosis. A review of the relevant literature is provided. PMID:23826058

  18. Metastatic adenocarcinoma of prostate in a 28-year-old male: The outcome is poor in young patients?

    Directory of Open Access Journals (Sweden)

    Renu Madan

    2015-01-01

    Full Text Available Prostate cancer is common in older patients. Rarity in younger population limits the study of natural history and prognosis in this population. Most of the published data has reported poor outcome in younger patients with metastatic prostate cancer. Here, we report a case of prostate cancer in 28-year-old male who presented with bone metastasis. After bilateral inguinal orchidectomy, he was started on anti-androgen therapy and received palliative radiotherapy for bone metastasis. There was only a slight decrease in prostate-specific antigen (PSA level and pelvic disease post treatment. Subsequently, he was started on opioid analgesics (by World Health Organization, WHO, step ladder in view of persistent pain. The index case is being presented for its rarity and probable poor outcome in young patients and to stress on the fact that the possibility of primary prostatic adenocarcinoma should be investigated in a male presenting with bone metastasis irrespective of the age.

  19. Contemporary agents in the management of metastatic castration-resistant prostate cancer

    Science.gov (United States)

    Kapoor, Anil; Wu, Christopher; Shayegan, Bobby; Rybak, Adrian P.

    2016-01-01

    Docetaxel-based chemotherapy has been the standard of care for metastatic castration-resistant prostate cancer (mCRPC) since 2004. Over the past few years, there has been a significant paradigm shift in the treatment landscape of this disease. A deeper understanding of prostate cancer biology, along with the development of novel agents has created hope towards treating chemotherapy-naïve and resistant disease. Following the implementation of docetaxel as the first-line therapy for mCRPC, five novel therapies have demonstrated survival benefit in mCRPC. Cabazitaxel, abiraterone acetate, and enzalutamide are three agents recently approved for the treatment of mCRPC, having shown overall survival benefit in patients previously treated with docetaxel, while both abiraterone acetate and enzalutamide have also shown promise in the pre-docetaxel setting. Sipuleucel-T has shown overall survival benefit in asymptomatic mCRPC, while radium-223 provides survival benefit to patients with mCRPC who are symptomatic from their skeletal metastases in both docetaxel-naïve patients and post-docetaxel patients. Denosumab, an anti-RANKL antibody, has been approved for the prevention of skeletal-related events in patients with prostate cancer bone metastases. This review examines the phase 3 trials supporting the use of theses novel agents in the treatment of mCRPC. While these agents provide incremental increases in patient survival, further study to determine the best choice, combination, and/or sequencing of administration is still necessary. PMID:28096932

  20. Combined effects of terazosin and genistein on a metastatic, hormone-independent human prostate cancer cell line.

    Science.gov (United States)

    Chang, Kee-Lung; Cheng, Hsiao-Ling; Huang, Li-Wen; Hsieh, Bau-Shan; Hu, Yu-Chen; Chih, Tsai-Tung; Shyu, Huey-Wen; Su, Shu-Jem

    2009-04-08

    Metastatic prostate cancer progresses from androgen-dependent to androgen-independent. Terazosin, a long-acting selective alpha1-adrenoreceptor antagonist, induces apoptosis of prostate cancer cells in an alpha1-adrenoreceptor-independent manner, while genistein, a major soy isoflavone, inhibits the growth of several types of cancer cells. The present study was designed to test the therapeutic potential of a combination of terazosin and genistein using a metastatic, hormone-independent prostatic cancer cell line, DU-145. Terazosin or genistein treatment inhibited the growth of DU-145 cells in a dose-dependent manner, whereas had no effect on normal prostate epithelial cells. Addition of 1 microg/ml of terazosin, which was inactive alone, augmented the growth inhibitory effect of 5 microg/ml of genistein. Co-treatment with terazosin resulted in the genistein-induced arrest of DU-145 cells in G2/M phase being overridden and an increase in apoptotic cells, as evidenced by procaspase-3 activation and PARP cleavage. The combination also caused a greater decrease in the levels of the apoptosis-regulating protein, Bcl-XL, and of VEGF165 and VEGF121 than genistein alone. In conclusion, the terazosin/genistein combination was more effective in inhibiting cell growth and VEGF expression as well as inducing apoptosis of the metastatic, androgen-independent prostate cancer cell line, DU-145, than either alone. The doses used in this study are in lower and nontoxic anticancer dosage range, suggesting this combination has potential for therapeutic use.

  1. uPAR Targeted Radionuclide Therapy with 177Lu-DOTA-AE105 Inhibits Dissemination of Metastatic Prostate Cancer

    DEFF Research Database (Denmark)

    Persson, Morten; Juhl, Karina; Rasmussen, Palle

    2014-01-01

    value of 100 nM in a competitive binding experiment. In vivo, uPAR targeted radionuclide therapy significantly reduced the number of metastatic lesions in the disseminated metastatic prostate cancer model, when compared to vehicle and nontargeted 177Lu groups (p bioluminescence imaging...... with bioluminescence imaging in a cohort of animals during the treatment study. In conclusion, uPAR targeted radiotherapy resulted in a significant reduction in the number of metastatic lesions in a human metastatic prostate cancer model. Furthermore, we have provided the first evidence of the potential...

  2. Update on options for treatment of metastatic castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Prakash Vishnu

    2010-03-01

    Full Text Available Prakash Vishnu, Winston W TanDivision of Hematology Oncology, Mayo Clinic, Jacksonville, FL, USABackground: Prostate cancer is one of the most common cancers in men in US and European countries. Despite having a favorable prognosis, the incidence of incurable metastatic disease and mortality in the US is about 28,000 per year. Although hormone-based androgen deprivation therapies typically result in rapid responses, nearly all patients eventually develop progressive castration-resistant disease state. With readily available prostate-specific antigen (PSA testing, most of these patients are asymptomatic and manifest progression simply as a rising PSA. In patients with castration-resistant prostate cancer (CRPC, the median survival is about 1–2 years, with improvements in survival seen mostly with docetaxel-based regimens. The purpose of this article is to review the recent developments in the treatment of advanced CRPC.Recent findings: Since the two landmark trials (TAX-327 and Southwest Oncology Group 99–16 in CRPC, several newer cytotoxic drugs (epothilones, satraplatin, targeted agents (abiraterone, MDV3100 and vaccines have been tested in phase II and III setting with promising results.Conclusions: The role of newer agents in the treatment of CRPC still needs to be validated by phase III trials, which are currently ongoing. Whilst the novel biomarkers, ‘circulating tumor cells’, have been shown to provide important prognostic information and are anticipated to be incorporated in future clinical decision-making, their exact utility and relevance calls for a larger prospective validation.Keywords: castration-resistant prostate cancer, novel therapies, mechanisms of resistance, circulating tumor cells

  3. Serum methionine metabolites are risk factors for metastatic prostate cancer progression.

    Directory of Open Access Journals (Sweden)

    Sally Stabler

    Full Text Available BACKGROUND: Clinical decision for primary treatment for prostate cancer is dictated by variables with insufficient specificity. Early detection of prostate cancer likely to develop rapid recurrence could support neo-adjuvant therapeutics and adjuvant options prior to frank biochemical recurrence. This study compared markers in serum and urine of patients with rapidly recurrent prostate cancer to recurrence-free patients after radical prostatectomy. Based on previous identification of urinary sarcosine as a metastatic marker, we tested whether methionine metabolites in urine and serum could serve as pre-surgical markers for aggressive disease. METHODOLOGY/PRINCIPAL FINDINGS: Urine and serum samples (n = 54 and 58, respectively, collected at the time of prostatectomy were divided into subjects who developed biochemical recurrence within 2 years and those who remained recurrence-free after 5 years. Multiple methionine metabolites were measured in urine and serum by GC-MS. The role of serum metabolites and clinical variables (biopsy Gleason grade, clinical stage, serum prostate specific antigen [PSA] on biochemical recurrence prediction were evaluated. Urinary sarcosine and cysteine levels were significantly higher (p = 0.03 and p = 0.007 respectively in the recurrent group. However, in serum, concentrations of homocysteine (p = 0.003, cystathionine (p = 0.007 and cysteine (p<0.001 were more abundant in the recurrent population. The inclusion of serum cysteine to a model with PSA and biopsy Gleason grade improved prediction over the clinical variables alone (p<0.001. CONCLUSIONS: Higher serum homocysteine, cystathionine, and cysteine concentrations independently predicted risk of early biochemical recurrence and aggressiveness of disease in a nested case control study. The methionine metabolites further supplemented known clinical variables to provide superior sensitivity and specificity in multivariable prediction models for

  4. Can we improve the definition of high-risk, hormone naïve, non-metastatic prostate cancer?

    Science.gov (United States)

    Tombal, Bertrand; Alcaraz, Antonio; James, Nicholas; Valdagni, Riccardo; Irani, Jacques

    2014-02-01

    To identify criteria beyond Tumour-Node-Metastasis (TMN)-, prostate-specific antigen (PSA)- and Gleason score-based standard classifications to enhance the stratification of non-metastatic high-risk prostate cancer. A detailed search of the literature was performed using PubMed. The authors reviewed the literature and used a modified Delphi approach to identify relevant approaches to enhance standard classifications. Specific criteria for high-risk prostate cancer vary across guidelines and clinical trials, reflecting the differing perspectives concerning the definition of 'risk' between different specialities within the urology/radiation oncology community. In addition to the present classifications, evidence exists that the measure of cancer volume can provide additional prognostic value. More accurate imaging, especially multiparametric magnetic resonance imaging can also provide information concerning staging and cancer volume, and thus may assist in the identification of patients with high-risk prostate cancer. A refined definition of non-metastatic high-risk prostate cancer is proposed. Within this high-risk cohort, patients with multiple high-risk criteria are especially at risk of prostate cancer-specific mortality.

  5. Maximal androgen blockade versus castration alone in patients with metastatic prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Abeer A.Mahmoud; Eman A.El-Sharawy; Mohamed M.El-Bassiouny; Ramy R.Ghali

    2014-01-01

    Objective: Maximum androgen blockade (MAB), consisting of an antiandrogen plus either a luteinizing hormone-releasing hormone agonist (LHRHA) or orchiectomy, is a standard care for patients with prostate cancer. Although, clinical trial results have been equivocal, none has shown a significant advantage in favor of MAB over castration alone in metastatic prostate cancer and MAB has been the subject of considerable controversy. The aim of this study was to compare MAB (orchiectomy or LHRHA “Goserelin”) and anti-androgen “Bicalutamide” with castration alone (orchiectomy or LHRHA) in previ-ously untreated metastatic prostate cancer patients.Methods: Hundred eligible patients with adequate performance status and adequate hematologic, hepatic and renal functions were included. MAB arm, fifty patients underwent castration either surgicaly by orchiectomy or medicaly by receiving Goserelin (3.6 mg) depot, which was injected subcutaneously every 28 days plus bicalutamide 50 mg once daily. Castration alone arm, fifty patients underwent castration alone either surgicaly by orchiectomy or medicaly by receiving Goserelin (3.6 mg) depot.Results: During the period from January 2011 to January 2013, with a median folow up of 18 months (range 6 to 24 months), there were eight deaths (16%), in MAB arm and ten deaths (20%) in castration alone arm. At three months, there were 35 patients (70%) with prostate specific antigen (PSA) normalization (≤ 4 mg/dL) in MAB arm versus 17 patients (34%) with PSA normalization in castration alone arm (P = 0.001). The median progression free survival (PFS) times were 22.18 months (95% CI, 19.7 to 24.2 months) for MAB arm versus 22 months in castration alone arm (95% CI, 18 to 25.9 months;P = 0.045). The survival rates for MAB arm were 82% at 18 months and 70.6% at 24 months versus 78.7% at 18 months and 75.1% at 24 months in castration alone arm (P > 0.05). The median overal survival (OS) was not reached in either arm. Both hematological

  6. Robotic Image-Guided Stereotactic Radiotherapy, for Isolated Recurrent Primary, Lymph Node or Metastatic Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Jereczek-Fossa, Barbara Alicja, E-mail: barbara.jereczek@ieo.it [Department of Radiotherapy, European Institute of Oncology, Milan (Italy); University of Milan, Milan (Italy); Beltramo, Giancarlo [CyberKnife Center CDI, Milan (Italy); Fariselli, Laura [Radiotherapy Unit, Carlo Besta Neurological Institute Foundation, Milan (Italy); Fodor, Cristiana [Department of Radiotherapy, European Institute of Oncology, Milan (Italy); Santoro, Luigi [Department of Epidemiology and Statistics, European Institute of Oncology, Milan (Italy); Vavassori, Andrea; Zerini, Dario [Department of Radiotherapy, European Institute of Oncology, Milan (Italy); Gherardi, Federica [Department of Radiotherapy, European Institute of Oncology, Milan (Italy); University of Milan, Milan (Italy); Ascione, Carmen [Department of Radiotherapy, European Institute of Oncology, Milan (Italy); Seconda Universita degli Studi di Napoli, Naples (Italy); Bossi-Zanetti, Isa; Mauro, Roberta [Department of Radiotherapy, European Institute of Oncology, Milan (Italy); University of Milan, Milan (Italy); Bregantin, Achille; Bianchi, Livia Corinna [CyberKnife Center CDI, Milan (Italy); De Cobelli, Ottavio [Department of Urology, European Institute of Oncology, Milan (Italy); Orecchia, Roberto [Department of Radiotherapy, European Institute of Oncology, Milan (Italy); University of Milan, Milan (Italy)

    2012-02-01

    Purpose: To evaluate the outcome of robotic CyberKnife (Accuray, Sunnyvale, CA)-based stereotactic radiotherapy (CBK-SRT) for isolated recurrent primary, lymph node, or metastatic prostate cancer. Methods and Materials: Between May 2007 and December 2009, 34 consecutive patients/38 lesions were treated (15 patients reirradiated for local recurrence [P], 4 patients reirradiated for anastomosis recurrence [A], 16 patients treated for single lymph node recurrence [LN], and 3 patients treated for single metastasis [M]). In all but 4 patients, [{sup 11}C]choline positron emission tomography/computed tomography was performed. CBK-SRT consisted of reirradiation and first radiotherapy in 27 and 11 lesions, respectively. The median CBK-SRT dose was 30 Gy in 4.5 fractions (P, 30 Gy in 5 fractions; A, 30 Gy in 5 fractions; LN, 33 Gy in 3 fractions; and M, 36 Gy in 3 fractions). In 18 patients (21 lesions) androgen deprivation was added to CBK-SRT (median duration, 16.6 months). Results: The median follow-up was 16.9 months. Acute toxicity included urinary events (3 Grade 1, 2 Grade 2, and 2 Grade 3 events) and rectal events (1 Grade 1 event). Late toxicity included urinary events (3 Grade 1, 2 Grade 2, and 2 Grade 3 events) and rectal events (1 Grade 1 event and 1 Grade 2 event). Biochemical response was observed in 32 of 38 evaluable lesions. Prostate-specific antigen stabilization was seen for 4 lesions, and in 2 cases prostate-specific antigen progression was reported. The 30-month progression-free survival rate was 42.6%. Disease progression was observed for 14 lesions (5, 2, 5, and 2 in Groups P, A, LN, and M respectively). In only 3 cases, in-field progression was seen. At the time of analysis (May 2010), 19 patients are alive with no evidence of disease and 15 are alive with disease. Conclusions: CyberKnife-based stereotactic radiotherapy is a feasible approach for isolated recurrent primary, lymph node, or metastatic prostate cancer, offering excellent in-field tumor

  7. A single-center experience with abiraterone as treatment for metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Thortzen, Anita; Thim, Stine; Røder, Martin Andreas;

    2016-01-01

    BACKGROUND: Continuous stimulation of the androgen receptor (AR) axis is a prerequisite for growth in castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA) is a potent inhibitor of extracellular and intracellular androgen synthesis by inhibition of the CYP-17 enzyme system, which...... has been shown to be up-regulated in CRPC. AA was recently introduced in the management of patients with metastatic CRPC (mCRPC) both before and after taxane-based chemotherapy. The purpose of this study is to report the initial clinical experience obtained from mCRPC patients managed on AA......% of the patients. Time to biochemical and radiological progression was 3.5 and 4.9 months, respectively. Overall survival was 13.2 months (95% CI: 9.0-17.4). CONCLUSION: Our initial experience with AA in the routine management of patients with mCRPC demonstrates an efficacy-effectiveness gap compared with clinical...

  8. Challenges to improved therapeutics for metastatic castrate resistant prostate cancer: from recent successes and failures

    Directory of Open Access Journals (Sweden)

    Huang Xuan

    2012-07-01

    Full Text Available Abstract Men with metastatic castration-resistant prostate cancer (mCRPC carry poor prognosis despite the use of docetaxel-based regimens which has modest survival benefit shown by randomized clinical trials. Significant progress in the discovery of novel therapeutic agents has been made in the past few years. While sipuleucel-T, cabazitaxel, and abiraterone gained regulatory approval in 2010 and 2011, several highly promising candidates/regimens have failed in large scale clinical trials. Challenges remain to optimize the design and interpretation of clinical trial results and develop more effective strategies for mCRPC. In this review, we examined the positive and negative clinical trials in mCRPC in the past and discussed the various aspects of clinical trial design including selection of targets and appropriate outcome measures, biomarker development and implementation, and strategies for combination therapy.

  9. Improved survival for patients with de novo metastatic prostate cancer in the last 20 years

    DEFF Research Database (Denmark)

    Berg, Kasper Drimer; Thomsen, Frederik Birkebæk; Mikkelsen, Marta K

    2017-01-01

    INTRODUCTION: During recent years, several new life-prolonging therapeutic options have been introduced for patients with metastatic prostate cancer (mPCa). The aim of the present study was to evaluate the changes in the survival of patients diagnosed with mPCa prior to and in the early period...... of the implementation of these new agents. PATIENTS AND METHODS: The study population consisted of 207 men diagnosed in 1997 and 316 men diagnosed in the period 2007-2013 with de novo mPCa and managed with initial endocrine therapy. Men were followed for overall survival and PCa-specific survival. RESULTS: At the time...... of diagnosis, men diagnosed in the period 2007-2013 had less co-morbidity, lower prostrate-specific antigen levels and lower clinical tumour categories than men diagnosed in 1997. A significantly higher proportion of men diagnosed in 1997 were managed with surgical castration (57% versus 9%). Only one patient...

  10. Factors Associated With Survival Following Radium-223 Treatment for Metastatic Castration-resistant Prostate Cancer.

    Science.gov (United States)

    Wong, William W; Anderson, Eric M; Mohammadi, Homan; Daniels, Thomas B; Schild, Steve E; Keole, Sameer R; Choo, C Richard; Tzou, Katherine S; Bryce, Alan H; Ho, Thai H; Quevedo, Fernando J; Vora, Sujay A

    2017-04-26

    Radium-223 ((223)Ra) improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). This retrospective analysis was performed to better understand its efficacy in routine clinical practice and identify factors associated with survival. Sixty-four patients with mCRPC who received (223)Ra between 2013 and 2015 were the basis of this retrospective study. Clinical outcomes and patient characteristics were obtained. Potential prognostic factors for survival were evaluated by univariate analysis using the log-rank test and multivariate analysis using the Cox proportional hazard method. The median survival was 12.9 months. Twenty-one patients (33%) developed a skeletal event, and the median time to the first skeletal event was 4.4 months. In univariate analysis, factors significantly associated with survival included: no prior chemotherapy, ≤ 5 bone metastases, baseline prostate-specific antigen (PSA) ≤ 36 ng/mL, baseline alkaline phosphatase (ALP)  12 g/dL, ALP response after (223)Ra treatment, PSA decrease during (223)Ra treatment, and absence of > 25% PSA increase during (223)Ra treatment. In multivariate analysis, 4 factors remained significant: no prior chemotherapy, ≤ 5 bone metastases, baseline ALP < 115 U/L, and ALP response after (223)Ra treatment. When (223)Ra is administered in routine clinical practice, clinical outcomes can be more variable than those reported in the randomized study owing to patient heterogeneity. Four factors were identified to be significantly associated with survival after (223)Ra treatment. These pretreatment factors may be used as stratification factors in future studies to investigate whether (223)Ra would be more effective for patients with newly diagnosed metastatic disease that is sensitive to androgen deprivation therapy. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Cabazitaxel: more than a new taxane for metastatic castrate-resistant prostate cancer?

    Science.gov (United States)

    Mita, Alain C; Figlin, Robert; Mita, Monica M

    2012-12-15

    The taxanes are recognized as a major class of chemotherapeutic agents; however, mechanisms of innate and acquired resistance can limit their usefulness. Cabazitaxel, a novel taxane with microtubule-stabilizing potency similar to docetaxel, exhibits activity against tumor cell lines resistant to paclitaxel and docetaxel. Cabazitaxel showed linear pharmacokinetics and a terminal elimination half-life comparable with that of docetaxel, findings which support dosing as a single infusion in three-week treatment cycles. Dose-ranging studies recommended doses of 20 or 25 mg/m(2) every three weeks. Antitumor activity was shown in patients with advanced cancer and chemotherapy failure (including taxane failure). Other early studies investigated the efficacy of cabazitaxel in pretreated metastatic breast cancer, either as a single agent or in combination with capecitabine. Objective antitumor response rates of up to 24% and sustained tumor stabilizations were also observed. The TROPIC phase III study, conducted in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel, established cabazitaxel as the first chemotherapeutic agent to offer a survival advantage in this patient population. Across these studies, the dose-limiting hematologic toxicity was neutropenia (including febrile neutropenia), usually controllable with colony-stimulating factor/granulocyte-colony stimulating factor support.

  12. Berberine inhibits the metastatic ability of prostate cancer cells by suppressing epithelial-to-mesenchymal transition (EMT)-associated genes with predictive and prognostic relevance.

    Science.gov (United States)

    Liu, Chia-Hung; Tang, Wan-Chun; Sia, Peik; Huang, Chi-Chen; Yang, Pei-Ming; Wu, Ming-Heng; Lai, I-Lu; Lee, Kuen-Haur

    2015-01-01

    Over 70% of cancer metastasis from prostate cancer develops bone metastases that are not sensitive to hormonal therapy, radiation therapy, or chemotherapy. The epithelial-to-mesenchymal transition (EMT) genetic program is implicated as a significant contributor to prostate cancer progression. As such, targeting the EMT represents an important therapeutic strategy for preventing or treating prostate cancer metastasis. Berberine is a natural alkaloid with significant antitumor activities against many types of cancer cells. In this study, we investigated the molecular mechanism by which berberine represses the metastatic potential of prostate cancer. The effects of berberine on cell migration and invasion were determined by transwell migration assay and Matrigel invasion assay. Expressions of EMT-related genes were determined by an EMT PCR Array and a quantitative RT-PCR. The prognostic relevance of berberine's modulation of EMT-related genes in prostate cancer was evaluated using Kaplan-Meier survival analysis. Berberine exerted inhibitory effects on the migratory and invasive abilities of highly metastatic prostate cancer cells. These inhibitory effects of berberine resulted in significant repression of a panel of mesenchymal genes that regulate the developmental EMT. Among EMT-related genes downregulated by berberine, high BMP7, NODAL and Snail gene expressions of metastatic prostate cancer tissues were associated with shorter survival of prostate cancer patients and provide potential therapeutic interventions. We concluded that berberine should be developed as a pharmacological agent for use in combination with other anticancer drug for treating metastatic prostate cancer.

  13. Effects of occupational therapy on quality of life of patients with metastatic prostate cancer

    Science.gov (United States)

    Huri, Meral; Huri, Emre; Kayihan, Hulya; Altuntas, Onur

    2015-01-01

    Objectives: To evaluate the efficiency of occupational therapy relative to a home program in improving quality of life (QoL) among men who were treated for metastatic prostate cancer (MPC). Methods: Fifty-five men were assigned randomly to either the 12-week cognitive behavioral therapy based occupational therapy (OT-CBSM) intervention (treatment group) or a home program (control group) between March 2012 and August 2014 in the Department of Occupational Therapy, Faculty of Health Sciences, Hacettepe University, Ankara, Turkey. The Canadian Occupational Performance Measure (COPM) was used to measure the occupational performance and identify difficulties in daily living activities. The QoL and symptom status were measured by The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 and its Prostate Cancer Module. A 12-week OT-CBSM intervention including client-centered training of daily living activities, recreational group activities, and cognitive behavioral stress management intervention were applied. Results: The COPM performance and satisfaction scores, which indicate occupational participation and QoL increased statistically in the treatment group in relation to men who were included in the home-program (p≤0.05). Conclusion: A 12-week OT-CBSM intervention was effective in improving QoL in men treated for MPC, and these changes were associated significantly with occupational performance. PMID:26219446

  14. Advantages and Disadvantages of Bone Protective Agents in Metastatic Prostate Cancer: Lessons Learned

    Directory of Open Access Journals (Sweden)

    Christian Thomas

    2016-08-01

    Full Text Available Nine out of ten metastatic prostate cancer (PCa patients will develop osseous metastases. Of these, every second will suffer from skeletal-related events (SRE. SRE are associated with an increased risk for death, which is markedly increased in the presence of pathological fracture. Moreover, health insurance costs nearly double in the presence of SRE. Zoledronic acid and denosumab are both approved drugs for the prevention or delay of SRE in castration-resistant prostate cancer (CRPC patients with osseous metastases. However, long-term treatment with one of these two drugs is associated with the development of medication-related osteonecrosis of the jaw (MRONJ. Routine inspections of the oral cavity before and during treatment are mandatory in these patients. Regarding imaging techniques, bone scintigraphy seems to be a promising tool to detect early stage MRONJ. Zoledronic acid does not reduce the incidence of SRE in hormone-sensitive PCa. First data shows 3-monthly application of zoledronic acid to be equi-effective to monthly application.

  15. Dose escalation study of rhenium-186 hydroxyethylidene diphosphonate in patients with metastatic prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Klerk, J.M.H. de (Dept. of Nuclear Medicine, Univ. Hospital, Utrecht (Netherlands)); Zonnenberg, B.A. (Oncology Section, Dept. of Internal Medicine, Univ. Hospital, Utrecht (Netherlands)); Schip, A.D. van het (Dept. of Nuclear Medicine, Univ. Hospital, Utrecht (Netherlands)); Dijk, A. van (Center for Hospital Pharmacy, Univ. Hospital, Utrecht (Netherlands)); Han, S.H. (Dept. of Nuclear Medicine, Univ. Hospital, Utrecht (Netherlands)); Quirijnen, J.M.S.P. (Dept. of Nuclear Medicine, Univ. Hospital, Utrecht (Netherlands)); Blijham, G.H. (Oncology Section, Dept. of Internal Medicine, Univ. Hospital, Utrecht (Netherlands)); Rijk, P.P. van (Dept. of Nuclear Medicine, Univ. Hospital, Utrecht (Netherlands))

    1994-10-01

    Rhenium-186 hydroxyethylidene diphosphonate ([sup 186]Re-HEDP) has been used for the palliative treatment of metastatic bone pain. A phase 1 dose escalation study was performed using [sup 186]Re-HEDP. Twenty-four patients with hormone-resistant prostate cancer entered the study. Each patient had at least four bone metastases and adequate haematological function. Groups of at least three consecutive patients were treated with doses starting at 1295 MBq and increasing to 3515 MBq (escalated in increments of 555 MBq). Thrombocytopenia proved to be the dose-limiting toxicity, while leucopenia played a minor role. Early death occurred in one patient (10 days after administration) without clear relationship to the [sup 186]Re-HEDP therapy. Transient neurological dysfunction was seen in two cases. Two patients who received 3515 MBq [sup 186]Re-HEDP showed grade 3 toxicity (thrombocytes 25-50 x 10[sup 9]/l), defined as unacceptable toxicity. After treatment alkaline phosphatase levels showed a transient decrease in all patients (mean: 26% [+-] 10% IU/l; range: 11%-44%). Prostate-specific antigen values showed a decline in eight patients, preceded by a temporary increase in three patients. From this study we conclude that the maximally tolerated dose of [sup 186]Re-HEDP is 2960 MBq. A placebo-controlled comparative study on the efficacy of [sup 186]Re-HEDP has been initiated. (orig.)

  16. Cabazitaxel for Metastatic Castration-Resistant Prostate Cancer: Retrospective Data Analysis from an Indian Centre

    Directory of Open Access Journals (Sweden)

    Vanita Noronha

    2016-08-01

    Full Text Available Objective: To determine the efficacy and safety of cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC patients from the named patient programme (NPP at our centre. Methods: mCRPC patients who progressed on docetaxel were given cabazitaxel intravenously every 3 weeks until disease progression or unacceptable toxicity occurred. Overall survival, progression-free survival, prostate-specific antigen response, quality of life (QOL changes, and safety were reported. Results: Nine men received cabazitaxel (median: 7 cycles; range: 1–27 under the NPP and were followed until death. Median survival was 14.07 months (1.07–23.80 and progression-free survival was 2.67 months (1.07–20.27. QOL was stable for most patients. Common adverse events (grade ≥3 were neutropenia (n = 8, anaemia (n = 4, and leucopenia (n = 4. Conclusion: These data from 9 patients are consistent with the results reported in the TROPIC study with a manageable safety profile.

  17. Sipuleucel-T for the Treatment of Patients With Metastatic Castrate-resistant Prostate Cancer: Considerations for Clinical Practice.

    Science.gov (United States)

    Pieczonka, Christopher M; Telonis, Dimitrios; Mouraviev, Vladimir; Albala, David

    2015-01-01

    Sipuleucel-T treatment is associated with a significant and consistent survival benefit in patients with metastatic castrate-resistant prostate cancer. Most adverse events are infusion related, manageable, and of short duration. Early screening and diagnosis of metastatic disease is important, as the greatest survival benefit may occur in patients with a lower disease burden. The short duration of sipuleucel-T treatment facilitates the use of subsequent therapies. Sipuleucel-T is now being used in the clinic for patients with a lower disease burden. We present our own experience with the use of sipuleucel-T in the setting of a large urology practice.

  18. Validation of TNM classification for metastatic prostatic cancer treated using primary androgen deprivation therapy.

    Science.gov (United States)

    Kadono, Yoshifumi; Nohara, Takahiro; Ueno, Satoru; Izumi, Kouji; Kitagawa, Yasuhide; Konaka, Hiroyuki; Mizokami, Atsushi; Onozawa, Mizuki; Hinotsu, Shiro; Akaza, Hideyuki; Namiki, Mikio

    2016-02-01

    The current tumor-node-metastasis (TNM) classification system has been used for many years. The prognosis of patients with metastatic prostate cancer (mPC) treated using primary androgen deprivation therapy (PADT) was analyzed according to the TNM classification. A total of 5618 cases with lymph node metastases only (N1M0), non-regional lymph node metastasis (M1a), bone metastasis (M1b), and distant metastasis (M1c) were selected from the Japanese Study Group of Prostate Cancer database. Overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS) rates were calculated using Kaplan-Meier analysis. The influence of clinical variables on patient prognosis was evaluated using the Cox proportional hazard regression model. The 5-year OS, CSS, and PFS were 76.0, 83.2, and 38.8% in N1M0, 57.5, 69.0, and 23.0% in M1a, 54.0, 63.1, and 23.0% in M1b, and 40.0, 51.5, and 16.6% in M1c, respectively. OS, CSS, and PFS worsened as the stages progressed. OS, CSS, and PFS were all significantly worse in N1M1b compared with N0M1b. Multivariate analysis revealed that OS and CSS were worse in patients with a Gleason score ≥8 and that combined androgen blockade (CAB) treatment provided better OS than non-CAB treatments at any tumor stage. However, OS and CSS were worse in individuals with a prostate-specific antigen >100 ng/ml only in M1b. Patient prognosis worsened with stage progression; therefore, current TNM classification system of mPC for PADT was shown to be trustworthy. Each PC cell that develops bone or lymphoid metastasis may exhibit different characteristics.

  19. Enzalutamide: targeting the androgen signalling pathway in metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Schalken, Jack; Fitzpatrick, John M

    2016-02-01

    Significant progress has been made in the understanding of the underlying cancer biology of castration-resistant prostate cancer (CRPC) with the androgen receptor (AR) signalling pathway remaining implicated throughout the prostate cancer disease continuum. Reactivation of the AR signalling pathway is considered to be a key driver of CRPC progression and, as such, the AR is a logical target for therapy in CRPC. The objective of this review was to understand the importance of AR signalling in the treatment of patients with metastatic CRPC (mCRPC) and to discuss the clinical benefits associated with inhibition of the AR signalling pathway. A search was conducted to identify articles relating to the role of AR signalling in CRPC and therapies that inhibit the AR signalling pathway. Current understanding of prostate cancer has identified the AR signalling pathway as a logical target for the treatment of CRPC. Available therapies that inhibit the AR signalling pathway include AR blockers, androgen biosynthesis inhibitors, and AR signalling inhibitors. Enzalutamide, the first approved AR signalling inhibitor, has a novel mode of action targeting AR signalling at three key stages. The direct mode of action of enzalutamide has been shown to translate into clinical responses in patients with mCRPC. In conclusion, the targeting of the AR signalling pathway in patients with mCRPC results in numerous clinical benefits. As the number of treatment options increase, more trials evaluating the sequencing and combination of treatments are required. This review highlights the continued importance of targeting a key driver in the progression of CRPC, AR signalling, and the clinical benefits associated with inhibition of the AR signalling pathway in the treatment of patients with CRPC.

  20. Identification of Bone-Derived Factors Conferring De Novo Therapeutic Resistance in Metastatic Prostate Cancer.

    Science.gov (United States)

    Lee, Yu-Chen; Lin, Song-Chang; Yu, Guoyu; Cheng, Chien-Jui; Liu, Bin; Liu, Hsuan-Chen; Hawke, David H; Parikh, Nila U; Varkaris, Andreas; Corn, Paul; Logothetis, Christopher; Satcher, Robert L; Yu-Lee, Li-Yuan; Gallick, Gary E; Lin, Sue-Hwa

    2015-11-15

    Resistance to currently available targeted therapies significantly hampers the survival of patients with prostate cancer with bone metastasis. Here we demonstrate an important resistance mechanism initiated from tumor-induced bone. Studies using an osteogenic patient-derived xenograft, MDA-PCa-118b, revealed that tumor cells resistant to cabozantinib, a Met and VEGFR-2 inhibitor, reside in a "resistance niche" adjacent to prostate cancer-induced bone. We performed secretome analysis of the conditioned medium from tumor-induced bone to identify proteins (termed "osteocrines") found within this resistance niche. In accordance with previous reports demonstrating that activation of integrin signaling pathways confers therapeutic resistance, 27 of the 90 osteocrines identified were integrin ligands. We found that following cabozantinib treatment, only tumor cells positioned adjacent to the newly formed woven bone remained viable and expressed high levels of pFAK-Y397 and pTalin-S425, mediators of integrin signaling. Accordingly, treatment of C4-2B4 cells with integrin ligands resulted in increased pFAK-Y397 expression and cell survival, whereas targeting integrins with FAK inhibitors PF-562271 or defactinib inhibited FAK phosphorylation and reduced the survival of PC3-mm2 cells. Moreover, treatment of MDA-PCa-118b tumors with PF-562271 led to decreased tumor growth, irrespective of initial tumor size. Finally, we show that upon treatment cessation, the combination of PF-562271 and cabozantinib delayed tumor recurrence in contrast to cabozantinib treatment alone. Our studies suggest that identifying paracrine de novo resistance mechanisms may significantly contribute to the generation of a broader set of potent therapeutic tools that act combinatorially to inhibit metastatic prostate cancer.

  1. Addressing the expected survival benefit for clinical trial design in metastatic castration-resistant prostate cancer: Sensitivity analysis of randomized trials.

    Science.gov (United States)

    Massari, Francesco; Modena, Alessandra; Ciccarese, Chiara; Pilotto, Sara; Maines, Francesca; Bracarda, Sergio; Sperduti, Isabella; Giannarelli, Diana; Carlini, Paolo; Santini, Daniele; Tortora, Giampaolo; Porta, Camillo; Bria, Emilio

    2016-02-01

    We performed a sensitivity analysis, cumulating all randomized clinical trials (RCTs) in which patients with metastatic castration-resistant prostate cancer (mCRPC) received systemic therapy, to evaluate if the comparison of RCTs may drive to biased survival estimations. An overall survival (OS) significant difference according to therapeutic strategy was more likely be determined in RCTs evaluating hormonal drugs versus those studies testing immunotherapy, chemotherapy or other strategies. With regard to control arm, an OS significant effect was found for placebo-controlled trials versus studies comparing experimental treatment with active therapies. Finally, regarding to docetaxel (DOC) timing, the OS benefit was more likely to be proved in Post-DOC setting in comparison with DOC and Pre-DOC. These data suggest that clinical trial design should take into account new benchmarks such as the type of treatment strategy, the choice of the comparator and the phase of the disease in relation to the administration of standard chemotherapy.

  2. Treatment of Hormone Resistance with Docetaxel in Metastatic Prostate Cancer Patients: Results of a Clinical Experience at Omid Hospital, Isfahan, Iran

    Directory of Open Access Journals (Sweden)

    Mina Tajvidi

    2017-01-01

    Full Text Available Background: Metastatic prostate cancer is one of the most important cancers among men worldwide. Androgen ablation therapy can be used in treatment of these patients; however, most will progress to metastatic hormone-refractory prostate cancer. In this regard, docetaxel has been approved to treat metastatic hormone-refractory prostate cancer in the United States. In this study, we aimed to investigate the results of this treatment modality in metastatic prostate cancer patients from Iran. Methods:We evaluated PSA response and bone pain relief in 18 metastatic prostate cancer patients who underwent treatment with docetaxel at a dose of 75 mg/m2 intravenously on the first day of treatment. The treatment was repeated every three weeks (6 cycles along with 10 mg of prednisolone. Results: Of 18 patients, 39% had >50% decline in PSA levels.There were 16% of the patients with a PSA decline of approximately 30% to 50% of the pre-treatment levels. In addition, 29% of the patients had progressive PSA levels during chemotherapy. Among them, 55% had significant pain relief. Conclusion: This research showed the effectiveness of docetaxel to decrease PSA levels in metastatic hormone-refractory prostate cancer patients from Iran. Docetaxel was also valuable in alleviation of pain in these patients. However, prospective studies should validate this approach.

  3. Abiraterone in the treatment of metastatic castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Mostaghel EA

    2014-01-01

    Full Text Available Elahe A Mostaghel Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA Abstract: Androgen deprivation therapy remains the single most effective treatment for the initial therapy of advanced prostate cancer, but is uniformly marked by progression to castration-resistant prostate cancer (CRPC. Residual tumor androgens and androgen axis activation are now recognized to play a prominent role in mediating CRPC progression. Despite suppression of circulating testosterone to castrate levels, castration does not eliminate androgens from the prostate tumor microenvironment and residual androgen levels are well within the range capable of activating the androgen receptor (AR and AR-mediated gene expression. Accordingly, therapeutic strategies that more effectively target production of intratumoral androgens are necessary. The introduction of abiraterone, a potent suppressor of cytochrome P450 17 α-hydroxysteroid dehydrogenase-mediated androgen production, has heralded a new era in the hormonal treatment of men with metastatic CRPC. Herein, the androgen and AR-mediated mechanisms that contribute to CRPC progression and establish cytochrome P450 17 α-hydroxysteroid dehydrogenase as a critical therapeutic target are briefly reviewed. The mechanism of action and pharmacokinetics of abiraterone are reviewed and its recently described activity against AR and 3-β-hydroxysteroid dehydrogenase is discussed. The Phase I and II data initially demonstrating the efficacy of abiraterone and Phase III data supporting its approval for patients with metastatic CRPC are reviewed. The safety and tolerability of abiraterone, including the incidence and management of side effects and potential drug interactions, are discussed. The current place of abiraterone in CRPC therapy is reviewed and early evidence regarding cross-resistance of abiraterone with taxane therapy, mechanisms of resistance to abiraterone, and observations of an

  4. Expert System for Bone Scan Interpretation Improves Progression Assessment in Bone Metastatic Prostate Cancer.

    Science.gov (United States)

    Haupt, Fabian; Berding, Georg; Namazian, Ali; Wilke, Florian; Böker, Alena; Merseburger, Axel; Geworski, Lilli; Kuczyk, Markus Antonius; Bengel, Frank Michael; Peters, Inga

    2017-04-01

    The bone scan index (BSI) was introduced as a quantitative tool for tumor involvement in bone of patients with metastatic prostate cancer (mPCa). The computer-aided diagnosis device for BSI analysis EXINIbone(BSI) seems to represent technical progress for the quantitative assessment of bone involvement. But it is not yet clear if the automated BSI (aBSI) could contribute to improved evaluation of progression in patients under antiandrogens or chemotherapy in contrast to the visual interpretation and/or conventional biomarkers such as the prostate-specific antigen (PSA). In 49 mPCa patients, bone scans were performed initially and during different therapy courses. Scans were evaluated visually and by the artificial-neural-network-based expert system EXINIbone(BSI). Progression of metastatic bone involvement was defined according to the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) criteria in the visual interpretation. The computer-assisted interpretation was based on different cutoff values in relative changes of the aBSI. Additionally, assessments according to bone scanning were compared to changes in the PSA value as a potential surrogate for treatment response. Using a sensitive cutoff value (5% or 10%) for the relative aBSI increase led to significantly increased progression determination compared to the visual interpretation of bone scans (49% and 43% vs. 27%, p < 0.001). In 63% of the cases PSA and BSI changes matched, whereas in 18% progression was only indicated by the aBSI. A relative cutoff of 5% for the aBSI decrease could reclassify 47 serial scan pairs which were visually interpreted as stable into 22 progressive and 25 remissive scans. Distinct thresholds of the relative aBSI could help to better assess disease progression in mPCa patients. Manual corrections of the BSI values are not required in most cases. The aBSI could serve as a useful additional parameter for therapy monitoring in mPCa patients in the future.

  5. Low-dose prednisolone in first-line docetaxel for patients with metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Kongsted, Per; Svane, Inge Marie; Lindberg, Henriette;

    2015-01-01

    BACKGROUND: Randomized studies have shown improved survival with the combination of docetaxel (D) and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively investigated whether coadministration of low-dose glucocorticoids has clinical benefits.......001). P did not influence progression-free survival (P = 0.692, log-rank test) or overall survival when adjusting for baseline levels of hemoglobin, alkaline phosphatase, lactate dehydrogenase, prostate-specific antigen, and Eastern Cooperative Oncology Group performance status (hazard ratioP = 0.98, 95...

  6. Repurposing Itraconazole as a Treatment for Advanced Prostate Cancer: A Noncomparative Randomized Phase II Trial in Men With Metastatic Castration-Resistant Prostate Cancer

    Science.gov (United States)

    Heath, Elisabeth I.; Smith, David C.; Rathkopf, Dana; Blackford, Amanda L.; Danila, Daniel C.; King, Serina; Frost, Anja; Ajiboye, A. Seun; Zhao, Ming; Mendonca, Janet; Kachhap, Sushant K.; Rudek, Michelle A.; Carducci, Michael A.

    2013-01-01

    Background. The antifungal drug itraconazole inhibits angiogenesis and Hedgehog signaling and delays tumor growth in murine prostate cancer xenograft models. We conducted a noncomparative, randomized, phase II study evaluating the antitumor efficacy of two doses of oral itraconazole in men with metastatic prostate cancer. Patients and Methods. We randomly assigned 46 men with chemotherapy-naïve metastatic castration-resistant prostate cancer (CRPC) to receive low-dose (200 mg/day) or high-dose (600 mg/day) itraconazole until disease progression or unacceptable toxicity. The primary endpoint was the prostate-specific antigen (PSA) progression-free survival (PPFS) rate at 24 weeks; a 45% success rate in either arm was prespecified as constituting clinical significance. Secondary endpoints included the progression-free survival (PFS) rate and PSA response rate (Prostate Cancer Working Group criteria). Exploratory outcomes included circulating tumor cell (CTC) enumeration, serum androgen measurements, as well as pharmacokinetic and pharmacodynamic analyses. Results. The high-dose arm enrolled to completion (n = 29), but the low-dose arm closed early (n = 17) because of a prespecified futility rule. The PPFS rates at 24 weeks were 11.8% in the low-dose arm and 48.0% in the high-dose arm. The median PFS times were 11.9 weeks and 35.9 weeks, respectively. PSA response rates were 0% and 14.3%, respectively. In addition, itraconazole had favorable effects on CTC counts, and it suppressed Hedgehog signaling in skin biopsy samples. Itraconazole did not reduce serum testosterone or dehydroepiandrostenedione sulfate levels. Common toxicities included fatigue, nausea, anorexia, rash, and a syndrome of hypokalemia, hypertension, and edema. Conclusion. High-dose itraconazole (600 mg/day) has modest antitumor activity in men with metastatic CRPC that is not mediated by testosterone suppression. PMID:23340005

  7. Piecing the Puzzle Together: Docetaxel Cycles and Current Considerations in the Treatment of Metastatic Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Feinman, Hannah E; Price, Douglas K; Figg, William D

    2017-02-25

    Docetaxel is the current first line therapy for metastatic castration-resistant prostate cancer (mCRPC), but there is no standard number of docetaxel cycles given to patients. In their post hoc analysis of the Mainsail study, de Morrée et al. show that the number of docetaxel cycles administered to a patient is a significant factor contributing to overall survival. These findings warrant further investigation into the standardization of the number of docetaxel cycles administered.

  8. SU-D-303-01: Spatial Distribution of Bone Metastases In Metastatic Castrate-Resistant Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Perk, T; Bradshaw, T; Harmon, S; Perlman, S; Liu, G; Jeraj, R [University of Wisconsin, Madison, WI (United States)

    2015-06-15

    Purpose: Identification of metastatic bone lesions is critical in prostate cancer, where treatments may be more effective in patients with fewer lesions. This study aims characterize the distribution and spread of bone lesions and create a probability map of metastatic spread in bone. Methods: Fifty-five metastatic castrate-resistant prostate cancer patients received up to 3 whole-body [F-18]NaF PET/CT scans. Lesions were identified by physician on PET/CT and contoured using a threshold of SUV>15. An atlas-based segmentation method was used to create CT regions, which determined skeletal location of lesions. Patients were divided into 3 groups with low (N<40), medium (40100) numbers of lesions. A combination of articulated and deformable registrations was used to register the skeletal segments and lesions of each patient to a single skeleton. All the lesion data was then combined to make a probability map. Results: A total of 4038 metastatic lesions (mean 74, range 2–304) were identified. Skeletal regions with highest occurrence of lesions included ribs, thoracic spine, and pelvis with 21%, 19%, and 15% of the total number lesions and 8%, 18%, and 31 % of the total lesion volume, respectively. Interestingly, patients with fewer lesions were found to have a lower proportion of lesions in the ribs (9% in low vs. 27% in high number of lesions). Additionally, the probability map showed specific areas in the spine and pelvis where over 75% of patients had metastases, and other areas in the skeleton with a less than 2% of metastases. Conclusion: We identified skeletal regions with higher incidence of metastases and specific sub-regions in the skeleton that had high or low probability of occurrence of metastases. Additionally, we found that metastatic lesions in the ribs and skull occur more commonly in advanced disease. These results may have future applications in computer-aided diagnosis. Funding from the Prostate Cancer Foundation.

  9. Successful sperm extraction and live birth after radiation, androgen deprivation and surgical castration for treatment of metastatic prostate cancer.

    Science.gov (United States)

    Wood, G J A; Hayden, R P; Tanrikut, C

    2017-02-01

    Fertility preservation has become an important aspect of cancer treatment given the gonadotoxic effects of oncologic therapies. It is now considered standard of care to offer sperm banking to men undergoing treatment for primaries that affect young individuals. Less is known regarding fertility preservation of patients afflicted with prostate cancer. This cohort has progressively expanded and grown younger in the post-PSA era. Prostatectomy, radiation, chemotherapy and androgen blockade all pose unique challenges to the infertility specialist. Optimum management becomes even more uncertain for those men with metastatic prostate cancer. Most of these individuals will have received multiple forms of therapy, each carrying a distinct insult to the patient's reproductive potential. We describe a case of successful ex vivo sperm extraction and live birth in a patient previously treated with radiation and chronic androgen deprivation for metastatic prostate cancer. The presented case demonstrates that conception after radiation therapy and chronic androgen deprivation is feasible. We propose that fertility counselling and sperm cryopreservation should be considered for all prostate cancer patients. Additionally, for those individuals undergoing external beam radiotherapy, testicular shielding should be routinely offered in the event further family building is desired.

  10. Strontium-89: treatment results and kinetics in patients with painful metastatic prostate and breast cancer in bone

    Energy Technology Data Exchange (ETDEWEB)

    Robinson, R.G.; Blake, G.M.; Preston, D.F.; McEwan, A.J.; Spicer, J.A.; Martin, N.L.; Wegst, A.V.; Ackery, D.M.

    1989-03-01

    Two hundred and two patients with bone pain from metastatic cancer were treated with 40 microCi/kg of Sr-89. Patients were followed with pain diaries, records of medication taken, sleep patterns, serial bone scans and a Karnofsky Index. One hundred and thirty-seven patients with adequate followup survived at least 3 months, including 100 with prostate and 28 with breast carcinoma. Eighty of the 100 patients with prostate cancer responded, and 25 of the 28 breast cancer patients improved. Ten patients with prostate cancer and five with breast cancer became pain free. Little hematologic depression was noted. Sr-89 kinetic studies showed that strontium taken up in osteoblastic areas remained for 100 days. The tumor-to-marrow absorbed dose ratio was 10:1.

  11. Strontium-89: treatment results and kinetics in patients with painful metastatic prostate and breast cancer in bone.

    Science.gov (United States)

    Robinson, R G; Blake, G M; Preston, D F; McEwan, A J; Spicer, J A; Martin, N L; Wegst, A V; Ackery, D M

    1989-03-01

    Two hundred and two patients with bone pain from metastatic cancer were treated with 40 microCi/kg of Sr-89. Patients were followed with pain diaries, records of medication taken, sleep patterns, serial bone scans and a Karnofsky Index. One hundred and thirty-seven patients with adequate followup survived at least 3 months, including 100 with prostate and 28 with breast carcinoma. Eighty of the 100 patients with prostate cancer responded, and 25 of the 28 breast cancer patients improved. Ten patients with prostate cancer and five with breast cancer became pain free. Little hematologic depression was noted. Sr-89 kinetic studies showed that strontium taken up in osteoblastic areas remained for 100 days. The tumor-to-marrow absorbed dose ratio was 10:1.

  12. Integrated clinical, whole-genome, and transcriptome analysis of multisampled lethal metastatic prostate cancer

    Science.gov (United States)

    Bova, G. Steven; Kallio, Heini M.L.; Annala, Matti; Kivinummi, Kati; Högnäs, Gunilla; Häyrynen, Sergei; Rantapero, Tommi; Kivinen, Virpi; Isaacs, William B.; Tolonen, Teemu; Nykter, Matti; Visakorpi, Tapio

    2016-01-01

    We report the first combined analysis of whole-genome sequence, detailed clinical history, and transcriptome sequence of multiple prostate cancer metastases in a single patient (A21). Whole-genome and transcriptome sequence was obtained from nine anatomically separate metastases, and targeted DNA sequencing was performed in cancerous and noncancerous foci within the primary tumor specimen removed 5 yr before death. Transcriptome analysis revealed increased expression of androgen receptor (AR)-regulated genes in liver metastases that harbored an AR p.L702H mutation, suggesting a dominant effect by the mutation despite being present in only one of an estimated 16 copies per cell. The metastases harbored several alterations to the PI3K/AKT pathway, including a clonal truncal mutation in PIK3CG and present in all metastatic sites studied. The list of truncal genomic alterations shared by all metastases included homozygous deletion of TP53, hemizygous deletion of RB1 and CHD1, and amplification of FGFR1. If the patient were treated today, given this knowledge, the use of second-generation androgen-directed therapies, cessation of glucocorticoid administration, and therapeutic inhibition of the PI3K/AKT pathway or FGFR1 receptor could provide personalized benefit. Three previously unreported truncal clonal missense mutations (ABCC4 p.R891L, ALDH9A1 p.W89R, and ASNA1 p.P75R) were expressed at the RNA level and assessed as druggable. The truncal status of mutations may be critical for effective actionability and merit further study. Our findings suggest that a large set of deeply analyzed cases could serve as a powerful guide to more effective prostate cancer basic science and personalized cancer medicine clinical trials. PMID:27148588

  13. Pharmacodynamic study of Disulfiram in Men with Non-metastatic Recurrent Prostate Cancer

    Science.gov (United States)

    Schweizer, Michael T.; Lin, Jianqing; Blackford, Amanda; Bardia, Aditya; King, Serina; Armstrong, Andrew J.; Rudek, Michelle A.; Yegnasubramanian, Srinivasan; Carducci, Michael A.

    2013-01-01

    Background Preclinical drug screens identified disulfiram as a potent in vitro inhibitor of prostate cancer cell growth. Although many mechanisms for its anticancer activity have been proposed, tumor suppressor gene re-expression through promoter demethylation emerged as one of the more plausible. Methods We conducted an open-label, dose escalation trial of disulfiram in men with non-metastatic recurrent prostate cancer after local therapy. Dose escalation occurred if a demethylating “response” [i.e. ≥10% decrease in peripheral blood mononuclear cell (PBMC) global 5meC content] was observed in <3 patients in cohort 1. Cohort 1 and 2 received disulfiram 250 mg and 500 mg daily respectively. The primary endpoint was the proportion of subjects with a demethylation response. Secondary endpoints included rate of PSA progression at 6 months, changes in PSA doubling time and safety/tolerability. Results Changes in global 5meC content were observed in 2 of 9 patients (22.2%) in cohort 1 and 3 of 10 (30.0%) in cohort 2. Only 5 subjects were on trial for ≥6 months, all were in cohort 1 and all had PSA progression by 6 months. No changes in PSA kinetics were observed in either cohort. Disulfiram was poorly tolerated with 6 patients experiencing grade 3 AEs (3 per cohort). Three of the responders displayed pre-treatment instability in their 5meC content. Conclusions A minority of patients had transient global PBMC demethylation changes. Instability in 5meC may limit the reproducibility of these findings, limiting our ability to confirm our hypothesis. Given the toxicities and no clinical benefits, further development of disulfiram should not be pursued in this population. PMID:23958896

  14. Metastatic castration-resistant prostate cancer in very elderly patients: challenges and solutions

    Directory of Open Access Journals (Sweden)

    Caffo O

    2016-12-01

    Full Text Available Orazio Caffo, Francesca Maines, Mimma Rizzo, Stefania Kinspergher, Antonello Veccia Medical Oncology Department, Santa Chiara Hospital, Trento, Italy Abstract: The treatment of elderly patients with cancer is usually viewed by clinicians as a challenge, because of the age-related decline in normal organ function and the frequent concomitant administration of multiple drugs for comorbid conditions. Clinicians therefore tend not to prescribe antineoplastic agents (mainly in the case of chemotherapy to elderly patients, with the fear of excess toxicity leading to an unfavorable cost:benefit ratio. The cutoff age defining a cancer patient as elderly is usually 70 years, but over the last 10 years clinicians have paid more attention to functional status, as evaluated by means of a comprehensive geriatric assessment and comorbidity burden, rather than chronological age. In the case of metastatic castration-resistant prostate cancer (mCRPC, depending on their age at the time of diagnosis of PC, many (if not most of the patients are more than 70 years old, and a fair number are very elderly patients aged ≥80 years. The availability of various agents capable of significantly prolonging survival has dramatically changed the therapeutic landscape of mCRPC patients, but very elderly patients are usually underrepresented in pivotal trials. This narrative review considers the available data concerning elderly and very elderly mCRPC patients enrolled in pivotal trials and the information provided by reports of everyday clinical practice, in order to explore the challenges related to the clinical management of this special population. Keywords: prostate cancer, elderly, castration-resistant

  15. Evaluation of urinary prostate cancer antigen-3 (PCA3) and TMPRSS2-ERG score changes when starting androgen-deprivation therapy with triptorelin 6-month formulation in patients with locally advanced and metastatic prostate cancer

    NARCIS (Netherlands)

    Martinez-Pineiro, L.; Schalken, J.A.; Cabri, P.; Maisonobe, P.; Taille, A. De La; Study, G.

    2014-01-01

    OBJECTIVE: To assess prostate cancer antigen-3 (PCA3) and TMPRSS2-ERG scores in patients with advanced and metastatic prostate cancer at baseline and after 6 months of treatment with triptorelin 22.5 mg, and analyse these scores in patient-groups defined by different disease characteristics. PATIENT

  16. Current paradigms and evolving concepts in metastatic castration-resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Snmanta Krnmar Pal; Oliver Sartor

    2011-01-01

    @@ Until recently,docetaxel-based therapy represented the only therapy shown to prolong survival in patients with metastatic castration-resistant prostate cancer (mCRPC).The past year and a half has been marked by unprecedented progress in treatments for this disease.Three positive phase III clinical trials have emerged,each evaluating agents (sipuleucel-T,cabazitaxel and abiraterone)with distinct mechanisms of action.Herein,the three pivotal trials are described alongside both past and current large phase III studies conducted in this mCRPC.The overall survival for patients with mCRPC treated in current clinical trials is considerably longer than noted in the past.We note that more recent trials with older agents have also shown improved survival and discuss potential non-therapeutic biases that influence this critical measure of outcome.The necessity for utilizing randomized trials when evaluating new therapeutics is emphasized given the changing prognosis in this mCRPC.

  17. Sequencing new agents after docetaxel in patients with metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Maines, Francesca; Caffo, Orazio; Veccia, Antonello; Trentin, Chiara; Tortora, Giampaolo; Galligioni, Enzo; Bria, Emilio

    2015-12-01

    Two new hormonal agents (NHAs), abiraterone and enzalutamide, and one chemotherapeutic agent, cabazitaxel (CABA) improved overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) who progress after docetaxel. Although several analyses of patient cohorts receiving a sequence of two different new agents (NAs) after docetaxel have been published, no definite conclusions can be drawn regarding the best treatment strategy. All published studies reporting monthly OS rates of mCRPC patients receiving third-line NA after having previously received docetaxel and another NA have been analyzed. The treatments were merged into three groups: one NHA followed by another, one NHA followed by CABA, and CABA followed by one NHA. The cumulative monthly OS rates in each group were determined using a weighted-average approach. Thirteen retrospective studies including 1016 patients who received NHA/NHA (469), NHA/CABA (318) or CABA/NHA (229) were evaluated. The 12-month OS rates were 28.5%, 61.3%, and 76.4%, respectively. There were no statistically significant differences in terms of known prognostic factors. Although the retrospective nature of the studies and potential selection biases, our data seem to confirm the potential cumulative survival benefit of using the NAs sequentially after docetaxel. There was no clear superiority of any one of the three strategies, but a sequence that includes CABA seems to suggest a possible OS advantage. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  18. Massive Bleeding as the First Clinical Manifestation of Metastatic Prostate Cancer due to Disseminated Intravascular Coagulation with Enhanced Fibrinolysis

    Science.gov (United States)

    Lopes, João Madeira; Victorino, Rui M. M.; Meneses Santos, João

    2016-01-01

    Disseminated intravascular coagulation (DIC) is the most frequent coagulation disorder associated with metastatic prostate adenocarcinoma. However, DIC with enhanced fibrinolysis as an initial presentation of prostate cancer is extremely rare. The appropriate treatment to control bleeding in these situations is challenging, controversial, and based on isolated case reports in the literature. A 66-year-old male presented at the emergency department with acute severe spontaneous ecchymoses localized to the limbs, laterocervical hematoma, and hemothorax. Prostate specific antigen level was 385 μg/L, bone scintigraphy revealed multiple bone metastases, and prostate biopsy confirmed adenocarcinoma (Gleason 9; 4 + 5). Laboratory investigation showed a pattern of enhanced fibrinolysis rather than the more common intravascular coagulation mechanism. Epsilon aminocaproic acid in monotherapy was initiated with a clear and rapid control of bleeding manifestations. This rare case of massive bleeding due to DIC with enhanced fibrinolysis as the first manifestation of prostate cancer suggests that in selected cases where the acute bleeding dyscrasia is clearly associated with a dominant fibrinolysis mechanism it is possible to use an approach of monotherapy with antifibrinolytics. PMID:27803823

  19. {sup 89}Zr-huJ591 immuno-PET imaging in patients with advanced metastatic prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Pandit-Taskar, Neeta; Solomon, Stephen B.; Durack, Jeremy C.; Carrasquillo, Jorge A.; Lefkowitz, Robert A.; Osborne, Joseph R. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Weill Cornell Medical College, Department of Radiology, New York, NY (United States); O' Donoghue, Joseph A. [Memorial Sloan Kettering Cancer Center, Department of Medical Physics, New York, NY (United States); Beylergil, Volkan; Ruan, Shutian; Cheal, Sarah M. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Lyashchenko, Serge [Memorial Sloan Kettering Cancer Center, Department of Radiochemistry and Molecular Imaging Probes Core, New York, NY (United States); Gonen, Mithat [Memorial Sloan Kettering Cancer Center, Department of Epidemiology and Biostatistics, New York, NY (United States); Lewis, Jason S. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Department of Radiochemistry and Molecular Imaging Probes Core, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Program in Molecular Pharmacology and Chemistry, New York, NY (United States); Weill Cornell Medical College, Department of Radiology, New York, NY (United States); Holland, Jason P. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Harvard Medical School, Department of Radiology of Massachusetts General Hospital, Boston, MA (United States); Reuter, Victor E. [Memorial Sloan Kettering Cancer Center, Department of Pathology, New York, NY (United States); Weill Cornell Medical College, Department of Pathology, New York, NY (United States); Loda, Massimo F. [Dana-Farber Cancer Institute, Boston, MA (United States); Broad Institute of Harvard and MIT, Cambridge, MA (United States); Smith-Jones, Peter M. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Department of Psychiatry and Behavioral Science of Stony Brook University, Stony Brook, NY (United States); Weber, Wolfgang A.; Larson, Steven M. [Memorial Sloan Kettering Cancer Center, Department of Radiology, New York, NY (United States); Memorial Sloan Kettering Cancer Center, Program in Molecular Pharmacology and Chemistry, New York, NY (United States); Weill Cornell Medical College, Department of Radiology, New York, NY (United States); Bander, Neil H. [Memorial Sloan Kettering Cancer Center, Department of Surgery, New York, NY (United States); Weill Cornell Medical College, Department of Urology, New York, NY (United States); Scher, Howard I.; Morris, Michael J. [Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, NY (United States); Weill Cornell Medical College, Department of Medicine, New York, NY (United States)

    2014-11-15

    Given the bone tropism of prostate cancer, conventional imaging modalities poorly identify or quantify metastatic disease. {sup 89}Zr-huJ591 positron emission tomography (PET) imaging was performed in patients with metastatic prostate cancer to analyze and validate this as an imaging biomarker for metastatic disease. The purpose of this initial study was to assess safety, biodistribution, normal organ dosimetry, and optimal imaging time post-injection for lesion detection. Ten patients with metastatic prostate cancer received 5 mCi of {sup 89}Zr-huJ591. Four whole-body scans with multiple whole-body count rate measurements and serum activity concentration measurements were obtained in all patients. Biodistribution, clearance, and lesion uptake by {sup 89}Zr-huJ591 immuno-PET imaging was analyzed and dosimetry was estimated using MIRD techniques. Initial assessment of lesion targeting of {sup 89}Zr-huJ591 was done. Optimal time for imaging post-injection was determined. The dose was well tolerated with mild chills and rigors seen in two patients. The clearance of {sup 89}Zr-huJ591 from serum was bi-exponential with biological half-lives of 7 ± 4.5 h (range 1.1-14 h) and 62 ± 13 h (range 51-89 h) for initial rapid and later slow phase. Whole-body biological clearance was 219 ± 48 h (range 153-317 h). The mean whole-body and liver residence time was 78.7 and 25.6 h, respectively. Dosimetric estimates to critical organs included liver 7.7 ± 1.5 cGy/mCi, renal cortex 3.5 ± 0.4 cGy/mCi, and bone marrow 1.2 ± 0.2 cGy/mCi. Optimal time for patient imaging after injection was 7 ± 1 days. Lesion targeting of bone or soft tissue was seen in all patients. Biopsies were performed in 8 patients for a total 12 lesions, all of which were histologically confirmed as metastatic prostate cancer. One biopsy-proven lesion was not positive on {sup 89}Zr-huJ591, while the remaining 11 lesions were {sup 89}Zr-huJ591 positive. Two biopsy-positive nodal lesions were noted only on

  20. Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells.

    Science.gov (United States)

    McConkey, D J; Lin, Y; Nutt, L K; Ozel, H Z; Newman, R A

    2000-07-15

    Cardiac glycosides are used clinically to increase contractile force in patients with cardiac disorders. Their mechanism of action is well established and involves inhibition of the plasma membrane Na+/K+-ATPase, leading to alterations in intracellular K+ and Ca(2+) levels. Here, we report that the cardiac glycosides oleandrin, ouabain, and digoxin induce apoptosis in androgen-independent human prostate cancer cell lines in vitro. Cell death was associated with early release of cytochrome c from mitochondria, followed by proteolytic processing of caspases 8 and 3. Oleandrin also promoted caspase activation, detected by cleavage poly(ADP-ribose) polymerase and hydrolysis of a peptide substrate (DEVD-pNA). Comparison of the rates of apoptosis in poorly metastatic PC3 M-Pro4 and highly metastatic PC3 M-LN4 subclones demonstrated that cell death was delayed in the latter because of a delay in mitochondrial cytochrome c release. Single-cell imaging of intracellular Ca(2+) fluxes demonstrated that the proapoptotic effects of the cardiac glycosides were linked to their abilities to induce sustained Ca(2+) increases in the cells. Our results define a novel activity for cardiac glycosides that could prove relevant to the treatment of metastatic prostate cancer.

  1. Safety and chemopreventive effect of Polyphenon E in preventing early and metastatic progression of prostate cancer in TRAMP mice.

    Science.gov (United States)

    Kim, Seung Joon; Amankwah, Ernest; Connors, Shahnjayla; Park, Hyun Y; Rincon, Maria; Cornnell, Heather; Chornokur, Ganna; Hashim, Arig Ibrahim; Choi, Junsung; Tsai, Ya-Yu; Engelman, Robert W; Kumar, Nagi; Park, Jong Y

    2014-04-01

    Prostate cancer treatment is often accompanied by untoward side effects. Therefore, chemoprevention to reduce the risk and inhibit the progression of prostate cancer may be an effective approach to reducing disease burden. We investigated the safety and efficacy of Polyphenon E, a green tea extract, in reducing the progression of prostate cancer in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice. A total of 119 male TRAMP and 119 C57BL/6J mice were treated orally with one of 3 doses of Polyphenon E (200, 500, and 1,000 mg/kg/day) in drinking water ad libitum replicating human achievable doses. Baseline assessments were performed before treatments. Safety and efficacy assessments during treatments were performed when mice were 12, 22, and 32 weeks old. The number and size of tumors in treated TRAMP mice were significantly decreased compared with untreated animals. In untreated 32 weeks old TRAMP mice, prostate carcinoma metastasis to distant sites was observed in 100% of mice (8/8), compared with 13% of mice (2/16) treated with high-dose Polyphenon E during the same period. Furthermore, Polyphenon E treatment significantly inhibited metastasis in TRAMP mice in a dose-dependent manner (P = 0.0003). Long-term (32 weeks) treatment with Polyphenon E was safe and well tolerated with no evidence of toxicity in C57BL/6J mice. Polyphenon E is an effective chemopreventive agent in preventing the progression of prostate cancer to metastasis in TRAMP mice. Polyphenon E showed no toxicity in these mouse models. Our findings provide additional evidence for the safety and chemopreventive effect of Polyphenon E in preventing metastatic progression of prostate cancer.

  2. Combined hormonal deprivation and radiotherapy in non-metastatic cancer of prostate; Hormono-radiotherapie des cancers de la prostate non metastatiques

    Energy Technology Data Exchange (ETDEWEB)

    Richaud, P. [Institut Bergonie, Centre Regional de Lutte Contre le Cancer, Service de Radiotherapie, 33 - Bordeaux (France); Mazeron, J.J. [Hopital Pitie-Salpetriere, Centre des Tumeurs, Service de Radiotherapie, 75 - Paris (France)

    2002-05-01

    Patients presenting with non-metastatic cancer of prostate have a high probability of relapse if they are treated by either surgery alone or irradiation alone, when poor prognosis factors are present. Clinical stage ({>=}T3a), Gleason score, and PSA level ({>=}20 ng/mL) are the more significant factors. It is likely that many patients can draw benefit of combined androgenic suppression and radiotherapy. However, despite results of European and American trials published the last decade, a number of questions remain without a clear response, especially on the modalities of treatment according to the characteristics of the disease. (author)

  3. Characterization of a rat model of metastatic prostate cancer bone pain

    Directory of Open Access Journals (Sweden)

    Paolo Donato De Ciantis

    2010-11-01

    Full Text Available Paolo Donato De Ciantis1, Kiran Yashpal2, James Henry3, Gurmit Singh11Department of Pathology and Molecular Pathology, 2Pain Research Laboratories, 3Department of Psychiatry and Behavioral Neurosciences, McMaster University, Hamilton, Ontario, CanadaPurpose: The objectives of this study were to establish and characterize a novel animal model of metastatic prostate cancer-induced bone pain.Methods: Copenhagen rats were injected with 106 MATLyLu (MLL prostate cancer cells or phosphate-buffered saline by per cutaneous intra femoral injections into the right hind leg distal epiphysis. Over 13 days, rats progressively developed a tumor within the distal femoral epiphysis. On days 3, 7, 10, and 13 post injection, rats were subjected to the incapacitance and Randall–Selitto behavioral tests as they are believed to be indirect reflections of tumor induced pain. Ipsilateral hind limbs were subjected to X-ray and computed tomography (CT scans and histological sections were stained with hematoxylin and eosin (H&E.Results: Intra femoral injections of MLL cells resulted in the progressive development of a tumor leading to bone destruction and nociceptive behaviors. Tumor development resulted in the redistribution of weight to the contralateral hind leg and significantly reduced the paw withdrawal threshold of the ipsilateral hind paw as observed via the incapacitance and Randall–Selitto tests, respectively. X-ray and computed tomography scans along with H&E stains indicated tumor-associated structural damage to the distal femur. This model was challenged with administration of meloxicam. Compared with vehicle-injected controls, the meloxicam-treated rats displayed smaller nociceptive responses as observed with the incapacitance and Randall–Selitto tests, suggesting that meloxicam was effective in reducing the pain-related symptoms displayed by model animals and that the model behaved in a predictable way to cyclooxygenase-2 treatment.Conclusions: This

  4. Multifocal septic osteomyelitis mimicking skeletal metastatic disease in a patient with prostate cancer.

    Science.gov (United States)

    Alexiou, Evangelos; Georgoulias, Panagiotis; Valotassiou, Varvara; Georgiou, Evangelia; Fezoulidis, Ioannis; Vlychou, Marianna

    2015-01-01

    We present an unusual case of a 59 years old patient with prostate cancer, who was referred to our hospital with pleurodenia, low back and other sites of bone ostalgia, for bone scintiscan. The patient underwent a whole body bone scanning after the intravenous administration of 740MBq (99m)Tc-methylene diphosphonate (MDP). The main findings of the study were: increased radiotracer uptake at the T5, T9-T10 vertebrae, the head of the 11th rib and the area of the left sternoclavicular joint (SCJ), which were initially attributed to skeletal metastatic lesions. Another "hot" area in the left knee, was consistent with severe arthritis. Physical examination revealed fever up to 38.7°C, tenderness and swelling of his left knee and various painful sites. Due to persistent fever and markedly raised inflammatory markers (ESR 102mm/h, CRP 73.8mg/L, WBC 16.800 cells/μ L - neutrophils 78%, lymphocytes 15%, monocytes 5%, eosinophils 1%), the patient was further referred for a magnetic resonance (MR) scan with specific interest on the thoracic spine and the SCJ. In the sagittal short-tau inversion recovery (STIR) MR image, abnormally high signal involving both T9 and T10 vertebral bodies due to bone marrow oedema and irregularity of the endplates with focal destruction areas, were observed. The T9-T10 intervertebral disc had an abnormally high signal suggestive of "hot disc" sign and also a prevertebral soft tissue mass abutting the anterior aspect of the involved vertebral bodies. The axial T1-weighted image with fat saturation post gadolinium (Gd), revealed diffuse strong enhancement in the vertebral body, the paraspinal soft tissue mass and the adjacent right rib. Circumferential epidural enhancement indicative of intra-canal spread of the infection, was also noticed. Additional MR sequences covered the level of the SCJ. Extensive subarticular and soft tissue changes with fluid collection and bone oedema of the left SCJ were shown with the typical pattern of diffuse

  5. Bone marrow recovery and subsequent chemotherapy following radiolabeled anti-prostate-specific membrane antigen (PSMA monoclonal antibody J591 in men with metastatic castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Scott T Tagawa

    2013-08-01

    Full Text Available Radioimmunotherapy has demonstrated efficacy with acceptable toxicity leading to approval in non-Hodgkin’s lymphoma, but has been slower to develop for the treatment of advanced solid tumors. Prostate cancer represents a good candidate for radioimmunotherapy based upon high exposure to circulating antibodies at common disease sites with a specific, highly expressed cell-surface antigen in prostate-specific membrane antigen. Four phase I and II trials utilizing 177Lu- or 90Y-J591 have been reported. Long-term toxicity and chemotherapy administration was analyzed. As expected, the only serious toxicity observed was myelosuppression. Grade 4 thrombocytopenia occurred in 33.3% without significant hemorrhage and grade 4 neutropenia occurred in 17.3% with 0.07% febrile neutropenia. Nearly all subjects (97.3% recovered to grade 0 or 1 platelets and all had complete neutrophil recovery. The majority (81.3% received chemotherapy at any time, with 61.3% receiving chemotherapy following radioimmunotherapy. Ten subjects underwent bone marrow biopsies at some point in their disease course following radioimmunotherapy for low counts; all had diffuse prostate cancer infiltration without evidence of myelodysplasia or leukemia. As expected, myelosuppression occurs following therapeutic doses of radioimmunotherapy for men with metastatic castration-resistant prostate cancer. However, toxicity is predictable and self-limited, with the majority of patients who do not refuse able to receive cytotoxic chemotherapy following radioimmunotherapy.

  6. Pleuropulmonary and Lymph Node Progression after Docetaxel - Benefits from Treatment with Cabazitaxel in Metastatic Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Angel Segura Huerta

    2013-07-01

    Full Text Available Introduction: To date, there are no guidelines for a rational and more favourable sequence of treatment after docetaxel. Two drugs (cabazitaxel and abiraterone have recently been approved as second-line treatment after docetaxel failure in metastatic castration-resistant prostate cancer (mCRPC, but there are no studies comparing abiraterone versus cabazitaxel. The most suitable drug is chosen based on the physician's opinion and the patient's characteristics. In patients with a good performance status who are able to receive either treatment, it would be convenient to begin with cabazitaxel and to reserve abiraterone in case there is a worsening of the general status, in consideration of abiraterone's more favourable toxicity profile. Case Report: We describe the case of a 74-year-old male with mCRPC who presented with an interesting and uncommon tumour dissemination (pleuropulmonary occurring after the first standard treatment with docetaxel. Intravenous treatment with cabazitaxel 25 mg/m2 and oral prednisone 10 mg continuously was initiated. The patient received a total of 8 cycles of chemotherapy. A reduction of mediastinal adenopathies and infrarenal para-aortic stable bone involvement and an absence of pleural effusion were observed. No relevant toxicity was noted. Since February 2012, a progressive PSA increase without clinical deterioration has been noted. Conclusions: The selection criteria for second- and third-line systemic treatment and the excellent response obtained with cabazitaxel in an unusual disease setting are described. The results confirm the long duration and quality of response of cabazitaxel treatment. Further therapeutic options in this group of patients are suggested.

  7. Incidence of high chromogranin A serum levels in patients with non metastatic prostate adenocarcinoma

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    Barnabei Agnese

    2010-12-01

    Full Text Available Abstract Background ChromograninA in prostate carcinoma (PC indicate NE differentiation. This tumour is more aggressive and resistant to hormone therapy. Patients and methods We analyzed the incidence of pre-operative ChromograninA serum levels in non metastatic PC patients. Serum PSA and ChromograninA were analyzed before treatment. Clinicopathological parameters were evaluated in relation to serum ChromograninA. 486 patients were enrolled. Results We found 352 pT2 and 134 pT3. 21 patients were N+. 278 patients had Gleason score levels 7. Median PSA pre-operative level was 7.61 ng/ml. PSA was significantly associated with pT stage (pT2 with PSA abnormal 23.6% vs pT3 48.5%, p 7 vs 29.5% in the Gleason score = 7 vs 27.3% in the Gleason score 7 (31.4% (p = 0.12. The serum ChromograninA levels in the two groups of patients were subdivided before and after 2005 on the basis of different used assays, showing no correlation with serum ChromograninA and other parameters. Conclusions This study showed that ChromograninA levels correlated to NE differentiation and possible aggressiveness of PC. Pre-operative circulating ChromograninA could complement PSA in selecting more aggressive PC cases, particularly in the presence of a higher Gleason score. Complementary information is provided by the absence of a correlation between serum ChromograninA and PSA levels.

  8. A survival score for patients with metastatic spinal cord compression from prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Rades, D.; Douglas, S. [Luebeck Univ. (Germany). Dept. of Radiation Oncology; Veninga, T. [Dr. Bernard Verbeeten Institute Tilburg (Netherlands). Dept. of Radiation Oncology; Bajrovic, A. [University Medical Center Hamburg-Eppendorf (Germany). Dept. of Radiation Oncology; Stalpers, L.J.A. [Academic Medical Center Amsterdam (Netherlands). Dept. of Radiotherapy; Hoskin, P.J. [Mount Vernon Center for Cancer Treatment, Northwood (United Kingdom). Dept. of Clinical Oncology; Rudat, V. [Saad Specialist Hospital Al-Khobar (Saudi Arabia). Dept. of Radiation Oncology; Schild, S.E. [Mayo Clinic Scottsdale, AZ (United States). Dept. of Radiation Oncology

    2012-09-15

    Background: This study aimed to develop and validate a survival scoring system for patients with metastatic spinal cord compression (MSCC) from prostate cancer. Patients and methods: Of 436 patients, 218 patients were assigned to the test group and 218 patients to the validation group. Eight potential prognostic factors (age, performance status, number of involved vertebrae, ambulatory status, other bone metastases, visceral metastases, interval from cancer diagnosis to radiotherapy of MSCC, time developing motor deficits) plus the fractionation regimen were retrospectively investigated for associations with survival. Factors significant in the multivariate analysis were included in the survival score. The score for each significant prognostic factor was determined by dividing the 6-month survival rate (%) by 10. The total score represented the sum of the scores for each factor. The prognostic groups of the test group were compared to the validation group. Results: In the multivariate analysis of the test group, performance status, ambulatory status, other bone metastases, visceral metastases, and interval from cancer diagnosis to radiotherapy were significantly associated with survival. Total scores including these factors were 20, 21, 22, 24, 26, 28, 29, 30, 31, 32, 33, 35, 37, or 39 points. In the test group, the 6-month survival rates were 6.5% for 20-24 points, 44.6% for 26-33 points, and 95.8% for 35-39 points (p < 0.0001). In the validation group, the 6-month survival rates were 7.4%, 45.4%, and 94.7%, respectively (p < 0.0001). Conclusions: Because the survival rates of the validation group were almost identical to the test group, this score can be considered valid and reproducible. (orig.)

  9. Use of prednisone with abiraterone acetate in metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Auchus, Richard J; Yu, Margaret K; Nguyen, Suzanne; Mundle, Suneel D

    2014-12-01

    Abiraterone acetate, a prodrug of the CYP17A1 inhibitor abiraterone that blocks androgen biosynthesis, is approved for treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) in combination with prednisone or prednisolone 5 mg twice daily. This review evaluates the basis for the effects of prednisone on mineralocorticoid-related adverse events that arise because of CYP17A1 inhibition with abiraterone. Coadministration with the recommended dose of glucocorticoid compensates for abiraterone-induced reductions in serum cortisol and blocks the compensatory increase in adrenocorticotropic hormone seen with abiraterone. Consequently, 5 mg prednisone twice daily serves as a glucocorticoid replacement therapy when coadministered with abiraterone acetate, analogous to use of glucocorticoid replacement therapy for certain endocrine disorders. We searched PubMed to identify safety concerns regarding glucocorticoid use, placing a focus on longitudinal studies in autoimmune and inflammatory diseases and cancer. In general, glucocorticoid-related adverse events, including bone loss, immunosuppression, hyperglycemia, mood and cognitive alterations, and myopathy, appear dose related and tend to occur at doses and/or treatment durations greater than the low dose of glucocorticoid approved in combination with abiraterone acetate for the treatment of mCRPC. Although glucocorticoids are often used to manage tumor-related symptoms or to prevent treatment-related toxicity, available evidence suggests that prednisone and dexamethasone might also offer modest therapeutic benefit in mCRPC. Given recent improvements in survival achieved for mCRPC with novel agents in combination with prednisone, the risks of these recommended glucocorticoid doses must be balanced with the benefits shown for these regimens.

  10. Combination of rapamycin, CI-1040, and 17-AAG inhibits metastatic capacity of prostate cancer via Slug inhibition.

    Directory of Open Access Journals (Sweden)

    Guanxiong Ding

    Full Text Available Though prostate cancer (PCa has slow progression, the hormone refractory (HRCP and metastatic entities are substantially lethal and lack effective treatments. Transcription factor Slug is critical in regulating metastases of various tumors including PCa. Here we studied targeted therapy against Slug using combination of 3 drugs targeting 3 pathways respectively converging via Slug and further regulating PCa metastasis. Using in vitro assays we confirmed that Slug up-regulation incurred inhibition of E-cadherin that was anti-metastatic, and inhibited Bim-regulated cell apoptosis in PCa. Upstream PTEN/Akt, mTOR, Erk, and AR/Hsp90 pathways were responsible for Slug up-regulation and each of these could be targeted by rapamycin, CI-1040, and 17-AAG respectively. In 4 PCa cell lines with different traits in terms of PTEN loss and androgen sensitivity we tested the efficacy of mono- and combined therapy with the drugs. We found that metastatic capacity of the cells was maximally inhibited only when all 3 drugs were combined, due to the crosstalk between the pathways. 17-AAG decreases Slug expression via blockade of HSP90-dependent AR stability. Combination of rapamycin and CI-1040 diminishes invasiveness more potently in PCa cells that are androgen insensitive and with PTEN loss. Slug inhibited Bim-mediated apoptosis that could be rescued by mTOR/Erk/HSP90 inhibitors. Using mouse models for circulating PCa DNA quantification, we found that combination of mTOR/Erk/HSP90 inhibitors reduced circulating PCa cells in vivo significantly more potently than combination of 2 or monotherapy. Conclusively, combination of mTOR/Erk/Hsp90 inhibits metastatic capacity of prostate cancer via Slug inhibition.

  11. Risk Factors for Metastatic Castration-Resistant Prostate Cancer (CRPC) Predict Long-Term Treatment with Docetaxel

    OpenAIRE

    Kawahara, Takashi; Miyoshi, Yasuhide; Sekiguchi, Zenkichi; Sano, Futoshi; Hayashi, Narihiko; Teranishi, Jun-ichi; Misaki, Hiroshi; Noguchi, Kazumi; Kubota, Yoshinobu; Uemura, Hiroji

    2012-01-01

    Purpose For patients with metastatic castration-resistant prostatic cancer (mCRPC), docetaxel plus prednisone leads to superior survival and a higher response rate compared with mitoxantrone plus prednisone. We analyzed the efficacy of long-term treatment with ≥10 cycles of docetaxel, and validated the risk group classification in predicting overall survival (OS) in Japanese patients with mCRPC. Patients and Methods Fifty-two patients with mCRPC were administered 55 mg/m2 docetaxel and 8 mg d...

  12. Further analysis of PREVAIL: Enzalutamide use in chemotherapy-naïve men with metastatic castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Jeanny B Aragon-Ching

    2014-12-01

    Full Text Available PREVAIL was a phase III multinational, double-blind, placebo-controlled trial that enrolled chemotherapy-naïve men with metastatic castration-resistant prostate cancer (mCRPC, which showed remarkable improvement in co-primary endpoints with an overall 81% reduction in the risk of radiographic progression, as well as 29% reduction in the risk of death in favor of the enzalutamide arm over placebo. All secondary endpoints including time to subsequent chemotherapy initiation and prostate specific antigen (PSA progression were in favor of the enzalutamide arm. The results of PREVAIL shows the utility of enzalutamide that would likely soon expand the indication to asymptomatic or minimally symptomatic men with mCRPC not previously treated with chemotherapy.

  13. Sustained complete response to CTLA-4 blockade in a patient with metastatic, castration-resistant prostate cancer.

    Science.gov (United States)

    Graff, Julie N; Puri, Sachin; Bifulco, Carlo B; Fox, Bernard A; Beer, Tomasz M

    2014-05-01

    We present the case of a man with metastatic, castration-resistant prostate cancer, who had a complete prostate-specific antigen (PSA) response after 2½ doses of ipilimumab. His treatment course was complicated by diarrhea and autoimmune hepatitis, both of which resolved within 4 months. Sera and biopsy specimens were accessed, and sera from pretreatment and day 113 were analyzed. Augmented antibody responses were detected against 11 potential tumor antigens, with responses ranging from 5- to 20-fold in day 113 sera compared with baseline. Genes that were targets of a strong antibody response (arbitrarily set at 10-fold or greater increase) were analyzed by real-time PCR for expression in the tumor biopsy cDNA. Of the top 5 genes, only 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) could be identified in the amplified tumor biopsy cDNA. Using an antibody to HIBCH, immunohistochemical analysis documented strong expression of the protein. Together, these data suggest that an augmented antibody response to HIBCH, an antigen that was expressed by the patient's prostate cancer, could have contributed to the clinical response. After 16 months of PSA stability, he discontinued his androgen-suppression therapy. With the return of his testosterone, his PSA increased slightly, likely originating from his intact prostate. He has been disease free for the past 6 years without any additional therapy.

  14. A Comprehensive Review of Contemporary Role of Local Treatment of the Primary Tumor and/or the Metastases in Metastatic Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Fouad Aoun

    2014-01-01

    Full Text Available To provide an overview of the currently available literature regarding local control of primary tumor and oligometastases in metastatic prostate cancer and salvage lymph node dissection of clinical lymph node relapse after curative treatment of prostate cancer. Evidence Acquisition. A systematic literature search was conducted in 2014 to identify abstracts, original articles, review articles, research articles, and editorials relevant to the local control in metastatic prostate cancer. Evidence Synthesis. Local control of primary tumor in metastatic prostate cancer remains experimental with low level of evidence. The concept is supported by a growing body of genetic and molecular research as well as analogy with other cancers. There is only one retrospective observational population based study showing prolonged survival. To eradicate oligometastases, several options exist with excellent local control rates. Stereotactic body radiotherapy is safe, well tolerated, and efficacious treatment for lymph node and bone lesions. Both biochemical and clinical progression are slowed down with a median time to initiate ADT of 2 years. Salvage lymph node dissection is feasible in patients with clinical lymph node relapse after local curable treatment. Conclusion. Despite encouraging oncologic midterm results, a complete cure remains elusive in metastatic prostate cancer patients. Further advances in imaging are crucial in order to rapidly evolve beyond the proof of concept.

  15. β-catenin is required for prostate development and cooperates with Pten loss to drive invasive carcinoma.

    Directory of Open Access Journals (Sweden)

    Jeffrey C Francis

    Full Text Available Prostate cancer is a major cause of male death in the Western world, but few frequent genetic alterations that drive prostate cancer initiation and progression have been identified. β-Catenin is essential for many developmental processes and has been implicated in tumorigenesis in many tissues, including prostate cancer. However, expression studies on human prostate cancer samples are unclear on the role this protein plays in this disease. We have used in vivo genetic studies in the embryo and adult to extend our understanding of the role of β-Catenin in the normal and neoplastic prostate. Our gene deletion analysis revealed that prostate epithelial β-Catenin is required for embryonic prostate growth and branching but is dispensable in the normal adult organ. During development, β-Catenin controls the number of progenitors in the epithelial buds and regulates a discrete network of genes, including c-Myc and Nkx3.1. Deletion of β-Catenin in a Pten deleted model of castration-resistant prostate cancer demonstrated it is dispensable for disease progression in this setting. Complementary overexpression experiments, through in vivo protein stabilization, showed that β-Catenin promotes the formation of squamous epithelia during prostate development, even in the absence of androgens. β-Catenin overexpression in combination with Pten loss was able to drive progression to invasive carcinoma together with squamous metaplasia. These studies demonstrate that β-Catenin is essential for prostate development and that an inherent property of high levels of this protein in prostate epithelia is to drive squamous fate differentiation. In addition, they show that β-Catenin overexpression can promote invasive prostate cancer in a clinically relevant model of this disease. These data provide novel information on cancer progression pathways that give rise to lethal prostate disease in humans.

  16. β-catenin is required for prostate development and cooperates with Pten loss to drive invasive carcinoma.

    Directory of Open Access Journals (Sweden)

    Jeffrey C Francis

    Full Text Available Prostate cancer is a major cause of male death in the Western world, but few frequent genetic alterations that drive prostate cancer initiation and progression have been identified. β-Catenin is essential for many developmental processes and has been implicated in tumorigenesis in many tissues, including prostate cancer. However, expression studies on human prostate cancer samples are unclear on the role this protein plays in this disease. We have used in vivo genetic studies in the embryo and adult to extend our understanding of the role of β-Catenin in the normal and neoplastic prostate. Our gene deletion analysis revealed that prostate epithelial β-Catenin is required for embryonic prostate growth and branching but is dispensable in the normal adult organ. During development, β-Catenin controls the number of progenitors in the epithelial buds and regulates a discrete network of genes, including c-Myc and Nkx3.1. Deletion of β-Catenin in a Pten deleted model of castration-resistant prostate cancer demonstrated it is dispensable for disease progression in this setting. Complementary overexpression experiments, through in vivo protein stabilization, showed that β-Catenin promotes the formation of squamous epithelia during prostate development, even in the absence of androgens. β-Catenin overexpression in combination with Pten loss was able to drive progression to invasive carcinoma together with squamous metaplasia. These studies demonstrate that β-Catenin is essential for prostate development and that an inherent property of high levels of this protein in prostate epithelia is to drive squamous fate differentiation. In addition, they show that β-Catenin overexpression can promote invasive prostate cancer in a clinically relevant model of this disease. These data provide novel information on cancer progression pathways that give rise to lethal prostate disease in humans.

  17. Predictive efficacy of the 2014 International Society of Urological Pathology Gleason grading system in initially diagnosed metastatic prostate cancer

    Science.gov (United States)

    Sun, Guang-Xi; Shen, Peng-Fei; Zhang, Xing-Ming; Gong, Jing; Gui, Hao-Jun; Shu, Kun-Peng; Liu, Jiang-Dong; Zhao, Jinge; Yang, Yao-Jing; Chen, Xue-Qin; Chen, Ni; Zeng, Hao

    2017-01-01

    We compared the predictive ability of the 2014 and 2005 Gleason grading systems in 568 patients initially diagnosed with metastatic prostate cancer (PCa). Outcomes included the duration of castration-resistant prostate cancer-free survival (CFS) and overall survival (OS). Univariate analyses and log-rank tests were used to identify prognosis indicators and assess univariable differences in CFS and OS in Gleason score (GS) groups. Cox proportional hazards and area under the curves of receiver operator characteristics methods were used to evaluate the predictive efficacy of the 2005 and 2014 ISUP grading systems. Univariate analyses showed that the 2005 and 2014 grading systems were prognosticators for CFS and OS; both systems could distinguish the clinical outcome of patients with GS 6, GS 7, and GS 8–10. Using the 2014 criteria, no statistical differences in patient survival were observed between GS 3 + 4 and GS 4 + 3 or GS 8 and GS 9–10. The predictive ability of the 2014 and 2005 grading systems was comparable for CFS and OS (P = 0.321). However, the 2014 grading system did not exhibit superior predictive efficacy in patients initially diagnosed with PCa and bone metastasis; trials using larger cohorts are required to confirm its predictive value. To the best of our knowledge, ours is the first study to compare the 2005 and 2014 grading systems in initially diagnosed PCa with bone metastasis. At present, we recommend that both systems should be used to predict the prognosis of patients with metastatic PCa. PMID:27569001

  18. Exosomal ITGA3 interferes with non-cancerous prostate cell functions and is increased in urine exosomes of metastatic prostate cancer patients

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    Irene V. Bijnsdorp

    2013-10-01

    Full Text Available Background: Cancer cells are able to change the protein expression and behavior of non-cancerous surrounding cells. Exosomes, secreted by prostate cancer (PCa cells, may have a functional role in cancer metastasis and present a promising source for protein biomarkers. The aim of the present study was to identify which proteins in exosomes can influence non-cancerous cells, and to determine whether we can use urine exosomal proteins to identify high-risk PCa patients. Method: Exosomes were isolated by ultracentrifugation. Migration and invasion were studied by the transwell (invasion assay. Proteomics was performed by LC-MS/MS and identified proteins were validated by Western blotting. Cellular uptake of fluorescent labeled PKH67-exosomes was measured by FACS. Results: Based on comparative protein profiling by mass spectrometry-based proteomics of LNCaP- and PC3-exosomes, we selected ITGA3 and ITGB1, involved in migration/invasion, for further analyses. Inhibition of exosomal ITGA3 reduced the migration and invasion of non-cancerous prostate epithelial cells (prEC almost completely. Cellular uptake of exosomes by prEC was higher with PC3-exosomes compared to LNCaP exosomes. Finally, ITGA3 and ITGB1 were more abundant in urine exosomes of metastatic patients (p<0.05, compared to benign prostate hyperplasia or PCa. Conclusion: These data indicate exosomal ITGA3 and ITGB1 may play a role in manipulating non-cancerous surrounding cells and that measurement of ITGA3 and ITGB1 in urine exosomes has the potential to identify patients with metastatic PCa in a non-invasive manner.

  19. Trends and outcome from radical therapy for primary non-metastatic prostate cancer in a UK population.

    Directory of Open Access Journals (Sweden)

    David C Greenberg

    Full Text Available Increasing proportions of men diagnosed with prostate cancer in the UK are presenting with non-metastatic disease. We investigated how treatment trends in this demographic have changed.Non-metastatic cancers diagnosed from 2000-2010 in the UK Anglian Cancer network stratified by age and risk group were analysed [n = 10,365]. Radiotherapy [RT] and prostatectomy [RP] cancer specific survival [CSS] were further compared [n = 4755].Over the decade we observed a fall in uptake of primary androgen deprivation therapy but a rise in conservative management [CM] and radical therapy [p<0.0001]. CM in particular has become the primary management for low-risk disease by the decade end [p<0.0001]. In high-risk disease however both RP and RT uptake increased significantly but in an age dependent manner [p<0.0001]. Principally, increased RP in younger men and increased RT in men ≥ 70y. In multivariate analysis of radically treated men both high-risk disease [HR 8.0 [2.9-22.2], p<0.0001] and use of RT [HR 1.9 [1.0-3.3], p = 0.024] were significant predictors of a poorer CSM. In age-stratified analysis however, the trend to benefit of RP over RT was seen only in younger men [≤ 60 years] with high-risk disease [p = 0.07]. The numbers needed to treat by RP instead of RT to save one cancer death was 19 for this group but 67 for the overall cohort.This study has identified significant shifts in non-metastatic prostate cancer management over the last decade. Low-risk disease is now primarily managed by CM while high-risk disease is increasingly treated radically. Treatment of high-risk younger men by RP is supported by evidence of better CSM but this benefit is not evident in older men.

  20. Radium-223 chloride: a potential new treatment for castration-resistant prostate cancer patients with metastatic bone disease

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    Harrison MR

    2013-01-01

    Full Text Available Michael R Harrison, Terence Z Wong, Andrew J Armstrong, Daniel J GeorgeDuke Cancer Institute, Durham, NC, USABackground: Radium-223 chloride (223Ra; Alpharadin is an alpha-emitting radioisotope that targets areas of osteoblastic metastasis and is excreted by the small intestine. When compared with beta-emitters (eg, strontium-89, samarium-153, 223Ra delivers a high quantity of energy per track length with short tissue penetration.Objective: This review describes the mechanism, radiobiology, and preclinical development of 223Ra and discusses the clinical data currently available regarding its safety and efficacy profile.Methods: Data from clinical trials including abstracts were collected and reviewed using the PubMed Database, as well as the American Society of Clinical Oncology abstract database.Conclusion: Current bone-targeted therapies fall into two main categories: antiresorptive agents (eg, zoledronic acid, denosumab, which have been shown to delay skeletal-related events, and radiopharmaceuticals (eg, samarium-153, which may have a role in pain palliation. Historically, neither antiresorptive agents nor radiopharmaceuticals have shown definitive evidence of improved overall survival or other antitumor effects in metastatic castrate-resistant prostate cancer (mCRPC. Radiopharmaceuticals are limited by myelosuppresion, thrombocytopenia, and renal excretion. In a recently reported randomized Phase III trial in men with symptomatic bone-metastatic CRPC who had received or were ineligible for docetaxel chemotherapy, 223Ra treatment resulted in improved overall survival and delayed skeletal-related events. Toxicity consisted of minor gastrointestinal side effects and mild neutropenia and thrombocytopenia that were rarely severe. Pending regulatory approval, 223Ra may represent a unique and distinct option for an important subgroup of patients with mCRPC; future trials should address its use in combination or in sequence with existing and novel

  1. Randomised study of Casodex 50 MG monotherapy vs orchidectomy in the treatment of metastatic prostate cancer. The Scandinavian Casodex Cooperative Group

    DEFF Research Database (Denmark)

    Iversen, P; Tveter, K; Varenhorst, E

    1996-01-01

    The effect of Casodex (ICI 176,334), a new, once-daily, selective antiandrogen, given as 50 mg monotherapy, was compared with orchidectomy in a randomised, multicentre, open study in 376 patients with metastatic prostate cancer. At 3 months, PSA was reduced by 86% in the Casodex group and by 96% ...

  2. Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer: results of the European compassionate-use programme

    NARCIS (Netherlands)

    Heidenreich, A.; Bracarda, S.; Mason, M.; Ozen, H.; Sengelov, L.; Oort, I.M. van; Papandreou, C.; Fossa, S.; Hitier, S.; Climent, M.A.

    2014-01-01

    BACKGROUND: Cabazitaxel/prednisone has been shown to prolong survival versus mitoxantrone/prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or after docetaxel. Subsequently, compassionate-use programmes (CUPs) and expanded-access programme

  3. Changes of biochemical markers of bone turnover and YKL-40 following hormonal treatment for metastatic prostate cancer are related to survival

    DEFF Research Database (Denmark)

    Johansen, Julia S; Brasso, Klaus; Iversen, Peter;

    2007-01-01

    Elevated serum levels of biochemical markers of bone turnover and YKL-40 in patients with metastatic prostate cancer (PC) at the time of diagnosis are associated to poor prognosis. In this study, we evaluated the value of these biomarkers in monitoring the patients during hormonal treatment....

  4. Automated Bone Scan Index as a quantitative imaging biomarker in metastatic castration-resistant prostate cancer patients being treated with enzalutamide

    DEFF Research Database (Denmark)

    Anand, Aseem; Morris, Michael J.; Larson, Steven M

    2016-01-01

    Background: Having performed analytical validation studies, we are now assessing the clinical utility of the upgraded automated Bone Scan Index (BSI) in metastatic castration-resistant prostate cancer (mCRPC). In the present study, we retrospectively evaluated the discriminatory strength of the a...

  5. Efficacy and Safety of Abiraterone Acetate in Elderly (75 Years or Older) Chemotherapy Naive Patients with Metastatic Castration Resistant Prostate Cancer

    NARCIS (Netherlands)

    Smith, M.R.; Rathkopf, D.E.; Mulders, P.F.A.; Carles, J.; Poppel, H. Van; Li, J.; Kheoh, T.; Griffin, T.W.; Molina, A.; Ryan, C.J.

    2015-01-01

    PURPOSE: Metastatic castration resistant prostate cancer primarily affects elderly men. In this post hoc analysis we investigated the safety and efficacy of abiraterone acetate in elderly (age 75 years or greater) and younger (less than 75 years) patient subgroups at the prespecified interim analysi

  6. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial

    DEFF Research Database (Denmark)

    de Bono, Johann Sebastian; Oudard, Stephane; Ozguroglu, Mustafa;

    2010-01-01

    Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer...

  7. Randomized, Placebo-Controlled, Phase III Trial of Sunitinib Plus Prednisone Versus Prednisone Alone in Progressive, Metastatic, Castration-Resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Michaelson, M Dror; Oudard, Stephane; Ou, Yen-Chuan

    2014-01-01

    PURPOSE: We evaluated angiogenesis-targeted sunitinib therapy in a randomized, double-blind trial of metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: Men with progressive mCRPC after docetaxel-based chemotherapy were randomly assigned 2:1 to receive sunitinib 37.5 mg...

  8. Randomised study of Casodex 50 MG monotherapy vs orchidectomy in the treatment of metastatic prostate cancer. The Scandinavian Casodex Cooperative Group

    DEFF Research Database (Denmark)

    Iversen, P; Tveter, K; Varenhorst, E

    1996-01-01

    The effect of Casodex (ICI 176,334), a new, once-daily, selective antiandrogen, given as 50 mg monotherapy, was compared with orchidectomy in a randomised, multicentre, open study in 376 patients with metastatic prostate cancer. At 3 months, PSA was reduced by 86% in the Casodex group and by 96% ...

  9. The Role of Docetaxel in Non-Castrate Resistant Metastatic Prostate Cancer: An Evidence-based Case Report

    Directory of Open Access Journals (Sweden)

    Fakhri Rahman

    2017-04-01

    Full Text Available Aim: to learn the role of docetaxel in non-castrate resistant prostate cancer patient. Methods: literature search was conducted to find relevant study comparing the combination of docetaxel and androgen deprivation therapy (ADT to ADT alone in non-castrate resistant prostate cancer using PubMed, Cohrane Library, Proquest, EBSCO, and Scopus database. Quality assessment of studies was done using Bond University Rapid Critical Appraisal of a Systematic Review. Results: we found 494 studies from literature search, but only two studies were included in final selection. Based on validity assessment, we chose one study to be discussed further. This study showed that combination of docetaxel and ADT is better than ADT alone in regards of overall survival (HR 0.64; 95% CI 0.55, 0.75; p<0.0001; NNT=3, biochemical progression free survival (HR 0.63; 95% CI 0.57, 0.69; p<0.0001; NNT=2 and clinical progression free survival (HR 0.73; 95% CI 0.64, 0.84; p<0.0001; NNT=2. Benefit of docetaxel and ADT combination was especially seen in high volume disease (HR 0.67; 95% CI 0.54, 0.83; p=0.0003; NNT=3. Conclusion: addition of docetaxel into ADT has beneficial effects in terms of overall survival and progression free survival in patients with non-castrate resistant metastatic prostate cancer.

  10. Evolving treatment approaches for the management of metastatic castration-resistant prostate cancer – role of radium-223

    Directory of Open Access Journals (Sweden)

    Mukherji D

    2014-05-01

    Full Text Available Deborah Mukherji,1 Imane El Dika,1 Sally Temraz,1 Mohammed Haidar,2 Ali Shamseddine11Department of Hematology/Oncology, 2Department of Nuclear Medicine, American University of Beirut Medical Center, Beirut, LebanonAbstract: Radium-223 is a first-in-class alpha particle-emitting radiopharmaceutical approved for the treatment of bone metastatic castration-resistant prostate cancer. Radium-223 is administered intravenously with no requirement for complex shielding and specifically targets areas of bone metastasis. In a randomized placebo-controlled Phase III study, treatment with radium-223 was shown to improve overall survival, time to skeletal-related events, and health-related quality of life. Apart from radium-223, the cytotoxic chemotherapy agents docetaxel and cabazitaxel, androgen biosynthesis inhibitor abiraterone acetate, novel anti-androgen enzalutamide, and immunotherapy sipuleucel-T have also been shown to improve survival of men with advanced prostate cancer in Phase III trials. This review will outline current treatment approaches for advanced prostate cancer with a focus on the role of radium-223 in changing treatment paradigms.Keywords: Alpharadin, alpha-emitting radionuclide, bone metastasis

  11. Development of sipuleucel-T: autologous cellular immunotherapy for the treatment of metastatic castrate resistant prostate cancer.

    Science.gov (United States)

    Sims, Robert B

    2012-06-19

    Sipuleucel-T, the first autologous cellular immunotherapy approved by the United States Food and Drug Administration, is designed to stimulate an immune response to prostate cancer. Sipuleucel-T is manufactured by culturing a patient's peripheral blood mononuclear cells, including autologous antigen presenting cells (APCs), with a recombinant protein comprising a tumor-associated antigen (prostatic acid phosphatase [PAP]) and granulocyte colony-macrophage stimulating factor (GM-CSF). A full course of treatment comprises 3 infusions of sipuleucel-T, given at approximately 2-week intervals. The pattern of APC activation is consistent with priming by the first infusion, and boosting by the second and third infusions. Preclinical and clinical studies have demonstrated evidence of a robust antigen-specific immune response that includes a progressive and persistent increase in antigen-specific cellular and humoral immune responses. Treatment with sipuleucel-T has demonstrated a survival benefit in Phase 3 studies of subjects with metastatic castrate resistant (hormone refractory) prostate cancer (mCRPC). Adverse events with sipuleucel-T were generally mild to moderate and resolved within 2 days. Serious adverse events, autoimmune events, and cerebrovascular events occurred at a similar rate to control subjects. As the first autologous cellular immunotherapy to demonstrate an improvement in overall survival in asymptomatic or minimally symptomatic mCRPC patients, sipuleucel-T represents a new treatment paradigm in oncology.

  12. The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma

    Directory of Open Access Journals (Sweden)

    Joanna Birch

    2016-10-01

    Full Text Available The cell's repertoire of transfer RNAs (tRNAs has been linked to cancer. Recently, the level of the initiator methionine tRNA (tRNAiMet in stromal fibroblasts has been shown to influence extracellular matrix (ECM secretion to drive tumour growth and angiogenesis. Here we show that increased tRNAiMet within cancer cells does not influence tumour growth, but drives cell migration and invasion via a mechanism that is independent from ECM synthesis and dependent on α5β1 integrin and levels of the translation initiation ternary complex. In vivo and ex vivo migration (but not proliferation of melanoblasts is significantly enhanced in transgenic mice which express additional copies of the tRNAiMet gene. We show that increased tRNAiMet in melanoma drives migratory, invasive behaviour and metastatic potential without affecting cell proliferation and primary tumour growth, and that expression of RNA polymerase III-associated genes (which drive tRNA expression are elevated in metastases by comparison with primary tumours. Thus, specific alterations to the cancer cell tRNA repertoire drive a migration/invasion programme that may lead to metastasis.

  13. The initiator methionine tRNA drives cell migration and invasion leading to increased metastatic potential in melanoma

    Science.gov (United States)

    Birch, Joanna; Clarke, Cassie J.; Campbell, Andrew D.; Campbell, Kirsteen; Mitchell, Louise; Liko, Dritan; Kalna, Gabriela; Strathdee, Douglas; Sansom, Owen J.; Neilson, Matthew; Blyth, Karen

    2016-01-01

    ABSTRACT The cell's repertoire of transfer RNAs (tRNAs) has been linked to cancer. Recently, the level of the initiator methionine tRNA (tRNAiMet) in stromal fibroblasts has been shown to influence extracellular matrix (ECM) secretion to drive tumour growth and angiogenesis. Here we show that increased tRNAiMet within cancer cells does not influence tumour growth, but drives cell migration and invasion via a mechanism that is independent from ECM synthesis and dependent on α5β1 integrin and levels of the translation initiation ternary complex. In vivo and ex vivo migration (but not proliferation) of melanoblasts is significantly enhanced in transgenic mice which express additional copies of the tRNAiMet gene. We show that increased tRNAiMet in melanoma drives migratory, invasive behaviour and metastatic potential without affecting cell proliferation and primary tumour growth, and that expression of RNA polymerase III-associated genes (which drive tRNA expression) are elevated in metastases by comparison with primary tumours. Thus, specific alterations to the cancer cell tRNA repertoire drive a migration/invasion programme that may lead to metastasis. PMID:27543055

  14. Sipuleucel-T in patients with metastatic castration-resistant prostate cancer: an insight for oncologists

    OpenAIRE

    Garcia, Jorge A.

    2011-01-01

    Sipuleucel-T represents a novel immunotherapeutic compound designed to stimulate an immune response against castration-resistant prostate cancer (CRPC). Sipuleucel-T is an autologous active cellular immunotherapy product, which includes autologous dendritic cells pulsed ex vivo with PAP2024, a recombinant fusion protein made of prostatic acid phosphatase and granulocyte-macrophag...

  15. Clinical appraisal of abiraterone in the treatment of metastatic prostatic cancer: patient considerations, novel opportunities, and future directions

    Directory of Open Access Journals (Sweden)

    Mitsiades N

    2013-01-01

    Full Text Available Diego J Bedoya,1 Nicholas Mitsiades2,31Clearview Cancer Institute, Huntsville, AL, USA; 2Department of Medicine, 3Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USAAbstract: While androgen-deprivation therapy can induce dramatic clinical responses in advanced and metastatic prostate cancer, refractory disease (castration-resistant prostate cancer [CRPC] eventually emerges. In recent years, several studies have demonstrated the importance of residual intratumoral androgens in maintaining androgen receptor (AR transcriptional activity in CRPC. The cytochrome P450 enzyme CYP17 is an obligatory step in androgen synthesis, and therefore a critical therapeutic target in CRPC. Abiraterone acetate is a selective, irreversible inhibitor of CYP17 and can suppress adrenal synthesis of androgen precursors, and possibly in situ steroidogenesis in the tumor microenvironment. In a phase III multicenter study, abiraterone in combination with prednisone improved median overall survival of men with docetaxel-refractory CRPC by 3.9 months compared to placebo plus prednisone, and also resulted in higher objective prostate-specific antigen and radiographic response rates. The study led to the FDA approval in April 2011 of abiraterone for treatment of chemotherapy-refractory CRPC patients, validating steroidogenesis and the AR axis in general as therapeutic targets in CRPC. The FDA indication for abiraterone was expanded to all CRPCs in December 2012, while evaluation in even earlier disease states is ongoing. We propose a comprehensive AR axis-targeting approach via simultaneous, frontline enzymatic blockade of several steroidogenic enzymes (eg, CYP17 and AKR1C3 in combination with gonadotropin-releasing hormone analogs and potent, second-generation AR antagonists (eg, enzalutamide in order to improve outcomes in patients with prostate cancer.Keywords: androgen synthesis, testosterone, dihydrotestosterone, CYP17, AKR1C3, MDV

  16. Number of metastatic lymph nodes as determinant of outcome after salvage radical prostatectomy for radiation-recurrent prostate cancer.

    Science.gov (United States)

    Gugliemetti, G; Sukhu, R; Conca Baenas, M A; Meeks, J; Sjoberg, D D; Eastham, J A; Scardino, P T; Touijer, K

    2016-09-01

    Presence of lymph node metástasis (LNM) at salvage radical prostatectomy (sRP) is associated with poor outcome. Predictors of outcome in this context remain undetermined. ThE objective was to assess the role of number of positive lymph node on outcome of patients with LNM after sRP and for radio-recurrent prostate cancer. We analyzed data from a consecutive cohort of 215 men treated with sRP at a single institution. We used univariate Cox proportional hazard regression models for biochemical recurrence (BCR) and metastatic outcomes, with prostate-specific antigen, Gleason score, extraprostatic extension, seminal vesicle invasion, time between radiation therapy and sRP, and number of positive nodes as predictors. Of the 47 patients with LNM, 37 developed BCR, 11 developed distant metastasis and 4 died with a median follow-up of 2.3 years for survivors. The risk of metastases increased with higher pre-operative PSA levels (HR 1.19 per 1ng/ml; 95% CI: 1.06-1.34; P=.003). The remaining predictors did not reach conventional levels of significance. However, removal of 3 or more positive lymph nodes demonstrated a positive association, as expected, with metastatic disease (HR 3.44; 95% CI: 0.91-13.05; P=.069) compared to one or 2 positive nodes. Similarly, the presence of extraprostatic extension, seminal vesicle invasion and Gleason grade greater than 7 also demonstrated a positive association with higher risk of metástasis, with hazard ratios of 3.97 (95% CI: 0.50, 31.4; P=.2), 3.72 (95% CI: 0.80-17.26; P=.1), and 1.45 (95% CI: 0.44-4.76; P=.5), respectively. In patients with LNM after sRP for radio-recurrent prostate cancer, the risk of distant metástasis is likely to be influenced by the number of positive nodes (3 or more), high preoperative PSA, Gleason grade and advanced pathologic stage. These results are consistent with the findings of number of nodes (1 to 2 vs. 3 or more nodes positive) as a prognostic indicator after primary radical prostatectomy and

  17. Human epidermal growth factor receptor type 2 protein expression in Chinese metastatic prostate cancer patients correlates with cancer specific survival and increases after exposure to hormonal therapy

    Institute of Scientific and Technical Information of China (English)

    Bo Dai; Yun-Yi Kong; Ding-Wei Ye; Chun-Guang Ma; Xiao-Yan Zhou; Xu-Dong Yao

    2008-01-01

    Aim: To investigate human epidermal growth factor receptor type 2 (HER2) protein expression and gene amplification in Chinese metastatic prostate cancer patients and their potential value as prognostic factors. Methods: Immuno-histochemistry (IHC) was performed to investigate HER2 protein expression in prostate biopsy specimens from 104 Chinese metastatic prostate cancer patients. After 3-11 months of hormonal therapy, 12 patients underwent transure- thral resection of the prostate (TURP). HER2 protein expression of TURP specimens was compared with that of the original biopsy specimens. Of these, 10 biopsy and 4 TURP specimens with HER2 IHC staining scores ≥ 2+ were investigated for HER2 gene amplification status by fluorescent in situ hybridization (FISH). Results: Of the 104 prostate biopsy specimens, HER2 protein expression was 0, 1+, 2+ and 3+ in 49 (47.1%), 45 (43.3%), 8 (7.7%) and 2 (1.9%) cases, respectively. There was a significant association between HER2 expression and Gleason score (P = 0.026). HER2 protein expression of prostate cancer tissues increased in 33.3% of patients after hormonal therapy. None of the 14 specimens with HER2 IHC scores > 2+ showed HER2 gene amplification. Patients with HER2 scores ≥ 2+ had a significantly higher chance of dying from prostate cancer than those with HER2 scores of 0 (P = 0.004) and 1+ (P = 0.034). Multivariate Cox regression analysis showed that HER2 protein expression intensity was an independent predictor of cancer-related death (P = 0.039). Conclusion: An HER2 IHC score ≥ 2+ should be defined as HER2 protein overexpression in prostate cancer. Overexpression of HER2 protein in cancer tissue might suggest an increased risk of dying from prostate cancer. HER2 protein expression increases in some individual patients after hormonal therapy.

  18. Budgetary Impact of Cabazitaxel Use After Docetaxel Treatment for Metastatic Castration-Resistant Prostate Cancer.

    Science.gov (United States)

    Flannery, Kyle; Drea, Ed; Hudspeth, Louis; Corman, Shelby; Gao, Xin; Xue, Mei; Miao, Raymond

    2017-04-01

    With the approval of several new treatments for metastatic castration-resistant prostate cancer (mCRPC), budgetary impact is a concern for health plan decision makers. Budget impact models (BIMs) are becoming a requirement in many countries as part of formulary approval or reimbursement decisions. Cabazitaxel is a second-generation taxane developed to overcome resistance to docetaxel and is approved for the treatment of patients with mCRPC previously treated with a docetaxel-containing regimen. To estimate a 1-year projected budget impact of varying utilization rates of cabazitaxel as a second-line treatment for mCRPC following docetaxel, using a hypothetical U.S. private managed care plan with 1 million members. A BIM was developed to evaluate costs for currently available treatment options for patients with mCRPC previously treated with docetaxel. Treatments included in the model were cabazitaxel, abiraterone acetate, enzalutamide, and radium-223, with utilization rates derived from market research data. Medication costs were calculated according to published pricing benchmarks factored by dosing and duration of therapy as stated in the prescribing information for each agent. Published rates and costs of grade 3-4 adverse events were also factored into the model. In addition, the model reports budget impact under 2 scenarios. In the first base-case scenario, patient out-of-pocket costs were subtracted from the total cost of treatment. In the second scenario, all treatment costs were assumed to be paid by the plan. In a hypothetical 1 million-member health plan population, 100 patients were estimated to receive second-line treatment for mCRPC after treatment with docetaxel. Using current utilization rates for the 4 agents of interest, the base-case scenario estimated the cost of second-line treatment after docetaxel to be $6,331,704, or $0.528 per member per month (PMPM). In a scenario where cabazitaxel use increases from the base-rate case of 24% to a

  19. Avascular Necrosis of the Femoral Head After Palliative Radiotherapy in Metastatic Prostate Cancer: Absence of a Dose Threshold?

    Science.gov (United States)

    Daoud, Alia M; Hudson, Mack; Magnus, Kenneth G; Huang, Fleur; Danielson, Brita L; Venner, Peter; Saluja, Ronak; LeGuerrier, Bronwen; Daly, Helene; Emmenegger, Urban; Fairchild, Alysa

    2016-03-06

    Avascular necrosis (AVN) is the final common pathway resulting from insufficient blood supply to bone, commonly the femoral head. There are many postulated etiologies of non-traumatic AVN, including corticosteroids, bisphosphonates, and radiotherapy (RT). However, it is unclear whether there is a dose threshold for the development of RT-induced AVN. In this case report, we describe a patient with prostate cancer metastatic to bone diagnosed with AVN after receiving single-fraction palliative RT to the left femoral head. Potential contributing factors are discussed, along with a review of other reported cases. At present, the RT dose threshold below which there is no risk for AVN is unknown, and therefore detrimental impact from the RT cannot be excluded. Given the possibility that RT-induced AVN is a stochastic effect, it is important to be aware of the possibility of this diagnosis in any patient with a painful hip who has received RT to the femoral head.

  20. Impact of a pharmacist-led oral chemotherapy-monitoring program in patients with metastatic castrate-resistant prostate cancer.

    Science.gov (United States)

    Patel, Jay M; Holle, Lisa M; Clement, Jessica M; Bunz, Thomas; Niemann, Christopher; Chamberlin, Kevin W

    2016-12-01

    With the introduction of oral chemotherapy, the paradigm for cancer treatment is shifting. Use of oral chemotherapy agents offers a non-invasive option for patients with metastatic castrate-resistant prostate cancer. However, these medications are not without challenges including strict adherence for optimal effects, novel toxicity profiles, frequent lab parameter monitoring, high cost, and proper handling and disposal methods. Pharmacists are positioned to play a key role in providing patients with the education required to assure an optimal treatment course is carried out. Two cohorts of patients receiving abiraterone, bicalutamide, or enzalutamide for metastatic castrate-resistant prostate cancer seen in our outpatient cancer center 21 months before and 24 months after the implementation of a pharmacist-led oral chemotherapy-monitoring program in December of 2012 were retrospectively compared. Patients were evaluated for number of interventions, adherence to lab parameter monitoring, and overall time on each therapy. Of the 64 patients identified, 31 patients fulfilled inclusion criteria. A significant increase in the average number of interventions per patient (6.9 vs. 2.6; P = 0.004) and adherence to lab parameter monitoring (10 vs. 3; P = 0.04) in the post-program implementation cohort was found. However, no significant difference in overall time on therapy (10.3 vs. 8.1; P = 0.341) between the two groups was observed. These results suggest a potential opportunity exists to maximize oral chemotherapy treatment outcomes with the addition of a formalized monitoring program directed by an oncology pharmacist. © The Author(s) 2015.

  1. Impact of local treatment on overall survival of patients with metastatic prostate cancer: systematic review and meta-analysis

    Science.gov (United States)

    Carneiro, Arie; Baccaglini, Willy; Glina, Felipe P.A.; Kayano, Paulo P.; Nunes, Victor M.; Smaletz, Oren; Bernardo, Wanderley Marques; de Carvalho, Icaro Thiago; Lemos, Gustavo Caserta

    2017-01-01

    ABSTRACT Context Currently, standard treatment of metastatic prostatic cancer (MPCa) is androgen-deprivation therapy (ADT). Recent studies suggested that local treatment of MPCa is related to increase of survival of those patients, as observed in other tumors. Objective To evaluate the impact of local treatment on overall survival and cancer specific survival in 3 and 5 years in patients with MPCa. Materials and Methods Systematic review and meta-analysis of population studies published at PubMed, Scielo, Lilacs, Cochrane and EMBASE databases until June 2016. Several large cohorts and Post-Roc studies were included, that evaluated patients with MPCa submitted to local treatment (LT) using radiotherapy (RDT), surgery (RP) or brachytherapy (BCT) or not submitted to local treatment (NLT). Results 34.338 patients were analyzed in six included papers, 31.653 submitted to NLT and 2.685 to LT. Overall survival in three years was significantly higher in patients submitted to LT versus NLT (64.2% vs. 44.5%; RD 0.19, 95% CI, 0.17-0.21; p<0.00001; I2=0%), as well as in five years (51.9% vs. 23.6%; RD 0.30, 95% CI, 0.11-0.49; p<0.00001; I2=97%). Sensitive analysis according to type of local treatment showed that surgery (78.2% and 45.0%; RD 0.31, 95% CI, 0.26-0.35; p<0.00001; I2=50%) and radiotherapy (60.4% and 44.5%; RD 0.17, 95% CI, 0.12-0.22; p<0.00001; I2=67%) presented better outcomes. Conclusion LT using RDT, RP or BCT seems to significantly improve overall survival and cancer-specific survival of patients with metastatic prostatic cancer. Prospective and randomized studies must be performed in order to confirm our results. PMID:27802009

  2. Predictive efficacy of the 2014 International Society of Urological Pathology Gleason grading system in initially diagnosed metastatic prostate cancer

    Directory of Open Access Journals (Sweden)

    Guang-Xi Sun

    2017-01-01

    Full Text Available We compared the predictive ability of the 2014 and 2005 Gleason grading systems in 568 patients initially diagnosed with metastatic prostate cancer (PCa. Outcomes included the duration of castration-resistant prostate cancer-free survival (CFS and overall survival (OS. Univariate analyses and log-rank tests were used to identify prognosis indicators and assess univariable differences in CFS and OS in Gleason score (GS groups. Cox proportional hazards and area under the curves of receiver operator characteristics methods were used to evaluate the predictive efficacy of the 2005 and 2014 ISUP grading systems. Univariate analyses showed that the 2005 and 2014 grading systems were prognosticators for CFS and OS; both systems could distinguish the clinical outcome of patients with GS 6, GS 7, and GS 8-10. Using the 2014 criteria, no statistical differences in patient survival were observed between GS 3 + 4 and GS 4 + 3 or GS 8 and GS 9-10. The predictive ability of the 2014 and 2005 grading systems was comparable for CFS and OS (P = 0.321. However, the 2014 grading system did not exhibit superior predictive efficacy in patients initially diagnosed with PCa and bone metastasis; trials using larger cohorts are required to confirm its predictive value. To the best of our knowledge, ours is the first study to compare the 2005 and 2014 grading systems in initially diagnosed PCa with bone metastasis. At present, we recommend that both systems should be used to predict the prognosis of patients with metastatic PCa.

  3. Is it really an abscess? An unusual case of metastatic stromal cell sarcoma of the prostate

    Directory of Open Access Journals (Sweden)

    Shehan Wickramasinghe

    2015-01-01

    Conclusion: The preferred treatment for prostatic stromal cell sarcoma is surgery by radical prostatectomy or cystoprostatectomy. There is currently not enough literature on the topic to elucidate the role of chemo- or radiotherapy in loco-regional or distant spread.

  4. Biological and Clinical Characterization of Novel lncRNAs Associated with Metastatic Prostate Cancer

    Science.gov (United States)

    2015-11-01

    Disclosure of Potential Conflicts of Interest J.R. Prensner has ownership interest as a co- inventor on prostate cancer ncRNA patent licensed to GenomeDx...named as co- inventors . Wafergen, Inc. has a non-exclusive license for creating commercial research assays for lncRNAs in prostate cancer...sion of aggressive cancers. URLs. Stellaris probe designer, http://www.singlemoleculefish.com; HT-Seq, http:// www -huber.embl.de/users/anders/HTSeq

  5. Abiraterone acetate plus prednisone versus prednisone alone in chemotherapy-naive men with metastatic castration-resistant prostate cancer: patient-reported outcome results of a randomised phase 3 trial

    NARCIS (Netherlands)

    Basch, E.; Autio, K.; Ryan, C.J.; Mulders, P.; Shore, N.; Kheoh, T.; Fizazi, K.; Logothetis, C.J.; Rathkopf, D.; Smith, M.R.; Mainwaring, P.N.; Hao, Y.; Griffin, T.; Li, S.; Meyers, M.L.; Molina, A.; Cleeland, C.

    2013-01-01

    BACKGROUND: Abiraterone acetate plus prednisone significantly improves radiographic progression-free survival in asymptomatic or mildly symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer compared with prednisone alone. We describe analyses of data for patie

  6. RANKL/RANK/MMP-1 molecular triad contributes to the metastatic phenotype of breast and prostate cancer cells in vitro.

    Directory of Open Access Journals (Sweden)

    Sandra Casimiro

    Full Text Available The osteolytic nature of bone metastasis results from a tumor-driven increased bone resorption. Bone remodeling is orchestrated by the molecular triad RANK-RANKL-OPG. This process is dysregulated in bone metastases, mostly via induction of RANKL by tumor-derived factors. These factors increase expression of RANKL, which induce osteoclast formation, function, and survival, thereby increasing bone resorption. RANK is unexpectedly expressed by cancer cells, and the activation of RANKL-RANK pathway correlates with an increased invasive phenotype. To investigate the interaction between RANK expression in human breast and prostate cancer cells and their pro-metastatic phenotype we analyzed the activation of RANKL-RANK pathway and its effects on cell migration, invasion, gene expression in vitro, and osteolysis-inducing ability in vivo. RANKL activates kinase signaling pathways, stimulates cell migration, increases cell invasion, and up-regulates MMP-1 expression. In vivo, MMP-1 knockdown resulted in smaller x-ray osteolytic lesions and osteoclastogenesis, and decreased tumor burden. Therefore, RANKL inhibition in bone metastatic disease may decrease the levels of the osteoclastogenesis inducer MMP-1, contributing to a better clinical outcome.

  7. Yes-mediated phosphorylation of focal adhesion kinase at tyrosine 861 increases metastatic potential of prostate cancer cells.

    Science.gov (United States)

    Chatterji, Tanushree; Varkaris, Andreas S; Parikh, Nila U; Song, Jian H; Cheng, Chien-Jui; Schweppe, Rebecca E; Alexander, Stephanie; Davis, John W; Troncoso, Patricia; Friedl, Peter; Kuang, Jian; Lin, Sue-Hwa; Gallick, Gary E

    2015-04-30

    To study the role of FAK signaling complexes in promoting metastatic properties of prostate cancer (PCa) cells, we selected stable, highly migratory variants, termed PC3 Mig-3 and DU145 Mig-3, from two well-characterized PCa cell lines, PC3 and DU145. These variants were not only increased migration and invasion in vitro, but were also more metastatic to lymph nodes following intraprostatic injection into nude mice. Both PC3 Mig-3 and DU145 Mig-3 were specifically increased in phosphorylation of FAK Y861. We therefore examined potential alterations in Src family kinases responsible for FAK phosphorylation and determined only Yes expression was increased. Overexpression of Yes in PC3 parental cells and src-/-fyn-/-yes-/- fibroblasts selectively increased FAK Y861 phosphorylation, and increased migration. Knockdown of Yes in PC3 Mig-3 cells decreased migration and decreased lymph node metastasis following orthotopic implantation of into nude mice. In human specimens, Yes expression was increased in lymph node metastases relative to paired primary tumors from the same patient, and increased pFAK Y861 expression in lymph node metastases correlated with poor prognosis. These results demonstrate a unique role for Yes in phosphorylation of FAK and in promoting PCa metastasis. Therefore, phosphorylated FAK Y861 and increased Yes expression may be predictive markers for PCa metastasis.

  8. A receptor tyrosine kinase, UFO/Axl, and other genes isolated by a modified differential display PCR are overexpressed in metastatic prostatic carcinoma cell line DU145.

    Science.gov (United States)

    Jacob, A N; Kalapurakal, J; Davidson, W R; Kandpal, G; Dunson, N; Prashar, Y; Kandpal, R P

    1999-01-01

    We have used a modified differential display PCR protocol for isolating 3' restriction fragments of cDNAs specifically expressed or overexpressed in metastatic prostate carcinoma cell line DU145. Several cDNA fragments were identified that matched to milk fat globule protein, UFO/Axl, a receptor tyrosine kinase, human homologue of a Xenopus maternal transcript, laminin and laminin receptor, human carcinoma-associated antigen, and some expressed sequence tags. The transcript for milk fat globule protein, a marker protein shown to be overexpressed in breast tumors, was elevated in DU145 cells. The expression of UFO/Axl, a receptor tyrosine kinase, was considerably higher in DU145 cells as compared to normal prostate cells and prostatic carcinoma cell line PC-3. The overexpression of UFO oncogene in DU145 cells is discussed in the context of prostate cancer metastasis.

  9. Changes in extracellular matrix (ECM and ECM-associated proteins in the metastatic progression of prostate cancer

    Directory of Open Access Journals (Sweden)

    Sikes Robert A

    2004-01-01

    Full Text Available Abstract Prostate cancer (PCa is no exception to the multi-step process of metastasis. As PCa progresses, changes occur within the microenvironments of both the malignant cells and their targeted site of metastasis, enabling the necessary responses that result in successful translocation. The majority of patients with progressing prostate cancers develop skeletal metastases. Despite advancing efforts in early detection and management, there remains no effective, long-term cure for metastatic PCa. Therefore, the elucidation of the mechanism of PCa metastasis and preferential establishment of lesions in bone is an intensive area of investigation that promises to generate new targets for therapeutic intervention. This review will survey what is currently know concerning PCa interaction with the extracellular matrix (ECM and the roles of factors within the tumor and ECM microenvironments that contribute to metastasis. These will be discussed within the context of changes in expression and functional heterodimerization patterns of integrins, changes in ECM expression and reorganization by proteases facilitating invasion. In this context we also provide a brief summary of how growth factors (GFs, cytokines and regulatory signaling pathways favor PCa metastasis to bone.

  10. Effects of occupational therapy on quality of life of patients with metastatic prostate cancer. A randomized controlled study.

    Science.gov (United States)

    Huri, Meral; Huri, Emre; Kayihan, Hulya; Altuntas, Onur

    2015-08-01

    To evaluate the efficiency of occupational therapy relative to a home program in improving quality of life (QoL) among men who were treated for metastatic prostate cancer (MPC). Fifty-five men were assigned randomly to either the 12-week cognitive behavioral therapy based occupational therapy (OT-CBSM) intervention (treatment group) or a home program (control group) between March 2012 and August 2014 in the Department of Occupational Therapy, Faculty of Health Sciences, Hacettepe University, Ankara, Turkey. The Canadian Occupational Performance Measure (COPM) was used to measure the occupational performance and identify difficulties in daily living activities. The QoL and symptom status were measured by The European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire C30 and its Prostate Cancer Module. A 12-week OT-CBSM intervention including client-centered training of daily living activities, recreational group activities, and cognitive behavioral stress management intervention were applied. The COPM performance and satisfaction scores, which indicate occupational participation and QoL increased statistically in the treatment group in relation to men who were included in the home-program (p less than or equal to 0.05). A 12-week OT-CBSM intervention was effective in improving QoL in men treated for MPC, and these changes were associated significantly with occupational performance.

  11. Radium-223 dichloride: illustrating the benefits of a multidisciplinary approach for patients with metastatic castration-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Renzulli II JF

    2015-06-01

    Full Text Available Joseph F Renzulli II, Jennifer Collins, Anthony Mega Genitourinary Multidisciplinary Clinic, The Miriam Hospital, Providence, RI, USAAbstract: Improving options for patients with metastatic castration-resistant prostate cancer (mCRPC provide latitude in designing treatment plans that meet patients' medical needs and personal goals. The field's rapid evolution opens avenues for contributions by multiple medical specialties and requires considering more options to ensure that each patient receives the most appropriate care. A multidisciplinary clinic (MDC focusing on patients with cancers of the genitourinary tract demonstrates an efficient and cost-effective means of integrating the diverse professional knowledge and skills needed to develop an optimal patient treatment plan. As a guide to establishing an MDC for patients with mCRPC, this article describes the operation of the Genitourinary MDC at The Miriam Hospital in Providence, RI – specifically, the successful incorporation of radium-223 dichloride (radium-223 into the treatment algorithm for men with mCRPC and symptomatic bone metastases. Radium-223 is a new treatment that, unlike earlier radionuclide therapies, has shown a survival advantage in a large randomized phase 3 trial (ALSYMPCA. The overall survival benefit was comparable to that of newer immuno- and hormonal therapies in similar populations. Radium-223 treatment also delayed onset of symptomatic skeletal events. Both benefits were independent of prior docetaxel therapy or concurrent bisphosphonate use. In our clinic, radium-223 is used primarily to extend patient survival. Patient selection, patient management, and treatment sequencing are discussed here in the context of a multidisciplinary environment. Keywords: radium-223 dichloride, prostate cancer, castration-resistant prostate cancer, multidisciplinary clinic, best practices

  12. CD57 Expression in Incidental, Clinically Manifest, and Metastatic Carcinoma of the Prostate

    Directory of Open Access Journals (Sweden)

    Holger Wangerin

    2014-01-01

    Full Text Available Objectives. CD57 is normally found on NK-cells, but little is known about its expression in prostatic tissue. Methods. We investigated CD57 expression by immunohistochemistry using tissue microarrays containing 3262 prostate cancers (PCa, lymph node metastases, and benign prostatic tissue. The results were compared with clinical and pathological parameters. Results. Overall, 87% of PCa showed a moderate or strong expression of CD57. There was no significant difference to corresponding benign prostatic tissue. CD57 was increasingly lost from incidental over clinically manifest cancers to metastases. It correlated significantly with Gleason grade and pT-category, but not with PSA tissue expression. Loss of CD57 expression was an independent risk factor for PSA recurrence after prostatectomy in a multivariate Cox regression analysis. In standard sections, CD57 expression was heterogeneous, especially in large, high-grade PCa. Conclusions. There is a peculiar expression of CD57 in PCa and benign prostatic tissue. CD57 loss is associated with tumor dedifferentiation and tumor size. However, the use of this marker for prognostic purposes is hampered by its heterogeneous expression.

  13. High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells.

    Science.gov (United States)

    da Silva, Patrícia Benites Gonçalves; Teixeira Dos Santos, Márcia Cristina; Rodini, Carolina Oliveira; Kaid, Carolini; Pereira, Márcia Cristina Leite; Furukawa, Gabriela; da Cruz, Daniel Sanzio Gimenes; Goldfeder, Mauricio Barbugiani; Rocha, Clarissa Ribeiro Reily; Rosenberg, Carla; Okamoto, Oswaldo Keith

    2017-03-21

    Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer.

  14. High OCT4A levels drive tumorigenicity and metastatic potential of medulloblastoma cells

    Science.gov (United States)

    Gonçalves da Silva, Patrícia Benites; Teixeira dos Santos, Márcia Cristina; Rodini, Carolina Oliveira; Kaid, Carolini; Leite Pereira, Márcia Cristina; Furukawa, Gabriela; Gimenes da Cruz, Daniel Sanzio; Goldfeder, Mauricio Barbugiani; Reily Rocha, Clarissa Ribeiro; Rosenberg, Carla; Okamoto, Oswaldo Keith

    2017-01-01

    Medulloblastoma is a highly aggressive pediatric brain tumor, in which sporadic expression of the pluripotency factor OCT4 has been recently correlated with poor patient survival. However the contribution of specific OCT4 isoforms to tumor aggressiveness is still poorly understood. Here, we report that medulloblastoma cells stably overexpressing the OCT4A isoform displayed enhanced clonogenic, tumorsphere generation, and invasion capabilities. Moreover, in an orthotopic metastatic model of medulloblastoma, OCT4A overexpressing cells generated more developed, aggressive and infiltrative tumors, with tumor-bearing mice attaining advanced metastatic disease and shorter survival rates. Pro-oncogenic OCT4A effects were expression-level dependent and accompanied by distinct chromosomal aberrations. OCT4A overexpression in medulloblastoma cells also induced a marked differential expression of non-coding RNAs, including poorly characterized long non-coding RNAs and small nucleolar RNAs. Altogether, our findings support the relevance of pluripotency-related factors in the aggravation of medulloblastoma traits classically associated with poor clinical outcome, and underscore the prognostic and therapeutic value of OCT4A in this challenging type of pediatric brain cancer. PMID:28186969

  15. Orteronel plus prednisone in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (ELM-PC 4): a double-blind, multicentre, phase 3, randomised, placebo-controlled trial

    NARCIS (Netherlands)

    Saad, F.; Fizazi, K.; Jinga, V.; Efstathiou, E.; Fong, P.C.; Hart, L.L.; Jones, R.; McDermott, R.; Wirth, M.; Suzuki, K.; MacLean, D.B.; Wang, L.; Akaza, H.; Nelson, J.; Scher, H.I.; Dreicer, R.; Webb, I.J.; Wit, R. de; Oort, I.M. van

    2015-01-01

    BACKGROUND: Orteronel is an investigational, partially selective inhibitor of CYP 17,20-lyase in the androgen signalling pathway, a validated therapeutic target for metastatic castration-resistant prostate cancer. We assessed orteronel in chemotherapy-naive patients with metastatic castration-resist

  16. Sipuleucel-T in patients with metastatic castration-resistant prostate cancer: an insight for oncologists.

    Science.gov (United States)

    Garcia, Jorge A

    2011-03-01

    Sipuleucel-T represents a novel immunotherapeutic compound designed to stimulate an immune response against castration-resistant prostate cancer (CRPC). Sipuleucel-T is an autologous active cellular immunotherapy product, which includes autologous dendritic cells pulsed ex vivo with PAP2024, a recombinant fusion protein made of prostatic acid phosphatase and granulocyte-macrophage colony-stimulating factor. Despite the lack of prostate-specific antigen and objective response, a recent phase III randomized trial demonstrated a significant improvement in overall survival in asymptomatic and minimally symptomatic CRPC patients. This review summarizes the clinical development of Sipuleucel-T in CRPC that led to the regulatory approval of this compound in the USA.

  17. The HIF1A functional genetic polymorphism at locus +1772 associates with progression to metastatic prostate cancer and refractoriness to hormonal castration.

    Science.gov (United States)

    Fraga, Avelino; Ribeiro, Ricardo; Príncipe, Paulo; Lobato, Carlos; Pina, Francisco; Maurício, Joaquina; Monteiro, Cátia; Sousa, Hugo; Calais da Silva, F; Lopes, Carlos; Medeiros, Rui

    2014-01-01

    The hypoxia inducible factor 1 alpha (HIF1a) is a key regulator of tumour cell response to hypoxia, orchestrating mechanisms known to be involved in cancer aggressiveness and metastatic behaviour. In this study we sought to evaluate the association of a functional genetic polymorphism in HIF1A with overall and metastatic prostate cancer (PCa) risk and with response to androgen deprivation therapy (ADT). The HIF1A +1772 C>T (rs11549465) polymorphism was genotyped, using DNA isolated from peripheral blood, in 1490 male subjects (754 with prostate cancer and 736 controls cancer-free) through Real-Time PCR. A nested group of cancer patients who were eligible for androgen deprivation therapy was followed up. Univariate and multivariate models were used to analyse the response to hormonal treatment and the risk for developing distant metastasis. Age-adjusted odds ratios were calculated to evaluate prostate cancer risk. Our results showed that patients under ADT carrying the HIF1A +1772 T-allele have increased risk for developing distant metastasis (OR, 2.0; 95%CI, 1.1-3.9) and an independent 6-fold increased risk for resistance to ADT after multivariate analysis (OR, 6.0; 95%CI, 2.2-16.8). This polymorphism was not associated with increased risk for being diagnosed with prostate cancer (OR, 0.9; 95%CI, 0.7-1.2). The HIF1A +1772 genetic polymorphism predicts a more aggressive prostate cancer behaviour, supporting the involvement of HIF1a in prostate cancer biological progression and ADT resistance. Molecular profiles using hypoxia markers may help predict clinically relevant prostate cancer and response to ADT.

  18. Low-molecular-weight protein tyrosine phosphatase predicts prostate cancer outcome by increasing the metastatic potential

    NARCIS (Netherlands)

    R.R. Ruela-de-Sousa (Roberta); E. Hoekstra (Elmer); A.M. Hoogland (Marije); K.C. de Souza Queiroz (Karla); M.P. Peppelenbosch (Maikel); A. Stubbs (Andrew); K.J. Pelizzaro-Rocha (Karin); G.J.H.L. Leenders (Geert); G.W. Jenster (Guido); H. Aoyama (Hiroshi); C.V. Ferreira (Carmen); G.M. Fuhler (Gwenny)

    2016-01-01

    textabstractBackground Low-risk patients suffering from prostate cancer (PCa) are currently placed under active surveillance rather than undergoing radical prostatectomy. However, clear parameters for selecting the right patient for each strategy are not available, and new biomarkers and treatment m

  19. Glyphosate Vedotin for Treatment of Bone Metastatic Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2015-07-01

    15, demonstrating PSA production via stimulation with DHT and dihydroxyepiandosterone at passage 5 but moving on to androgen insensitivity at passage...10, follistatin, activin-A, and DHT . Int J Oncol 14: 1185-1195. PMID: 10339677 90. Dunning WF (1963) Prostate Cancer in the Rat. Natl Cancer Inst

  20. Orofacial pain and numb chin syndrome as the presenting symptoms of a metastatic prostate cancer.

    Directory of Open Access Journals (Sweden)

    Gaver A

    2002-10-01

    Full Text Available We describe a patient with orofacial pain as the presenting symptom caused by a mandibular metastasis from a previously undiagnosed cancer of the prostate. This possibility should be considered in the differential diagnosis of male patients presenting with orofacial pain.

  1. Improving radionuclide therapy in prostate cancer patients with metastatic bone pain

    NARCIS (Netherlands)

    Lam, M.G.E.H.

    2009-01-01

    Bone seeking radiopharmaceuticals are indicated in cancer patients with multiple painful skeletal metastases. The majority of these patients are hormone-refractory prostate cancer patients in an advanced stage of their disease. Bone seeking radiopharmaceuticals relieve pain and improve the patients

  2. Integrated Multimodal Imaging of Dynamic Bone-Tumor Alterations Associated with Metastatic Prostate Cancer

    NARCIS (Netherlands)

    Brisset, Jean-Christophe; Hoff, Benjamin A.; Chenevert, Thomas L.; Jacobson, Jon A.; Boes, Jennifer L.; Galban, Stefanie; Rehemtulla, Alnawaz; Johnson, Timothy D.; Pienta, Kenneth J.; Galban, Craig J.; Meyer, Charles R.; Schakel, Timothy; Nicolay, Klaas; Alva, Ajjai S.; Hussain, Maha; Ross, Brian D.; Schakel, Tim

    2015-01-01

    Bone metastasis occurs for men with advanced prostate cancer which promotes osseous growth and destruction driven by alterations in osteoblast and osteoclast homeostasis. Patients can experience pain, spontaneous fractures and morbidity eroding overall quality of life. The complex and dynamic cellul

  3. Toward Maximizing Immunotherapy in Metastatic Castration Resistant Prostate Cancer – Rationale for Combinatorial Approaches Using Chemotherapy

    Directory of Open Access Journals (Sweden)

    Susan F Slovin

    2012-05-01

    Full Text Available Prostate cancer is particularly suited for active immunotherapy because of the expression of a distinctive number of antigens which are overexpressed on prostate cancer cells and cell lines. There is evidence in this disease that tumors promote immune tolerance starting early in the disease course. As such, chemotherapy, by suppressing tumors and activating immune system homeostatic mechanisms, may help overcome this tumor-induced immune tolerance. Sipuleucel-T which has recently been approved in the US, is an autologous cellule product immunotherapy that induces immune activity likely through activation of dendritic cells. This was associated with a survival benefit in the absence of significant toxicity. However, a post hoc analysis of phase III trial participants found a substantial survival benefit to receiving docetaxel some months after sipuleucel-T. However, another phase III immunotherapy trial combining a prostate cancer therapeutic vaccine G-VAX plus docetaxel versus standard docetaxel therapy in advanced prostate cancer, observed a lower overall survival with the vaccine regimen. These trials highlight major unresolved questions concerning the optimum choice, dosing, and timing of chemotherapy relative to active immunotherapy and the overall merits of considering this approach. The ideal treatment approach remains unclear; advances in biomarker validation and trial design may likely improve our ability to assess biologic benefit irrespective of the development of true anti-tumor immunity.

  4. Noninvasive Detection of AR-FL/AR-V7 as a Predictive Biomarker for Therapeutic Resistance in Men with Metastatic Castration-Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    Accomplishments 4 4. Impact 9 5. Changes /Problems 11 6. Products 12 7. Participants & Other Collaborating Organizations 15 8. Special Reporting...AWARD NUMBER: W81XWH-15-2-0052 TITLE: Noninvasive Detection of AR-FL/AR-V7 as a Predictive Biomarker for Therapeutic Resistance in Men with...Metastatic Castration- Resistant Prostate Cancer PRINCIPAL INVESTIGATOR: Stephen Plymate RECIPIENT: University of Washington Seattle, WA 98195

  5. Comprehensive gene expression microarray analysis of Ets-1 blockade in PC3 prostate cancer cells and correlations with prostate cancer tissues: Insights into genes involved in the metastatic cascade.

    Science.gov (United States)

    Shaikhibrahim, Zaki; Lindstrot, Andreas; Langer, Berit; Buettner, Reinhard; Wernert, Nicolas

    2011-06-01

    Ets-1 is the prototype of the ETS family of transcription factors and is suggested to play an important role in the malignant progression of prostatic carcinomas. Therefore, in this study we investigated the effect of blocking Ets-1 in PC3 prostate cancer cells on genes involved in the metastatic cascade, and correlated these findings with prostate cancer tissues. Two stable PC3 cell cultures were established by transfection with either an Ets-1 inverse antisense expression vector or a mock control vector. The effect of blocking Ets-1 on genes involved in the metastatic cascade was assessed by a comprehensive gene expression microarray analysis of Ets-1 inverse and mock control cells. Correlating the sets of genes found in the PC3 microarray data with prostate cancer tissues was performed by verifying the genes in a comprehensive gene expression microarray analysis of RNA extracted from laser microdissected normal prostate glands and from carcinoma glands taken from prostate cancer patients. Western blot analysis confirmed the presence of Ets-1 in mock cells and its absence in Ets-1 inverse cells. In the Ets-1 blockade microarray, many differentially expressed genes were found; however, only genes with a greater than 10-fold up- or down-regulation between the Ets-1 blockade and mock control were considered significant. The genes were placed into four groups that play a role in the so-called metastatic cascade based on their known functions in proliferation, apoptosis, migration and angiogenesis. The genes found in the Ets-1 blockade microarray analysis were verified for their presence in the microarray analysis of prostate cancer tissues. Genes found in the microarray analysis of prostate cancer tissues with an >2-fold change and a p-value tissues, we identified 16 genes that are up- or down-regulated in healthy compared to tumor prostate glands. Further investigation revealed that 4 out of the 16 genes have been reported to be regulated by members of the ETS

  6. Phase IIa Clinical Trial of Trans-1-Amino-3-18F-Fluoro- Cyclobutane Carboxylic Acid in Metastatic Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Yusuke Inoue

    2014-10-01

    Full Text Available Objective(s: We performed a phase IIa clinical trial of trans-1-amino-3-18Ffluoro-cyclobutane carboxylic acid (anti-18F-FACBC, a synthetic amino acid analog for PET, in patients with metastatic prostate cancer. Methods: The study subjects consisted of 10 untreated prostate cancer patients having lymph node and/or bone metastasis. Five patients underwent whole-body PET 5 and 30 min after intravenous injection of anti-18F-FACBC. The other five patients underwent 60 min dynamic PET of the pelvis. Safety assessment was performed before and 24 h after injection. PET/CT images were assessed visually, and time courses of anti-18F-FACBC uptake were evaluated from dynamic imaging. Results: Two mild adverse events were observed and resolved without treatment. All 10 patients showed increased accumulation of anti-18F-FACBC in the primary prostate lesion. CT revealed five enlarged lymph nodes indicating metastasis, and all showed increased uptake. Additionally, anti-18F-FACBC PET delineated unenlarged lymph nodes as hot spots. Anti-18F-FACBC PET demonstrated metastatic bone lesions, similar to conventional imaging. In one of two patients with lung metastasis, some lesions showed increased uptake. Regarding the time course, increased uptake of anti-18F-FACBC in the lesion was demonstrated immediately after injection, followed by gradual washout. Conclusion: The results of this phase IIa clinical trial indicated the safety of anti-18F-FACBC in patients with prostate cancer and the potential of anti-18F-FACBC PET to delineate primary prostate lesions and metastatic lesions. This clinical trial was registered as JapicCTI-101326.

  7. Phase IIa Clinical Trial of Trans-1-Amino-3-18F-Fluoro-Cyclobutane Carboxylic Acid in Metastatic Prostate Cancer

    Science.gov (United States)

    Inoue, Yusuke; Asano, Yuji; Satoh, Takefumi; Tabata, Ken-ichi; Kikuchi, Kei; Woodhams, Reiko; Baba, Shiro; Hayakawa, Kazushige

    2014-01-01

    Objective(s): We performed a phase IIa clinical trial of trans-1-amino-3-18F-fluoro-cyclobutane carboxylic acid (anti-18F-FACBC), a synthetic amino acid analog for PET, in patients with metastatic prostate cancer. Methods: The study subjects consisted of 10 untreated prostate cancer patients having lymph node and/or bone metastasis. Five patients underwent whole-body PET 5 and 30 min after intravenous injection of anti-18F-FACBC. The other five patients underwent 60 min dynamic PET of the pelvis. Safety assessment was performed before and 24 h after injection. PET/CT images were assessed visually, and time courses of anti-18F-FACBC uptake were evaluated from dynamic imaging. Results: Two mild adverse events were observed and resolved without treatment. All 10 patients showed increased accumulation of anti-18F-FACBC in the primary prostate lesion. CT revealed five enlarged lymph nodes indicating metastasis, and all showed increased uptake. Additionally, anti-18F-FACBC PET delineated unenlarged lymph nodes as hot spots. Anti-18F-FACBC PET demonstrated metastatic bone lesions, similar to conventional imaging. In one of two patients with lung metastasis, some lesions showed increased uptake. Regarding the time course, increased uptake of anti-18F-FACBC in the lesion was demonstrated immediately after injection, followed by gradual washout. Conclusion: The results of this phase IIa clinical trial indicated the safety of anti-18F-FACBC in patients with prostate cancer and the potential of anti-18F-FACBC PET to delineate primary prostate lesions and metastatic lesions. This clinical trial was registered as JapicCTI-101326. PMID:27408864

  8. Epidermal growth factor potentiates in vitro metastatic behaviour of human prostate cancer PC-3M cells: involvement of voltage-gated sodium channel

    Directory of Open Access Journals (Sweden)

    Uysal-Onganer Pinar

    2007-11-01

    Full Text Available Abstract Background Although a high level of functional voltage-gated sodium channel (VGSC expression has been found in strongly metastatic human and rat prostate cancer (PCa cells, the mechanism(s responsible for the upregulation is unknown. The concentration of epidermal growth factor (EGF, a modulator of ion channels, in the body is highest in prostatic fluid. Thus, EGF could be involved in the VGSC upregulation in PCa. The effects of EGF on VGSC expression in the highly metastatic human PCa PC-3M cell line, which was shown previously to express both functional VGSCs and EGF receptors, were investigated. A quantitative approach, from gene level to cell behaviour, was used. mRNA levels were determined by real-time PCR. Protein expression was studied by Western blots and immunocytochemistry and digital image analysis. Functional assays involved measurements of transverse migration, endocytic membrane activity and Matrigel invasion. Results Exogenous EGF enhanced the cells' in vitro metastatic behaviours (migration, endocytosis and invasion. Endogenous EGF had a similar involvement. EGF increased VGSC Nav1.7 (predominant isoform in PCa mRNA and protein expressions. Co-application of the highly specific VGSC blocker tetrodotoxin (TTX suppressed the effect of EGF on all three metastatic cell behaviours studied. Conclusion 1 EGF has a major involvement in the upregulation of functional VGSC expression in human PCa PC-3M cells. (2 VGSC activity has a significant intermediary role in potentiating effect of EGF in human PCa.

  9. A retrospective feasibility study of biweekly, reduced-dose docetaxel in Asian patients with castrate-resistant, metastatic prostate cancer.

    Science.gov (United States)

    Kim, Hae Su; Lee, Ji Yun; Lee, Su Jin; Lim, Ho Yeong; Sung, Hyun Hwan; Jeon, Hwang Gyun; Jeong, Byong Chang; Seo, Seong Il; Jeon, Seong Soo; Lee, Hyun Moo; Choi, Han-Yong; Park, Se Hoon

    2017-08-22

    The aim of this retrospective study was to evaluate the clinical outcomes of reduced dose, biweekly docetaxel chemotherapy for Korean patients with castrate-resistant prostate cancer (CRPC). We retrospectively reviewed the medical records of 48 patients with metastatic CRPC who were treated with a biweekly regimen (intravenous docetaxel 40 mg/m(2) on day 1 plus prednisolone 5 mg twice daily) between 2012 and 2015 at Samsung Medical Center (Seoul, Korea). Prior to the adoption of a biweekly regimen in Oct 2013, our institutional standard chemotherapy was docetaxel 75 mg/m(2) every 3 weeks for patients with CRPC (n = 24). After Oct 2013, all chemotherapy-naïve patients with CRPC received a 40 mg/m(2) biweekly regimen (n = 24). The primary end point was a PSA response, defined as a greater than 50% decline in PSA level from baseline. The baseline characteristics of the patients in the two treatment groups were similar. The most common cause of treatment discontinuation was disease progression, which was exhibited by 17 patients (71%) in the 3-weekly group and 20 (75%) in the biweekly group. PSA responses were observed in 12 (50%) and 11 (46%) patients in the 3-weekly and biweekly groups, respectively (p = 0.683). Time to treatment failure (TTTF, 4.5 vs 3.9 months) and time-to-progression (TTP, 5.0 vs 4.2 months) were not significantly different between the 3-weekly and biweekly groups. Within the limitations of a retrospective study, the biweekly reduced dose docetaxel regimen was active and well-tolerated in Korean patients with metastatic CRPC.

  10. [Metastatic cancer of the prostate in a 40-year-old HIV-infected male patient].

    Science.gov (United States)

    Furco, A; Bani-Sadr, F; Guymar, S; Molina, J-M

    2003-04-12

    Cancer of the prostate in HIV-infected patients has rarely been reported in the literature. A 40-year-old man presented with an adenocarcinoma of the prostate and bone and glandular metastases. The patient exhibited HIV seropositivity stage B1, the immune-virology of which was well controlled by antiretroviral tritherapy. The relationship between cancer and HIV has been established for certain cancers such as Hodgkin's disease, non-Hodgkin malignant lymphoma, Kaposi's sarcoma and invasive cancers of the uterine neck in women. The significant increase in some cancers in patients infected by HIV (lung, penis, soft tissue, lips, seminoma) suggests the potential association with immunodepression unless it corresponds to a risk induced by antiretroviral treatments in the long term.

  11. Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space

    Directory of Open Access Journals (Sweden)

    Sartor A Oliver

    2011-04-01

    Full Text Available Abstract Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC. Despite this designation, however, there is evidence that androgen receptor (AR-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone, or treatment with the antiandrogen abiraterone (with prednisone could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR

  12. Progression of metastatic castrate-resistant prostate cancer: impact of therapeutic intervention in the post-docetaxel space.

    Science.gov (United States)

    Sartor, A Oliver

    2011-04-23

    Despite the proven success of hormonal therapy for prostate cancer using chemical or surgical castration, most patients eventually will progress to a phase of the disease that is metastatic and shows resistance to further hormonal manipulation. This has been termed metastatic castrate-resistant prostate cancer (mCRPC). Despite this designation, however, there is evidence that androgen receptor (AR)-mediated signaling and gene expression can persist in mCRPC, even in the face of castrate levels of androgen. This may be due in part to the upregulation of enzymes involved in androgen synthesis, the overexpression of AR, or the emergence of mutant ARs with promiscuous recognition of various steroidal ligands. The therapeutic options were limited and palliative in nature until trials in 2004 demonstrated that docetaxel chemotherapy could significantly improve survival. These results established first-line docetaxel as the standard of care for mCRPC. After resistance to further docetaxel therapy develops, treatment options were once again limited. Recently reported results from phase 3 trials have shown that additional therapy with the novel taxane cabazitaxel (with prednisone), or treatment with the antiandrogen abiraterone (with prednisone) could improve survival for patients with mCRPC following docetaxel therapy. Compared with mitoxantrone/prednisone, cabazitaxel/prednisone significantly improved overall survival, with a 30% reduction in rate of death, in patients with progression of mCRPC after docetaxel therapy in the TROPIC trial. Similarly, abiraterone acetate (an inhibitor of androgen biosynthesis) plus prednisone significantly decreased the rate of death by 35% compared with placebo plus prednisone in mCRPC patients progressing after prior docetaxel therapy in the COU-AA-301 trial. Results of these trials have thus established two additional treatment options for mCRPC patients in the "post-docetaxel space." In view of the continued AR-mediated signaling on m

  13. Cell Competition Drives the Formation of Metastatic Tumors in a Drosophila Model of Epithelial Tumor Formation

    DEFF Research Database (Denmark)

    Eichenlaub, Teresa; Cohen, Stephen M; Herranz, Héctor

    2016-01-01

    Cell competition is a homeostatic process in which proliferating cells compete for survival. Elimination of otherwise normal healthy cells through competition is important during development and has recently been shown to contribute to maintaining tissue health during organismal aging. The mechan......Cell competition is a homeostatic process in which proliferating cells compete for survival. Elimination of otherwise normal healthy cells through competition is important during development and has recently been shown to contribute to maintaining tissue health during organismal aging....... The mechanisms that allow for ongoing cell competition during adult life could, in principle, contribute to tumorigenesis. However, direct evidence supporting this hypothesis has been lacking. Here, we provide evidence that cell competition drives tumor formation in a Drosophila model of epithelial cancer. Cells...... of the Septin family protein Peanut. Cytokinesis failure due to downregulation of Peanut is required for tumorigenesis. This study provides evidence that the cellular mechanisms that drive cell competition during normal tissue growth can be co-opted to drive tumor formation and metastasis. Analogous mechanisms...

  14. Oncogenic LINE-1 Retroelements Sustain Prostate Tumor Cells and Promote Metastatic Progression

    Science.gov (United States)

    2015-10-01

    elements in prostate cancer contribute to its progression by activating oncogenic DNA sequences, or silencing tumor suppressor like sequences. We have...the use of animals and the use of recombinant DNA /lentiviral vectors. All of these approvals have now been obtained. For Task 1, we cloned the LINE...Books or other non-periodical, one-time publications. Report any book, monograph , dissertation, abstract, or the like published as or in a

  15. Biological and Clinical Characterization of Novel lncRNAs Associated with Metastatic Prostate Cancer

    Science.gov (United States)

    2014-10-01

    T. et al. A tissue biomarker panel predicting systemic progression after PSA recurrence post- definitive prostate cancer therapy. PLoS ONE 3, e2318...blocked for 90 min in block- ing buffer (5% milk in a solution of 0.1% Tween-20 in Tris-buffered saline (TBS-T)). Membranes were incubated overnight at 4...grey zone approach for evaluation of 15 short tandem repeat loci in sibship analysis: a pilot study in Indian subjects. Journal of Forensic and Legal

  16. Extracellular Hsp90 as a Novel Epigenetic of EMT and Metastatic Risk in Prostate Cancer

    Science.gov (United States)

    2015-12-01

    cadherin can also stimulate Wnt activation, and lead to EMT events, we also utilized CRISPR technology to downregulate E-cadherin (Task 3b). Although this...studies also suggest that eHsp90 may enhance the stem-like cell diversity existing within populations, which would be predicted to further confound...reported that secreted extracellular Hsp90 (eHsp90) initiates EMT in prostate cancer cells, coincident with its enhanced expression in mesenchymal models

  17. Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone.

    Science.gov (United States)

    Sharma, Sambad; Xing, Fei; Liu, Yin; Wu, Kerui; Said, Neveen; Pochampally, Radhika; Shiozawa, Yusuke; Lin, Hui-Kuan; Balaji, K C; Watabe, Kounosuke

    2016-09-09

    Prostate cancer is known to frequently recur in bone; however, how dormant cells switch its phenotype leading to recurrent tumor remains poorly understood. We have isolated two syngeneic cell lines (indolent and aggressive) through in vivo selection by implanting PC3mm stem-like cells into tibial bones. We found that indolent cells retained the dormant phenotype, whereas aggressive cells grew rapidly in bone in vivo, and the growth rates of both cells in culture were similar, suggesting a role of the tumor microenvironment in the regulation of dormancy and recurrence. Indolent cells were found to secrete a high level of secreted protein acidic and rich in cysteine (SPARC), which significantly stimulated the expression of BMP7 in bone marrow stromal cells. The secreted BMP7 then kept cancer cells in a dormant state by inducing senescence, reducing "stemness," and activating dormancy-associated p38 MAPK signaling and p21 expression in cancer cells. Importantly, we found that SPARC was epigenetically silenced in aggressive cells by promoter methylation, but 5-azacytidine treatment reactivated the expression. Furthermore, high SPARC promoter methylation negatively correlated with disease-free survival of prostate cancer patients. We also found that the COX2 inhibitor NS398 down-regulated DNMTs and increased expression of SPARC, which led to tumor growth suppression in bone in vivo These findings suggest that SPARC plays a key role in maintaining the dormancy of prostate cancer cells in the bone microenvironment.

  18. Predictors of Chemotherapy-Induced Toxicity and Treatment Outcomes in Elderly Versus Younger Patients With Metastatic Castration-Resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Kongsted, Per; Svane, Inge Marie; Lindberg, Henriette

    2016-01-01

    BACKGROUND: In the present study, we examined possible predictors of chemotherapy-induced toxicity, treatment outcomes, and the consequences of dose reductions in patients with metastatic castration-resistant prostate cancer (mCRPC) receiving standard docetaxel. PATIENTS AND METHODS: Medical...... records from 421 consecutive patients treated with first-line docetaxel (75 mg/m(2) every 3 weeks) and low-dose prednisolone from 2007 to 2013 at Herlev University Hospital were reviewed. Common Terminology Criteria for Adverse Events, version 4.0, and the Prostate Cancer Working Group 2 guidelines were...... (hazard ratio [HR], 1.00), baseline hemoglobin levels (HR, 0.85), Eastern Cooperative Oncology Group performance status > 0 to 1 (HR, 1.44), lactate dehydrogenase greater than the upper limit of normal (HR, 1.64), and prostate-specific antigen levels (HR, 1.00) were predictors of OS. CONCLUSIONS: OS...

  19. Cost-effectiveness analysis of abiraterone and sipuleucel-T in asymptomatic metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Gong, Cynthia L; Hay, Joel W

    2014-10-01

    Of patients diagnosed with prostate cancer, 0% to 20% experience disease progression to metastatic castration-resistant prostate cancer (mCRPC). Recently, 4 novel therapies have been introduced for the treatment of mCRPC; of these, abiraterone and sipuleucel-T have been studied in the asymptomatic, pre-docetaxel population. Both have shown clinical benefits compared with placebo. This study evaluated the cost-effectiveness of abiraterone acetate and sipuleucel-T compared with prednisone in asymptomatic, pre-docetaxel mCRPC from a US societal perspective. A Markov model was constructed to simulate stable disease, progressed disease, and death. Survival and event rates were derived from published clinical trial data. Costs were derived from the literature and government reimbursement schedules. Outcomes were measured as average cost-effectiveness ratios (ACERs), incremental cost-effectiveness ratios (ICERs), and net monetary benefits (NMBs). One-way and probabilistic sensitivity analyses were conducted to test the robustness of the model. The base-case ACER was $114K/quality-adjusted life-years (QALY) for abiraterone, $85K/QALY for sipuleucel-T, and $31K/QALY for prednisone. The base-case ICER was $389K/QALY for abiraterone and $547K/QALY for sipuleucel-T. Prednisone dominates both abiraterone and sipuleucel-T in terms of NMB at willingness-to-pay (WTP) thresholds of $400K or less. One-way sensitivity analyses revealed that the model was most sensitive to overall survival and utility inputs. Probabilistic sensitivity analyses showed abiraterone to be cost-effective 50% or more of the time at a WTP of greater than $400K, whereas sipuleucel-T was cost-effective 50% or more of the time at a WTP of greater than $270K. Neither abiraterone nor sipuleucel-T was found to be cost-effective compared with prednisone in the treatment of asymptomatic, pre-docetaxel mCRPC.

  20. Repeated PSMA-targeting radioligand therapy of metastatic prostate cancer with {sup 131}I-MIP-1095

    Energy Technology Data Exchange (ETDEWEB)

    Afshar-Oromieh, Ali; Haberkorn, Uwe [Heidelberg University Hospital, Department of Nuclear Medicine, Heidelberg (Germany); German Cancer Research Center, Clinical Cooperation Unit Nuclear Medicine, Heidelberg (Germany); Zechmann, Christian; Mier, Walter; Spohn, Fabian; Debus, Nils; Kratochwil, Clemens [Heidelberg University Hospital, Department of Nuclear Medicine, Heidelberg (Germany); Armor, Thomas [Progenics Pharmaceuticals, Inc., New York, NY (United States); Holland-Letz, Tim [German Cancer Research Center, Department of Biostatistics, Heidelberg (Germany); Babich, John [Weill Cornell Medicine, Division of Radiopharmaceutical Sciences, Department of Radiology, New York, NY (United States); Weill Cornell Medicine, Citigroup Biomedical Imaging Center, New York, NY (United States); Weill Cornell Medicine, Meyer Cancer Center, New York, NY (United States)

    2017-06-15

    Prostate-specific membrane antigen (PSMA)-targeting radioligand therapy (RLT) was introduced in 2011. The first report described the antitumor and side effects of a single dose. The aim of this analysis was to evaluate toxicity and antitumor activity after single and repetitive therapies. Thirty-four men with metastatic castration-resistant prostate cancer received PSMA-RLT with {sup 131}I-MIP-1095. Twenty-three patients received a second, and three patients a third dose, timed at PSA progression after an initial response to the preceding therapy. The applied doses were separated in three groups: <3.5, 3.5-5.0 and >5.0 GBq. Antitumor and side-effects were analyzed by blood samples and other clinical data. Follow-up was conducted for up to 5 years. The best therapeutic effect was achieved by the first therapy. A PSA decline of ≥50% was achieved in 70.6% of the patients. The second and third therapies were significantly less effective. There was neither an association between the applied activity and PSA response or the time-to-progression. Hematologic toxicities were less prevalent but presented in a higher percentage of patients with increasing number of therapies. After hematologic toxicities, xerostomia was the second most frequent side effect and presented more often and with higher intensity after the second or third therapy. The first dose of RLT with {sup 131}I-MIP-1095 presented with low side effects and could significantly reduce the tumor burden in a majority of patients. The second and third therapies were less effective and presented with more frequent and more intense side effects, especially hematologic toxicities and xerostomia. (orig.)

  1. The Prevalence and Importance of Epithelial Plasticity in Metastatic Prostate Cancer

    Science.gov (United States)

    2014-10-01

    34Cancer#13,ඩV110.൛" De"Gasperi,"R.,"Rocher,"A."B.,"Sosa,"M."A.,"Wearne,"S."L.," Perez ,"G."M.,"Friedrich,"V."L.,"Jr.,"Hof,"P."R.,"and൜" Elder,"G."A...34 Nieto ,"M."A."(2012)."Metastatic"colonization"requires"the"repression"of"the"epithelialV36" mesenchymal"transition"inducer"Prrx1."Cancer"Cell#22,螕V724

  2. Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Alfonso Urbanucci

    2017-06-01

    Full Text Available Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4 have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC. Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC. We show that the deregulation of androgen receptor (AR expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10 for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses.

  3. Androgen Receptor Deregulation Drives Bromodomain-Mediated Chromatin Alterations in Prostate Cancer.

    Science.gov (United States)

    Urbanucci, Alfonso; Barfeld, Stefan J; Kytölä, Ville; Itkonen, Harri M; Coleman, Ilsa M; Vodák, Daniel; Sjöblom, Liisa; Sheng, Xia; Tolonen, Teemu; Minner, Sarah; Burdelski, Christoph; Kivinummi, Kati K; Kohvakka, Annika; Kregel, Steven; Takhar, Mandeep; Alshalalfa, Mohammed; Davicioni, Elai; Erho, Nicholas; Lloyd, Paul; Karnes, R Jeffrey; Ross, Ashley E; Schaeffer, Edward M; Vander Griend, Donald J; Knapp, Stefan; Corey, Eva; Feng, Felix Y; Nelson, Peter S; Saatcioglu, Fahri; Knudsen, Karen E; Tammela, Teuvo L J; Sauter, Guido; Schlomm, Thorsten; Nykter, Matti; Visakorpi, Tapio; Mills, Ian G

    2017-06-06

    Global changes in chromatin accessibility may drive cancer progression by reprogramming transcription factor (TF) binding. In addition, histone acetylation readers such as bromodomain-containing protein 4 (BRD4) have been shown to associate with these TFs and contribute to aggressive cancers including prostate cancer (PC). Here, we show that chromatin accessibility defines castration-resistant prostate cancer (CRPC). We show that the deregulation of androgen receptor (AR) expression is a driver of chromatin relaxation and that AR/androgen-regulated bromodomain-containing proteins (BRDs) mediate this effect. We also report that BRDs are overexpressed in CRPCs and that ATAD2 and BRD2 have prognostic value. Finally, we developed gene stratification signature (BROMO-10) for bromodomain response and PC prognostication, to inform current and future trials with drugs targeting these processes. Our findings provide a compelling rational for combination therapy targeting bromodomains in selected patients in which BRD-mediated TF binding is enhanced or modified as cancer progresses. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

  4. Microenvironment-Programmed Metastatic Prostate Cancer Stem Cells (mPCSCs)

    Science.gov (United States)

    2015-10-01

    prostate cancer patients’ outcome. Lab Invest. 2010; 90:234–244. 18. van den Hoogen C, van der Horst G, Cheung H, Buijs JT, Lippitt JM, Guzman- Ramirez N...oncotarget 36. Wan X, Corn PG, Yang J, Palanisamy N, Starbuck MW, Efstathiou E, Tapia EM, Zurita AJ, Aparicio A, Ravoori MK, Vazquez ES, Robinson DR...Urology 170 1817–1821. (doi:10.1097/01.ju.0000091873.09677.f4) Germann M, Wetterwald A, Guzman- Ramirez N, van der Pluijm G, Culig Z, Cecchini MG, Williams

  5. Improving radionuclide therapy in prostate cancer patients with metastatic bone pain

    OpenAIRE

    2009-01-01

    Bone seeking radiopharmaceuticals are indicated in cancer patients with multiple painful skeletal metastases. The majority of these patients are hormone-refractory prostate cancer patients in an advanced stage of their disease. Bone seeking radiopharmaceuticals relieve pain and improve the patients quality of life. The mostly used radiopharmaceuticals are 89SrCl2 (Metastron), 153Sm-EDTMP (Quadramet) and 186Re-HEDP. Differences between 89SrCl2, 153Sm-EDTMP and 186Re-HEDP were investigated. It ...

  6. New drugs in the treatment of elderly patients with metastatic castration-resistance prostate cancer.

    Science.gov (United States)

    Genestreti, Giovenzio; Di Battista, Monica; Cavallo, Giovanna; Brandes, Alba A

    2016-08-03

    Treatment of prostate cancer is continually evolving and new therapies have become available. However, the management of elderly patients is challenging due to their age and comorbidities. Androgen deprivation therapy remains the mainstay treatment of hormonal-sensitive disease. Nevertheless, when disease becomes resistant to castration, docetaxel-based chemotherapy represents the standard rescue therapy irrespective of patient age. Recently, chemotherapeutic agents such as cabazitaxel and hormonal therapies such as abiraterone acetate and enzalutamide have been shown to improve survival in patients with progression of disease before or following docetaxel. This review focuses on the safety and efficacy results of these new drugs in elderly patients.

  7. Tumor-associated Endo180 requires stromal-derived LOX to promote metastatic prostate cancer cell migration on human ECM surfaces.

    Science.gov (United States)

    Caley, Matthew P; King, Helen; Shah, Neel; Wang, Kai; Rodriguez-Teja, Mercedes; Gronau, Julian H; Waxman, Jonathan; Sturge, Justin

    2016-02-01

    The diverse composition and structure of extracellular matrix (ECM) interfaces encountered by tumor cells at secondary tissue sites can influence metastatic progression. Extensive in vitro and in vivo data has confirmed that metastasizing tumor cells can adopt different migratory modes in response to their microenvironment. Here we present a model that uses human stromal cell-derived matrices to demonstrate that plasticity in tumor cell movement is controlled by the tumor-associated collagen receptor Endo180 (CD280, CLEC13E, KIAA0709, MRC2, TEM9, uPARAP) and the crosslinking of collagen fibers by stromal-derived lysyl oxidase (LOX). Human osteoblast-derived and fibroblast-derived ECM supported a rounded 'amoeboid-like' mode of cell migration and enhanced Endo180 expression in three prostate cancer cell lines (PC3, VCaP, DU145). Genetic silencing of Endo180 reverted PC3 cells from their rounded mode of migration towards a bipolar 'mesenchymal-like' mode of migration and blocked their translocation on human fibroblast-derived and osteoblast-derived matrices. The concomitant decrease in PC3 cell migration and increase in Endo180 expression induced by stromal LOX inhibition indicates that the Endo180-dependent rounded mode of prostate cancer cell migration requires ECM crosslinking. In conclusion, this study introduces a realistic in vitro model for the study of metastatic prostate cancer cell plasticity and pinpoints the cooperation between tumor-associated Endo180 and the stiff microenvironment imposed by stromal-derived LOX as a potential target for limiting metastatic progression in prostate cancer.

  8. Prostatitis

    OpenAIRE

    Domingue, Gerald J.; Hellstrom, Wayne J.G.

    1998-01-01

    The laboratory diagnosis of acute bacterial prostatitis is straightforward and easily accomplished in clinical laboratories. Chronic bacterial prostatitis, and especially chronic idiopathic prostatitis (most often referred to as abacterial prostatitis), presents a real challenge to the clinician and clinical microbiologist. Clinically, the diagnosis of chronic idiopathic prostatitis is differentiated from that of acute prostatitis by a lack of prostatic inflammation and no “significant” (cont...

  9. Unusual presentations of metastatic prostate carcinoma as detected by anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (anti-3-[18F] FACBC) PET-CT

    Science.gov (United States)

    Amzat, Rianot; Taleghani, Pooneh; Savir-Baruch, Bital; Nieh, Peter T.; Master, Viraj A.; Halkar, Raghuveer K.; Lewis, Melinda M.; Faurot, Michelle; Bellamy, Leah M.; Goodman, Mark M.; Schuster, David M.

    2013-01-01

    Prostate carcinoma is the second most common cause of cancer related mortality in males in the United States. The pattern of metastatic disease of prostate cancer is well recognized, frequently involving sclerotic bone lesions and abdomino-pelvic lymph nodes. Anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid (anti-3-[18F] FACBC) is a synthetic amino acid analog positron emission tomography (PET) radiotracer with reported utility in the detection of prostate carcinoma. We present two cases of unusual presentations of prostate carcinoma, one with malignant ascitis and omental implants and the other with lytic bone lesions detected with anti-3-[18F]FACBC. PMID:21825855

  10. Evolving landscape and novel treatments in metastatic castrate-resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Paul J Toren; Martin E Gleave

    2013-01-01

    Treatment options for castrate-resistant prostate cancer (CRPC) have advanced in recent years and significantly improved the outlook for patients with this aggressive and lethal disease.Further understanding of the biologyof CRPC has led to several new targeted therapies and continues to emphasize the importance of androgen receptor (AR) directed therapy.The treatment landscape is rapidly changing and further biologically rationale,biomarker-based ongoing clinical trials are needed.We review the recent results of major clinical trials in CRPC.New and investigational agents now in clinical evaluation are reviewed including inhibitors of angiogenesis,microtubules,chaperones,AR and intracellular kinases,as well as immunotherapy,radiopharmaceuticals and bone-targeted agents.The recent improvement in prognosis for CRPC brings continued optimism for further improvements.Thoughtful planning of clinical trials and further understanding of the mechanisms of resistance to therapies will allow for continued progress in patient care.

  11. The prognostic factors of effective ketoconazole treatment for metastatic castration-resistant prostate cancer: who can benefit from ketoconazole therapy?

    Institute of Scientific and Technical Information of China (English)

    Guo-Wen Lin; Xu-Dong Yao; Ding-Wei Ye; Yao Zhu; Shi-Lin Zhang; Bo Dai; Hai-Liang Zhang; Yi-Jun Shen; Chun-Guang Ma

    2012-01-01

    We investigated the prognostic value of some variables of effective ketoconazole treatment for metastatic castration-resistant prostate cancer (mCRPC).In total,163 patients with mCRPC were eligible,receiving ketoconazole 200-400 mg three times daily with replacement doses of prednisone.Progression-free survival (PFS) was calculated from the beginning of the ketoconazole therapy to the onset of disease progression.The prognostic value of different variables for PFS was assessed by Cox regression analysis.The median PFS was 2.6 months (0.5-8.6 months) for these patients.The serum testosterone level changed during therapy,which decreased when the prostate-specific antigen (PSA) declined; the serum testosterone level increased as the levels of PSA relapsed.The median PFS values for patients associated with different factors were the following:1.4 and 3.5 months for a nadir PSA of ≥ 0.2 and <0.2 ng ml-1,respectively (hazard rate (HR)=4.767,P<0.001); 3.1 and 1.6 months for a baseline testosterone of ≥-0.1 and <0.1 ng ml-1,respectively (HR=2.865,P=0.012); 2.8 and 1.9 months for a baseline haemoglobin of ≥ 120 and < 120 gl-1,respectively (HR=1.605,P<0.001); and 3.0 and 1.9 months for a PSA doubling time (PSADT) of ≥ 2.0 and <2.0 months,respectively (HR=1.454,P=0.017).A risk model was constructed according to the four factors that divided patients into three subgroups of low risk (0-1 factors),moderate risk (2 factors) and high risk (3-4 factors) with PFS values of 3.6,3.0 and 1∶4 months,respectively (HR=1.619,P<0.001).A nadir PSA of ≥ 0.2 ng ml-1,a baseline testosterone of <0.1 ng ml-1,a baseline haemoglobin of < 120 gl-1 and a PSADT of <2 months were associated with a poor PFS.This risk model could provide evidence to predict the survival benefit of ketoconazole therapy.

  12. The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer

    DEFF Research Database (Denmark)

    Evans, Christopher P; Higano, Celestia S; Keane, Thomas;

    2016-01-01

    in men with chemotherapy-naïve metastatic castration-resistant prostate cancer, with or without visceral disease, low- or high-volume bone disease, or lymph node only disease. PATIENT SUMMARY: Patients with metastatic castration-resistant prostate cancer-including those with or without visceral disease......BACKGROUND: Enzalutamide, an oral androgen receptor inhibitor, significantly improved overall survival (OS) and radiographic progression-free survival (rPFS) versus placebo in the PREVAIL trial of men with chemotherapy-naïve metastatic castration-resistant prostate cancer. OBJECTIVE: To assess...... the effects of enzalutamide versus placebo in patients from PREVAIL based on site and extent of baseline disease. DESIGN, SETTING, AND PARTICIPANTS: One thousand seven hundred and seventeen asymptomatic or minimally symptomatic patients were randomized to enzalutamide (n=872) or placebo (n=845). Subgroup...

  13. Effects of Surgery and Chemotherapy on Metastatic Progression of Prostate Cancer: Evidence from the Natural History of the Disease Reconstructed through Mathematical Modeling

    Directory of Open Access Journals (Sweden)

    Leonid Hanin

    2011-09-01

    Full Text Available This article brings mathematical modeling to bear on the reconstruction of the natural history of prostate cancer and assessment of the effects of treatment on metastatic progression. We present a comprehensive, entirely mechanistic mathematical model of cancer progression accounting for primary tumor latency, shedding of metastases, their dormancy and growth at secondary sites. Parameters of the model were estimated from the following data collected from 12 prostate cancer patients: (1 age and volume of the primary tumor at presentation; and (2 volumes of detectable bone metastases surveyed at a later time. This allowed us to estimate, for each patient, the age at cancer onset and inception of the first metastasis, the expected metastasis latency time and the rates of growth of the primary tumor and metastases before and after the start of treatment. We found that for all patients: (1 inception of the first metastasis occurred when the primary tumor was undetectable; (2 inception of all or most of the surveyed metastases occurred before the start of treatment; (3 the rate of metastasis shedding is essentially constant in time regardless of the size of the primary tumor and so it is only marginally affected by treatment; and most importantly, (4 surgery, chemotherapy and possibly radiation bring about a dramatic increase (by dozens or hundred times for most patients in the average rate of growth of metastases. Our analysis supports the notion of metastasis dormancy and the existence of prostate cancer stem cells. The model is applicable to all metastatic solid cancers, and our conclusions agree well with the results of a similar analysis based on a simpler model applied to a case of metastatic breast cancer.

  14. Effects of Surgery and Chemotherapy on Metastatic Progression of Prostate Cancer: Evidence from the Natural History of the Disease Reconstructed through Mathematical Modeling.

    Science.gov (United States)

    Hanin, Leonid; Zaider, Marco

    2011-09-20

    This article brings mathematical modeling to bear on the reconstruction of the natural history of prostate cancer and assessment of the effects of treatment on metastatic progression. We present a comprehensive, entirely mechanistic mathematical model of cancer progression accounting for primary tumor latency, shedding of metastases, their dormancy and growth at secondary sites. Parameters of the model were estimated from the following data collected from 12 prostate cancer patients: (1) age and volume of the primary tumor at presentation; and (2) volumes of detectable bone metastases surveyed at a later time. This allowed us to estimate, for each patient, the age at cancer onset and inception of the first metastasis, the expected metastasis latency time and the rates of growth of the primary tumor and metastases before and after the start of treatment. We found that for all patients: (1) inception of the first metastasis occurred when the primary tumor was undetectable; (2) inception of all or most of the surveyed metastases occurred before the start of treatment; (3) the rate of metastasis shedding is essentially constant in time regardless of the size of the primary tumor and so it is only marginally affected by treatment; and most importantly, (4) surgery, chemotherapy and possibly radiation bring about a dramatic increase (by dozens or hundred times for most patients) in the average rate of growth of metastases. Our analysis supports the notion of metastasis dormancy and the existence of prostate cancer stem cells. The model is applicable to all metastatic solid cancers, and our conclusions agree well with the results of a similar analysis based on a simpler model applied to a case of metastatic breast cancer.

  15. Risk factors for metastatic castration-resistant prostate cancer (CRPC predict long-term treatment with docetaxel.

    Directory of Open Access Journals (Sweden)

    Takashi Kawahara

    Full Text Available PURPOSE: For patients with metastatic castration-resistant prostatic cancer (mCRPC, docetaxel plus prednisone leads to superior survival and a higher response rate compared with mitoxantrone plus prednisone. We analyzed the efficacy of long-term treatment with ≥10 cycles of docetaxel, and validated the risk group classification in predicting overall survival (OS in Japanese patients with mCRPC. PATIENTS AND METHODS: Fifty-two patients with mCRPC were administered 55 mg/m(2 docetaxel and 8 mg dexamethasone, every 3 or 4 weeks, simultaneously with hormonal therapy and daily oral dexamethasone. They were divided into two groups, short-term (9 or fewer cycles and long-term (10 or more cycles. Four risk factors including the presence of anemia, bone metastases, significant pain and visceral metastases were utilized for the risk group classification. RESULTS: Fourteen patients (27% had an elevation of PSA in spite of docetaxel treatment, while 23 patients (44% had a decline in PSA level, including 9 patients (17% whose PSA level declined by ≥50%. The median duration of OS after the initiation of this therapy was 11.2 months in the short-term group and 28.5 months in the long-term group. The good risk group showed a significant difference in OS compared with the intermediate and poor risk groups (P<0.001. The median number of cycles of treatment was 14, 4 and 3 for each risk group, respectively (p<0.01. CONCLUSIONS: The present study indicated that ≥10 cycles of this docetaxel therapy can significantly prolong survival in Japanese men with CRPC. This risk group classification for men with mCRPC at the initiation of this chemotherapy is useful.

  16. Food effects on abiraterone pharmacokinetics in healthy subjects and patients with metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Chi, Kim N; Spratlin, Jennifer; Kollmannsberger, Christian; North, Scott; Pankras, Catherine; Gonzalez, Martha; Bernard, Apexa; Stieltjes, Hans; Peng, Lixian; Jiao, James; Acharya, Milin; Kheoh, Thian; Griffin, Thomas W; Yu, Margaret K; Chien, Caly; Tran, Nam Phuong

    2015-12-01

    Food effect on abiraterone pharmacokinetics and safety on abiraterone acetate coadministration with low-fat or high-fat meals was examined in healthy subjects and metastatic castration-resistant prostate cancer (mCRPC) patients. Healthy subjects (n = 36) were randomized to abiraterone acetate (single dose, 1000 mg) + low-fat meal, + high-fat meal, and fasted state. mCRPC patients received repeated doses (abiraterone acetate 1000 mg + 5 mg prednisone twice daily; days 1-7) in a modified fasting state followed by abiraterone acetate plus prednisone within 0.5 hours post-low-fat (n = 6) or high-fat meal (n = 18; days 8-14). In healthy subjects, geometric mean (GM) abiraterone area under plasma concentration-time curve (AUC) increased ∼5- and ∼10-fold, respectively, with low-fat and high-fat meals versus fasted state (GM [coefficient of variation], 1942 [48] and 4077 [37] ng · h/mL vs 421 [67] ng · h/mL, respectively). In mCRPC patients, abiraterone AUC was ∼2-fold higher with a high-fat meal and similar with a low-fat meal versus modified fasting state (GM [coefficient of variation]: 1992 [34] vs 973 [58] ng · h/mL and 1264 [65] vs 1185 [90] ng · h/mL, respectively). Adverse events (all grade ≤ 3) were similar, with high-fat/low-fat meals or fasted/modified fasting state. Short-term dosing with food did not alter abiraterone acetate safety.

  17. Therapeutic options in docetaxel-refractory metastatic castration-resistant prostate cancer: a cost-effectiveness analysis.

    Directory of Open Access Journals (Sweden)

    Lixian Zhong

    Full Text Available BACKGROUND: Docetaxel is an established first-line therapy to treat metastatic castration-resistant prostate cancer (mCRPC. Recently, abiraterone and cabazitaxel were approved for use after docetaxel failure, with improved survival. National Institute for Health and Clinical Excellence (NICE preliminary recommendations were negative for both abiraterone (now positive in final recommendation and cabazitaxel (negative in final recommendation. OBJECTIVE: To evaluate the cost-effectiveness of abiraterone, cabazitaxel, mitoxantrone and prednisone for mCRPC treatment in US. METHODS: A decision-tree model was constructed to compare the two mCRPC treatments versus two placebos over 18 months from a societal perspective. Chance nodes include baseline pain as a severity indicator, grade III/IV side-effects, and survival at 18 months. Probabilities, survival and health utilities were from published studies. Model cost inputs included drug treatment, side-effect management and prevention, radiation for pain, and death associated costs in 2010 US dollars. RESULTS: Abiraterone is a cost-effective choice at $94K/QALY (quality adjusted life years compared to placebo in our base-case analysis. Cabazitaxel and abiraterone are the most effective, yet also most expensive agents. The incremental cost-effectiveness ratios (ICER at base-case are $101K/QALY (extended dominated for mitoxantrone vs. placebo, $91K/QALY for abiraterone vs. mitoxantrone, $956K/QALY for cabazitaxel vs. abiraterone. Abiraterone becomes less cost-effective as its AWP increases, or if the cost of mitoxantrone side-effect management decreases. Increases in the percentage of patients with baseline pain leads to an increased ICER for both mitoxantrone and abiraterone, but mitoxantrone does relatively better. Cabazitaxel remains not cost-effective. CONCLUSION: Our base case model suggests that abiraterone is a cost-effective option in docetaxel-refractory mCRPC patients. Newer treatments will also

  18. Multi-scale mechanical characterization of prostate cancer cell lines: Relevant biological markers to evaluate the cell metastatic potential.

    Science.gov (United States)

    Zouaoui, J; Trunfio-Sfarghiu, A M; Brizuela, L; Piednoir, A; Maniti, O; Munteanu, B; Mebarek, S; Girard-Egrot, A; Landoulsi, A; Granjon, T

    2017-09-09

    Considering the importance of cellular mechanics in the birth and evolution of cancer towards increasingly aggressive stages, we compared nano-mechanical properties of non-tumoral (WPMY-1) and highly aggressive metastatic (PC-3) prostate cell lines both on cell aggregates, single cells, and membrane lipids. Cell aggregate rheological properties were analyzed during dynamic compression stress performed on a homemade rheometer. Single cell visco-elasticity measurements were performed by Atomic Force Microscopy using a cantilever with round tip on surface-attached cells. At a molecular level, the lateral diffusion coefficient of total extracted lipids deposited as a Langmuir monolayer on an air-water interface was measured by the FRAP technique. At cellular pellet scale, and at single cell scale, PC-3 cells were less stiff, less viscous, and thus more prone to deformation than the WPMY-1 control. Interestingly, stress-relaxation curves indicated a two-step response, which we attributed to a differential response coming from two cell elements, successively stressed. Both responses are faster for PC-3 cells. At a molecular scale, the dynamics of the PC-3 lipid extracts are also faster than that of WPMY-1 lipid extracts. As the evolution of cancer towards increasingly aggressive stages is accompanied by alterations both in membrane composition and in cytoskeleton dynamical properties, we attribute differences in viscoelasticity between PC-3 and WPMY-1 cells to modifications of both elements. A decrease in stiffness and a less viscous behavior may be one of the diverse mechanisms that cancer cells adopt to cope with the various physiological conditions that they encounter. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Progression-free and overall survival in metastatic castration-resistant prostate cancer treated with abiraterone acetate can be predicted with serial C11-acetate PET/CT

    OpenAIRE

    Farnebo, Jacob; Wadelius, Agnes; Sandström, Per; Nilsson, Sten; Jacobsson, Hans; Blomqvist, Lennart; Ullén, Anders

    2016-01-01

    Abstract In this retrospective study, we evaluated the benefit of repeated carbon 11 (C11)-acetate positron emission tomography/computed tomography (PET/CT) to assess response in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA). A total of 30 patients with mCRPC were monitored with C11-acetate PET/CT and PSA levels during their treatment with AA. Retrospective evaluation of their response was made after 102 days (median; range 70–155)...

  20. An elevated serum miR-141 level in patients with bone-metastatic prostate cancer is correlated with more bone lesions

    Institute of Scientific and Technical Information of China (English)

    Hai-Liang Zhang; Xiao-Jian Qin; Da-Long Cao; Yao Zhu; Xu-Dong Yao; Shi-Lin Zhang; Bo Dai

    2013-01-01

    The skeleton is the most common metastatic organ in patients with prostate cancer (PCa).Non-invasive biomarkers that can facilitate the detection and monitoring of bone metastases are highly desirable.We designed this study to assess the expression patterns of serum miR-141 in patients with bone-metastatic PCa.Serum samples were collected to measure the miR-141 level in 56 patients,including six with benign prostatic hyperplasia (BPH),20 with localized PCa and 30 with bone-metastatic PCa (10 with hormone-naive PCa,10 with hormone-sensitive PCa and 10 with hormone-refractory PCa).A bone scan was performed for each patient with PCa to assess the number of bone lesions.The quantification of serum miR-141 levels was assayed by specific TaqMan qRT-PCR.The results showed that serum miR-141 levels were elevated in patients with bone metastasis (P<0.001).There was no statistically significant difference in the serum miR-141 levels between patients with BPH and patients with localized PCa.Using Kendall's bivariate correlation test,both the Gleason score and the number of bone-metastatic lesions were found to correlate with serum miR-141 levels (P=0.012 and P<0.001,respectively).The serum miR-141 level was found to be positively correlated with alkaline phosphatase (ALP) level in patients with skeletal metastasis,using Pearson's bivariate correlation test.No relationship was found between the serum miR-141 level and the serum prostate-specific antigen (PSA) level.We concluded that serum miR-141 levels are elevated in patients with bone-metastatic PCa and that patients with higher levels of serum miR-141 developed more bone lesions.Furthermore,serum miR-141 levels are correlated with serum ALP levels but not serum PSA levels.

  1. Mapping the FACT-P to the preference-based EQ-5D questionnaire in metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Skaltsa, Konstantina; Longworth, Louise; Ivanescu, Cristina; Phung, De; Holmstrom, Stefan

    2014-03-01

    To develop a mapping algorithm for estimating EuroQol five-dimensional (EQ-5D) questionnaire values from the prostate cancer-specific health-related quality-of-life (HRQOL) instrument Functional Assessment of Cancer Therapy-Prostate (FACT-P) instrument. The EQ-5D questionnaire and FACT-P instrument data were collected for a subset of patients with metastatic castration-resistant prostate cancer in a multicenter, randomized, double-blind, placebo-controlled phase 3 trial. We compared three statistical techniques to estimate patients' EQ-5D questionnaire index scores determined by using the UK tariff: 1) generalized estimating equations, 2) two-part model combining logistic regression and generalized estimating equation, and 3) separate mapping algorithms for patients with poor health defined as a FACT-P score of 76 or less (group-specific model). Four different sets of explanatory variables were compared. The models were cross-validated by using a 10-fold in-sample cross-validation. Values for both instruments were available for 236 patients with metastatic castration-resistant prostate cancer. The group-specific model including the FACT-P subscale scores and baseline variables had the best predictive performance with R(2) 0.718, root mean square error 0.162, and mean absolute error 0.117. The two-part model and the generalized estimating equation model including the FACT-P subdomain scores and baseline variables also had good predictive performance. The developed algorithms for mapping the FACT-P instrument to the EQ-5D questionnaire enable the estimation of preference-based health-related quality-of-life scores for use in cost-effectiveness analyses when directly elicited EQ-5D questionnaire data are missing. Copyright © 2014 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

  2. Associations between aerobic exercise levels and physical and mental health outcomes in men with bone metastatic prostate cancer: a cross-sectional investigation.

    Science.gov (United States)

    Zopf, E M; Newton, R U; Taaffe, D R; Spry, N; Cormie, P; Joseph, D; Chambers, S K; Baumann, F T; Bloch, W; Galvão, D A

    2016-09-20

    Cancer patients with bone metastases have previously been excluded from participation in physical activity programmes due to concerns of skeletal fractures. Our aim was to provide initial information on the association between physical activity levels and physical and mental health outcomes in prostate cancer patients with bone metastases. Between 2012 and 2015, 55 prostate cancer patients (mean age 69.7 ± 8.3; BMI 28.6 ± 4.0) with bone metastases (58.2% >2 regions affected) undertook assessments for self-reported physical activity, physical and mental health outcomes (SF-36), objective physical performance measures and body composition by DXA. Sixteen men (29%) met the current aerobic exercise guidelines for cancer survivors, while 39 (71%) reported lower aerobic exercise levels. Men not meeting aerobic exercise guidelines had lower physical functioning (p = .004), role functioning (physical and emotional) (p health scores (p = .014) as well all lower measures of physical performance (p exercise are associated with reduced physical and mental health outcomes in prostate cancer patients with bone metastases. While previous research has focused primarily in those with non-metastatic disease, our initial results suggest that higher levels of aerobic exercise may preserve physical and mental health outcomes in prostate cancer patients with bone metastases.

  3. Potential utility of cancer-specific biomarkers for assessing response to hormonal treatments in metastatic prostate cancer

    NARCIS (Netherlands)

    Schalken, J.; Dijkstra, S.; Baskin-Bey, E.; Oort, I. van

    2014-01-01

    Prostate cancer is the second leading cause of cancer death in men and there is an urgent clinical need to improve its detection and treatment. The introduction of prostate-specific antigen (PSA) as a biomarker for prostate cancer several decades ago represented an important step forward in our abil

  4. Automated Bone Scan Index as a quantitative imaging biomarker in metastatic castration-resistant prostate cancer patients being treated with enzalutamide

    DEFF Research Database (Denmark)

    Anand, Aseem; Morris, Michael J; Larson, Steven M;

    2016-01-01

    BACKGROUND: Having performed analytical validation studies, we are now assessing the clinical utility of the upgraded automated Bone Scan Index (BSI) in metastatic castration-resistant prostate cancer (mCRPC). In the present study, we retrospectively evaluated the discriminatory strength of the a......BACKGROUND: Having performed analytical validation studies, we are now assessing the clinical utility of the upgraded automated Bone Scan Index (BSI) in metastatic castration-resistant prostate cancer (mCRPC). In the present study, we retrospectively evaluated the discriminatory strength......-specific antigen (PSA), hemoglobin (HgB), and alkaline phosphatase (ALP) were obtained at baseline. Change in automated BSI and PSA were obtained from patients who have had bone scan at week 12 of treatment follow-up. Automated BSI was obtained using the analytically validated EXINI Bone(BSI) version 2. Kendall...... alone (C-index 0.73), p = 0.041. CONCLUSIONS: The upgraded and analytically validated automated BSI was found to be a strong predictor of OS in mCRPC patients. Additionally, the change in automated BSI demonstrated an additive clinical value to the change in PSA in mCRPC patients being treated...

  5. Metronomic Treatment with Low-Dose Trofosfamide Leads to a Long-Term Remission in a Patient with Docetaxel-Refractory Advanced Metastatic Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Jochen Greiner

    2010-01-01

    Full Text Available The treatment of metastatic prostate cancer patients refractory to androgen withdrawal and docetaxel therapy is currently discouraging and new therapeutic approaches are vastly needed. Here, we report a long-term remission over one year in a 68-year-old patient with metastatic docetaxel-refractory prostate cancer employing low-dose trofosfamide. The patient suffered from distant failure with several bone lesions and lymph node metastases depicted by a (11 C-Choline positron emission tomography/computerized tomography (PET/CT. After initiation of trofosfamide 100 mg taken orally once a day we observed a steadily decreasing PSA value from initial 46.6 down to 2.1 g/l. The Choline-PET/CT was repeated after 10 months of continuous therapy and demonstrated a partial remission of the bone lesions and a regression of all involved lymph nodes but one. Taken together we found an astonishing and durable activity of the alkylating agent trofosfamide given in a metronomic fashion. We rate the side effects as low and state an excellent therapeutic ratio of this drug in our patient.

  6. Periprostatic adipocytes act as a driving force for prostate cancer progression in obesity.

    Science.gov (United States)

    Laurent, Victor; Guérard, Adrien; Mazerolles, Catherine; Le Gonidec, Sophie; Toulet, Aurélie; Nieto, Laurence; Zaidi, Falek; Majed, Bilal; Garandeau, David; Socrier, Youri; Golzio, Muriel; Cadoudal, Thomas; Chaoui, Karima; Dray, Cedric; Monsarrat, Bernard; Schiltz, Odile; Wang, Yuan Yuan; Couderc, Bettina; Valet, Philippe; Malavaud, Bernard; Muller, Catherine

    2016-01-12

    Obesity favours the occurrence of locally disseminated prostate cancer in the periprostatic adipose tissue (PPAT) surrounding the prostate gland. Here we show that adipocytes from PPAT support the directed migration of prostate cancer cells and that this event is strongly promoted by obesity. This process is dependent on the secretion of the chemokine CCL7 by adipocytes, which diffuses from PPAT to the peripheral zone of the prostate, stimulating the migration of CCR3 expressing tumour cells. In obesity, higher secretion of CCL7 by adipocytes facilitates extraprostatic extension. The observed increase in migration associated with obesity is totally abrogated when the CCR3/CCL7 axis is inhibited. In human prostate cancer tumours, expression of the CCR3 receptor is associated with the occurrence of aggressive disease with extended local dissemination and a higher risk of biochemical recurrence, highlighting the potential benefit of CCR3 antagonists in the treatment of prostate cancer.

  7. Cysteine (C-x-C receptor 4 undergoes transportin 1-dependent nuclear localization and remains functional at the nucleus of metastatic prostate cancer cells.

    Directory of Open Access Journals (Sweden)

    Ayesha S Don-Salu-Hewage

    Full Text Available The G-protein coupled receptor (GPCR, Cysteine (C-X-C Receptor 4 (CXCR4, plays an important role in prostate cancer metastasis. CXCR4 is generally regarded as a plasma membrane receptor where it transmits signals that support transformation, progression and eventual metastasis. Due to the central role of CXCR4 in tumorigenesis, therapeutics approaches such as antagonist and monoclonal antibodies have focused on receptors that exist on the plasma membrane. An emerging concept for G-protein coupled receptors is that they may localize to and associate with the nucleus where they retain function and mediate nuclear signaling. Herein, we demonstrate that CXCR4 associated with the nucleus of malignant prostate cancer tissues. Likewise, expression of CXCR4 was detected in nuclear fractions among several prostate cancer cell lines, compared to normal prostate epithelial cells. Our studies identified a nuclear pool of CXCR4 and we defined a nuclear transport pathway for CXCR4. We reveal a putative nuclear localization sequence (NLS, 'RPRK', within CXCR4 that contributed to nuclear localization. Additionally, nuclear CXCR4 interacted with Transportinβ1 and Transportinβ1-binding to CXCR4 promoted its nuclear translocation. Importantly, Gαi immunoprecipitation and calcium mobilization studies indicated that nuclear CXCR4 was functional and participated in G-protein signaling, revealing that the nuclear pool of CXCR4 retained function. Given the suggestion that functional, nuclear CXCR4 may be a mechanism underlying prostate cancer recurrence, increased metastatic ability and poorer prognosis after tumors have been treated with therapy that targets plasma membrane CXCR4, these studies addresses a novel mechanism of nuclear signaling for CXCR4, a novel mechanism of clinical targeting, and demonstrate an active nuclear pool that provides important new information to illuminate what has been primarily clinical reports of nuclear CXCR4.

  8. Dosimetry for {sup 177}Lu-DKFZ-PSMA-617: a new radiopharmaceutical for the treatment of metastatic prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Delker, Andreas; Fendler, Wolfgang Peter; Brunegraf, Anika; Gosewisch, Astrid; Gildehaus, Franz Josef; Bartenstein, Peter; Boening, Guido [Ludwig-Maximilians-University of Munich, Department of Nuclear Medicine, Munich (Germany); Kratochwil, Clemens; Haberkorn, Uwe [Heidelberg University Hospital, Department for Nuclear Medicine, Heidelberg (Germany); Tritschler, Stefan; Stief, Christian Georg [Ludwig-Maximilians-University of Munich, Department of Urology, Munich (Germany); Kopka, Klaus [German Cancer Research Center (dkfz), Division of Radiopharmaceutical Chemistry, Heidelberg (Germany)

    2016-01-15

    Dosimetry is critical to achieve the optimal therapeutic effect of radioligand therapy (RLT) with limited side effects. Our aim was to perform image-based absorbed dose calculation for the new PSMA ligand {sup 177}Lu-DKFZ-PSMA-617 in support of its use for the treatment of metastatic prostate cancer. Whole-body planar images and SPECT/CT images of the abdomen were acquired in five patients (mean age 68 years) for during two treatment cycles at approximately 1, 24, 48 and 72 h after administration of 3.6 GBq (range 3.4 to 3.9 GBq) {sup 177}Lu-DKFZ-PSMA-617. Quantitative 3D SPECT OSEM reconstruction was performed with corrections for photon scatter, photon attenuation and detector blurring. A camera-specific calibration factor derived from phantom measurements was used for quantitation. Absorbed doses were calculated for various organs from the images using a combination of linear approximation, exponential fit, and target-specific S values, in accordance with the MIRD scheme. Absorbed doses to bone marrow were estimated from planar and SPECT images and with consideration of the blood sampling method according to the EANM guidelines. The average (± SD) absorbed doses per cycle were 2.2 ± 0.6 Gy for the kidneys (0.6 Gy/GBq), 5.1 ± 1.8 Gy for the salivary glands (1.4 Gy/GBq), 0.4 ± 0.2 Gy for the liver (0.1 Gy/GBq), 0.4 ± 0.1 Gy for the spleen (0.1 Gy/GBq), and 44 ± 19 mGy for the bone marrow (0.012 Gy/GBq). The organ absorbed doses did not differ significantly between cycles. The critical absorbed dose reported for the kidneys (23 Gy) was not reached in any patient. At 24 h there was increased uptake in the colon with 50 - 70 % overlap to the kidneys on planar images. Absorbed doses for tumour lesions ranged between 1.2 and 47.5 Gy (13.1 Gy/GBq) per cycle. The salivary glands and kidneys showed high, but not critical, absorbed doses after RLT with {sup 177}Lu-DKFZ-PSMA-617. We suggest that {sup 177}Lu-DKFZ-PSMA-617 is suitable for radiotherapy, offering tumour

  9. Impact of new generation hormone-therapy on cognitive function in elderly patients treated for a metastatic prostate cancer: Cog-Pro trial protocol.

    Science.gov (United States)

    Lange, Marie; Laviec, Heidi; Castel, Hélène; Heutte, Natacha; Leconte, Alexandra; Léger, Isabelle; Giffard, Bénédicte; Capel, Aurélie; Dubois, Martine; Clarisse, Bénédicte; Coquan, Elodie; Di Fiore, Frédéric; Gouérant, Sophie; Bartélémy, Philippe; Pierard, Laure; Fizazi, Karim; Joly, Florence

    2017-08-16

    New generation hormone-therapies (NGHT) targeting the androgen signalling pathway are nowadays proposed to elderly patients with metastatic castration-resistant prostate cancer (CRPCa). The impact of these treatments on cognitive function has never been evaluated whereas cognitive impairment may have an impact on the autonomy and the treatment adherence. The aim of this study is to prospectively assess the incidence of cognitive impairment in elderly men after treatment by NGHT for a metastatic CRPCa. The Cog-Pro study is a multicentre longitudinal study including CRPCa patients ≥70 years old treated with NGHT (n = 134), control metastatic prostate cancer patients without castration resistance treated with first generation androgen deprivation therapy (n = 55), and healthy participants (n = 33), matched on age and education. Cognitive, geriatric and quality of life assessment and biological tests will be performed at baseline, 3, 6 and 12 months after start of the treatment (inclusion time). The primary endpoint is the proportion of elderly patients receiving a NGHT who will experience a decline in cognitive performances within 3 months after study enrollment. Secondary endpoints concern: autonomy, quality of life, anxiety, depression, cognitive reserve, adherence to hormone-therapy, comparison of the cognitive impact of 2 different NGHT (abiraterone acetate and enzalutamide), impact of co-morbidities and biological assessments. Evaluating, understanding and analyzing the incidence, severity of cognitive impairments and their impact on quality of life, autonomy and adherence in this group of patients with advanced disease is a challenge. This study should help to improve cancer care of elderly patients and secure the use of oral treatments as the risk of non-observance does exist. Our results will provide up-to date information for patients and caregivers on impact of these treatments on cognitive function in order to help the physicians in the choice of

  10. Detection of live circulating tumor cells by a class of near-infrared heptamethine carbocyanine dyes in patients with localized and metastatic prostate cancer.

    Science.gov (United States)

    Shao, Chen; Liao, Chun-Peng; Hu, Peizhen; Chu, Chia-Yi; Zhang, Lei; Bui, Matthew H T; Ng, Christopher S; Josephson, David Y; Knudsen, Beatrice; Tighiouart, Mourad; Kim, Hyung L; Zhau, Haiyen E; Chung, Leland W K; Wang, Ruoxiang; Posadas, Edwin M

    2014-01-01

    Tumor cells are inherently heterogeneous and often exhibit diminished adhesion, resulting in the shedding of tumor cells into the circulation to form circulating tumor cells (CTCs). A fraction of these are live CTCs with potential of metastatic colonization whereas others are at various stages of apoptosis making them likely to be less relevant to understanding the disease. Isolation and characterization of live CTCs may augment information yielded by standard enumeration to help physicians to more accurately establish diagnosis, choose therapy, monitor response, and provide prognosis. We previously reported on a group of near-infrared (NIR) heptamethine carbocyanine dyes that are specifically and actively transported into live cancer cells. In this study, this viable tumor cell-specific behavior was utilized to detect live CTCs in prostate cancer patients. Peripheral blood mononuclear cells (PBMCs) from 40 patients with localized prostate cancer together with 5 patients with metastatic disease were stained with IR-783, the prototype heptamethine cyanine dye. Stained cells were subjected to flow cytometric analysis to identify live (NIR(+)) CTCs from the pool of total CTCs, which were identified by EpCAM staining. In patients with localized tumor, live CTC counts corresponded with total CTC numbers. Higher live CTC counts were seen in patients with larger tumors and those with more aggressive pathologic features including positive margins and/or lymph node invasion. Even higher CTC numbers (live and total) were detected in patients with metastatic disease. Live CTC counts declined when patients were receiving effective treatments, and conversely the counts tended to rise at the time of disease progression. Our study demonstrates the feasibility of applying of this staining technique to identify live CTCs, creating an opportunity for further molecular interrogation of a more biologically relevant CTC population.

  11. Detection of live circulating tumor cells by a class of near-infrared heptamethine carbocyanine dyes in patients with localized and metastatic prostate cancer.

    Directory of Open Access Journals (Sweden)

    Chen Shao

    Full Text Available Tumor cells are inherently heterogeneous and often exhibit diminished adhesion, resulting in the shedding of tumor cells into the circulation to form circulating tumor cells (CTCs. A fraction of these are live CTCs with potential of metastatic colonization whereas others are at various stages of apoptosis making them likely to be less relevant to understanding the disease. Isolation and characterization of live CTCs may augment information yielded by standard enumeration to help physicians to more accurately establish diagnosis, choose therapy, monitor response, and provide prognosis. We previously reported on a group of near-infrared (NIR heptamethine carbocyanine dyes that are specifically and actively transported into live cancer cells. In this study, this viable tumor cell-specific behavior was utilized to detect live CTCs in prostate cancer patients. Peripheral blood mononuclear cells (PBMCs from 40 patients with localized prostate cancer together with 5 patients with metastatic disease were stained with IR-783, the prototype heptamethine cyanine dye. Stained cells were subjected to flow cytometric analysis to identify live (NIR(+ CTCs from the pool of total CTCs, which were identified by EpCAM staining. In patients with localized tumor, live CTC counts corresponded with total CTC numbers. Higher live CTC counts were seen in patients with larger tumors and those with more aggressive pathologic features including positive margins and/or lymph node invasion. Even higher CTC numbers (live and total were detected in patients with metastatic disease. Live CTC counts declined when patients were receiving effective treatments, and conversely the counts tended to rise at the time of disease progression. Our study demonstrates the feasibility of applying of this staining technique to identify live CTCs, creating an opportunity for further molecular interrogation of a more biologically relevant CTC population.

  12. GPNMB/OA protein increases the invasiveness of human metastatic prostate cancer cell lines DU145 and PC3 through MMP-2 and MMP-9 activity

    Energy Technology Data Exchange (ETDEWEB)

    Fiorentini, Chiara; Bodei, Serena; Bedussi, Francesca; Fragni, Martina; Bonini, Sara Anna [Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, V.le Europa 11, 25124 Brescia (Italy); Simeone, Claudio; Zani, Danilo [Division of Urology, Department of Surgery, Radiology and Public Health, University of Brescia, P.le Spedali Civili 1, 25124 Brescia (Italy); Berruti, Alfredo [Medical Oncology, Department of Surgery, Radiology, and Public Health, University of Brescia, P.le Spedali Civili 1, 25124 Brescia (Italy); Missale, Cristina; Memo, Maurizio; Spano, PierFranco [Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, V.le Europa 11, 25124 Brescia (Italy); Sigala, Sandra, E-mail: sigala@med.unibs.it [Section of Pharmacology, Department of Molecular and Translational Medicine, University of Brescia, V.le Europa 11, 25124 Brescia (Italy)

    2014-04-15

    Non-metastatic glycoprotein melanoma protein B (GPNMB), also known as osteoactivin (OA) is expressed in a wide array of tumors and represents an emerging target for drug development. In this study, we investigated the role of GPNMB/OA in the progression of human metastatic DU145 and PC3 prostate cancer cells. GPNMB/OA contribution in PCa malignant phenotype has been analyzed by small interfering RNA-induced GPNMB/OA silencing. We found that following GPNMB/OA silencing the migration capability of both DU145 and PC3 cells, evaluated by using in vitro invasivity assay, as well as the metalloproteinases MMP-2 and MMP-9 activity were equally strongly inhibited. By contrast knocking down GPNMB/OA weakly attenuated cell proliferation rate of DU145, an effect that paralleled with an increase number of apoptotic cells. However, PC3 cell growth seems to be not affected by GPNMB/OA. Together, these data reveal that GPNMB/OA acts as a critical molecular mediator promoting the acquisition of the more aggressive, pro-metastatic phenotype distinctive of human DU145 and PC3 cell lines. - Highlights: • GPNMB/OA expression correlates with DU145 and PC3 cells malignant phenotype. • GPNMB/OA silencing affects the migration capability of both DU145 and PC3 cells. • GPNMB/OA increases invasiveness by up-regulating MMPs activity. • GPNMB/OA promotes DU145 and PC3 cells progression into a more aggressive phenotype.

  13. Effects of androgen deprivation therapy and bisphosphonate treatment on bone in patients with metastatic castration-resistant prostate cancer: results from the University of Washington Rapid Autopsy Series.

    Science.gov (United States)

    Morrissey, Colm; Roudier, Martine P; Dowell, Alex; True, Lawrence D; Ketchanji, Melanie; Welty, Christopher; Corey, Eva; Lange, Paul H; Higano, Celestia S; Vessella, Robert L

    2013-02-01

    Qualitative and quantitative bone features were determined in nondecalcified and decalcified bone from 20 predetermined bone sites in each of 44 patients who died with castration-resistant prostate cancer (CRPC), some of which received bisphosphonate treatment (BP) in addition to androgen-deprivation therapy (ADT). Thirty-nine of the 44 patients (89%) had evidence of bone metastases. By histomorphometric analysis, these bone metastases were associated with a range of bone responses from osteoblastic to osteolytic with a wide spectrum of bone responses often seen within an individual patient. Overall, the average bone volume/tissue volume (BV/TV) was 25.7%, confirming the characteristic association of an osteoblastic response to prostate cancer bone metastasis when compared with the normal age-matched weighted mean BV/TV of 14.7%. The observed new bone formation was essentially woven bone, and this was a localized event. In comparing BV/TV at metastatic sites between patients who had received BP treatment and those who had not, there was a significant difference (28.6% versus 19.3%, respectively). At bone sites that were not invaded by tumor, the average BV/TV was 10.1%, indicating significant bone loss owing to ADT that was not improved (11%) in those patients who had received BPs. Surprisingly, there was no significant difference in the number of osteoclasts present at the metastatic sites between patients treated or not treated with BPs, but in bone sites where the patient had been treated with BPs, giant osteoclasts were observed. Overall, 873 paraffin-embedded specimens and 661 methylmethacrylate-embedded specimens were analyzed. Our results indicate that in CRPC patients, ADT induces serious bone loss even in patients treated with BP. Furthermore, in this cohort of patients, BP treatment increased BV and did not decrease the number of osteoclasts in prostate cancer bone metastases compared with bone metastases from patients who did not receive BP.

  14. Spironolactone, a possible selective androgen receptor modulator, should be used with caution in patients with metastatic carcinoma of the prostate.

    Science.gov (United States)

    Sundar, Santhanam; Dickinson, Peter D

    2012-02-25

    The authors report the case of an 80-year-old man who had heavily pretreated castration refractory carcinoma of the prostate and heart failure. Following the introduction of spironolactone to manage his heart failure, the patient experienced clinical and biochemical progression of his prostate cancer. Within 2 weeks of withdrawing spironolactone the patient's prostate-specific antigen returned its previous level. This is the first reported case of clinical and biochemical progression of prostate cancer following the introduction of spironolactone. The authors propose that spironolactone is a selective androgen receptor modulator. Spironolactone should be used in caution with men with prostate cancer, and should not be used to treat oedema, hypokalaemia and hypertension associated with the newly licensed hormonal therapy abiraterone acetate.

  15. Upregulation of vascular endothelial growth factor by cobalt chloride-simulated hypoxia is mediated by persistent induction of cyclooxygenase-2 in a metastatic human prostate cancer cell line.

    Science.gov (United States)

    Liu, X H; Kirschenbaum, A; Yao, S; Stearns, M E; Holland, J F; Claffey, K; Levine, A C

    1999-01-01

    Upregulation of vascular endothelial growth factor (VEGF) expression induced by hypoxia is crucial event leading to neovascularization. Cyclooxygenase-2, an inducible enzyme that catalyzes the formation of prostaglandins (PGs) from arachidonic acid, has been demonstrated to be induced by hypoxia and play role in angiogenesis and metastasis. To investigate the potential effect of COX-2 on hypoxia-induced VEGF expression in prostate cancer. We examined the relationship between COX-2 expression and VEGF induction in response to cobalt chloride (CoCl2)-simulated hypoxia in three human prostate cancer cell lines with differing biological phenotypes. Northern blotting and ELISA revealed that all three tested cell lines constitutively expressed VEGF mRNA, and secreted VEGF protein to different degrees (LNCaP > PC-3 > PC3ML). However, these cell lines differed in the ability to produce VEGF in the presence of CoCl2-simulated hypoxia. CoCl2 treatment resulted in 40% and 75% increases in VEGF mRNA, and 50% and 95% in protein secretion by LNCaP and PC-3 cell lines, respectively. In contrast, PC-3ML cell line, a PC-3 subline with highly invasive, metastatic phenotype, exhibits a dramatic upregulation of VEGF, 5.6-fold in mRNA and 6.3-fold in protein secretion after treatment with CoCl2. The upregulation of VEGF in PC-3ML cells is accompanied by a persistent induction of COX-2 mRNA (6.5-fold) and protein (5-fold). Whereas COX-2 expression is only transiently induced in PC-3 cells and not affected by CoCl2 in LNCaP cells. Moreover, the increases in VEGF mRNA and protein secretion induced by CoCl2 in PC-3ML cells were significantly suppressed following exposure to NS398, a selective COX-2 inhibitor. Finally, the effect of COX-2 inhibition on CoCl2-induced VEGF production was reversed by the treatment with exogenous PGE2. Our data demonstrate that VEGF induction by cobalt chloride-simulated hypoxia is maintained by a concomitant, persistent induction of COX-2 expression and

  16. BRCA1 loss pre-existing in small subpopulations of prostate cancer is associated with advanced disease and metastatic spread to lymph nodes and peripheral blood

    Energy Technology Data Exchange (ETDEWEB)

    Bednarz, Natalia; Eltze, Elke; Semjonow, Axel; Rink, Michael; Andreas, Antje; Mulder, Lennart; Hannemann, Juliane; Fisch, Margit; Pantel, Klaus; Weier, Heinz-Ulrich G.; Bielawski, Krzysztof P.; Brandt, Burkhard

    2010-03-19

    A recent study concluded that serum prostate specific antigen (PSA)-based screening is beneficial for reducing the lethality of PCa, but was also associated with a high risk of 'overdiagnosis'. Nevertheless, also PCa patients who suffered from organ confined tumors and had negative bone scans succumb to distant metastases after complete tumor resection. It is reasonable to assume that those tumors spread to other organs long before the overt manifestation of metastases. Our current results confirm that prostate tumors are highly heterogeneous. Even a small subpopulation of cells bearing BRCA1 losses can initiate PCa cell regional and distant dissemination indicating those patients which might be at high risk of metastasis. A preliminary study performed on a small cohort of multifocal prostate cancer (PCa) detected BRCA1 allelic imbalances (AI) among circulating tumor cells (CTCs). The present analysis was aimed to elucidate the biological and clinical role of BRCA1 losses on metastatic spread and tumor progression in prostate cancer patients. Experimental Design: To map molecular progression in PCa outgrowth we used FISH analysis of tissue microarrays (TMA), lymph node sections and CTC from peripheral blood. We found that 14% of 133 tested patients carried monoallelic BRCA1 loss in at least one tumor focus. Extended molecular analysis of chr17q revealed that this aberration was often a part of larger cytogenetic rearrangement involving chr17q21 accompanied by AI of the tumor suppressor gene PTEN and lack of the BRCA1 promoter methylation. The BRCA1 losses correlated with advanced T stage (p < 0.05), invasion to pelvic lymph nodes (LN, p < 0.05) as well as BR (p < 0.01). Their prevalence was twice as high within 62 LN metastases (LNMs) as in primary tumors (27%, p < 0.01). The analysis of 11 matched primary PCa-LNM pairs confirmed the suspected transmission of genetic abnormalities between those two sites. In 4 of 7 patients with metastatic disease, BRCA1

  17. Efficient delivery of micro RNA to bone-metastatic prostate tumors by using aptamer-conjugated atelocollagen in vitro and in vivo.

    Science.gov (United States)

    Hao, Zhao; Fan, Wei; Hao, Jian; Wu, Xin; Zeng, Guo Qing; Zhang, Li Juan; Nie, Sui Feng; Wang, Xu Dong

    2016-01-01

    Bone is the primary site of skeletal metastasis in prostate cancer (PCa). Atelocollagen (ATE)-mediated siRNA delivery system can be used to silence endogenous genes involved in PCa metastatic tumor cell growth. However, we hope that the delivery system can target PCa cells to reduce damage to the bone tissue and improve the therapeutic effect. RNA aptamer (APT) A10-3.2 has been used as a ligand to target PCa cells that express prostate-specific membrane antigen (PSMA). APT was investigated as a PSMA-targeting ligand in the design of an ATE-based microRNA (miRNA; miR-15a and miR-16-1) vector to PCa bone metastasis. To observe the targeted delivery and transfection efficiency of ATE-APT in PSMA-overexpressing cells, luciferase activity and biodistribution of nanoparticles in Balb/c mice was analyzed. The anticancer effect of nanoparticles in vivo was investigated using the survival times of human PCa bone metastasis mice model. Luciferase assays of pGL-3 expression against PC3 (PSMA(-)) and LNCaP (PSMA(+)) cells showed that the transfection efficiency of the synthesized DNA/ATE-APT complex was higher than that of the DNA/ATE complex. The anticancer efficacy of miRNA/ATE-APT was superior to those of other treatments in vivo. This PSMA-targeted system may prove useful in widening the therapeutic window and allow for selective killing of PCa cells in bone metastatic foci.

  18. Overexpression of vascular endothelial growth factor C increases growth and alters the metastatic pattern of orthotopic PC-3 prostate tumors

    Directory of Open Access Journals (Sweden)

    Väänänen H Kalervo

    2009-10-01

    Full Text Available Abstract Background Prostate cancer metastasizes to regional lymph nodes and distant sites but the roles of lymphatic and hematogenous pathways in metastasis are not fully understood. Methods We studied the roles of VEGF-C and VEGFR3 in prostate cancer metastasis by blocking VEGFR3 using intravenous adenovirus-delivered VEGFR3-Ig fusion protein (VEGFR3-Ig and by ectopic expression of VEGF-C in PC-3 prostate tumors in nude mice. Results VEGFR3-Ig decreased the density of lymphatic capillaries in orthotopic PC-3 tumors (p p p p Conclusion The data suggest that even though VEGF-C/VEGFR3 pathway is primarily required for lymphangiogenesis and lymphatic metastasis, an increased level of VEGF-C can also stimulate angiogenesis, which is associated with growth of orthotopic prostate tumors and a switch from a primary pattern of lymph node metastasis to an increased proportion of metastases at distant sites.

  19. High-Throughput Sequencing of Germline and Tumor From Men with Early-Onset Metastatic Prostate Cancer

    Science.gov (United States)

    2016-12-01

    specimens as initially proposed. Concurrently, Dr. Tomlins developed state of the art technologies to use FFPE prostate cancer specimens for molecular...capture based NGS and qPCR approaches, and multiplexed PCR NGS based approaches. Therefore, we modified our approach to use archived FFPE biopsy and...tissue, we had the opportunity to molecularly profile both the initial prostate cancer (PR-259, DOD_03a) and the liver biopsy which contained

  20. Optimal duration of androgen deprivation therapy following radiation therapy in intermediate- or high-risk non-metastatic prostate cancer: a systematic review and meta-analysis

    Energy Technology Data Exchange (ETDEWEB)

    Leal, Frederico; Figueiredo, Maximiliano Augusto Novis de; Sasse, Andre Deeke, E-mail: sasse@cevon.com.br [Universidade Estadual de Campinas (UNICAMP), SP (Brazil)

    2015-05-15

    Objectives: to investigate current evidence on the optimal duration of adjuvant hormone deprivation for prostate cancer treated with radiation therapy with curative intent. Materials and Methods: A systematic search was performed in electronic databases. Data from randomized trials comparing different durations of hormone blockade was collected for pooled analysis. Overall survival, disease-free survival, disease-specific survival and toxicity were the outcomes of interest. Meta-analyses were performed using random-effects model. Results: Six studies met the eligibility criteria. For overall survival, the pooled data from the studies demonstrated a statistically significant benefit for longer hormone deprivation (Hazard Ratio 0.84; 95% CI 0.74 - 0.96). A statistically significant benefit was also found for disease-free survival (Hazard Ratio 0.74; 95% CI 0.62 - 0.89), and disease-specific survival (Hazard Ratio 0.73; 95% CI 0.62 - 0.85). Studies with longer blockade duration arm demonstrated greater benefit. Toxicity was low, with no increase in cardiovascular events. Conclusions: Longer duration of androgen deprivation combined to radiotherapy prolongs OS, DFS and DSS in patients with intermediate and high-risk non-metastatic prostate cancer. However, this evidence is based on trials using older radiation techniques, and further research of combination of androgen deprivation and new RT technologies may be warranted. (author)

  1. Sipuleucel-T (Provenge) autologous vaccine approved for treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer.

    Science.gov (United States)

    Gardner, Thomas A; Elzey, Bennett D; Hahn, Noah M

    2012-04-01

    Sipuleucel-T (Provenge) (Sip-T) is first -in class as a therapeutic autologous vaccine approved for the treatment of men with asymptomatic or minimally symptomatic castrate-resistant metastatic prostate cancer. This product is the culmination of decades of basic immunological and prostate cancer investigations and 13 y of clinical trial investigations. Sip-T represents a paradigm shift in cancer therapeutics and represents the first approved autologous therapeutic cancer vaccine, which has demonstrated a survival benefit. The potential benefit of this product is the excellent risk to benefit ratio, which will allow for the combination of this approach with other more toxic therapies. The favorable risk to benefit will also afford the opportunity for trials investigating this product earlier in the disease state and in combination with local therapies. The ability to target more localized or lower volume disease will maximize the therapeutic benefit over a longer period of time. The novelty of the platform of this approach could be used to treat any cancer with a tumor-specific cell surface target. The main product of Sip-T is the re-infusion of a patient's antigen presenting cells from leukapheresis after ex-vivo exposure to a chimeric protein of human GM-CSF and PAP. In metastatic CRPC patients three infusions of these activated cells over a month lead to statistically significant 4.1 mo increase in median survival and a 22.5% reduction in risk of death. The main side effect from this re-infusion of activated immune cells is a "flu-like" syndrome that includes chills, fatigue, fevers, back pain, nausea, joints aches and headaches in decreasing order of frequency. Immune monitoring during the clinical trials also demonstrated a specific cellular and antibody immune response, suggesting the proposed mechanism of adoptive immunotherapy to PAP was behind this survival benefit. This product also serves as a proof of principle for targeted immunotherapy for others

  2. Health Economics and Radium-223 (Xofigo®) in the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Case History and a Systematic Review of the Literature

    OpenAIRE

    Norum, Jan; Traasdahl, Erik R.; Totth, Arpad; Nieder, Carsten; Olsen, Jan Abel

    2015-01-01

    DOI: 10.5539/gjhs.v8n4p1 Creative Commons Attribution License 3.0 OBJECTIVES: Prostate cancer (PC) is the most common cancer in Western countries. Recent advances in the treatment of metastatic castration resistant prostate cancer (mCRPC) have caused significant pressure on health care budgets. We aimed to exemplify this dilemma presenting an example, radium-223 (Xofigo®), and review the literature. METHODS: A 74-year-old man diagnosed with mCRPC was referred to our department in O...

  3. Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer: part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5

    DEFF Research Database (Denmark)

    Hedlund, P.O.; Damber, J.E.; Hagerman, I.;

    2008-01-01

    To compare parenteral estrogen therapy in the form of high-dose polyestradiol phosphate (PEP; Estradurin) with combined androgen deprivation (CAD) in the treatment of prostate cancer patients with skeletal metastases. The aim of the study was to compare anticancer efficacy and adverse events...

  4. Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer -- Scandinavian Prostatic Cancer Group (SPCG) Study No. 5

    DEFF Research Database (Denmark)

    Hedlund, Per Olov; Ala-Opas, Martti; Brekkan, Einar

    2002-01-01

    In the mid-1980s, interest in parenteral estrogen therapy for prostate cancer was renewed when it was found that it influenced liver metabolism only marginally and had very few cardiovascular side-effects. In this study high-dose polyestradiol phosphate (PEP; Estradurin) was compared to combined...

  5. Two Domains of Vimentin Are Expressed on the Surface of Lymph Node, Bone and Brain Metastatic Prostate Cancer Lines along with the Putative Stem Cell Marker Proteins CD44 and CD133

    Energy Technology Data Exchange (ETDEWEB)

    Steinmetz, Nicole F. [Case Western Reserve University, Department of Biomedical Engineering, 10900 Euclid Ave, Cleveland, OH 44106 (United States); Maurer, Jochen [Sanford-Burnham, Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037 (United States); Sheng, Huiming [Torrey Pines Institute for Molecular Studies, Division of Immune Regulation, 3550 General Atomics Court, San Diego, CA 92121 (United States); Bensussan, Armand [INSERM U976, Hôpital Saint Louis, F-75475 Paris (France); Department of Immunology, Dermatology and Oncology, Univ Paris Diderot, Sorbonne Paris Cité, UMRS976 F-75475 Paris (France); Maricic, Igor; Kumar, Vipin [Torrey Pines Institute for Molecular Studies, Laboratory of Autoimmunity, 3550 General Atomics Court, San Diego, CA 92121 (United States); Braciak, Todd A., E-mail: tbraciak@tpims.org [Torrey Pines Institute for Molecular Studies, Division of Immune Regulation, 3550 General Atomics Court, San Diego, CA 92121 (United States)

    2011-07-13

    Vimentin was originally identified as an intermediate filament protein present only as an intracellular component in many cell types. However, this protein has now been detected on the surface of a number of different cancer cell types in a punctate distribution pattern. Increased vimentin expression has been indicated as an important step in epithelial-mesenchymal transition (EMT) required for the metastasis of prostate cancer. Here, using two vimentin-specific monoclonal antibodies (SC5 and V9 directed against the coil one rod domain and the C-terminus of the vimentin protein, respectively), we examined whether either of these domains would be displayed on the surface of three commonly studied prostate cancer cell lines isolated from different sites of metastases. Confocal analysis of LNCaP, PC3 and DU145 prostate cancer cell lines (derived from lymph node, bone or brain prostate metastases, respectively) demonstrated that both domains of vimentin are present on the surface of these metastatic cancer cell types. In addition, flow cytometric analysis revealed that vimentin expression was readily detected along with CD44 expression but only a small subpopulation of prostate cancer cells expressed vimentin and the putative stem cell marker CD133 along with CD44. Finally, Cowpea mosaic virus (CPMV) nanoparticles that target vimentin could bind and internalize into tested prostate cancer cell lines. These results demonstrate that at least two domains of vimentin are present on the surface of metastatic prostate cancer cells and suggest that vimentin could provide a useful target for nanoparticle- or antibody- cancer therapeutic agents directed against highly invasive cancer and/or stem cells.

  6. Adipose Stem Cell-Based Therapeutic Targeting of Residual Androgens in African Americans With Bone-Metastatic Prostate Cancer

    Science.gov (United States)

    2014-09-01

    al. (1988) The combined effects of dietary protein and fat intake during the promotion phase of 7,12-dimethylbenz(a)anthracene-induced breast cancer...Belanger B, Belanger A, Labrie F, et al. Comparison of residual C-19 steroids in plasma and prostatic tissue of human, rat and guinea pig after

  7. [Metastatic cancer of the prostate in a young 40 year-old HIV-infected male patient].

    Science.gov (United States)

    Furco, A; Bani-Sadr, F; Guymar, S; Molina, J-M

    2003-06-07

    Cancer of the prostate in HIV-infected patients has rarely been reported in the literature. A 40 year-old man presented with an adenocarcinoma of the prostate and bone and glandular metastases. The patient exhibited HIV seropositivity stage B1, the immune-virology of which was well controlled by antiretroviral tritherapy. The relationship between cancer and HIV has been established for certain cancers such as Hodgkin's disease, non-Hodgkin malignant lymphoma, Kaposi's sarcoma and invasive cancers of the uterine neck in women. The significant increase in some cancers in patients infected by HIV (lung, penis, soft tissue, lips, seminoma) suggests the potential association with immunodepression unless it corresponds to a risk induced by antiretroviral treatments in the long term.

  8. Bone Scan Index as an Imaging Biomarker in Metastatic Castration-resistant Prostate Cancer: A Multicentre Study Based on Patients Treated with Abiraterone Acetate (Zytiga) in Clinical Practice.

    Science.gov (United States)

    Reza, Mariana; Ohlsson, Mattias; Kaboteh, Reza; Anand, Aseem; Franck-Lissbrant, Ingela; Damber, Jan-Erik; Widmark, Anders; Thellenberg-Karlsson, Camilla; Budäus, Lars; Steuber, Thomas; Eichenauer, Till; Wollmer, Per; Edenbrandt, Lars; Trägårdh, Elin; Bjartell, Anders

    2016-12-01

    Abiraterone acetate (AA) prolongs survival in metastatic castration-resistant prostate cancer (mCRPC) patients. To measure treatment response accurately in bone, quantitative methods are needed. The Bone Scan Index (BSI), a prognostic imaging biomarker, reflects the tumour burden in bone as a percentage of the total skeletal mass calculated from bone scintigraphy. To evaluate the value of BSI as a biomarker for outcome evaluation in mCRPC patients on treatment with AA according to clinical routine. We retrospectively studied 104 mCRPC patients who received AA following disease progression after chemotherapy. All patients underwent whole-body bone scintigraphy before and during AA treatment. Baseline and follow-up BSI data were obtained using EXINI Bone(BSI) software (EXINI Diagnostics AB, Lund, Sweden). Associations between change in BSI, clinical parameters at follow-up, and overall survival (OS) were evaluated using the Cox proportional hazards regression models and Kaplan-Meier estimates. Discrimination between variables was assessed using the concordance index (C-index). Patients with an increase in BSI at follow-up of at most 0.30 (n=54) had a significantly longer median survival time than those with an increase of BSI >0.30 (n=50) (median: 16 vs 10 mo; p=0.001). BSI change was also associated with OS in a multivariate Cox analysis including commonly used clinical parameters for prognosis (C-index=0.7; hazard ratio: 1.1; p=0.03). The retrospective design was a limitation. Change in BSI was significantly associated with OS in mCRPC patients undergoing AA treatment following disease progression in a postchemotherapy setting. BSI may be a useful imaging biomarker for outcome evaluation in this group of patients, and it could be a valuable complementary tool in monitoring patients with mCRPC on second-line therapies. Bone Scan Index (BSI) change is related to survival time in metastatic castration-resistant prostate cancer (mCRPC) patients on abiraterone acetate

  9. Exoftalmo unilateral por metástase orbitária de carcinoma de próstata Unilateral exophthalmos secondary to orbital metastatic carcinoma of the prostate: a case report

    Directory of Open Access Journals (Sweden)

    José Carlos Corrêa Barbosa

    1972-06-01

    Full Text Available É relatado um caso de exoftalmo ou proptose unilateral direita, causado por metástase orbitária de carcinoma da próstata em paciente negro, na 6.ª década de vida, com evolução de 9 meses. O exame neuro-ocular revelou acentuada diminuição da agudeza visual, perturbação para visão de cores, perda da convergência, diminuição dos reflexos à luz e acomodação e restrição dos movimentos oculares. O paciente apresentava discreta disbasia esquerda por metástase no fêmur. Exames laboratoriais, radiológicos e a biópsia confirmaram a etiologia carcinomatosa da manifestação ocular.A case of right unilateral exophthalmos secondary to metastatic carcinoma of the prostate, in a 68 years old negro patient in which the ocular manifestation lasted 9 months is reported The extrinsic movements of the eye were limited. Pupils reacted slightly to light and accommodation. There was no ocular convergence. The vision of the right eye was blurred and there was mild color vision. The prostate was found to be petrous by touch specially in the right portion. The laboratory findings pointed to a prostatic carcinoma. Bone X-rays were strongly suggestive of metastatic tumour. The histological examination of the orbital tumour showed prostatic tumour cells.

  10. Selective Activation of a Perforin-Granzyme B Fusion Protein Toxin by PSA as Therapy for Metastatic Prostate Cancer

    Science.gov (United States)

    2016-10-01

    SUPPLEMENTARY NOTES 14. ABSTRACT Protein toxins represent a class of agents that can kill cells in a proliferation independent manner. Many such...and kill non-proliferating prostate cancer could be highly effective in this disease. Protein toxins represent a class of agents that can kill cells...containing serum ( middle ) or media with serum and 1 uM GZMB (right) and incubated for 48 hours at 37 degrees. Magnification is 10X (A). Quantitation of

  11. High-Throughput Sequencing of Germline and Tumor From Men with Early-Onset Metastatic Prostate Cancer

    Science.gov (United States)

    2015-10-01

    molecularly profile both the initial prostate cancer (PR-259) and the liver biopsy which contained histologically-confirmed small cell/neuroendocrine...Therefore, we modified our approach to use archived FFPE biopsy and prostatectomy tumor specimen and to analyze these specimens using a qPCR...number alterations are indicated. 4 with small cell carcinoma of the liver and eventually succumbed from this disease approximately one year from

  12. Prostate cancer progression attributed to autonomic nerve development: Potential for therapeutic prevention of localized and metastatic disease

    OpenAIRE

    2013-01-01

    In a study recently published in Science, Magnon et al. show that both the sympathetic and parasympathetic components of the autonomic nervous system play an integral part in the development and dissemination of prostate cancer (PCa). Inhibition of the sympathetic nervous system (SNS) and disruption of the adrenergic receptors, specifically Ardβ2, resulted in the prevention of primary PCa tumor development in mice. The authors found that inhibition of the SNS is only successful in preventing ...

  13. Mapping FACT-P to EQ-5D in a large cross-sectional study of metastatic castration-resistant prostate cancer patients.

    Science.gov (United States)

    Diels, J; Hamberg, P; Ford, D; Price, P Wheatley; Spencer, M; Dass, R N

    2015-03-01

    To construct a model to predict preference-adjusted EuroQol 5D (EQ-5D) health utilities for patients with metastatic castrate-resistant prostate cancer (mCRPC) using the disease-specific health-related quality of life (HRQoL) measure, functional assessment of cancer therapy-prostate (FACT-P). HRQoL data were collected from patients with mCRPC who were enrolled in an observational study conducted in 47 centers across six European Union countries. Utility values were generated using a UK-specific EQ-5D value set. The predictive validity of the five FACT-P subscales, patient demographics, comorbidities and prior chemotherapy was tested using ordinary least squares (OLS), median, Gamma and Tobit multivariate regression models. FACT-P and EQ-5D questionnaires were completed by 602 (86 %) patients. Mean age [standard deviation (SD)] was 72.1 (7.9) years, mean time from diagnosis (SD) was 5.4 (4.4) years, and mean time since failure of androgen deprivation therapy (SD) was 1.0 (1.6) years. At study inclusion, 39 % of patients were chemotherapy-naïve, 37 % were undergoing chemotherapy, and 24 % were post-chemotherapy. Mean FACT-P and EQ-5D utility values were 104 and 0.66, respectively. OLS regression was the best-performing model, explaining 61.2 % of the observed EQ-5D variation. All FACT-P subscales were significantly predictive; the physical and functional well-being subscales had the highest explanatory value (coefficient 0.023 and 0.001, respectively, p < 0.0001). The other variables did not add additional explanatory value. The algorithm developed enables translation of cancer-specific HRQoL measures to preference-adjusted health status in patients with mCRPC. The function may be useful in calculating EQ-5D scores when EQ-5D data have not been gathered directly.

  14. A transient increase in eosinophils is associated with prolonged survival in men with metastatic castration-resistant prostate cancer who receive sipuleucel-T.

    Science.gov (United States)

    McNeel, Douglas G; Gardner, Thomas A; Higano, Celestia S; Kantoff, Philip W; Small, Eric J; Wener, Mark H; Sims, Robert B; DeVries, Todd; Sheikh, Nadeem A; Dreicer, Robert

    2014-10-01

    Sipuleucel-T is an autologous cellular immunotherapy used to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). Traditional short-term indicators of clinical response commonly used with chemotherapy have not correlated with survival in patients treated with sipuleucel-T. This retrospective study aimed to evaluate laboratory parameters as possible early biomarkers associated with clinical benefit following sipuleucel-T treatment. Patients treated with sipuleucel-T from three randomized, controlled, phase III clinical trials in mCRPC were considered: IMPACT (NCT00065442; n = 512), D9901 (NCT00005947; n = 127), and D9902A (NCT01133704; n = 98). Patients from these trials were included in this study if their samples were analyzed by the central laboratory and if data were available from baseline and ≥ 1 posttreatment time point (n = 377). We found that sipuleucel-T treatment was associated with a transient increase in serum eosinophil count at week 6 that resolved by week 14 in 28% of patients (105 of 377). This eosinophil increase correlated with induced immune response, longer prostate cancer-specific survival [HR, 0.713; 95% confidence interval (CI), 0.525-0.970; P = 0.031], and a trend in overall survival (HR, 0.753; 95% CI, 0.563-1.008; P = 0.057). Median serum globulin protein levels also increased transiently, which was associated with antigen-specific antibody responses; however, this finding did not correlate with longer survival. We conclude that transient increases in eosinophils at week 6 may be a useful, objective, short-term indicator of global immune activation and survival benefit with sipuleucel-T in patients with mCRPC. This observation warrants prospective evaluation in future clinical trials.

  15. miR-9 Acts as an OncomiR in Prostate Cancer through Multiple Pathways That Drive Tumour Progression and Metastasis.

    Directory of Open Access Journals (Sweden)

    S J Seashols-Williams

    Full Text Available Identification of dysregulated microRNAs (miRNAs in prostate cancer is critical not only for diagnosis, but also differentiation between the aggressive and indolent forms of the disease. miR-9 was identified as an oncomiR through both miRNA panel RT-qPCR as well as high-throughput sequencing analysis of the human P69 prostate cell line as compared to its highly tumorigenic and metastatic subline M12, and found to be consistently upregulated in other prostate cell lines including DU-145 and PC3. While miR-9 has been characterized as dysregulated either as an oncomiR or tumour suppressor in a variety of other cancers including breast, ovarian, and nasopharyngeal carcinomas, it has not been previously evaluated and proven as an oncomiR in prostate cancer. miR-9 was confirmed an oncomiR when found to be overexpressed in tumour tissue as compared to adjacent benign glandular epithelium through laser-capture microdissection of radical prostatectomy biopsies. Inhibition of miR-9 resulted in reduced migratory and invasive potential of the M12 cell line, and reduced tumour growth and metastases in male athymic nude mice. Analysis showed that miR-9 targets e-cadherin and suppressor of cytokine signalling 5 (SOCS5, but not NF-ĸB mRNA. Expression of these proteins was shown to be affected by modulation in expression of miR-9.

  16. Quality of life and pain relief in men with metastatic castration-resistant prostate cancer on cabazitaxel: the non-interventional 'QoLiTime' study.

    Science.gov (United States)

    Hofheinz, Ralf-Dieter; Lange, Carsten; Ecke, Thorsten; Kloss, Susanne; Linsse, Burkhard; Windemuth-Kieselbach, Christine; Hammerer, Peter; Al-Batran, Salah-Eddin

    2017-05-01

    To examine health-related quality of life (QoL) in men with metastatic castration-resistant prostate cancer (mCRPC) on cabazitaxel. Men with mCRPC receiving cabazitaxel (25 mg/m², every 3 weeks) and 10 mg/day oral prednis(ol)one were enrolled (2011-2014) in the non-interventional prospective 'QoLiTime' study. Primary outcome was change in QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 30-item) with respect to prostate-specific antigen (PSA) response after four cycles of cabazitaxel. Secondary outcomes included occurrence of adverse events (AEs). Of 527 men, 348 received four cycles of cabazitaxel and 266 had the necessary PSA level measurements. After four cycles, 92 (34.6%) men had a PSA level decrease ≥50% (responders). QoL remained stable throughout the study (P = 0.62). Change in QoL did not differ between responders and non-responders (P = 0.69). Change in PSA level and global health status between baseline and four cycles showed an inversely proportional relationship (correlation coefficient -0.14; 95% confidence interval -0.26 to -0.01; P = 0.03), with increasing PSA level corresponding to lower health status. Responders showed no change in physical functioning vs baseline (-1.75, P = 0.12); non-responders showed a reduction vs baseline (-7.00, P < 0.001) and responders (P = 0.05). Responders showed an improvement in pain vs baseline (-7.61, P = 0.05) and vs non-responders (P = 0.01). AEs occurred in 292 patients (55.4%), most commonly anaemia (16.5%), fatigue (12.3%) and diarrhoea (11.8%). Neutropenia and febrile neutropenia were reported in 3.8% and 3.6% of patients, respectively. Prostate-specific antigen level response was associated with stable physical functioning and improvement in pain. Symptom increases were seen in areas typical of chemotoxicity, but QoL was maintained. © 2016 The Authors BJU International © 2016 BJU International Published by John Wiley & Sons Ltd.

  17. Devising and external validation of a prognostic classification of metastatic involvement risk to pelvic lymph nodes in patients with newly diagnosed prostate cancer

    Directory of Open Access Journals (Sweden)

    E. A. Leusik

    2015-01-01

    Full Text Available Objective – assessing the predictive significance of clinical, histologic and biochemical factors for prediction of metastases in pelvic lymph nodes (MPLN, devising and validating of prognostic classification.Materials and methods. The study enrolled 1140 patients subjected to radical prostatectomy (RPE with standard pelvic lymphadenectomy for prostate adenocarcinoma: 865 of them at the classification devising stage and 275 in the course of validation.Results. According to the findings of multivariate logistic regression analysis, PSA level, the tumor cT stage and Gleason score are independent predictors of MPLN detection after RPE (p < 0.05. The prognostic factors were stratified by score for assessing the detection of regional metastases after RPE, depending on the combination of predictors. In the group of patients with a score estimate of prognostic factors < 10, the MPLN detection rate was significantly lower than in the group of with a score estimate > 15, accounting for 3.5 % and 23.7 % respectively (р < 0.0001. In the course of validating the obtained findings in clinic, metastatic involvement of pelvic lymph nodes found in the result of RPE was diagnosed in 40.0 % of the patients with a score estimate > 15 and only in 1.3 % of those with a total estimate of prognostic factors < 10 (р < 0.0001.

  18. The Role of the Neutrophil to Lymphocyte Ratio for Survival Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone.

    Science.gov (United States)

    Boegemann, Martin; Schlack, Katrin; Thomes, Stefan; Steinestel, Julie; Rahbar, Kambiz; Semjonow, Axel; Schrader, Andres Jan; Aringer, Martin; Krabbe, Laura-Maria

    2017-02-11

    The purpose of this study was to examine the prognostic capability of baseline neutrophil-to-lymphocyte-ratio (NLR) and NLR-change under Abiraterone in metastatic castration-resistant prostate cancer patients. The impact of baseline NLR and change after eight weeks of treatment on progression-free survival (PFS) and overall survival (OS) was analyzed using Kaplan-Meier-estimates and Cox-regression. 79 men with baseline NLR 5 were analyzed. In baseline analysis of PFS NLR >5 was associated with non-significantly shorter median PFS (five versus 10 months) (HR: 1.6 (95%CI:0.9-2.8); p = 0.11). After multivariate adjustment (MVA), ECOG > 0-1, baseline LDH>upper limit of normal (UNL) and presence of visceral metastases were independent prognosticators. For OS, NLR >5 was associated with shorter survival (seven versus 19 months) (HR: 2.3 (95%CI:1.3-4.0); p 0-1 and baseline LDH > UNL remained independent prognosticators. After 8 weeks of Abiraterone NLR-change to change to change to 5, NLR-change to <5 after eight weeks of Abiraterone was associated with worse survival and should be interpreted carefully.

  19. Changes in skeletal tumor activity on {sup 18}F-choline PET/CT in patients receiving {sup 223}radium radionuclide therapy for metastatic prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Miyazaki, Kyle S. [Oncology Research Dept. and Hamamatsu/Queen' s PET Imaging Center, The Queen' s Medical Center, Honolulu (United States); Kang, Yu; Kwee, Sandi A. [Dept. of Medical Physics, School of Allied Health Sciences, University of Nevada Las Vegas, Las Vegas (United States)

    2015-06-15

    Radium-223 dichloride is an alpha-emitting radiopharmaceutical shown to prolong survival in patients with castrate-resistant prostate cancer (CRPC) and symptomatic skeletal metastases. This report describes in two patients the acute changes in bone metastatic activity detected by F-18 choline PET/CT imaging midway during treatment with radium-223 dichloride. In addition to visual and standardized uptake value analysis, changes in the whole-body tumor burden were quantified by measuring the difference in net metabolically active tumor volume (MATV) and total lesion activity (TLA) between pre- and mid-treatment PET scans. After the third dose of radium-223 dichloride, near-total disappearance of abnormal skeletal activity was observed in one case (net MATV change from 260.7 to 0.8 cc; net TLA change from 510.7 to 2.1), while a heterogeneous tumor response was observed in the other (net MATV change from 272.2 to 241.3 cc; net TLA change from 987.1 to 779.4). Corresponding normalization and persistent elevation in serum alkaline phosphatase levels were observed in these cases, respectively. Further research is needed to determine the predictive value of serial F-18 choline PET/CT imaging in patients receiving radium-223 dichloride for CRPC.

  20. Immunotherapy with Sipuleucel-T (APC8015 in patients with metastatic castration-refractory prostate cancer (mCRPC: a systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Tobias Engel Ayer Botrel

    2012-12-01

    Full Text Available Objective To perform a systematic review and meta-analysis of all randomized controlled trials comparing the efficacy of Sipuleucel-T versus placebo for asymptomatic or minimally symptomatic metastatic castration-refractory prostate cancer (mCRPC. Materials ans Methods Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The endpoints were overall survival (OS, time to progression (TTP and side effects. We performed a meta-analysis (MA of the published data. The results are expressed as Hazard Ratio (HR or Risk Ratio (RR, with their corresponding 95% confidence intervals (CI 95%. Results The final analysis included 3 trials comprising 737 patients. The TTP was similar in patients who received Sipuleucel-T or placebo (fixed effect: HR = 0.89; CI 95% = 0.75 to 1.05; p = 0.16, with no heterogeneity detected on this analysis (Chi2 = 2.14, df = 2 (P = 0.34; I2 = 6%. The results showed a higher overall survival in patients treated with Sipuleucel-T (fixed effect: HR = 0.74; CI 95% = 0.61 to 0.89; p = 0.001; NNT = 3. We found no heterogeneity on this analysis either (Chi2 = 1.46, df = 2 (P = 0.48; I2 = 0%. The incidence of adverse events (grade > 3 was the same in both groups. Conclusion Sipuleucel-T prolongs overall survival in patients with asymptomatic or minimally symptomatic mCRPC.

  1. The Role of the Neutrophil to Lymphocyte Ratio for Survival Outcomes in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Abiraterone

    Science.gov (United States)

    Boegemann, Martin; Schlack, Katrin; Thomes, Stefan; Steinestel, Julie; Rahbar, Kambiz; Semjonow, Axel; Schrader, Andres Jan; Aringer, Martin; Krabbe, Laura-Maria

    2017-01-01

    The purpose of this study was to examine the prognostic capability of baseline neutrophil-to-lymphocyte-ratio (NLR) and NLR-change under Abiraterone in metastatic castration-resistant prostate cancer patients. The impact of baseline NLR and change after eight weeks of treatment on progression-free survival (PFS) and overall survival (OS) was analyzed using Kaplan-Meier-estimates and Cox-regression. 79 men with baseline NLR 5 were analyzed. In baseline analysis of PFS NLR >5 was associated with non-significantly shorter median PFS (five versus 10 months) (HR: 1.6 (95%CI:0.9–2.8); p = 0.11). After multivariate adjustment (MVA), ECOG > 0–1, baseline LDH>upper limit of normal (UNL) and presence of visceral metastases were independent prognosticators. For OS, NLR >5 was associated with shorter survival (seven versus 19 months) (HR: 2.3 (95%CI:1.3–4.0); p 0–1 and baseline LDH > UNL remained independent prognosticators. After 8 weeks of Abiraterone NLR-change to 5, NLR-change to <5 after eight weeks of Abiraterone was associated with worse survival and should be interpreted carefully. PMID:28208664

  2. Phase I clinical trial of sipuleucel-T combined with escalating doses of ipilimumab in progressive metastatic castrate-resistant prostate cancer

    Directory of Open Access Journals (Sweden)

    Scholz M

    2017-03-01

    Full Text Available Mark Scholz,1 Sabrina Yep,1 Micah Chancey,1 Colleen Kelly,1 Ken Chau,1 Jeffrey Turner,1 Richard Lam,1 Charles G Drake,2,3 1Prostate Oncology Specialists, Inc., Marina del Rey, CA, 2The Sidney Kimmel Cancer Center, 3The James Buchanan Brady Urological Institute, John Hopkins Medical Institutions, Baltimore, MD, USA Background: Sipuleucel-T (SIP-T, which functions by stimulating cancer-specific dendritic cells, prolongs survival in men with prostate cancer. Ipilimumab (IPI achieved a borderline survival advantage in a large randomized trial. SIP-T and IPI are potentially synergistic. Patients and Methods: Nine men with progressive metastatic castrate-resistant prostate cancer (mCRPC were treated prospectively with SIP-T followed immediately by IPI with one of the following doses of IPI: 1 mg/kg at 1 week after SIP-T; 1 mg/kg at 1 and 4 weeks after SIP-T; or 1 mg/kg at 1, 4, and 7 weeks after SIP-T. Three patients were evaluated at each level. Cancer-specific immunoglobulins directed at granulocyte-macrophage-colony-stimulating factor/prostatic acid phosphatase (PAP fusion protein (PA2024 and PAP were measured prior to SIP-T, after SIP-T, 1 week after IPI, every other month for 5 months, then every 3 months for an additional 12 months. Results: Adverse events of SIP-T were consistent with previous reports. IPI only caused a transient grade 1 rash in one patient. Median age, Gleason score, and number of previous hormonal interventions were 77 years, 8, and 3, respectively. Eight men had bone metastases and one had lymph node metastasis. Statistically significant increases in serum immunoglobulin G (IgG and IgG-IgM specific for PA2024 and PAP occurred after SIP-T. An additional statistically significant increase in the aforementioned immunoglobulins – above the levels achieved by SIP-T – occurred after IPI. Median clinical follow-up was 36 months (range: 26–40. Three patients died from progressive disease after 9, 18, and 20 months. Out of the

  3. Sipuleucel-T for the Treatment of Metastatic Hormone-Relapsed Prostate Cancer: A NICE Single Technology Appraisal; An Evidence Review Group Perspective.

    Science.gov (United States)

    Simpson, Emma L; Davis, Sarah; Thokala, Praveen; Breeze, Penny R; Bryden, Peter; Wong, Ruth

    2015-11-01

    The National Institute for Health and Care Excellence (NICE) invited Dendreon, the company manufacturing sipuleucel-T, to submit evidence for the clinical and cost effectiveness of sipuleucel-T for asymptomatic or minimally symptomatic, metastatic, non-visceral hormone-relapsed prostate cancer patients in whom chemotherapy is not yet clinically indicated, as part of NICE's single technology appraisal process. The comparator was abiraterone acetate (AA) or best supportive care (BSC). The School of Health and Related Research at the University of Sheffield was commissioned to act as the Evidence Review Group (ERG). This paper describes the company submission (CS), ERG review, and subsequent decision of the NICE Appraisal Committee (AC). The ERG produced a critical review of the clinical and cost-effectiveness evidence of sipuleucel-T based upon the CS. Clinical-effectiveness data relevant to the decision problem were taken from three randomised controlled trials (RCTs) of sipuleucel-T and a placebo (PBO) comparator of antigen-presenting cells (APC) being re-infused (APC-PBO) (D9901, D9902A and D9902B), and one RCT (COU-AA-302) of AA plus prednisone vs. PBO plus prednisone. Two trials reported a significant advantage for sipuleucel-T in median overall survival compared with APC-PBO: for trial D9901, an adjusted hazard ratio (HR) 0.47; (95 % confidence interval [CI] 0.29, 0.76) p Sipuleucel-T and APC-PBO groups did not differ significantly in time to disease progression, in any of the three RCTs. Most adverse events developed within 1 day of the infusion, and resolved within 2 days. The CS included an indirect comparison of sipuleucel-T (D9902B) and AA plus prednisone (COU-AA-302). As trials differed in prior use of chemotherapy, an analysis of only chemotherapy-naïve patients was included, in which the overall survival for sipuleucel-T and AA was not significantly different, HR 0.94 (95 % CI 0.69, 1.28) p = 0.699. The ERG had several concerns regarding the data and

  4. The Genomic Evolution of Prostate Cancer

    Science.gov (United States)

    2015-10-01

    addition, multiple genetic alterations are associated with disease evolution in response to therapy. This project aims to characterize evolution of...of castrate resistant metastatic cancer from primary foci. 15. SUBJECT TERMS Cancer genetics , tumor evolution , tumor heterogeneity, prostate cancer...progression of localized prostate cancer to metastatic disease. Keywords Cancer genetics , tumor evolution , tumor heterogeneity, prostate cancer

  5. Prostatic melanosis

    Directory of Open Access Journals (Sweden)

    Kemal DENİZ

    2007-09-01

    Full Text Available Prostatic melanosis is a rare lesion that is characterized by melanin-containing spindle cells mainly located in the stroma of the prostate gland. This lesion is certainly benign and not a precursor of malignant melanoma. However, differential diagnosis of melanosis with primary and metastatic malignant melanoma is extremely important because of the different biological nature and clinical behavior of these two entities. Recognition of the spectrum of pigmented lesions in the prostate gland is essential to take into consideration of the diagnosis of melanocytic lesions.In this paper, a case of melanosis

  6. {sup 18}F-Fluorocholine PET/CT for early response assessment in patients with metastatic castration-resistant prostate cancer treated with enzalutamide

    Energy Technology Data Exchange (ETDEWEB)

    De Giorgi, Ugo; Conteduca, Vincenza; Burgio, Salvatore Luca; Menna, Cecilia; Rossi, Lorena; Amadori, Dino [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Department of Medical Oncology, Meldola (Italy); Caroli, Paola; Paganelli, Giovanni; Matteucci, Federica [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Diagnostic Nuclear Medicine Unit, Meldola (Italy); Scarpi, Emanuela [Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Unit of Biostatistics and Clinical Trials, Meldola (Italy); Moretti, Andrea; Galassi, Riccardo [Morgagni-Pierantoni Hospital, Nuclear Medicine Unit, Forli (Italy)

    2015-07-15

    We investigated the role of {sup 18}F-methylcholine (FCH) PET/CT in the early evaluation of patients with metastatic castration-resistant prostate cancer (mCRPC) treated with enzalutamide. The study group comprised 36 patients with a median age of 72 years (range 48-90 years) who were treated with enzalutamide 160 mg once daily after at least one chemotherapeutic regimen with docetaxel. Patients were evaluated monthly for serological prostate-specific antigen (PSA) response. FCH PET/CT was performed at baseline and repeated after 3-6 weeks. Univariate and multivariate Cox regression models addressed potential predictors of progression-free survival (PFS) and overall survival (OS). At a median follow-up of 24.2 months (range 1.8-27.3 months), 34 patients were evaluable for early FCH PET/CT evaluation of response, and of these 17 showed progressive disease (PD) and 17 had stable disease or a partial response. A decrease in PSA level of more than 50 % was observed in 21 patients. Early FCH PET/CT PD predicted radiological PD 3 months in advance of CT in 12 of 18 patients (66 %) and was discordant with the decrease in PSA level in 13 patients. In 6 of these, biochemical PD was confirmed in 2 months. In multivariate analysis, only decrease in PSA level and FCH PET/CT were significant predictors of PFS (p = 0.0005 and p = 0.029, respectively), whereas decrease in PSA level alone was predictive of OS (p = 0.007). This is one of the first studies to evaluate the role of FCH PET/CT as an early predictor of outcome in mCRPC patients treated with enzalutamide. Our preliminary results suggest that the combination of FCH PET/CT and decrease in PSA level could be a valid tool to predict PFS in mCRPC patients. PSA remains the single most important prognostic factor, while FCH PET/CT does not add more information on OS beyond that obtained from PSA. Further studies in larger populations are needed to confirm these data and to clarify the role of FCH PET/CT in predicting response

  7. Automated Bone Scan Index as a quantitative imaging biomarker in metastatic castration-resistant prostate cancer patients being treated with enzalutamide.

    Science.gov (United States)

    Anand, Aseem; Morris, Michael J; Larson, Steven M; Minarik, David; Josefsson, Andreas; Helgstrand, John T; Oturai, Peter S; Edenbrandt, Lars; Røder, Martin Andreas; Bjartell, Anders

    2016-12-01

    Having performed analytical validation studies, we are now assessing the clinical utility of the upgraded automated Bone Scan Index (BSI) in metastatic castration-resistant prostate cancer (mCRPC). In the present study, we retrospectively evaluated the discriminatory strength of the automated BSI in predicting overall survival (OS) in mCRPC patients being treated with enzalutamide. Retrospectively, we included patients who received enzalutamide as a clinically approved therapy for mCRPC and had undergone bone scan prior to starting therapy. Automated BSI, prostate-specific antigen (PSA), hemoglobin (HgB), and alkaline phosphatase (ALP) were obtained at baseline. Change in automated BSI and PSA were obtained from patients who have had bone scan at week 12 of treatment follow-up. Automated BSI was obtained using the analytically validated EXINI Bone(BSI) version 2. Kendall's tau (τ) was used to assess the correlation of BSI with other blood-based biomarkers. Concordance index (C-index) was used to evaluate the discriminating strength of automated BSI in predicting OS. Eighty mCRPC patients with baseline bone scans were included in the study. There was a weak correlation of automated BSI with PSA (τ = 0.30), with HgB (τ = -0.17), and with ALP (τ = 0.56). At baseline, the automated BSI was observed to be predictive of OS (C-index 0.72, standard error (SE) 0.03). Adding automated BSI to the blood-based model significantly improved the C-index from 0.67 to 0.72, p = 0.017. Treatment follow-up bone scans were available from 62 patients. Both change in BSI and percent change in PSA were predictive of OS. However, the combined predictive model of percent PSA change and change in automated BSI (C-index 0.77) was significantly higher than that of percent PSA change alone (C-index 0.73), p = 0.041. The upgraded and analytically validated automated BSI was found to be a strong predictor of OS in mCRPC patients. Additionally, the change in automated BSI

  8. Androgen receptor (AR) expression in AR-negative prostate cancer cells results in differential effects of DHT and IGF-I on proliferation and AR activity between localized and metastatic tumors.

    Science.gov (United States)

    Plymate, Stephen R; Tennant, Marie K; Culp, Stephen H; Woodke, Lillie; Marcelli, Marco; Colman, Ilsa; Nelson, Peter S; Carroll, Julie M; Roberts, Charles T; Ware, Joy L

    2004-11-01

    Two features of the progression from organ-confined to metastatic prostate cancer are dysregulation of the androgen receptor (AR) and a decrease in insulin-like growth factor-type-I receptor (IGF-IR) expression. The purpose of this study was to determine the effect of changes in IGF-IR expression on AR activity. M12 human prostate cells were stably transfected with an AR expression construct to produce the M12-AR parental (PAR) cell line. PAR cells were implanted orthotopically into nude mice and M12-AR primary (PRI) cell lines were derived from intraprostatic tumors and metastatic cell lines (MET) were derived from PRI tumors that had metastasized to diaphragm or lung. Tumor formation in the prostate by PAR cells was decreased significantly compared to M12 controls. PAR, PRI, and MET cells expressed equivalent amounts of AR protein; however, IGF-IR expression was increased significantly in PAR and PRI cells. IGF-IR expression decreased in MET lines to the levels seen in M12 control cells. IGF-I significantly enhanced dihydrotestosterone (DHT)-stimulated, but not basal, AR transcriptional activity in PRI cells. In MET cells, IGF-I significantly suppressed DHT-stimulated transcriptional activity. In MET cells in which the IGF-IR was re-expressed from a retroviral vector, the effects of DHT and IGF-I on AR activity were similar to those seen in PRI cells. This study demonstrates that the changes in IGF-IR expression exhibited by this model of metastatic progression cause significant alterations in AR signaling and suggest that this interaction may be an important aspect of the changes seen in AR function in disease progression in vivo. 2004 Wiley-Liss, Inc.

  9. Prostate cancer progression attributed to autonomic nerve development: potential for therapeutic prevention of localized and metastatic disease.

    Science.gov (United States)

    Fernández, Elena V; Price, Douglas K; Figg, William D

    2013-11-01

    In a study recently published in Science, Magnon et al. show that both the sympathetic and parasympathetic components of the autonomic nervous system play an integral part in the development and dissemination of prostate cancer (PCa). Inhibition of the sympathetic nervous system (SNS) and disruption of the adrenergic receptors, specifically Ardβ 2, resulted in the prevention of primary PCa tumor development in mice. The authors found that inhibition of the SNS is only successful in preventing murine tumor development if completed early enough, and the parasympathetic nervous system (PNS) predominates in later stages of PCa. Inhibition of the PNS by way of the cholinergic receptor, muscarinic 1 (Chrm1), caused mice to develop less metastases to the pelvic lymph nodes, intestines, and bones. A PCa progression scheme has been outlined where initial tumor engraftment is controlled by the SNS but then becomes less prominent than the PNS, which promotes metastasis. The investigators showed the dependence of the autonomic nervous system on development of PCa and present opportunities for prevention; further studies are needed to confirm these results in humans.

  10. Preliminary study of the specific endothelin a receptor antagonist zibotentan in combination with docetaxel in patients with metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Trump, Donald L; Payne, Heather; Miller, Kurt; de Bono, Johann S; Stephenson, Joe; Burris, Howard A; Nathan, Faith; Taboada, Maria; Morris, Thomas; Hubner, Andreas

    2011-09-01

    This two-part study assessed the safety and tolerability of combined treatment with zibotentan (ZD4054), a specific endothelin A receptor antagonist, plus docetaxel in patients with metastatic castration-resistant prostate cancer. Part A was an open-label, dose-finding phase to determine the safety and toxicity profile of zibotentan in combination with docetaxel. Patients received once-daily oral zibotentan 10 mg (initial cohort) or 15 mg in combination with docetaxel 75 mg/m(2) (administered on day 1 of each 21-day cycle) for up to 10 cycles. Part B was a double-blind phase which evaluated the safety and preliminary activity of zibotentan plus docetaxel. Patients were randomized 2:1 to receive zibotentan (at the highest tolerated dose identified in part A) plus docetaxel or placebo plus docetaxel. Six patients were enrolled in part A (n  = 3, zibotentan 10 mg; n = 3, zibotentan 15 mg). No dose-limiting toxicity was observed, thus zibotentan 15 mg in combination with docetaxel was evaluated in part B (n = 20, zibotentan plus docetaxel; n = 11, placebo plus docetaxel). CTCAE grade ≥3, most commonly neutropenia or leucopenia, were reported in 10 (50%) and nine (82%) patients in the zibotentan and placebo groups, respectively. One (17%) patient receiving placebo achieved complete response, two (22%) patients receiving zibotentan achieved partial response and stable disease occurred in six (67%) and three (50%) patients receiving zibotentan and placebo, respectively. The tolerability of zibotentan plus docetaxel was consistent with the known profiles of each drug. Sufficient preliminary activity was seen with this combination to merit continued development. Copyright © 2011 Wiley-Liss, Inc.

  11. Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study.

    Science.gov (United States)

    Beer, Tomasz M; Armstrong, Andrew J; Rathkopf, Dana; Loriot, Yohann; Sternberg, Cora N; Higano, Celestia S; Iversen, Peter; Evans, Christopher P; Kim, Choung-Soo; Kimura, Go; Miller, Kurt; Saad, Fred; Bjartell, Anders S; Borre, Michael; Mulders, Peter; Tammela, Teuvo L; Parli, Teresa; Sari, Suha; van Os, Steve; Theeuwes, Ad; Tombal, Bertrand

    2017-02-01

    Enzalutamide significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) among men with chemotherapy-naïve metastatic castration-resistant prostate cancer at the prespecified interim analysis of PREVAIL, a phase 3, double-blind, randomized study. We evaluated the longer-term efficacy and safety of enzalutamide up to the prespecified number of deaths in the final analysis, which included an additional 20 mo of follow-up for investigator-assessed rPFS, 9 mo of follow-up for OS, and 4 mo of follow-up for safety. Enzalutamide reduced the risk of radiographic progression or death by 68% (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.28-0.37; p<0.0001) and the risk of death by 23% (HR 0.77, 95% CI 0.67-0.88; p=0.0002). Median investigator-assessed rPFS was 20.0 mo (95% CI 18.9-22.1) in the enzalutamide arm and 5.4 mo (95% CI 4.1-5.6) in the placebo arm. Median OS was 35.3 mo (95% CI 32.2-not yet reached) in the enzalutamide arm and 31.3 mo (95% CI 28.8-34.2) in the placebo arm. At the time of the OS analysis, 167 patients in the placebo arm had crossed over to receive enzalutamide. The most common adverse events in the enzalutamide arm were fatigue, back pain, constipation, and arthralgia. This final analysis of PREVAIL provides more complete assessment of the clinical benefit of enzalutamide. PREVAIL is registered on ClinicalTrials.gov as NCT01212991.

  12. 转移性去势抵抗性前列腺癌化疗后预后的影响因素%Factors Influencing Prognosis of Metastatic Castration-resistant Prostate Cancer after Chemotherapy

    Institute of Scientific and Technical Information of China (English)

    庞华

    2014-01-01

    Objective To investigate prognostic factors of metastatic castration-resistant prostate cancer ( mCRPC ) trea-ted with docetaxel chemotherapy .Methods Age,Gleason score ,prostate-specific antigen ,blood baseline condition and hormone-sensitive time of 46 patients with mCRPC were recorded .Results Overall survival time of all patients was 3-45 months,the aver-age survival time was (21.34 ±2.13) months,median survival time was 19.36 months;cox regression analysis showed that Glea-son score,hemoglobin,hormone-sensitive time were related with the patient's survival time,RR values were 1.782,2.363 and 2.012,and P<0.05.Conclusion Gleason score,hemoglobin concentration ,and hormone-sensitive time before chemotherapy are prognostic factors of metastatic castration resistant prostate cancer .%目的:探讨采用多西紫杉醇化疗的转移性去势抵抗性前列腺癌( metastatic castration-resistant prostate canc-er,MCRPC)患者预后影响因素。方法以转移性去势抵抗性前列腺癌患者46例作为观察对象,记录患者化疗前年龄、Gleason评分、前列腺特异抗原(prostate-specific antigen,PSA)值、血常规等基线情况及激素敏感时间。结果患者总生存时间为3~45个月,平均生存期为(21.34±2.13)个月,中位生存时间为19.36个月;Cox回归结果提示,Gleason评分、血红蛋白水平、激素敏感时间与患者生存时间相关,RR值分别为1.782、2.363和2.012,且P<0.05。结论多西他赛化疗前Gleason评分、血红蛋白浓度及激素敏感时间,是转移性去势抵抗性前列腺癌患者的预后因素。

  13. 雄激素非依赖性晚期转移性前列腺癌生存预后分析%The survival analysis of the advanced metastatic castration-resistant prostate cancer

    Institute of Scientific and Technical Information of China (English)

    马春光; 施国海; 秦晓健; 林国文; 杨立峰; 杨柏帅; 肖文军; 叶定伟; 姚旭东; 张世林; 戴波; 张海梁; 朱耀; 沈益君; 朱一平

    2009-01-01

    目的 分析雄激素非依赖性晚期转移性前列腺癌的预后相关因素.方法 1996年12月至2008年3月250例晚期转移性前列腺癌患者在内分泌治疗期间进展为雄激素非依赖性前列腺癌,对其进行随访,末次随访时间为2008年3月31日,中位随访时间为24个月(3~135个月).末次随访时131例生存,105例死亡,14例失访.利用统计学软件进行生存预后分析.结果 中位生存时间为30个月.1年牛存率79%,2年生存率59%,3年生存率41%.单因素分析及多因素分析显示:内分泌治疗过程中PSA最低值、达到PSA最低值时间、进展为雄激素非依赖性前列腺癌时PSA速率、内分泌治疗有效时间为独立预后冈素.结论 内分泌治疗过程中PSA最低值、达到PSA最低值时间、进展为雄激素非依赖性前列腺癌时的PSA速率和内分泌治疗有效时间为雄激素非依赖性晚期转移性前列腺癌生存时间的独立预后因素.%Objective To analyze predictive factors of advanced metastatic castration-resistant prostate cancer.Methods From December 1996 to March 2008,250 cases of advanced metastatic prostate cancer progressed into the stage of hormonal independent prostate cancer.The last follow-up date was 31 March 2008 and the median follow-up time was 24 months.During the follow-up,131 cases were alive,105cases were dead and 14 cases were lost to follow-up.Clinical and pathological information of the cases was analyzed to find the predictive factors that related to the prognosis.Results The median survival time of advanced metastatic castration-resistant prostate cancer was 30 months,and the one-year,two-year,three-year survival rate was 79%,59%,and 41%.The univariate analysis indicated that prostate specific antigen (PSA) at diagnosis,clinical stage,the PSA nadir during hormonal therapy,the time form the start of hormonal therapy to the PSA nadir,the time of response duration during hormonal therapy,PSA velocity (PSAV) and PSA doubling

  14. ERK and AKT signaling drive MED1 overexpression in prostate cancer in association with elevated proliferation and tumorigenicity.

    Science.gov (United States)

    Jin, Feng; Irshad, Shazia; Yu, Wei; Belakavadi, Madesh; Chekmareva, Marina; Ittmann, Michael M; Abate-Shen, Cory; Fondell, Joseph D

    2013-07-01

    MED1 is a key coactivator of the androgen receptor (AR) and other signal-activated transcription factors. Whereas MED1 is overexpressed in prostate cancer cell lines and is thought to coactivate distinct target genes involved in cell-cycle progression and castration-resistant growth, the underlying mechanisms by which MED1 becomes overexpressed and its oncogenic role in clinical prostate cancer have remained unclear. Here, we report that MED1 is overexpressed in the epithelium of clinically localized human prostate cancer patients, which correlated with elevated cellular proliferation. In a Nkx3.1:Pten mutant mouse model of prostate cancer that recapitulates the human disease, MED1 protein levels were markedly elevated in the epithelium of both invasive and castration-resistant adenocarcinoma prostate tissues. Mechanistic evidence showed that hyperactivated ERK and/or AKT signaling pathways promoted MED1 overexpression in prostate cancer cells. Notably, ectopic MED1 overexpression in prostate cancer xenografts significantly promoted tumor growth in nude mice. Furthermore, MED1 expression in prostate cancer cells promoted the expression of a number of novel genes involved in inflammation, cell proliferation, and survival. Together, these findings suggest that elevated MED1 is a critical molecular event associated with prostate oncogenesis.

  15. Dying for love: Perimenopausal degeneration of vaginal microbiome drives the chronic inflammation-malignant transformation of benign prostatic hyperplasia to prostatic adenocarcinoma.

    Science.gov (United States)

    Reece, Albert Stuart

    2017-04-01

    Prostatic carcinoma is the second commonest cancer in males and is so common as to become almost holoendemic with advancing age. The recent demonstration that far from being benign, "benign" prostatic hypertrophy is a likely a reaction of the prostate to chronic untreated lower genital tract infection, and that this chronic inflammation is likely the usual precursor to the frequent occurrence of prostatic carcinoma has far reaching implications. The obvious source for the chronic inflammatory stimulus in the prostate is the documented dramatically altered lower female genital microbiota associated with the menopause. Hence the major hypothesis is that prostatic cancer may arise due to chronic infection and inflammation in the prostate gland consequent upon the altered microbiome of the menopausal female genital tract. This has implications for testing and diagnosis, treatment, population health and personal hygiene practices. It suggests that male dyspareunia, although almost never encountered in clinical practice may in fact be relatively common in older males, and in particular if diagnosed, represents a critical opportunity for therapeutic intervention to interrupt the chronic inflammation - cancer transformation and progression which has been well documented in other tissues. It implies that the coordinated application of next generation sequencing to the microbiome of the lower genital tracts of male and female couples, including seminal fluid, will have both research applications to further explore this sequence, as well as finding application as a potential population level screening procedure as is presently done for the "Thin Prep" cervical screening for human papillomavirus in females. Moreover this insight opens up new opportunities for chemointervention and chemoprevention for this important clinicopathological progression. These considerations give rise to the exciting possibility that prostatic malignancy may be preventable by various methods of local

  16. {sup 177}Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer: safety, efficacy, and quality of life assessment

    Energy Technology Data Exchange (ETDEWEB)

    Yadav, Madhav Prasad; Ballal, Sanjana; Tripathi, Madhavi; Damle, Nishikant Avinash; Bal, Chandrasekhar [All India Institute of Medical Sciences, Department of Nuclear Medicine, Ansari Nagar, New Delhi (India); Sahoo, Ranjit Kumar [All India Institute of Medical Sciences, Department of Medical Oncology, BR Ambedkar Rotary Cancer Hospital, New Delhi (India); Seth, Amlesh [All India Institute of Medical Sciences, Department of Urology, New Delhi (India)

    2017-01-15

    The purpose of this study was to evaluate the efficacy and safety of a novel theranostic agent, {sup 177}Lu-DKFZ-PSMA-617 therapy in metastatic castration resistant prostate cancer (mCRPC). Thirty-one mCRPC patients with progressive disease despite second-line hormonal therapy and/or docetaxel chemotherapy were recruited for the study. All patients underwent diagnostic{sup 68}Ga-PSMA-HBED-CCPET/CT, prior to inclusion for therapy. Included patients then underwent quarterly {sup 177}Lu-DKFZ-PSMA-617 therapy. Hematological, kidney function, liver function tests, and serum PSA levels were recorded before and after therapy at 2 weeks, 4 weeks, and 3 month intervals. Biochemical response was assessed with trend in serum PSA levels. Metabolic response was assessed by PERCIST 1 criteria. Clinical response was assessed by visual analogue score (VASmax) analgesic score (AS), Karanofsky performance status (KPS), and toxicity and response criteria of the Eastern Cooperative Oncology Group (ECOG) criteria. The mean age of patients was 65.93 ± 9.77 years (range: 38-81 years). The mean activity administered in the 31 patients was 5069 ± 1845 MBq ranging from one to four cycles. There was a decline in the mean serum PSA levels from the baseline (baseline: 275 ng/mL, post 1st cycle therapy: 141.75 ng/mL). Based on biochemical response criteria 2/31, 20/31, 3/31, and 6/31 had complete response (CR), partial response(PR), stable disease (SD), and progressive disease (PD), respectively. Metabolic response revealed 2/6 patients with CR, and the remaining 3/6 patients with PR and 1/6 patients with SD. The mean VASmax score decreased from 7.5 to 3. The mean analgesic score decreased from 2.5 to 1.8 after therapy. The mean KPS score improved from 50.32 to 65.42 after therapies. The mean ECOG performance status improved from 2.54 to 1.78 after therapy. Two patients experienced grade I and grade II hemoglobin toxicity each. None of the patients experienced nephrotoxicity or hepatotoxicity

  17. Clinical benefit of bone-targeted radiometabolic therapy with {sup 153}Sm-EDTMP combined with chemotherapy in patients with metastatic hormone-refractory prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Ricci, Sergio; Pastina, Ilaria; Cianci, Claudia; Orlandini, Cinzia; Chioni, Aldo; Di Donato, Samantha [Hospital, Nuclear Medicine Service-PET Center, Rovigo (Italy); Boni, Giuseppe; Genovesi, Dario; Grosso, Mariano; AlSharif, Abedallatif; Mariani, Giuliano [Univ. of Pisa (Italy). Regional Center of Nuclear Medicine; Chiacchio, Serena [Univ. of Pisa (Italy). Regional Center of Nuclear Medicine; CNR Inst. of Clinical Physiology, Pisa (Italy); Francesca, Francesco [University Hospital, Pisa (Italy). Div. of Urology; Selli, Cesare [Univ. of Pisa (Italy). Section Urology; Rubello, Domenico [Nuclear Medicine Service-PET, Rovigo (Italy)

    2007-07-15

    Bone metastases are responsible for most of the morbidity associated with hormone-refractory prostate cancer (HRPC). {sup 153}Sm-ethylenediaminetetramethylene phosphonate ({sup 153}Sm-EDTMP) has been approved for palliation of painful skeletal metastases. We retrospectively investigated the possible synergistic effect on survival of {sup 153}Sm-EDTMP (given to HRPC patients for bone pain palliation) and chemotherapy. Forty-five HRPC patients were evaluated, with a median age of 71 years. The number of metastatic bone sites was {<=}10 in 25 patients and >10 in 20 patients. Median serum PSA was 224 ng/ml. Bone pain was mild in 6 patients, moderate in 16, severe in 22 and intolerable in 1. Fifteen patients were only treated with {sup 153}Sm-EDTMP (group A), while 30 patients also received chemotherapy (estramustine phosphate or mitoxantrone plus prednisone) at variable times: between 3 and 5 months after {sup 153}Sm-EDTMP (14 patients, group B) or within 1 month after {sup 153}Sm-EDTMP (16 patients, group C). Haematological toxicities observed after either regimen were in general mild, consistent with common observations after either {sup 153}Sm-EDTMP or chemotherapy, and without any additive adverse effects in the patients receiving both {sup 153}Sm-EDTMP and chemotherapy. Bone pain palliation to some degree was induced by {sup 153}Sm-EDTMP in 32/45 patients (71.1%), the proportion of patients with a favourable clinical response being significantly higher in group C than in group A (87.5% vs 53.3%, p = 0.0388). Also in terms of biochemical response (serum PSA levels), patients of group C performed significantly better than patients of group A (p = 0.0235). Overall median survival from the time of administration of {sup 153}Sm-EDTMP was 15 months in the total cohort of 45 patients, and was significantly longer in group C than in either group B (30 months vs 11 months, p = 0.023) or group A (30 months vs 10 months, p = 0.008). The results of this study confirm that

  18. {sup 99m}Tc(V)DMSA quantitatively predicts {sup 188}Re(V)DMSA distribution in patients with prostate cancer metastatic to bone

    Energy Technology Data Exchange (ETDEWEB)

    Blower, P.J.; Kettle, A.G.; O' Doherty, M.J.; Coakley, A.J. [Kent and Canterbury Hospital, Canterbury (United Kingdom). Nuclear Medicine Dept.; Knapp, F.F. Jr. [Nuclear Medicine Group, Oak Ridge National Lab., Oak Ridge, TN (United States)

    2000-09-01

    Rhenium-188 dimercaptosuccinic acid complex [{sup 188}Re(V)DMSA], a potential therapeutic analogue of the tumour imaging agent {sup 99m}Tc(V)DMSA, is selectively taken up in bone metastases in patients with prostate cancer. It would be helpful in planning palliative radionuclide therapy if {sup 99m}Tc(V)DMSA could be used to predict tumour and kidney retention of {sup 188}Re(V)DMSA. The aim of this study was to determine the correlation between tumour-to-normal tissue ratios and kidney-to-soft tissue ratios of {sup 99m}Tc(V)DMSA and {sup 188}Re(V)DMSA. This would determine whether a scan with {sup 99m}Tc(V)DMSA, could be used to identify patients for whom {sup 188}Re(V)DMSA treatment would be contra-indicated, and enable prediction of relative kidney and tumour radiation absorbed dose in {sup 188}Re(V)DMSA treatment. Ten patients with prostate carcinoma were recruited following observation of disseminated bone metastases on a recent {sup 99m}Tc-hydroxydiphosphonate bone scan. Whole-body planar scans were obtained at ca. 4 h and 24 h after hydration and injection of 600 MBq {sup 99m}Tc(V)DMSA, and a week later, at similar times after hydration and injection of 370 MBq {sup 188}Re(V)DMSA. A triple-energy window (TEW) scatter correction was applied to the {sup 188}Re scans. Counts per pixel were determined in regions of interest drawn over metastatic sites, kidneys and normal soft tissue. Tumour-to-soft tissue ratios were significantly lower (by a factor of approximately 0.8 after the TEW was applied) on {sup 188}Re scans than on {sup 99m}Tc scans, but the two were highly linearly correlated both in all individual patients and in tumours pooled from all patients together both at 4 h and at 24 h. Kidney-to-soft tissue ratios were similarly correlated and were lower for {sup 188}Re than for {sup 99m}Tc by a similar factor. Both tumour- and kidney-to-soft tissue ratios increased between 4 and 24 h but the latter increased more. In conclusion, only minor differences were

  19. Gray level entropy matrix is a superior predictor than multiplex ELISA in the detection of reactive stroma and metastatic potential of high-grade prostatic adenocarcinoma.

    Science.gov (United States)

    Jia, Xiaopeng; Sun, Yanan; Wang, Baozhi

    2014-12-01

    Recent reports have indicated that not only the primary glandular tissue but also the surrounding stromal tissue plays an active role in the progression of carcinoma. Such is true for cancer tissues arising in the prostate. However, the precise role of stromal tissue in benign prostatic hyperplasia (BPH) and prostate adenocarcinoma is not well described. We undertook this current investigation to examine the changes in orientation of the extracellular matrix and correlate with prostatic cancer progression. We used a novel form of image analysis called gray level entropy matrix (GLEM) texture analysis to evaluate morphometric changes in stromal tissues. We used normal prostatic tissue obtained from cadaveric specimen and compared with BPH, prostatic intraepithelium neoplastic, hormone responsive prostatic adenocarcinoma and castration-resistant prostatic adenocarcinoma tissues. GLEM showed higher entropy in disease-resistant prostatic tissues, compared with benign forms of all spectra of pathologically diagnosed prostatic tissues (P entropy is reflective of the disorganized morphological organization of the stroma, possibly reflecting the reactive matrix. In contrast, ELISA revealed that although individually correlated with the progressive stages of benign and carcinomatous prostatic tissues and trend correlation between groups, intergroup comparisons failed to arrive at statistical significance of comparisons between markers of neovasculogenesis, vascular endothelial growth factor, epithelial-mesenchymal transition (beta1-integrin, E-cadherin, MMP3) and osteogenic metastasis (RANKL and osteoprotegerin). The results of our study demonstrate the potential of GLEM entropy of gray level pixel in providing quasiquantitative estimate of a reactive stroma in advance stages of prostatic adenocarcinoma and thus can be routinely used in clinical decision making.

  20. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5

    NARCIS (Netherlands)

    K. Fizazi (Karim); R. Jones (Robert); S. Oudard (Stéphane); E. Efstathiou (Eleni); F. Saad (Fred); R. de Wit (Ronald); J.S. de Bono (Johann); F.M. Cruz (Felipe Melo); G. Fountzilas (George); A. Ulys (Albertas); F. Carcano (Flavio); N. Agarwal (Neeraj); D. Agus (David); J. Bellmunt (Joaquim); D.P. Petrylak (Daniel P); S.-Y. Lee (Shih-Yuan); I.J. Webb (Iain J.); B. Tejura (Bindu); N. Borgstein (Niels); R. Dreicer (Robert)

    2015-01-01

    textabstractPurpose: Orteronel (TAK-700) is an investigational, nonsteroidal, reversible, selective 17,20-lyase inhibitor. This study examined orteronel in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel therapy. Patients and Methods: In our study, 1,099

  1. Apicidin and Docetaxel Combination Treatment Drives CTCFL Expression and HMGB1 Release Acting as Potential Antitumor Immune Response Inducers in Metastatic Breast Cancer Cells

    Directory of Open Access Journals (Sweden)

    Maria Buoncervello

    2012-09-01

    Full Text Available Currently approved combination regimens available for the treatment of metastatic tumors, such as breast cancer, have been shown to increase response rates, often at the cost of a substantial increase in toxicity. An ideal combination strategy may consist of agents with different mechanisms of action leading to complementary antitumor activities and safety profiles. In the present study, we investigated the effects of the epigenetic modulator apicidin in combination with the cytotoxic agent docetaxel in tumor breast cell lines characterized by different grades of invasiveness. We report that combined treatment of apicidin and docetaxel, at low toxicity doses, stimulates in metastatic breast cancer cells the expression of CTCF-like protein and other cancer antigens, thus potentially favoring an antitumor immune response. In addition, apicidin and docetaxel co-treatment specifically stimulates apoptosis, characterized by an increased Bax/Bcl-2 ratio and caspase-8 activation. Importantly, following combined exposure to these agents, metastatic cells were also found to induce signals of immunogenic apoptosis such as cell surface expression of calreticulin and release of considerable amounts of high-mobility group box 1 protein, thus potentially promoting the translation of induced cell death into antitumor immune response. Altogether, our results indicate that the combined use of apicidin and docetaxel, at a low toxicity profile, may represent a potential innovative strategy able to activate complementary antitumor pathways in metastatic breast cancer cells, associated with a potential control of metastatic growth and possible induction of antitumor immunity.

  2. HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network

    Science.gov (United States)

    Ramos-Montoya, Antonio; Lamb, Alastair D; Russell, Roslin; Carroll, Thomas; Jurmeister, Sarah; Galeano-Dalmau, Nuria; Massie, Charlie E; Boren, Joan; Bon, Helene; Theodorou, Vasiliki; Vias, Maria; Shaw, Greg L; Sharma, Naomi L; Ross-Adams, Helen; Scott, Helen E; Vowler, Sarah L; Howat, William J; Warren, Anne Y; Wooster, Richard F; Mills, Ian G; Neal, David E

    2014-01-01

    Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient-specific therapeutic strategies. PMID:24737870

  3. HES6 drives a critical AR transcriptional programme to induce castration-resistant prostate cancer through activation of an E2F1-mediated cell cycle network.

    Science.gov (United States)

    Ramos-Montoya, Antonio; Lamb, Alastair D; Russell, Roslin; Carroll, Thomas; Jurmeister, Sarah; Galeano-Dalmau, Nuria; Massie, Charlie E; Boren, Joan; Bon, Helene; Theodorou, Vasiliki; Vias, Maria; Shaw, Greg L; Sharma, Naomi L; Ross-Adams, Helen; Scott, Helen E; Vowler, Sarah L; Howat, William J; Warren, Anne Y; Wooster, Richard F; Mills, Ian G; Neal, David E

    2014-05-01

    Castrate-resistant prostate cancer (CRPC) is poorly characterized and heterogeneous and while the androgen receptor (AR) is of singular importance, other factors such as c-Myc and the E2F family also play a role in later stage disease. HES6 is a transcription co-factor associated with stem cell characteristics in neural tissue. Here we show that HES6 is up-regulated in aggressive human prostate cancer and drives castration-resistant tumour growth in the absence of ligand binding by enhancing the transcriptional activity of the AR, which is preferentially directed to a regulatory network enriched for transcription factors such as E2F1. In the clinical setting, we have uncovered a HES6-associated signature that predicts poor outcome in prostate cancer, which can be pharmacologically targeted by inhibition of PLK1 with restoration of sensitivity to castration. We have therefore shown for the first time the critical role of HES6 in the development of CRPC and identified its potential in patient-specific therapeutic strategies.

  4. Loss of somatostatin receptor subtype 2 in prostate cancer is linked to an aggressive cancer phenotype, high tumor cell proliferation and predicts early metastatic and biochemical relapse.

    Directory of Open Access Journals (Sweden)

    Jan K Hennigs

    Full Text Available Somatostatin receptor subtype 2 (SSTR2 is the most frequently expressed SSTR subtype in normal human tissues. SSTR2 expression is differentially regulated in various tumor types and therapeutic somatostatin analogs binding to SSTR2 are in clinical use. In prostate cancers highly contradictory results in terms of SSTR2 expression and its consequences have been published over the past years. The aim of this study was to clarify prevalence and clinical significance of SSTR2 expression in prostate cancer. Therefore, quantitative immunohistochemistry (IHC using a tissue microarray containing samples from 3,261 prostate cancer patients with extensive clinical and molecular cancer characteristics and oncological follow-up data was performed. IHC data was compared to publicly available Gene Expression Omnibus datasets of human prostate cancer gene expression arrays. While membranous SSTR2 staining was always seen in normal prostate epithelium, SSTR2 staining was absent in more than half (56.1% of 2,195 interpretable prostate cancer samples. About 13% of all analyzed prostate cancers showed moderate to strong cytoplasmic and membranous SSTR2 staining. Staining intensities were inversely correlated with high Gleason grade, advanced pT category, high tumor cell proliferation (p<0.0001 each, high pre-operative PSA levels, (p = 0.0011 and positive surgical margins (p = 0.006. In silico analysis confirmed lower SSTR2 gene expression in prostate cancers vs. normal adjacent tissue (p = 0.0424, prostate cancer metastases vs. primary cancers (p = 0.0011 and recurrent vs. non-recurrent prostate cancers (p = 0.0438. PSA-free survival gradually declined with SSTR2 staining intensity (p<0.0001. SSTR2-negative cancers were more likely to develop metastases over time (p<0.05. In conclusion, most prostate cancers are indeed SSTR2-negative and loss of SSTR2 strongly predicts an unfavorable tumor phenotype and poor prognosis. Therefore, SSTR2

  5. Prostate cancer is not breast cancer

    Directory of Open Access Journals (Sweden)

    Ajit Venniyoor

    2016-01-01

    Full Text Available Cancers of the prostate and breast are hormone dependent cancers. There is a tendency to equate them and apply same algorithms for treatment. It is pointed out that metastatic prostate cancer with bone-only disease is a potentially fatal condition with a much poorer prognosis than metastatic breast cancer and needs a more aggressive approach.

  6. Evaluation of Alpha-Therapy with Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer—the Role of Gamma Scintigraphy in Dosimetry and Pharmacokinetics

    Directory of Open Access Journals (Sweden)

    Kalevi Kairemo

    2015-07-01

    Full Text Available Radium-223-dichloride (223RaCl2 is a new bone-seeking calcium analogue alpha-emitter, which has obtained marketing authorization for the treatment skeletal metastases of hormone-refractory prostate cancer. The current treatment regimen is based on six consecutive doses of 223RaCl2 at 4 week intervals and the administered activity dose, 50 kBq/kg per cycle is based on patient weight. We analyzed two patients using quantitative serial gamma imaging to estimate dosimetry in tumors and see possible pharmacokinetic differences in the treatment cycles. The lesions were rather well visualized in gamma scintigraphy in spite of low gamma activity (<1.1% gamma radiation at 0, 7 and 28 days using 30–60 min acquisition times. Both our patients analyzed in serial gamma imagings, had two lesions in the gamma imaging field, the mean counts of the relative intensity varied from 27.8 to 36.5 (patient 1, and from 37.4 to 82.2 (patient 2. The half-lives varied from 1.8 days to 4.5 days during the six cycles (patient 1, and from 1.5 days to 3.6 days (patient 2, respectively. In the lesion half-lives calculated from the imaging the maximum difference between the treatment cycles in the same lesion was 2.0-fold (1.8 vs. 3.6. Of these patients, patient 1 demonstrated a serum PSA response, whereas there was no PSA response in patient 2. From our data, there were maximally up to 4.0-fold differences (62.1 vs. 246.6 between the relative absorbed radiation doses between patients as calculated from the quantitative standardized imaging to be delivered in only two lesions, and in the same lesion the maximum difference in the cycles was up to 2.3-fold (107.4 vs. 246.6. Our recommendation based on statistical simulation analysis, is serial measurement at days 0–8 at least 3 times, this improve the accuracy significantly to study the lesion activities, half-lives or calculated relative absorbed radiation doses as calculated from the imaging. Both our patients had

  7. Efficacy and safety of second-line agents for treatment of metastatic castration-resistant prostate cancer progressing after docetaxel. A systematic review and meta-analysis

    Directory of Open Access Journals (Sweden)

    Gianpaolo Perletti

    2015-07-01

    Full Text Available Objective: We performed a systematic review of the literature to assess the efficacy and the safety of second-line agents targeting metastatic castration-resistant prostate cancer (mCRPC that has progressed after docetaxel. Pooled-analysis was also performed, to assess the effectiveness of agents targeting the androgen axis via identical mechanisms of action (abiraterone acetate, orteronel. Materials and Methods: We included phase III randomized controlled trials that enrolled patients with mCRPC progressing during or after first-line docetaxel treatment. Trials were identified by electronic database searching. The primary outcome of the review was overall survival. Secondary outcomes were radiographic progression-free survival (rPFS and severe adverse effects (grade 3 or higher. Results: Ten articles met the inclusion criteria for the review. These articles reported the results of five clinical trials, enrolling in total 5047 patients. The experimental interventions tested in these studies were enzalutamide, ipilimumab, abiraterone acetate, orteronel and cabazitaxel. Compared to control cohorts (active drug-treated or placebotreated, the significant overall survival advantages achieved were 4.8 months for enzalutamide (hazard ratio for death vs. placebo: 0.63; 95% CI 0.53 to 0.75, P < 0.0001, 4.6 months for abiraterone (hazard ratio for death vs. placebo: 0.66, 95% CI 0.58 to 0.75, P < 0.0001 and 2.4 months for cabazitaxel (hazard ratio for death vs. mitoxantrone-prednisone: 0.70, 95% CI 0.59 to 0.83, p < 0.0001. Pooled analysis of androgen synthesis inhibitors orteronel and abiraterone resulted in significantly increased overall and progression-free survival for anti-androgen agents, compared to placebo (hazard ratio for death: 0.76, 95% CI 0.67 to 0.87, P < 0.0001; hazard ratio for radiographic progression: 0.7, 95% CI 0.63 to 0.77, P < 0.00001. Androgen synthesis inhibitors induced significant increases in risk ratios for adverse effects

  8. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial

    NARCIS (Netherlands)

    Eertwegh, A.J. van den; Versluis, J.; Berg, H.P. van den; Santegoets, S.J.; Moorselaar, R.J. van; Sluis, T.M. van der; Gall, H.E.; Harding, T.C.; Jooss, K.; Lowy, I.; Pinedo, H.M.; Scheper, R.J.; Stam, A.G.; Blomberg, B.M. von; Gruijl, T.D. de; Hege, K.; Sacks, N.; Gerritsen, W.R.

    2012-01-01

    BACKGROUND: The granulocyte-macrophage colony-stimulating factor-transduced allogeneic prostate cancer cells vaccine (GVAX) has antitumour activity against prostate cancer; preclinical studies have shown potent synergy when combined with ipilimumab, an antibody that blocks cytotoxic T-lymphocyte ant

  9. Immunotherapy and Immune Evasion in Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Thakur, Archana, E-mail: thakur@karmanos.org; Vaishampayan, Ulka [Department of Oncology, Wayne State University, Detroit, MI 48201 (United States); Lum, Lawrence G., E-mail: thakur@karmanos.org [Department of Oncology, Wayne State University, Detroit, MI 48201 (United States); Department of Medicine, Wayne State University, Detroit, MI 48201 (United States); Department of Immunology and Microbiology, Wayne State University, Detroit, MI 48201 (United States)

    2013-05-24

    Metastatic prostate cancer remains to this day a terminal disease. Prostatectomy and radiotherapy are effective for organ-confined diseases, but treatment for locally advanced and metastatic cancer remains challenging. Although advanced prostate cancers treated with androgen deprivation therapy achieves debulking of disease, responses are transient with subsequent development of castration-resistant and metastatic disease. Since prostate cancer is typically a slowly progressing disease, use of immune-based therapies offers an advantage to target advanced tumors and to induce antitumor immunity. This review will discuss the clinical merits of various vaccines and immunotherapies in castrate resistant prostate cancer and challenges to this evolving field of immune-based therapies.

  10. Neuroendocrine differentiation in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    Jiaoti Huang

    2008-01-01

    @@ The treatment of choice for advanced/metastatic prostate cancer(PC) is hormonal therapy. Although patients respond initially to this therapy, the tumor will recur and enter the androgen-independent state, which is the major obstacle in therapy.

  11. Prostatitis: Inflammation of the Prostate

    Science.gov (United States)

    ... the Prostate Prostate Enlargement (Benign Prostatic Hyperplasia) Prostatitis: Inflammation of the Prostate What is prostatitis? Prostatitis is a frequently painful condition that involves inflammation of the prostate and sometimes the areas around ...

  12. Health Economics and Radium-223 (Xofigo®) in the Treatment of Metastatic Castration-Resistant Prostate Cancer (mCRPC): A Case History and a Systematic Review of the Literature.

    Science.gov (United States)

    Norum, Jan; Traasdahl, Erik R; Totth, Arpad; Nieder, Carsten; Olsen, Jan Abel

    2015-07-30

    Prostate cancer (PC) is the most common cancer in Western countries. Recent advances in the treatment of metastatic castration resistant prostate cancer (mCRPC) have caused significant pressure on health care budgets. We aimed to exemplify this dilemma presenting an example, radium-223 (Xofigo®), and review the literature. A 74-year-old man diagnosed with mCRPC was referred to our department in October 2014 for radium-223 therapy. We faced the following dilemma: is radium-223 standard therapy? Is it cost-effective? Medline was searched employing the following search criteria: "radium-223", "alpharadin", "Xofigo" and "prostate". Exclusion and inclusion criteria were applied. Guidelines and cost-effectiveness analyses were focused. We also searched the websites of ASCO, ESMO and ISPOR. The web was searched, using Yahoo and Google search engines, for Health Technology Assessments (HTAs). 181 publications were identified in the Medline database. Only four studies included the word "cost", three "economics" and none "budget" in heading or abstract. None of the publications were thorough of cost analysis (cost-effectiveness, cost-utility, cost-minimizing or cost-of-illness analysis). Six HTAs and eight national guidelines were identified. The cost per quality adjusted life years was indicated €80.000-94,000. HTAs concluded reimbursement being not recommendable or no ultimate statement could be made. One pointed towards a limited use with caution. Guidelines were based on data from randomized clinical trials (RCTs). Health economics was not considered when guidelines were made. Most HTAs concluded this therapy not cost-effective or there was insufficient data for final conclusions. Licensing and reimbursement processes should be run simultaneously.

  13. Molecular Staging of Prostate-Bone Materials

    Science.gov (United States)

    1999-10-01

    LNCaP tumours in both intact and castrated SCID mice, and derived a series of sublines from these mice with different levels of androgen-dependence...features. support the role of bFGF in prostate cancer progression. Canine prostate carci- The metastatic PC-3, DU145, and TSU-Prl cell lines showed...contrast, the poorly metastatic, canine prostate carcinoma xenografts. androgen-dependent LNCaP cell line lacked vimentin expression and showed poor

  14. Pharmacotherapy of prostatitis.

    Science.gov (United States)

    Snow, Devon C; Shoskes, Daniel A

    2010-10-01

    Prostatitis is a prevalent and morbid condition with a significant impact on a patient's quality of life. The four distinct prostatitis syndromes have different pathophysiologies, therapy and prognosis. Acute and chronic bacterial prostatitis is best treated with appropriate antibiotics that penetrate the prostate and kill the causative organisms. The most challenging category to treat is category III or chronic prostatitis/chronic pelvic pain syndrome. This review covers the categories of prostatitis and currently recommended therapies, as well as novel approaches on the horizon. Knowledge of the current framework for the diagnosis and management of the diverse prostatitis spectrum. Prostatitis is a diverse group of syndromes. Chronic prostatitis/chronic pelvic pain syndrome is a multifactorial syndrome that requires a multimodal approach to effectively treat the patient. The UPOINT technique is used to clinically phenotype these patients and drive the selection of multimodal therapy.

  15. Apigenin drives the production of reactive oxygen species and initiates a mitochondrial mediated cell death pathway in prostate epithelial cells.

    Science.gov (United States)

    Morrissey, Colm; O'Neill, Amanda; Spengler, Barbara; Christoffel, Volker; Fitzpatrick, John M; Watson, R William G

    2005-05-01

    Phytoestrogens may reduce tumorigenesis in prostate cancer. We screened five phytoestrogens for their effect on cell growth and apoptosis in PWR-1E, LNCaP, PC-3, and DU145 prostate epithelial cells in vitro. We assessed cell number, proliferation, and apoptosis using crystal violet assays, flow cytometric analysis, and TUNEL. Focusing specifically on apigenin we assessed the ability of calpain, serine protease, caspase, estrogen receptor, and ceramide synthase inhibitors to block apigenin induced apoptosis. We also analyzed caspase 3, 7, 8, 9, Bcl-2, Bax, Bid, and cytochrome C by Western analysis, and mitochondrial permeability and reactive oxygen species production by flow cytometry using mitosensor(TM) and DCFH-DA, respectively. Apigenin and silybinin significantly reduced cell number, with apigenin inducing apoptosis in PWR-1E, LNCaP, PC-3, and DU145 cells. The PC-3 and DU145 cells were less susceptible to apigenin induced apoptosis then LNCaP and PWR-1E cells. The induction of apoptosis by apigenin was caspase dependent. Apigenin generated reactive oxygen species, a loss of mitochondrial Bcl-2 expression, mitochondrial permeability, cytochrome C release, and the cleavage of caspase 3, 7, 8, and 9 and the concomitant cleavage of the inhibitor of apoptosis protein, cIAP-2. The overexpression of Bcl-2 in LNCaP B10 cells reduced the apoptotic effects of apigenin. Apigenin induces cell death in prostate epithelial cells using a mitochondrial mediated cell death pathway. Bcl-2 has a role in inhibiting apigenin induced cell death in prostate epithelial cells. (c) 2004 Wiley-Liss, Inc.

  16. A randomised comparison of bicalutamide ('Casodex') 150 mg versus placebo as immediate therapy either alone or as adjuvant to standard care for early non-metastatic prostate cancer. First report from the Scandinavian Prostatic Cancer Group Study No. 6

    DEFF Research Database (Denmark)

    Iversen, P; Tammela, T L J; Vaage, S

    2002-01-01

    To assess the efficacy and tolerability of bicalutamide 150 mg ('Casodex'(1)) as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with early (T1b-T4, any N, M0) prostate cancer.......To assess the efficacy and tolerability of bicalutamide 150 mg ('Casodex'(1)) as immediate therapy, either alone or as adjuvant to treatment of curative intent, in patients with early (T1b-T4, any N, M0) prostate cancer....

  17. Early Growth Inhibition Is Followed by Increased Metastatic Disease with Vitamin D (Calcitriol) Treatment in the TRAMP Model of Prostate Cancer

    Science.gov (United States)

    Karasik, Ellen; Gillard, Bryan; Moser, Michael T.; Johnson, Candace S.; Trump, Donald L.; Foster, Barbara A.

    2014-01-01

    The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (calcitriol) has antiproliferative effects in non-aggressive prostate cancer, however, its effects in more aggressive model systems are still unclear. In these studies, effects of calcitriol and a less-calcemic vitamin D analog, QW-1624F2-2 (QW), were tested in vivo, using the aggressive autochthonous transgenic adenocarcinoma of mouse prostate (TRAMP) model. To study prevention of androgen-stimulated prostate cancer, vehicle, calcitriol (20 µg/kg), or QW (50 µg/kg) were administered to 4 week-old TRAMP mice intraperitoneal (i.p.) 3×/week on a MWF schedule for 14 weeks. Calcitriol and QW slowed progression of prostate cancer as indicated by reduced urogenital tract (p = 0.0022, calcitriol; p = 0.0009, QW) and prostate weights (p = 0.0178, calcitriol; p = 0.0086, QW). However, only calcitriol increased expression of the pro-differentiation marker, cadherin 1 (p = 0.0086), and reduced tumor proliferation (p = 0.0467). By contrast, neither vitamin D analog had any effect on castration resistant prostate cancer in mice treated pre- or post-castration. Interestingly, although vitamin D showed inhibitory activity against primary tumors in hormone-intact mice, distant organ metastases seemed to be enhanced following treatment (p = 0.0823). Therefore, TRAMP mice were treated long-term with calcitriol to further examine effects on metastasis. Calcitriol significantly increased the number of distant organ metastases when mice were treated from 4 weeks-of-age until development of palpable tumors (20–25 weeks-of-age)(p = 0.0003). Overall, data suggest that early intervention with vitamin D in TRAMP slowed androgen-stimulated tumor progression, but prolonged treatment resulted in development of a resistant and more aggressive disease associated with increased distant organ metastasis. PMID:24586868

  18. Early growth inhibition is followed by increased metastatic disease with vitamin D (calcitriol treatment in the TRAMP model of prostate cancer.

    Directory of Open Access Journals (Sweden)

    Adebusola Alagbala Ajibade

    Full Text Available The active metabolite of vitamin D3, 1,25-dihydroxyvitamin D3 (calcitriol has antiproliferative effects in non-aggressive prostate cancer, however, its effects in more aggressive model systems are still unclear. In these studies, effects of calcitriol and a less-calcemic vitamin D analog, QW-1624F2-2 (QW, were tested in vivo, using the aggressive autochthonous transgenic adenocarcinoma of mouse prostate (TRAMP model. To study prevention of androgen-stimulated prostate cancer, vehicle, calcitriol (20 µg/kg, or QW (50 µg/kg were administered to 4 week-old TRAMP mice intraperitoneal (i.p. 3×/week on a MWF schedule for 14 weeks. Calcitriol and QW slowed progression of prostate cancer as indicated by reduced urogenital tract (p = 0.0022, calcitriol; p = 0.0009, QW and prostate weights (p = 0.0178, calcitriol; p = 0.0086, QW. However, only calcitriol increased expression of the pro-differentiation marker, cadherin 1 (p = 0.0086, and reduced tumor proliferation (p = 0.0467. By contrast, neither vitamin D analog had any effect on castration resistant prostate cancer in mice treated pre- or post-castration. Interestingly, although vitamin D showed inhibitory activity against primary tumors in hormone-intact mice, distant organ metastases seemed to be enhanced following treatment (p = 0.0823. Therefore, TRAMP mice were treated long-term with calcitriol to further examine effects on metastasis. Calcitriol significantly increased the number of distant organ metastases when mice were treated from 4 weeks-of-age until development of palpable tumors (20-25 weeks-of-age(p = 0.0003. Overall, data suggest that early intervention with vitamin D in TRAMP slowed androgen-stimulated tumor progression, but prolonged treatment resulted in development of a resistant and more aggressive disease associated with increased distant organ metastasis.

  19. Correlation between frequencies of blood monocytic myeloid-derived suppressor cells, regulatory T cells and negative prognostic markers in patients with castration-resistant metastatic prostate cancer

    DEFF Research Database (Denmark)

    Idorn, Manja; Køllgaard, Tania; Kongsted, Per

    2014-01-01

    and function of immune suppressive cell subsets in the peripheral blood of 41 patients with prostate cancer (PC) and 36 healthy donors (HD) showed a significant increase in circulating CD14(+) HLA-DR(low/neg) monocytic MDSC (M-MDSC) and Tregs in patients with PC compared to HD. Furthermore, M-MDSC frequencies...... with known negative prognostic markers in patients with PC including elevated levels of lactate dehydrogenase and prostate-specific antigen. Accordingly, high levels of M-MDSC were associated with a shorter median overall survival. Our data strongly suggest that M-MDSC, possibly along with Tregs, play a role...

  20. PSA Response to Lenalidomide Therapy in a Pre-Treated Patient with Metastatic Prostate Cancer Refractory to Hormones and Chemotherapy: A Case Report

    Directory of Open Access Journals (Sweden)

    Joan Manel Gasent Blesa

    2012-04-01

    Full Text Available Hormone-resistant prostate cancer (HRPC occurs when prostate cancer is no longer responsive to hormone therapy. Treatment options are limited, and there is a clear necessity for therapies that improve outcome. Preclinical and clinical evidence supports the role of the immunomodulatory agent lenalidomide in HRPC. In this paper, we report that lenalidomide showed antitumoral activity in a patient with HRPC and bone metastases pre-treated with chemotherapy, decreased the PSA level and improved the patient’s health status for the first 5 months. It is important to emphasize that it was not associated with hematologic toxicity.

  1. Prostate; Prostate

    Energy Technology Data Exchange (ETDEWEB)

    Rouviere, O.; Valette, O.; Grivolat, S.; Colin-Pangaud, C.; Bouvier, R.; Chapelon, J.Y.; Gelet, A.; Lyonnet, D.; Rouviere, O.; Mege-Lechevallier, F.; Chapelon, J.Y.; Gelet, A.; Bouvier, R.; Boutitie, F.; Lyonnet, D. [69 - Lyon (France)

    2005-10-15

    Two methods to detect recurrence of prostate cancer are presented. Dynamic magnetic resonance imaging after radiotherapy and color doppler after high intensity focused ultrasounds (but with patients that have not received a hormones therapy). These two methods presents an useful contribution. (N.C.)

  2. Prediagnostic Serum Organochlorine Concentrations and Metastatic Prostate Cancer : A Nested Case-Control Study in the Norwegian Janus Serum Bank Cohort

    NARCIS (Netherlands)

    Koutros, Stella; Langseth, Hilde; Grimsrud, Tom K; Barr, Dana Boyd; Vermeulen, Roel|info:eu-repo/dai/nl/216532620; Portengen, Lützen|info:eu-repo/dai/nl/269224742; Wacholder, Sholom; Freeman, Laura E Beane; Blair, Aaron; Hayes, Richard B; Rothman, Nathaniel; Engel, Lawrence S

    BACKGROUND: Organochlorine (OC) insecticides and polychlorinated biphenyls (PCBs) have been shown to have estrogenic, antiestrogenic, or antiandrogenic properties; as a result, the impact of exposure to these compounds and risk of hormonal cancers, such as prostate cancer, is a concern. OBJECTIVES:

  3. Coactivator SRC-2-dependent metabolic reprogramming mediates prostate cancer survival and metastasis.

    Science.gov (United States)

    Dasgupta, Subhamoy; Putluri, Nagireddy; Long, Weiwen; Zhang, Bin; Wang, Jianghua; Kaushik, Akash K; Arnold, James M; Bhowmik, Salil K; Stashi, Erin; Brennan, Christine A; Rajapakshe, Kimal; Coarfa, Cristian; Mitsiades, Nicholas; Ittmann, Michael M; Chinnaiyan, Arul M; Sreekumar, Arun; O'Malley, Bert W

    2015-03-02

    Metabolic pathway reprogramming is a hallmark of cancer cell growth and survival and supports the anabolic and energetic demands of these rapidly dividing cells. The underlying regulators of the tumor metabolic program are not completely understood; however, these factors have potential as cancer therapy targets. Here, we determined that upregulation of the oncogenic transcriptional coregulator steroid receptor coactivator 2 (SRC-2), also known as NCOA2, drives glutamine-dependent de novo lipogenesis, which supports tumor cell survival and eventual metastasis. SRC-2 was highly elevated in a variety of tumors, especially in prostate cancer, in which SRC-2 was amplified and overexpressed in 37% of the metastatic tumors evaluated. In prostate cancer cells, SRC-2 stimulated reductive carboxylation of α-ketoglutarate to generate citrate via retrograde TCA cycling, promoting lipogenesis and reprogramming of glutamine metabolism. Glutamine-mediated nutrient signaling activated SRC-2 via mTORC1-dependent phosphorylation, which then triggered downstream transcriptional responses by coactivating SREBP-1, which subsequently enhanced lipogenic enzyme expression. Metabolic profiling of human prostate tumors identified a massive increase in the SRC-2-driven metabolic signature in metastatic tumors compared with that seen in localized tumors, further implicating SRC-2 as a prominent metabolic coordinator of cancer metastasis. Moreover, SRC-2 inhibition in murine models severely attenuated the survival, growth, and metastasis of prostate cancer. Together, these results suggest that the SRC-2 pathway has potential as a therapeutic target for prostate cancer.

  4. A phase 2 study of high-activity {sup 186}Re-HEDP with autologous peripheral blood stem cell transplant in progressive hormone-refractory prostate cancer metastatic to bone

    Energy Technology Data Exchange (ETDEWEB)

    O' Sullivan, J.M. [Queen' s University Belfast/Belfast City Hospital, Department of Oncology, Belfast (United Kingdom); Norman, A.R. [Royal Marsden Foundation NHS Trust, Department of Computing, Sutton, Surrey (United Kingdom); McCready, V.R.; Flux, G.; Buffa, F.M. [Royal Marsden Foundation NHS Trust, Department of Physics, Sutton, Surrey (United Kingdom); Johnson, B. [Royal Marsden Foundation NHS Trust, Bob Champion Unit, Sutton, Surrey (United Kingdom); Coffey, J.; Horwich, A.; Huddart, R.A.; Parker, C.C.; Dearnaley, D.P. [Royal Marsden Foundation NHS Trust, Academic Unit of Urology, Sutton, Surrey (United Kingdom); Cook, G. [Royal Marsden Foundation NHS Trust, Department of Nuclear Medicine, Sutton, Surrey (United Kingdom); Treleaven, J. [Royal Marsden Foundation NHS Trust, Department of Haematology, Sutton, Surrey (United Kingdom)

    2006-09-15

    We investigated the potential for improvement in disease control by use of autologous peripheral blood stem cell transplant (PBSCT) to permit administration of high activities of {sup 186}Re-hydroxyethylidene diphosphonate (HEDP) in patients with progressive hormone-refractory prostate cancer (HRPC). Eligible patients had progressive HRPC metastatic to bone, good performance status and minimal soft tissue disease. Patients received 5,000 MBq of {sup 186}Re-HEDP i.v., followed 14 days later by PBSCT. Response was assessed using PSA, survival, pain scores and quality of life. Thirty-eight patients with a median age of 67 years (range 50-77) and a median PSA of 57 ng/ml (range 4-3,628) received a median activity of 4,978 MBq {sup 186}Re-HEDP (range 4,770-5,100 MBq). The most serious toxicity was short-lived grade 3 thrombocytopenia in 8 (21%) patients. The median survival of the group is 21 months (95%CI 18-24 months) with Kaplan-Meier estimated 1- and 2-year survival rates of 83% and 40% respectively. Thirty-one patients (81%, 95% CI 66-90%) had stable or reduced PSA levels 3 months post therapy while 11 (29%, 95% CI 15-49%) had PSA reductions of >50% lasting >4 weeks. Quality of life measures were stable or improved in 27 (66%) at 3 months. We have shown that it is feasible and safe to deliver high-activity radioisotope therapy with PBSCT to men with metastatic HRPC. Response rates and survival data are encouraging; however, further research is needed to define optimal role of this treatment approach. (orig.)

  5. A phase I study of combined docetaxel and repeated high activity {sup 186}Re-HEDP in castration-resistant prostate cancer (CRPC) metastatic to bone (the TAXIUM trial)

    Energy Technology Data Exchange (ETDEWEB)

    Dodewaard-de Jong, Joyce M. van; Bloemendal, Haiko J. [Meander Medical Centre, Department of Internal Medicine, Amersfoort (Netherlands); Klerk, John M.H. de; Haas, Marie J. de [Meander Medical Centre, Department of Nuclear Medicine, Amersfoort (Netherlands); Bezooijen, Bart P.J. van [Meander Medical Centre, Department of Urology, Amersfoort (Netherlands); Wilson, Richard H.; O' Sullivan, Joe M. [Queen' s University Belfast, Centre for Cancer Research and Cell Biology, Belfast, N. Ireland (United Kingdom)

    2011-11-15

    Bone-seeking radiopharmaceuticals have palliative benefit in castration-resistant prostate cancer (CRPC) metastatic to bone. Recent studies have shown improvement of survival and quality of life when radiopharmaceuticals were given repeatedly or in combination with chemotherapy. We designed a phase I study combining docetaxel and {sup 186}Re-labelled hydroxyethylidene diphosphonate (HEDP) in men with CRPC and bone metastases to evaluate toxicity. A dose escalation schedule was designed consisting of four dose levels with a standard dosage of docetaxel (75 mg/m{sup 2} 3-weekly). {sup 186}Re-HEDP was given in increasing activities (1,250 MBq up to 2,500 MBq) after the third and sixth cycle of docetaxel. Dose limiting toxicity (DLT) was defined as any grade 4 toxicity lasting more than 7 days or any grade 3 toxicity that did not recover within 10 days. Three patients were planned for each dose level expanding to six if a DLT occurred. Fourteen patients were recruited with a median age of 64.6 years. One DLT, grade 3 thrombocytopenia lasting >10 days, occurred at dose level 3 leading to expansion of this group to six. One of these patients had an episode of acute renal failure which resolved. Because of production problems of {sup 186}Re-HEDP dose level 4 was not started. Combined therapy with docetaxel and {sup 186}Re-HEDP is generally well tolerated in patients with CRPC metastatic to bone. We will conduct a randomized phase II study using three cycles of docetaxel 75 mg/m{sup 2} 3-weekly followed by {sup 188}Re-HEDP 40 MBq/kg body weight, followed by another three cycles of docetaxel 75 mg/m{sup 2}, followed by {sup 188}Re-HEDP 20 MBq/kg body weight. (orig.)

  6. Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer

    DEFF Research Database (Denmark)

    Graff, J N; Baciarello, G; Armstrong, A J;

    2016-01-01

    for an overall higher incidence of falls among elderly patients than younger patients [84/609 (13.8%) versus 62/1106 (5.6%)] and among elderly patients receiving enzalutamide than those receiving placebo [61/317 (19.2%) versus 23/292 (7.9%)]. CONCLUSIONS: Elderly men benefited from treatment with enzalutamide...... in terms of OS and rPFS. Enzalutamide was well tolerated in the elderly subgroup and those aged falls. CLINICAL TRIAL IDENTIFIER: NCT01212991, ClinicalTrials.gov.......BACKGROUND: Prostate cancer disproportionately affects older men. Because age affects treatment decisions, it is important to understand the efficacy and tolerability of therapies for advanced prostate cancer in elderly men. This analysis describes efficacy and safety outcomes in men aged ≥75 years...

  7. The HGF/c-MET Axis as a Critical Driver of Resistance to Androgen Suppression in Metastatic Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2015-10-01

    aspirates from 5 patients. We have obtained 6 blood samples for CTC analyses from 4 patients on abiraterone and 3 blood samples from 2 patients on...bone marrow aspirates has been slower than anticipated. We have addressed this in a number of ways, including pre- screening clinics for eligible...a graphene oxide based microfluidic device (GO Chip) to prostate cancer circulating tumor cell capture and analysis, AACR, 2015. *Patnaik, A

  8. The HGF/c-MET Axis as a Critical Driver of Resistance to Androgen Suppression in Metastatic Castrate-Resistant Prostate Cancer

    Science.gov (United States)

    2016-10-01

    resistant prostate cancer PRINCIPAL INVESTIGATOR: Todd M. Morgan CONTRACTING ORGANIZATION: University of Michigan Ann Arbor, MI REPORT DATE: October...NAME(S) AND ADDRESS(ES) University of Michigan Ann Arbor, MI 8. PERFORMING ORGANIZATION REPORT NUMBER University of Michigan Ann Arbor, Michigan...efficacious than either inhibitor alone . These data support the concept that the MET pathway may be an key mechanism of resistance in men with CRPC

  9. Beyond evidence-based data: scientific rationale and tumor behavior to drive sequential and personalized therapeutic strategies for the treatment of metastatic renal cell carcinoma.

    Science.gov (United States)

    Incorvaia, Lorena; Bronte, Giuseppe; Bazan, Viviana; Badalamenti, Giuseppe; Rizzo, Sergio; Pantuso, Gianni; Natoli, Clara; Russo, Antonio

    2016-04-19

    The recent advances in identification of the molecular mechanisms related to tumorigenesis and angiogenesis, along with the understanding of molecular alterations involved in renal cell carcinoma (RCC) pathogenesis, has allowed the development of several new drugs which have revolutionized the treatment of metastatic renal cell carcinoma (mRCC).This process has resulted in clinically significant improvements in median overall survival and an increasing number of patients undergoes two or even three lines of therapy. Therefore, it is necessary a long-term perspective of the treatment: planning a sequential and personalized therapeutic strategy to improve clinical outcome, the potential to achieve long-term response, and to preserve quality of life (QOL), minimizing treatment-related toxicity and transforming mRCC into a chronically treatable condition.Because of the challenges still encountered to draw an optimal therapeutic sequence, the main focus of this article will be to propose the optimal sequencing of existing, approved, oral targeted agents for the treatment of mRCC using evidence-based data along with the knowledge available on the tumor behavior and mechanisms of resistance to anti-angiogenic treatment to provide complementary information and to help the clinicians to maximize the effectiveness of targeted agents in the treatment of mRCC.

  10. Impact of Bone-targeted Therapies in Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer Patients Treated with Abiraterone Acetate: Post Hoc Analysis of Study COU-AA-302

    Science.gov (United States)

    Saad, Fred; Shore, Neal; Van Poppel, Hendrik; Rathkopf, Dana E.; Smith, Matthew R.; de Bono, Johann S.; Logothetis, Christopher J.; de Souza, Paul; Fizazi, Karim; Mulders, Peter F.A.; Mainwaring, Paul; Hainsworth, John D.; Beer, Tomasz M.; North, Scott; Fradet, Yves; Griffin, Thomas A.; De Porre, Peter; Londhe, Anil; Kheoh, Thian; Small, Eric J.; Scher, Howard I.; Molina, Arturo; Ryan, Charles J.

    2016-01-01

    Background Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy. Objective Investigation of outcomes for concomitant BTT in a post hoc analysis of the COU-AA-302 trial, which demonstrated an overall clinical benefit of abiraterone acetate (AA) plus prednisone over placebo plus prednisone in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients. Design, setting, and participants This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial. Intervention Patients were grouped by concomitant BTT use or no BTT use. Outcome measurements and statistical analysis Radiographic progression-free survival and OS were coprimary end points. This report describes the third interim analysis (prespecified at 55% OS events) and involves patients treated with or without concomitant BTT during the COU-AA-302 study. Median follow-up for OS was 27.1 mo. Median time-to-event variables with 95% confidence intervals (CIs) were estimated using the Kaplan-Meier method. Adjusted hazard ratios (HRs), 95% CIs, and p values for concomitant BTT versus no BTT were obtained via Cox models. Results and limitations While the post hoc nature of the analysis is a limitation, superiority of AA and prednisone versus prednisone alone was demonstrated for clinical outcomes with or without BTT use. Compared with no BTT use, concomitant BTT significantly improved OS (HR 0.75; p = 0.01) and increased the time to ECOG deterioration (HR 0.75; p < 0.001) and time to opiate use for cancer-related pain (HR 0.80; p = 0.036). The safety profile of concomitant BTT with AA was similar to that reported for AA in the overall intent-to-treat population. Osteonecrosis of the jaw (all grade 1/2) with concomitant BTT use was reported in <3% of patients. Conclusions AA with concomitant BTT was safe and well tolerated in men with chemotherapy

  11. Translational and clinical implications of the genetic landscape of prostate cancer.

    Science.gov (United States)

    Spratt, Daniel E; Zumsteg, Zachary S; Feng, Felix Y; Tomlins, Scott A

    2016-10-01

    Over the past several years, analyses of data from high-throughput studies have elucidated many fundamental insights into prostate cancer biology. These insights include the identification of molecular alterations and subtypes that drive tumour progression, recurrent aberrations in signalling pathways, the existence of substantial intertumoural and intratumoural heterogeneity, Darwinian evolution in response to therapeutic pressures and the complicated multidirectional patterns of spread between primary tumours and metastatic sites. However, these concepts have not yet been fully translated into clinical tools to improve prognostication, prediction and personalization of treatment of patients with prostate cancer. The current and future clinical implications of 'omics' level knowledge is not only revolutionizing our understanding of prostate cancer biology, but is also shaping ongoing, and future clinical investigations and practice. In this Review, we summarize these advances, and the remaining challenges surrounding tumour heterogeneity and the ability to overcome treatment resistance are also described.

  12. Intermittent Chemotherapy as a Platform for Testing Novel Agents in Patients With Metastatic Castration-Resistant Prostate Cancer: A Department of Defense Prostate Cancer Clinical Trials Consortium Randomized Phase II Trial of Intermittent Docetaxel With Prednisone With or Without Maintenance GM-CSF.

    Science.gov (United States)

    Aggarwal, Rahul R; Beer, Tomasz M; Weinberg, Vivian K; Higano, Celestia; Taplin, Mary-Ellen; Ryan, Charles J; Lin, Amy M; Alumkal, Joshi; Graff, Julie N; Nordquist, Luke T; Herrera, Isheen; Small, Eric J

    2015-06-01

    Immunotherapy with granulocyte-macrophage colony-stimulating factor (GM-CSF), an agent that previously demonstrated antitumor activity, was evaluated within an intermittent chemotherapy framework of docetaxel with prednisone (D+P) in metastatic castration-resistant prostate cancer (mCRPC). mCRPC patients with ≥ 50% prostate-specific antigen (PSA) decline after 6 cycles of D+P were randomized to either GM-CSF or observation (Obs). At disease progression (PD), D+P was reinitiated for 6 cycles followed by the same "off chemotherapy" regimen in patients eligible for chemotherapy interruption. The sequence was repeated until PD during chemotherapy, lack of PSA response to chemotherapy, or unacceptable toxicity. The primary end point was time to chemotherapy resistance (TTCR). Of 125 patients enrolled, 52 (42%) experienced ≥ 50% PSA decline on induction D+P and were randomized to GM-CSF (n = 27) or Obs (n = 25). The median time to PD was 3.3 months (95% confidence interval [CI], 2.4-3.5) and 1.5 months (95% CI, 1.5-2.4) during the initial course of GM-CSF and Obs, respectively. Twelve of 26 (46%) patients responded to a second course of D+P. Eleven randomized patients (21%) experienced PD during chemotherapy, precluding accurate assessment of TTCR. The remaining 41 randomized patients discontinued study for lack of PSA response to chemotherapy (n = 8), patient choice to not restart chemotherapy with PSA PD (n = 13), toxicity (n = 7), or study withdrawal (n = 13). Conducting a prospective study in mCRPC with maintenance immunotherapy within the framework of intermittent chemotherapy was feasible. The use of PSA instead of radiographic end points limited the number of evaluable patients. This study provides important insight into designing contemporary intermittent chemotherapy trials with maintenance immunotherapy in patients with advanced prostate cancer. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. Efficacy and Safety of Combined Androgen Deprivation Therapy (ADT and Docetaxel Compared with ADT Alone for Metastatic Hormone-Naive Prostate Cancer: A Systematic Review and Meta-Analysis.

    Directory of Open Access Journals (Sweden)

    Tobias Engel Ayer Botrel

    Full Text Available Prostate cancer is the most common nonskin cancer and second most common cause of cancer mortality in older men in the United States (USA and Western Europe. Androgen-deprivation therapy alone (ADT remains the first line of treatment in most cases, for metastatic disease. We performed a systematic review and meta-analysis of all randomized controlled trials (RCT that compared the efficacy and adverse events profile of a chemohormonal therapy (ADT ± docetaxel for metastatic hormone-naive prostate cancer (mHNPC.Several databases were searched, including MEDLINE, EMBASE, LILACS, and CENTRAL. The primary endpoint was overall survival. Data extracted from the studies were combined by using the hazard ratio (HR or risk ratio (RR with their corresponding 95% confidence intervals (95% CI.The final analysis included 3 trials comprising 2,264 patients (mHNPC. Patients who received the chemohormonal therapy had a longer clinical progression-free survival interval (HR = 0.64; 95% CI: 0.55 to 0.75; p<0.00001, and no heterogeneity (Chi2 = 0.64; df = 1 [p = 0.42]; I2 = 0%. The biochemical progression-free survival (bPFS also was higher in patients treated with ADT plus docetaxel (HR = 0.63; 95% CI: 0.57 to 0.69; p<0.00001, also with no heterogeneity noted (Chi2 = 0.48; df = 2 [p = 0.79]; I2 = 0%. Finally, the combination of ADT with docetaxel showed a superior overall survival (OS compared with ADT alone (HR = 0.73; 95% CI: 0.64 to 0.84; p<0.0001, with moderate heterogeneity (Chi2 = 3.84; df = 2 [p = 0.15]; I2 = 48%. A random-effects model analysis was performed, and the results remained favorable to the use of ADT plus docetaxel (HR = 0.73; 95% CI: 0.60 to 0.89; p = 0.002. In the final combined analysis of the high-volume disease patients, the use of the combination therapy also favored an increased overall survival (HR = 0.67; 95% CI: 0.54 to 0.83; p = 0.0003. Regarding adverse events and severe toxicity (grade ≥3, the group receiving the combined therapy

  14. Radium-223-Dichloride in Castration Resistant Metastatic Prostate Cancer—Preliminary Results of the Response Evaluation Using F-18-Fluoride PET/CT

    Directory of Open Access Journals (Sweden)

    Kalevi Kairemo

    2015-10-01

    Full Text Available The purpose of this study was to evaluate the outcome after Radium-223-dichloride (223RaCl2 treatment of patients with skeletal metastases of castration resistant prostate cancer using whole-body 18F-Fluoride PET/CT. Sodium 18F-fluoride [18F]-NaF PET/CT was performed prior the treatment of 223RaCl2, after the first cycle and after the sixth cycle. The skeletal metastases were analyzed quantitatively using modified PET response evaluation PERCIST criteria. The patients were also analyzed for S-PSA. All ten patients responded in [18F]-NaF scans after 6 cycles, but interim analysis after the 1st cycle did not give additional information about the outcome. The S-PSA decrease correlated with [18F]-NaF response, only 1 patient demonstrated progressive disease, i.e., >25% increase in S-PSA values during 223RaCl2. Our results (although preliminary suggest that 18F-Fluoride PET/CT is useful in the follow-up of castration resistant prostate cancer with skeletal metastases.

  15. By inhibiting snail signaling and miR-23a-3p, osthole suppresses the EMT-mediated metastatic ability in prostate cancer.

    Science.gov (United States)

    Wen, Yu-Ching; Lee, Wei-Jiunn; Tan, Peng; Yang, Shun-Fa; Hsiao, Michael; Lee, Liang-Ming; Chien, Ming-Hsien

    2015-08-28

    Here we showed that Osthole, 7-methoxy-8-(3-methyl-2-butenyl) coumarin, a bioactive coumarin derivative extracted from medicinal plants, inhibited migration, invasion, epithelial to mesenchymal transition (EMT) in androgen-independent prostate cancer (AIPC) cells in vitro and metastasis of AIPC in vivo. In patients, high Snail levels were correlated with a higher histological Gleason sum and poor survival rates. Osthole inhibited the TGF-β/Akt/MAPK pathways, reduced Snail-DNA-binding activity and induced E-cadherin. We found that osthole decreased miR-23a-3p. Ectopic miR-23a-3p suppressed E-cadherin 3' untranslated region reporter activity and E-cadherin expression, and relieved the motility suppression caused by osthole treatment.

  16. The E1 copper binding domain of full-length amyloid precursor protein mitigates copper-induced growth inhibition in brain metastatic prostate cancer DU145 cells

    Energy Technology Data Exchange (ETDEWEB)

    Gough, Mallory, E-mail: m.gough1@lancaster.ac.uk; Blanthorn-Hazell, Sophee, E-mail: s.blanthorn-hazell@lancaster.ac.uk; Delury, Craig, E-mail: c.delury@lancaster.ac.uk; Parkin, Edward, E-mail: e.parkin@lancaster.ac.uk

    2014-10-31

    Highlights: • Copper levels are elevated in the tumour microenvironment. • APP mitigates copper-induced growth inhibition of DU145 prostate cancer (PCa) cells. • The APP intracellular domain is a prerequisite; soluble forms have no effect. • The E1 CuBD of APP is also a prerequisite. • APP copper binding potentially mitigates copper-induced PCa cell growth inhibition. - Abstract: Copper plays an important role in the aetiology and growth of tumours and levels of the metal are increased in the serum and tumour tissue of patients affected by a range of cancers including prostate cancer (PCa). The molecular mechanisms that enable cancer cells to proliferate in the presence of elevated copper levels are, therefore, of key importance in our understanding of tumour growth progression. In the current study, we have examined the role played by the amyloid precursor protein (APP) in mitigating copper-induced growth inhibition of the PCa cell line, DU145. A range of APP molecular constructs were stably over-expressed in DU145 cells and their effects on cell proliferation in the presence of copper were monitored. Our results show that endogenous APP expression was induced by sub-toxic copper concentrations in DU145 cells and over-expression of the wild-type protein was able to mitigate copper-induced growth inhibition via a mechanism involving the cytosolic and E1 copper binding domains of the full-length protein. APP likely represents one of a range of copper binding proteins that PCa cells employ in order to ensure efficient proliferation despite elevated concentrations of the metal within the tumour microenvironment. Targeting the expression of such proteins may contribute to therapeutic strategies for the treatment of cancers.

  17. Exosomes from bulk and stem cells from human prostate cancer have a differential microRNA content that contributes cooperatively over local and pre-metastatic niche.

    Science.gov (United States)

    Sánchez, Catherine A; Andahur, Eliana I; Valenzuela, Rodrigo; Castellón, Enrique A; Fullá, Juan A; Ramos, Christian G; Triviño, Juan C

    2016-01-26

    The different prostate cancer (PCa) cell populations (bulk and cancer stem cells, CSCs) release exosomes that contain miRNAs that could modify the local or premetastatic niche. The analysis of the differential expression of miRNAs in exosomes allows evaluating the differential biological effect of both populations on the niche, and the identification of potential biomarkers and therapeutic targets. Five PCa primary cell cultures were established to originate bulk and CSCs cultures. From them, exosomes were purified by precipitation for miRNAs extraction to perform a comparative profile of miRNAs by next generation sequencing in an Illumina platform. 1839 miRNAs were identified in the exosomes. Of these 990 were known miRNAs, from which only 19 were significantly differentially expressed: 6 were overexpressed in CSCs and 13 in bulk cells exosomes. miR-100-5p and miR-21-5p were the most abundant miRNAs. Bioinformatics analysis indicated that differentially expressed miRNAs are highly related with PCa carcinogenesis, fibroblast proliferation, differentiation and migration, and angiogenesis. Besides, miRNAs from bulk cells affects osteoblast differentiation. Later, their effect was evaluated in normal prostate fibroblasts (WPMY-1) where transfection with miR-100-5p, miR-21-5p and miR-139-5p increased the expression of metalloproteinases (MMPs) -2, -9 and -13 and RANKL and fibroblast migration. The higher effect was achieved with miR21 transfection. As conclusion, miRNAs have a differential pattern between PCa bulk and CSCs exosomes that act collaboratively in PCa progression and metastasis. The most abundant miRNAs in PCa exosomes are interesting potential biomarkers and therapeutic targets.

  18. A short account of metastatic bone disease

    Directory of Open Access Journals (Sweden)

    Lemmer Johan

    2011-07-01

    Full Text Available Abstract In adults, bone is the preferential target site for metastases from primary cancers of prostate, breast, lungs and thyroid. The tendency of these cancers to metastasize to bone is determined by the anatomical distribution of the blood vessels, by the genetic profile of the cancer cells and by the biological characteristics of the bone microenvironment that favour the growth of metastatic cells of certain cancers. Metastases to bone may have either an osteolytic or an ostoblastic phenotype. The interaction in the bone microenvironment between biological factors secreted by metastatic cells, and by osteoblasts and osteoclasts, and the osteolytic and osteoblastic factors released from the organic matrix mediate a vicious cycle characterized by metastatic growth and by ongoing progressive bone destruction. This interaction determines the phenotype of the metastatic bone disease.

  19. Targeting Neuropilin-1 in Prostate Cancer Bone Metastasis

    Science.gov (United States)

    2010-04-01

    leukemia (Mcl-1) as a novel downstream target of NRP1 signaling in metastatic prostate cancer cells. During the third year of the supporting period...supporting period, we identified myeloid cell leukemia -1 (Mcl-1) as a novel downstream target of NRP1 signaling in bone metastatic prostate cancer cells...myeloid cell leukemia -1 expression through neuropilin-1-dependent activation of c-MET signaling in human prostate cancer cells. Molecular Cancer , 2010

  20. The E1 copper binding domain of full-length amyloid precursor protein mitigates copper-induced growth inhibition in brain metastatic prostate cancer DU145 cells.

    Science.gov (United States)

    Gough, Mallory; Blanthorn-Hazell, Sophee; Delury, Craig; Parkin, Edward

    2014-10-31

    Copper plays an important role in the aetiology and growth of tumours and levels of the metal are increased in the serum and tumour tissue of patients affected by a range of cancers including prostate cancer (PCa). The molecular mechanisms that enable cancer cells to proliferate in the presence of elevated copper levels are, therefore, of key importance in our understanding of tumour growth progression. In the current study, we have examined the role played by the amyloid precursor protein (APP) in mitigating copper-induced growth inhibition of the PCa cell line, DU145. A range of APP molecular constructs were stably over-expressed in DU145 cells and their effects on cell proliferation in the presence of copper were monitored. Our results show that endogenous APP expression was induced by sub-toxic copper concentrations in DU145 cells and over-expression of the wild-type protein was able to mitigate copper-induced growth inhibition via a mechanism involving the cytosolic and E1 copper binding domains of the full-length protein. APP likely represents one of a range of copper binding proteins that PCa cells employ in order to ensure efficient proliferation despite elevated concentrations of the metal within the tumour microenvironment. Targeting the expression of such proteins may contribute to therapeutic strategies for the treatment of cancers.

  1. The Effect of Prior Androgen Synthesis Inhibition on Outcomes of Subsequent Therapy with Docetaxel in Patients with Metastatic Castrate Resistant Prostate Cancer: Results from a Retrospective Analysis of a Randomized Phase 3 Clinical Trial (CALGB 90401) (Alliance)

    Science.gov (United States)

    Aggarwal, Rahul; Halabi, Susan; Kelly, William Kevin; George, Daniel; Mahoney, John F.; Millard, Frederick; Stadler, Walter M.; Morris, Michael J.; Kantoff, Philip; Monk, J. Paul; Carducci, Michael; Small, Eric J.

    2013-01-01

    Background Preliminary data suggests a potential decreased benefit of docetaxel in metastatic castration-resistant prostate cancer (mCRPC) patients previously treated with abiraterone acetate, a novel androgen synthesis inhibitor (ASI). CALGB 90401 (Alliance), a phase 3 trial of mCRPC patients treated with docetaxel-based chemotherapy, offered the opportunity to evaluate effect of prior ketoconazole, an earlier generation ASI, on clinical outcomes following docetaxel. Methods CALGB 90401 randomized 1050 men with chemotherapy-naïve, mCRPC to treatment with docetaxel and prednisone with either bevacizumab or placebo. 1005 men (96%) had data available regarding prior ketoconazole therapy. The effect of prior ketoconazole on overall survival (OS), progression-free survival (PFS), PSA decline, and objective response rate (ORR) observed was assessed using proportional hazards and Poisson regression method adjusted for validated prognostic factors and treatment arm. Results Baseline characteristics between patients with (N=277) and without (N=728) prior ketoconazole therapy were similar. There were no statistically significant differences between patients with and without prior ketoconazole therapy with respect to OS (median OS 21.1 vs. 22.3 months, stratified log-rank p-value=0.635); PFS (median PFS 8.1 vs. 8.6 months, stratified log-rank p-value=0.342); ≥50% PSA decline (61% vs. 66%, relative risk=1.09, adjusted p-value=0.129); or ORR (39% vs. 43%, relative risk=1.11, adjusted p-value=0.366). Conclusions As measured by OS, PFS, PSA and ORR, there is no evidence that prior treatment with ketoconazole impacts clinical outcomes in mCRPC patients treated with subsequent docetaxel-based therapy. Prospective studies are needed to assess for potential cross-resistance with novel ASIs and to define the optimal sequence of therapy in mCRPC. PMID:23913744

  2. Orbital metastases of prostatic carcinoma in a tropical African ...

    African Journals Online (AJOL)

    A tru-cut biopsy of the prostate revealed adenocarcinoma of the prostate gland. ... because of the risk to the eye. He had ..... ocular metastases as an initial sign of metastatic lung can- cer. Ophthalmic ... related risk factors for prostate cancer.

  3. Organoid culture systems for prostate epithelial and cancer tissue

    NARCIS (Netherlands)

    Drost, Jarno; Karthaus, Wouter R; Gao, Dong; Driehuis, Else; Sawyers, Charles L; Chen, Yu; Clevers, Hans

    2016-01-01

    This protocol describes a strategy for the generation of 3D prostate organoid cultures from healthy mouse and human prostate cells (either bulk or FACS-sorted single luminal and basal cells), metastatic prostate cancer lesions and circulating tumor cells. Organoids derived from healthy material cont

  4. Prostate Ultrasound

    Medline Plus

    Full Text Available ... the prostate is enlarged, also known as benign prostatic hyperplasia (BPH) , with measurements acquired as needed for any ... size with caption Related Articles and Media Benign Prostatic Hyperplasia (BPH) Prostate Cancer Ultrasound- and MRI-Guided Prostate ...

  5. Prostate Ultrasound

    Medline Plus

    Full Text Available ... prostate is enlarged, also known as benign prostatic hyperplasia (BPH) , with measurements acquired as needed for any ... with caption Related Articles and Media Benign Prostatic Hyperplasia (BPH) Prostate Cancer Ultrasound- and MRI-Guided Prostate ...

  6. Collision tumor of kidney: A case of renal cell carcinoma with metastases of prostatic adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Monika Vyas

    2013-01-01

    Full Text Available Simultaneous occurrence of prostatic adenocarcinoma and renal cell carcinoma is well documented in the literature. However, metastatic prostatic adenocarcinoma in a kidney harboring a renal cell carcinoma (RCC is quite rare. Although renal cell carcinoma is the most common tumor that can harbor metastasis, metastatic prostatic adenocarcinoma in a kidney harboring a RCC is quite rare. There are four cases in the literature showing metastasis of prostatic adenocarcinoma to RCC. However, as per our knowledge, this is the first case of a collision between RCC and metastatic prostatic adenocarcinoma.

  7. Clinical Implications of Hedgehog Pathway Signaling in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Daniel L. Suzman

    2015-09-01

    Full Text Available Activity in the Hedgehog pathway, which regulates GLI-mediated transcription, is important in organogenesis and stem cell regulation in self-renewing organs, but is pathologically elevated in many human malignancies. Mutations leading to constitutive activation of the pathway have been implicated in medulloblastoma and basal cell carcinoma, and inhibition of the pathway has demonstrated clinical responses leading to the approval of the Smoothened inhibitor, vismodegib, for the treatment of advanced basal cell carcinoma. Aberrant Hedgehog pathway signaling has also been noted in prostate cancer with evidence suggesting that it may render prostate epithelial cells tumorigenic, drive the epithelial-to-mesenchymal transition, and contribute towards the development of castration-resistance through autocrine and paracrine signaling within the tumor microenvironment and cross-talk with the androgen pathway. In addition, there are emerging clinical data suggesting that inhibition of the Hedgehog pathway may be effective in the treatment of recurrent and metastatic prostate cancer. Here we will review these data and highlight areas of active clinical research as they relate to Hedgehog pathway inhibition in prostate cancer.

  8. Prostate-specific antigen-activated thapsigargin prodrug as targeted therapy for prostate cancer

    DEFF Research Database (Denmark)

    Denmeade, Samuel R; Jakobsen, Carsten M; Janssen, Samuel

    2003-01-01

    Standard anti-proliferative chemotherapy is relatively ineffective against slowly proliferating androgen-independent prostate cancer cells within metastatic sites. In contrast, the lipophilic cytotoxin thapsigargin, which causes apoptosis by disrupting intracellular free Ca2+ levels, is effective...

  9. First Line Androgen Deprivation Therapy Duration Is Associated with the Efficacy of Abiraterone Acetate Treated Metastatic Castration-Resistant Prostate Cancer after Docetaxel

    Science.gov (United States)

    Li, Jian-Ri; Wang, Shian-Shiang; Yang, Cheng-Kuang; Chen, Chuan-Su; Ho, Hao-Chung; Chiu, Kun-Yuan; Hung, Chi-Feng; Cheng, Chen-Li; Yang, Chi-Rei; Chen, Cheng-Che; Wang, Shu-Chi; Lin, Chia-Yen; Ou, Yen-Chuan

    2017-01-01

    Introduction: We performed a chart review study in our castration-resistant prostate cancer (CRPC) patients who received Abiraterone acetate (AA) treatment after docetaxel and identified clinical markers which can predict treatment outcome. Materials and Methods: From 2012 to 2016, 64 patients who received docetaxel after CRPC followed by AA treatment were included. Clinical parameters were recorded and analysis was performed to identify associations between pre-treatment variables and treatment outcome. Results: Thirty three patients (51.6%) achieved a decrease in PSA of 50%. The median PSA progression-free survival and overall survival in the total cohort of 64 patients were 6.6 and 24 months, respectively. Adverse events (AEs) in all grades developed in 35.9% (23/64) patients and mostly were grade 1 or 2. The most common AEs were gastric upset, hypokalemia and elevated liver function tests. Of the eight variables analyzed, first line androgen deprivation therapy (ADT) duration showed positive association to progression free survival (HR 0.98, 95% CI [0.96–0.99], p = 0.012) and overall survival (HR 0.97, 95% CI [0.94–0.99], p = 0.019). Pre-AA PSA and PSA progression ratio showed negative association only to progression free survival (HR 1.0, 95% CI [1.000–1.002], p = 0.025, HR 1.01, 95% CI [1.00–1.01], p < 0.001, respectively). Conclusion: First line ADT duration was positively associated with AA treatment efficacy in progression free survival and overall survival. It can be used as a pre-treatment predictor. PMID:28243202

  10. Prostate Cancer Presenting with Parietal Bone Metastasis

    Science.gov (United States)

    Pare, Abdoul Karim; Abubakar, Babagana Mustapha; Kabore, Moussa

    2017-01-01

    Bone metastases from prostate cancer are very common. They are usually located on the axial skeleton. However, cranial bone metastases especially to the parietal bone are rare. We report a case of metastatic prostate cancer presenting with left parietal bone metastasis in a patient with no urological symptoms or signs. We should consider prostate cancer in any man above 60 years presenting unusual bone lesions.

  11. Number needed to treat and associated incremental costs of treatment with enzalutamide versus abiraterone acetate plus prednisone in chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.

    Science.gov (United States)

    Massoudi, Marjan; Balk, Mark; Yang, Hongbo; Bui, Cat N; Pandya, Bhavik J; Guo, Jenny; Song, Yan; Wu, Eric Q; Brown, Bruce; Barlev, Arie; Flanders, Scott

    2017-02-01

    Enzalutamide (ENZA) and abiraterone acetate plus prednisone (AA) are approved second-generation hormone therapies for chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). This study compared ENZA with AA in chemotherapy-naïve mCRPC by calculating the number needed to treat (NNT) and associated incremental costs to achieve one additional chemotherapy-naïve patient with mCRPC free of radiographic progression, chemotherapy, or death over a 1-year time horizon. Clinical outcomes were obtained from the PREVAIL and COU-AA-302 trials. Three outcomes were evaluated: radiographic progression-free survival, time to cytotoxic chemotherapy initiation, and overall survival at 1 year. NNT was calculated as the reciprocal of the outcome event rate difference for ENZA compared with AA. The incremental costs to achieve one additional outcome at 1 year were calculated as the difference in cost per treated patient multiplied by the NNT. Per-treated-patient costs were considered from a US payer perspective and included medications, monitoring, adverse events, post-progression treatments, and end-of-life care. Within a 1-year time horizon, the total cost per treated patient for ENZA was $2,666 less than AA. Compared with AA, treating 14 patients with ENZA resulted in one additional patient free of progression or death over 1 year; treating 26 patients with ENZA resulted in one additional patient with chemotherapy delayed over 1 year; and treating 91 patients with ENZA resulted in one additional patient free of death over 1 year. Therefore, ENZA is cost-effective compared with AA for all three outcomes evaluated, and the modeled results suggest ENZA is associated with potentially improved clinical outcomes in delaying chemotherapy initiation and disease progression for chemotherapy-naïve patients. The results are robust in sensitivity analyses, where the effect of changes in key model inputs and assumptions were tested. The results modeled in the present study

  12. Treatment of metastatic bone pain with strontium-89.

    Science.gov (United States)

    Robinson, R G; Spicer, J A; Preston, D F; Wegst, A V; Martin, N L

    1987-01-01

    We have utilized 89Sr as palliative treatment for bone pain secondary to metastatic cancer in the skeleton of over 200 patients. The best results have been in patients with carcinoma of the prostate (80% response rate) and breast (89%). Results in a small number of patients with a variety of other cell types were not nearly as encouraging. Strontium-89 provides excellent palliation in the management of bone pain secondary to prostate and breast carcinoma.

  13. Prostate Ultrasound

    Medline Plus

    Full Text Available ... as detailed as with the transrectal probe. An MRI of the pelvis may be obtained as an ... Benign Prostatic Hyperplasia (BPH) Prostate Cancer Ultrasound- and MRI-Guided Prostate Biopsy Images related to Ultrasound - Prostate ...

  14. Prostate Ultrasound

    Medline Plus

    Full Text Available ... patient consultation. View full size with caption Related Articles and Media Benign Prostatic Hyperplasia (BPH) (Enlargement of the Prostate) Prostate Cancer Ultrasound- and MRI-Guided Prostate Biopsy Images related ...

  15. Prostate Ultrasound

    Science.gov (United States)

    ... News Physician Resources Professions Site Index A-Z Ultrasound - Prostate Ultrasound of the prostate uses sound waves ... the limitations of Prostate Ultrasound Imaging? What is Ultrasound Imaging of the Prostate? Ultrasound is safe and ...

  16. 前列腺癌组织中雄激素受体剪接变异体7的表达对转移性前列腺癌患者总生存的影响%Impact of AR-V7 expression on overall survival for patients with metastatic prostate cancer

    Institute of Scientific and Technical Information of China (English)

    瞿元元; 叶定伟; 戴波; 孔蕴毅; 常坤; 顾成元; 孙自捷; 张海梁; 朱耀

    2014-01-01

    Objective To investigate the impact of androgen receptor splice variant 7 (AR-V7) expression on overall survival for patients with metastatic prostate cancer.Methods The data of 113 diagnosed metastatic prostate cancer patients from January 2002 to June 2010 were collected retrospectively,including patient's age at diagnosis,prostate-specific antigen (PSA) level at diagnosis,Gleason score,clinical stage,PSA nadir during hormonal therapy,the time to PSA nadir,vital status,survival time and cause of death.The expression of AR-V7 in prostate cancer tissue was detected by using immunohistochemical staining.The correlation of AR-V7 expression and patient clinicopathological characteristics in all patients were analysed using Student t-test or Chi-square test.Cox proportional hazards regression models were used to evaluate the predictive role of AR-V7 expression and patient characteristics for overall survival.Results The median PSA nadir was 0.7 μg/L (ranged from 0.0 to 143.0 μg/L).The median time to PSA nadir was 8.1 months (ranged from 0.9 to 71.0 months).The follow-up was performed until March 12,2014.During the follow-up period,67 of 113 metastatic prostate cancer patients (59.3%) died and the median overall survival was 96 months (ranged from 5 to 135 months).The AR-V7 detection rate was 20.4% (23/113).The serum PSA level in patients with positively expression of AR-V7 was significantly higher than that without AR-V7 expression (t =2.521,P =0.013).Multivariate Cox regression analysis indicated that the expression of AR-V7 (HR =2.421,P =0.002) and time to PSA nadir (HR =1.019,P =0.022) were independent prognostic factors of overall survival for metastatic prostate cancer patients.Conclusions The expression of AR-V7 in prostate cancer tissues and time to PSA nadir during hormonal therapy are independent prognostic factors of overall survival for metastatic prostate cancer patients.Therapy targeting AR-V7 may improve prognosis of metastatic prostate cancer

  17. VEGF and prostatic cancer: a systematic review.

    Science.gov (United States)

    Botelho, Francisco; Pina, Francisco; Lunet, Nuno

    2010-09-01

    Elevated vascular endothelial growth factor (VEGF) blood concentration reflects its prostatic production, making this a potentially interesting tumour marker to support the decision of submitting a patient for prostatic biopsy. The objective was to review systematically the evidence on the role of VEGF blood concentration in prostate cancer detection. Published studies addressing the relation between serum or plasma VEGF levels and prostate cancer were identified by searching Pubmed, ISI Web of Knowledge, SCOPUS and LILACS up to January 2010, and reviewed following a standardized protocol. Three studies reported higher plasma VEGF (pg/ml) in patients with localized prostate cancer than in healthy controls (7.0 vs. 0.0, 9.9 vs. 2.2, and 210 vs. 26.5, Pprostate cancer patients than in patients with benign prostate hypertrophy (518.9 vs. 267.9, Pbenign prostate hypertrophy, localized or metastatic prostate cancer. The three studies that used controls with previous suspicion of prostatic cancer but a negative biopsy reported non-statistically significant difference in VEGF serum levels (pg/ml) between controls and localized prostate cancer patients (241 vs. 206; 69.5 vs. 55; 215.2 vs. 266.4). Higher VEGF plasma levels are observed in prostatic cancer patients compared with healthy controls, but serum levels do not appear to be useful in differentiating benign from malignant prostatic disease using, as controls, individuals with high risk of prostate cancer and negative biopsy.

  18. Generalized Lymphadenopathy: Unusual Presentation of Prostate Adenocarcinoma

    Directory of Open Access Journals (Sweden)

    Bulent Cetin

    2011-01-01

    Full Text Available Generalized lymphadenopathy is a rare manifestation of metastatic prostate cancer. Here, we report the case of a 59-year-old male patient with supraclavicular, mediastinal, hilar, and retroperitoneal and inguinal lymphadenopathy, which suggested the diagnosis of lymphoma. There were no urinary symptoms. A biopsy of the inguinal lymph node was compatible with adenocarcinoma, whose prostatic origin was shown by immunohistochemical staining with PSA. The origin of the primary tumor was confirmed by directed prostate biopsy. We emphasize that a suspicion of prostate cancer in men with adenocarcinoma of undetermined origin is important for an adequate diagnostic and therapeutic approach.

  19. Pattern of metastatic deposits of malignant neoplasms to the chest ...

    African Journals Online (AJOL)

    Pattern of metastatic deposits of malignant neoplasms to the chest seen on plain ... chest x-ray (CXR) is a veritable tool in the survey of metastases to the lung. ... from breast, prostate, thyroid and cervix Rare from osteosarcoma and melanoma.

  20. Prostate specific membrane antigen- a target for imaging and therapy with radionuclides

    DEFF Research Database (Denmark)

    Bouchelouche, Kirsten; Choyke, Peter L; Capala, Jacek

    2010-01-01

    Prostate cancer continues to represent a major health problem, and yet there is no effective treatment available for advanced metastatic disease. Thus, there is an urgent need for the development of more effective treatment modalities that could improve the outcome. Because prostate specific memb...... to become both diagnostic and/or therapeutic agents. The use of PSMA binding agents, labelled with diagnostic and therapeutic radio-isotopes, opens up the potential for a new era of personalized management of metastatic prostate cancer....

  1. Parathyroid hormone-related protein drives a CD11b+Gr1+ cell-mediated positive feedback loop to support prostate cancer growth.

    Science.gov (United States)

    Park, Serk In; Lee, Changki; Sadler, W David; Koh, Amy J; Jones, Jacqueline; Seo, Jung Won; Soki, Fabiana N; Cho, Sun Wook; Daignault, Stephanie D; McCauley, Laurie K

    2013-11-15

    In the tumor microenvironment, CD11b(+)Gr1(+) bone marrow-derived cells are a predominant source of protumorigenic factors such as matrix metalloproteinases (MMP), but how distal tumors regulate these cells in the bone marrow is unclear. Here we addressed the hypothesis that the parathyroid hormone-related protein (PTHrP) potentiates CD11b(+)Gr1(+) cells in the bone marrow of prostate tumor hosts. In two xenograft models of prostate cancer, levels of tumor-derived PTHrP correlated with CD11b(+)Gr1(+) cell recruitment and microvessel density in the tumor tissue, with evidence for mediation of CD11b(+)Gr1(+) cell-derived MMP-9 but not tumor-derived VEGF-A. CD11b(+)Gr1(+) cells isolated from mice with PTHrP-overexpressing tumors exhibited relatively increased proangiogenic potential, suggesting that prostate tumor-derived PTHrP potentiates this activity of CD11b(+)Gr1(+) cells. Administration of neutralizing PTHrP monoclonal antibody reduced CD11b(+)Gr1(+) cells and MMP-9 in the tumors. Mechanistic investigations in vivo revealed that PTHrP elevated Y418 phosphorylation levels in Src family kinases in CD11b(+)Gr1(+) cells via osteoblast-derived interleukin-6 and VEGF-A, thereby upregulating MMP-9. Taken together, our results showed that prostate cancer-derived PTHrP acts in the bone marrow to potentiate CD11b(+)Gr1(+) cells, which are recruited to tumor tissue where they contribute to tumor angiogenesis and growth. ©2013 AACR

  2. The European Medicines Agency Review of Abiraterone for the Treatment of Metastatic Castration-Resistant Prostate Cancer in Adult Men After Docetaxel Chemotherapy and in Chemotherapy-Naïve Disease: Summary of the Scientific Assessment of the Committee for Medicinal Products for Human Use

    Science.gov (United States)

    Lopez, Arantxa Sancho; Hemmings, Robert James; Jiménez, Jorge Camarero; Garcia-Carbonero, Rocio; Gallego, Isabel García; Giménez, Elena Valencia; O'Connor, Daniel; Giuliani, Rosa; Salmonson, Tomas; Pignatti, Francesco

    2013-01-01

    On September 5, 2011, abiraterone was approved in the European Union in combination with prednisone or prednisolone for the treatment of metastatic castration-resistant prostate cancer (CRPC) in adult men whose disease has progressed on or after a docetaxel-based chemotherapy regimen. On December 18, 2012, the therapeutic indication was extended to include the use of abiraterone in combination with prednisone or prednisolone for the treatment of metastatic CRPC in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated. Abiraterone is a selective, irreversible inhibitor of cytochrome P450 17α, an enzyme that is key in the production of androgens. Inhibition of androgen biosynthesis deprives prostate cancer cells from important signals for growth, even in cases of resistance to castration. At the time of European Union approval and in a phase III trial in CRPC patients who had failed at least one docetaxel-based chemotherapy regimen, median overall survival for patients treated with abiraterone was 14.8 months versus 10.9 months for those receiving placebo (hazard ratio, 0.65; 95% confidence interval 0.54–0.77; p < .0001). In a subsequent phase III trial in a similar but chemotherapy-naïve patient population, median radiographic progression-free survival was 16.5 months for patients in the abiraterone treatment arm versus 8.3 months for patients in the placebo arm (hazard ratio, 0.53; 95% confidence interval, 0.45–0.62; p < .0001). Abiraterone was most commonly associated with adverse reactions resulting from increased or excessive mineralocorticoid activity. These were generally manageable with basic medical interventions. The most common side effects (affecting more than 10% of patients) were urinary tract infection, hypokalemia, hypertension, and peripheral edema. PMID:23966222

  3. 非转移性细胞蛋白1基因在前列腺癌中的表达及临床意义%Non metastatic cell protein 1 expression and clinical significance in prostate cancer

    Institute of Scientific and Technical Information of China (English)

    伍信阳; 毕学成; 何慧婵; 江福能; 冯自卫; 付欣; 邓业瀚; 钟惟德

    2013-01-01

    目的 检测非转移性细胞蛋白1基因(NME1基因)在前列腺癌组织中的表达,探讨NME1在前列腺癌中的分子机制和临床意义.方法 应用基因芯片筛选出在前列腺癌与前列腺增生组织特异性表达的基因NME1,运用蛋白组学检测前列腺癌组织标本54例、癌旁组织29例、组织中NME1基因结合蛋白差异表达程度.免疫组织化学结合NME1免疫组织化学评分对前列腺癌患者的临床病理参数进行分析.结果 通过基因芯片筛选,可见NME1在前列腺癌组织中表达上调,达2.24倍(P<0.01).双向差异凝胶电泳(2D-DIGE)技术亦发现相对于癌旁组织NME1基因结合蛋白在前列腺癌组织中表达上调,达2.36倍(P<0.01).通过免疫组织化学染色,可见NME1在前列腺癌组织中的表达明显强于癌旁组织(P<0.01),在前列腺癌并转移组织中的表达亦明显强于原位前列腺癌组织(P<0.01).NME1表达与前列腺癌患者血清前列腺特异抗原(PSA)水平(P<0.05)、Gleason评分(P<0.01)和肿瘤TNM分期(P<0.05)、是否转移(P<0.01)呈正相关,而与患者年龄无明显相关(P>0.05).NME1阳性的前列腺癌患者预后不良(Log Rank=11.117,P<0.01).结论 NME1低表达与肿瘤的恶性程度相关,NME1缺失可能导致恶性肿瘤细胞迅速生长,可结合血清PSA水平对前列腺癌疑似患者进行早期诊断及初步判断肿瘤恶性程度.%Objective To explore the role of non metastatic cell protein 1 (NME1) in diagnosing prostate cancer (PCa) and judging early metastasis of PCa.Methods The gene chip was used to screen NME1 in PCa and benign prostatic hyperplasia (BPH) tissues,the differential expression of NME1 prostein in PCa and adjacent tissues was analyzed by using fluorescence 2-D difference gel electrophoresis (2DDIGE) technology,and validated by using immunohistochemistry (IHC).The NME1 IHC score and clinicopathological parameters of PCa patients were analyzed.Results Relative to BPH tissues

  4. The Multifaceted Roles of STAT3 Signaling in the Progression of Prostate Cancer

    Energy Technology Data Exchange (ETDEWEB)

    Bishop, Jennifer L.; Thaper, Daksh; Zoubeidi, Amina, E-mail: azoubeidi@prostatecentre.com [The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, 2660 Oak Street, Vancouver British Columbia, V6H 3Z6 (Canada)

    2014-04-09

    The signal transducer and activator of transcription (STAT)3 governs essential functions of epithelial and hematopoietic cells that are often dysregulated in cancer. While the role for STAT3 in promoting the progression of many solid and hematopoietic malignancies is well established, this review will focus on the importance of STAT3 in prostate cancer progression to the incurable metastatic castration-resistant prostate cancer (mCRPC). Indeed, STAT3 integrates different signaling pathways involved in the reactivation of androgen receptor pathway, stem like cells and the epithelial to mesenchymal transition that drive progression to mCRPC. As equally important, STAT3 regulates interactions between tumor cells and the microenvironment as well as immune cell activation. This makes it a major factor in facilitating prostate cancer escape from detection of the immune response, promoting an immunosuppressive environment that allows growth and metastasis. Based on the multifaceted nature of STAT3 signaling in the progression to mCRPC, the promise of STAT3 as a therapeutic target to prevent prostate cancer progression and the variety of STAT3 inhibitors used in cancer therapies is discussed.

  5. Liposomal nanomedicines in the treatment of prostate cancer

    NARCIS (Netherlands)

    Kroon, Jan; Metselaar, Josbert M; Storm, G|info:eu-repo/dai/nl/073356328; van der Pluijm, Gabri

    2014-01-01

    Prostate cancer is the most common cancer type and the second leading cause of death from cancer in males. In most cases, no curative treatment options are available for metastatic castration-resistant prostate cancer as these tumors are highly resistant to chemotherapy. Targeted drug delivery,

  6. Hormone-refractory prostate cancer and the skeleton

    NARCIS (Netherlands)

    Soerdjbalie-Maikoe, Vidija

    2006-01-01

    Prostate cancer is the second most common cancer in men in the UK. Androgen ablation with luteinising hormone-releasing hormone agonists (LHRH agonists) alone, or in combination with anti-androgens is the standard treatment for men with metastatic prostate cancer. Unfortunately, despite maximal andr

  7. Enzalutamide monotherapy in hormone-naive prostate cancer

    DEFF Research Database (Denmark)

    Tombal, Bertrand; Borre, Michael; Rathenborg, Per

    2014-01-01

    BACKGROUND: The androgen receptor inhibitor enzalutamide is approved for the treatment of metastatic castration-resistant prostate cancer that has progressed on docetaxel. Our aim was to assess the activity and safety of enzalutamide monotherapy in men with hormone-naive prostate cancer. METHODS:...

  8. Prostate Ultrasound

    Medline Plus

    Full Text Available ... Prostate Ultrasound Imaging? What is Ultrasound Imaging of the Prostate? Ultrasound is safe and painless, and produces ... of page What are some common uses of the procedure? A transrectal ultrasound of the prostate gland ...

  9. Prostate Ultrasound

    Medline Plus

    Full Text Available ... are the limitations of Prostate Ultrasound Imaging? What is Ultrasound Imaging of the Prostate? Ultrasound is safe ... transducer into the body. top of page How is the procedure performed? In men, the prostate gland ...

  10. Prostate Ultrasound

    Medline Plus

    Full Text Available ... Ultrasound - Prostate Ultrasound of the prostate uses sound waves to produce pictures of a man’s prostate gland ... of the inside of the body using sound waves. Ultrasound imaging, also called ultrasound scanning or sonography , ...

  11. Prostate Ultrasound

    Medline Plus

    Full Text Available ... Z Ultrasound - Prostate Ultrasound of the prostate uses sound waves to produce pictures of a man’s prostate ... pictures of the inside of the body using sound waves. Ultrasound imaging, also called ultrasound scanning or ...

  12. Prostate Ultrasound

    Medline Plus

    Full Text Available ... Prostate Ultrasound Imaging? What is Ultrasound Imaging of the Prostate? Ultrasound is safe and painless, and produces ... of page What are some common uses of the procedure? A transrectal ultrasound of the prostate gland ...

  13. Mitochondria, prostate cancer, and biopsy sampling error.

    Science.gov (United States)

    Parr, Ryan L; Mills, John; Harbottle, Andrew; Creed, Jennifer M; Crewdson, Gregory; Reguly, Brian; Guimont, François S

    2013-04-01

    Mitochondria and their associated genome are emerging as sophisticated indicators of prostate cancer biology. Alterations in the mitochondrial genome (mtgenome) have been implicated in cell proliferation, metastatic behavior, androgen independence, as a signal for apoptosis, and as a predictor of biochemical recurrence. Somatic mutation patterns in complete mtgenomes are associated with prostate specific antigen levels (PSA) in prostate cancer patients and a large-scale mtgenome deletion (3.4 kb) is consistent with a prostate "cancerization" field effect. This review will focus on the biological characteristics of mitochondria and their direct clinical application to prostate cancer. Mitochondrial science is currently influencing clinical prostate cancer diagnostics and the rapid progress in this area indicates future, break-through contributions in the general field of oncology.

  14. Epithelial-mesenchymal transition in prostate cancer: an overview.

    Science.gov (United States)

    Montanari, Micaela; Rossetti, Sabrina; Cavaliere, Carla; D'Aniello, Carmine; Malzone, Maria Gabriella; Vanacore, Daniela; Di Franco, Rossella; La Mantia, Elvira; Iovane, Gelsomina; Piscitelli, Raffaele; Muscariello, Raffaele; Berretta, Massimiliano; Perdonà, Sisto; Muto, Paolo; Botti, Gerardo; Bianchi, Attilio Antonio Montano; Veneziani, Bianca Maria; Facchini, Gaetano

    2017-05-23

    Prostate cancer is a main urological disease associated with significant morbidity and mortality. Radical prostatectomy and radiotherapy are potentially curative for localized prostate cancer, while androgen deprivation therapy is the initial systemic therapy for metastatic prostate disease. However, despite temporary response, most patients relapse and evolve into castration resistant cancer.Epithelial-mesenchymal transition (EMT) is a complex gradual process that occurs during embryonic development and/or tumor progression. During this process, cells lose their epithelial characteristics and acquire mesenchymal features. Increasing evidences indicate that EMT promotes prostate cancer metastatic progression and it is closely correlated with increased stemness and drug resistance.In this review, we discuss the main molecular events that directly or indirectly govern the EMT program in prostate cancer, in order to better define the role and the mechanisms underlying this process in prostate cancer progression and therapeutic resistance.

  15. Sipuleucel-T for the treatment of advanced prostate cancer.

    Science.gov (United States)

    Frohlich, Mark W

    2012-06-01

    Sipuleucel-T is an autologous cellular immunotherapy designed to stimulate an immune response to prostate cancer that prolongs the overall survival of men with asymptomatic or minimally symptomatic metastatic castrate-resistant prostate cancer (CRPC). The clinical development program and key efficacy, safety, and immune response findings from the phase III studies are presented. The integration of sipuleucel-T into the treatment paradigm of advanced prostate cancer and future directions for research are discussed.

  16. Evolving perspectives of the role of novel agents in androgen-independent prostate cancer

    Directory of Open Access Journals (Sweden)

    Sujith Kalmadi

    2008-01-01

    Full Text Available Metastatic androgen-independent prostate cancer presents an intriguing clinical challenge, with a subtle interaction between hormone-responsive and refractory tumor cell elements. The treatment of advanced prostate carcinoma, which had remained stagnant for several decades following the understanding of the link between androgenic stimulation and carcinogenesis, has now started to make steady headway with chemotherapy and targeted approaches. Metastatic prostate cancer is almost always treated with initial androgen deprivation, in various forms. However, despite such treatment androgen-independent prostate cancer cells eventually emerge and progress to threaten life. The therapeutic objectives for treatment of metastatic prostate cancer are to maintain the quality of life and prolong survival. The out-dated nihilistic dogma of deferring chemotherapy until the most advanced stages in advanced prostate cancer is now falling by the wayside with the development of newer effective, tolerable agents.

  17. MiR-203 controls proliferation, migration and invasive potential of prostate cancer cell lines

    DEFF Research Database (Denmark)

    Viticchiè, Giuditta; Lena, Anna Maria; Latina, Alessia;

    2011-01-01

    transition and invasion of healthy tissues (usually bones). MicroRNA-203 (miR-203) is a tumor suppressor microRNA often silenced in different malignancies. Here, we show that miR-203 is downregulated in clinical primary prostatic tumors compared to normal prostate tissue, and in metastatic prostate cancer...... cell lines compared to normal epithelial prostatic cells. Overexpression of miR-203 in brain or bone metastatic prostate cell lines (DU145 and PC3) is sufficient to induce a mesenchymal to epithelial transition with inhibition of cell proliferation, migration and invasiveness. We have identified CKAP2......, LASP1, BIRC5, WASF1, ASAP1 and RUNX2 as new miR-203 direct target mRNAs involved in these events. Therefore, miR-203 could be a potentially new prognostic marker and therapeutic target in metastatic prostate cancer....

  18. Hetero-bivalent Imaging Agents for Simultaneous Targeting Prostate-Specific Membrane Antigen (PSMA) and Hepsin

    Science.gov (United States)

    2013-09-01

    11, 12) Hepsin is a type II transmembrane serine protease which is preferentially expressed in neoplastic prostate over benign prostate . (13) In...addition, the mRNA level of hepsin was elevated in ~ 90% of PCa specimens and was > 10-fold higher in metastatic PCa than in normal prostate or benign ... prostatic hyperplasia (BPH). Hepsin is composed of 413 amino acids and a large C-terminal residue is located in the extracellular region. The serine

  19. Hormonal therapy and chemotherapy in patients with hormone-sensitive prostate cancer

    Directory of Open Access Journals (Sweden)

    R. A. Gafanov

    2016-01-01

    Full Text Available Prostate cancer is the most common men`s cancer in men in developed world and the second cause of death in this population. This review focuses on management of advanced castration resistant prostate cancer (CRPC has been rapidly changing and is still evolving. In the last years, there has been an increasing knowledge of prostate cancer biology. New therapeutic agents and approaches have been evaluated demonstrating benefits in survival and quality of life in patients with metastatic prostate cancer.

  20. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial

    DEFF Research Database (Denmark)

    Kwon, Eugene D; Drake, Charles G; Scher, Howard I;

    2014-01-01

    chemotherapy. METHODS: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one...

  1. Metabolic imbalance and prostate cancer progression

    Science.gov (United States)

    Burton, Anya J; Tilling, Kate M; Holly, Jeff M; Hamdy, Freddie C; Rowlands, Mari-Anne E; Donovan, Jenny L; Martin, Richard M

    2010-01-01

    There is substantial evidence implicating environmental factors in the progression of prostate cancer. The metabolic consequences of a western lifestyle, such as obesity, insulin resistance and abnormal hormone production have been linked to prostate carcinogenesis through multiple overlapping pathways. Insulin resistance results in raised levels of the mitogens insulin and insulin-like growth factor-1, both of which may affect prostate cancer directly, or through their effect on other metabolic regulators. Obesity is associated with abnormal levels of adipocyte-derived peptides (adipokines), sex hormones and inflammatory cytokines. Adipokines have been shown to influence prostate cancer in both cell culture studies and observational, population level studies. Testosterone appears to have a complex relationship with prostate carcinogenesis, and it has been suggested that the lower levels associated with obesity may select for more aggressive androgen independent prostate cancer cells. Prostatic inflammation, caused by infection, urinary reflux or dietary toxins, frequently occurs prior to cancer development and may influence progression to advanced disease. High levels of ω-6 fatty acids in the diet may lead to the production of further inflammatory molecules that may influence prostate cancer. Increased fatty acid metabolism occurs within tumour cells, providing a potential target for prostate cancer therapies. Aberrations in amino acid metabolism have also been identified in prostate cancer tissue, particularly in metastatic cancer. This evidence indicates lifestyle interventions may be effective in reducing the incidence of clinical disease. However, much more research is needed before recommendations are made. PMID:21532839

  2. Changes in cytoskeletal dynamics and nonlinear rheology with metastatic ability in cancer cell lines

    Science.gov (United States)

    Coughlin, Mark F.; Fredberg, Jeffrey J.

    2013-12-01

    Metastatic outcome is impacted by the biophysical state of the primary tumor cell. To determine if changes in cancer cell biophysical properties facilitate metastasis, we quantified cytoskeletal biophysics in well-characterized human skin, bladder, prostate and kidney cell line pairs that differ in metastatic ability. Using magnetic twisting cytometry with optical detection, cytoskeletal dynamics was observed through spontaneous motion of surface bound marker beads and nonlinear rheology was characterized through large amplitude forced oscillations of probe beads. Measurements of cytoskeletal dynamics and nonlinear rheology differed between strongly and weakly metastatic cells. However, no set of biophysical parameters changed systematically with metastatic ability across all cell lines. Compared to their weakly metastatic counterparts, the strongly metastatic kidney cancer cells exhibited both increased cytoskeletal dynamics and stiffness at large deformation which are thought to facilitate the process of vascular invasion.

  3. Staging of prostate cancer.

    Science.gov (United States)

    Cheng, Liang; Montironi, Rodolfo; Bostwick, David G; Lopez-Beltran, Antonio; Berney, Daniel M

    2012-01-01

    Prostatic carcinoma (PCa) is a significant cause of cancer morbidity and mortality worldwide. Accurate staging is critical for prognosis assessment and treatment planning for PCa. Despite the large volume of clinical activity and research, the challenge to define the most appropriate and clinically relevant staging system remains. The pathologically complex and uncertain clinical course of prostate cancer further complicates the design of staging classification and a substaging system suitable for individualized care. This review will focus on recent progress and controversial issues related to prostate cancer staging. The 2010 revision of the American Joint Committee on Cancer/Union Internationale Contre le Cancer (AJCC/UICC) tumour, node and metastasis (TNM) system is the most widely used staging system at this time. Despite general acceptance of the system as a whole, there is controversy and uncertainty about its application, particularly for T2 subclassification. The three-tiered T2 classification system for organ-confined prostate cancer is superfluous, considering the biology and anatomy of PCa. A tumour size-based substaging system may be considered in the future TNM subclassification of pT2 cancer. Lymph node status is one of the most important prognostic factors for prostate cancer. Nevertheless, clinical outcomes in patients with positive lymph nodes are variable. Identification of patients at the greatest risk of systemic progression helps in the selection of appropriate therapy. The data suggest that the inherent aggressiveness of metastatic prostate cancer is closely linked to the tumour volume of lymph node metastasis. We recommend that a future TNM staging system should consider subclassification of node-positive cancer on the basis of nodal cancer volume, using the diameter of the largest nodal metastasis and/or the number of positive nodes.

  4. Prostate cancer

    Energy Technology Data Exchange (ETDEWEB)

    Murphy, G.P.; Kuss, R., Khoury, S.; Chatelain, C.; Denis, L.

    1987-01-01

    This book contains over 70 selections. Some of the titles are: Place of the Computed Tomography in the Staging of Prostatic Cancer; Magnetic Resonance Imaging (MRI) in Staging of the Prostatic Cancer; Magnetic Resonance Imaging of the Prostate; Long-Term Results in Radiotherapy of Prostatic Cancer; Interstitial Irradiation Using I-125 Seeds; and Treatment of Cancer of the Prostate by Use of Physiotherapy: Long-Term Results.

  5. Targeting Quiescence in Prostate Cancer

    Science.gov (United States)

    2016-10-01

    can be used to monitor and isolate cancer cells that are quiescent vs. actively proliferating. With these new tools we verified that prostate...Collagen Implants with labeled cancer cells 3wk Optimization in progress Subtask 2: Remove Collagen Implants 1 Subtask 3: Isolate tissues and...Subtask 4: Isolate tissues and perform flow cytometry to identify cell cycle distributions of metastatic populations* (Timepoints throughout 1-7 months

  6. The genomic landscape of prostate cancer

    Directory of Open Access Journals (Sweden)

    Sylvan eBaca

    2012-05-01

    Full Text Available Prostate cancer is a common malignancy in men, with a markedly variable clinical course. Somatic alterations in DNA drive the growth of prostate cancers and may underlie the behavior of aggressive versus indolent tumors. The accelerating application of genomic technologies over the last two decades has identified mutations that drive prostate cancer formation, progression, and therapeutic resistance. Here, we discuss exemplary somatic mutations in prostate cancer, and highlight mutated cellular pathways with biological and possible therapeutic importance. Examples include mutated genes involved in androgen signaling, cell cycle regulation, signal transduction and development. Some genetic alterations may also predict the clinical course of disease or response to therapy, although the molecular heterogeneity of prostate tumors poses challenges to genomic biomarker identification. The widespread application of massively parallel sequencing technology to the analysis of prostate cancer genomes should continue to advance both discovery-oriented and diagnostic avenues.

  7. Metastasis of Prostate Adenocarcinoma to the Testis

    Science.gov (United States)

    Campara, Zoran; Simic, Dejan; Aleksic, Predrag; Spasic, Aleksandar; Milicevic, Snjezana

    2016-01-01

    Introduction: Prostate carcinoma is the most frequently diagnosed carcinoma in the male population. The most typical places of the metastases are pelvic lymphatic glands, bones and lungs, and very rarely it metastasizes into a testis. The prognostic importance of testicular metastasis of prostate cancer is not yet well-known, due to a very few published cases. According to the known facts, it is certain that a metastasis of the prostate carcinoma into a testis is a sign of an advanced disease. Case report: This work presents a 48-year-old patient, to whom an adenocarcinoma of the prostate has been proven by the pathohistological finding of transrectal biopsy, performed due to the elevated level of prostate-specific antigen (PSA). Nine years after the initial diagnosis, due to a gradual rise of PSA and tumorous enlargement of the left testis, left inguinal orchectomy and right orchectomy were performed. Metastatic dissemination of prostate adenocarcinoma into a testis was determined by a pathohistological analysis of the left testis. Conclusion: The metastasis of the prostate carcinoma into a testis, as a rare localization of the metastatic dissemination, after additionally performed orchectomy along with further oncological therapy, can provide a continuation of a good life quality as well as a control of the disease in a longer time period. PMID:27703299

  8. Identification of Prostate Cancer Prognostic Markers

    Science.gov (United States)

    2015-10-01

    targets. Specific aims are: 1) To profile bone metastasis samples to identify genomic alterations of PCa metastases that can be retrieved in their...Current markers - preoperative serum prostate specific antigen (PSA) levels, tumor stage and biopsy Gleason score (GS) - cannot accurately predict...individual patient outcome. For advanced and metastatic disease there is no curative treatment. Genomic profiling studies have identified specific genomic

  9. Glucocorticoids and prostate cancer treatment:friend or foe?

    Institute of Scientific and Technical Information of China (English)

    Bruce Montgomery; Heather H Cheng; James Drechsler; Elahe A Mostaghel

    2014-01-01

    Glucocorticoids have been used in the treatment of prostate cancer to slow disease progression, improve pain control and offset side effects of chemo-and hormonal therapy. However, they may also have the potential to drive prostate cancer growth via mutated androgen receptors or glucocorticoid receptors (GRs). In this review we examine historical and contemporary use of glucocorticoids in the treatment of prostate cancer, review potential mechanisms by which they may inhibit or drive prostate cancer growth, and describe potential means of deifning their contribution to the biology of prostate cancer.

  10. Molecular imaging of prostate cancer with PET.

    Science.gov (United States)

    Jadvar, Hossein

    2013-10-01

    Molecular imaging is paving the way for precision and personalized medicine. In view of the significant biologic and clinical heterogeneity of prostate cancer, molecular imaging is expected to play an important role in the evaluation of this prevalent disease. The natural history of prostate cancer spans from an indolent localized process to biochemical relapse after radical treatment with curative intent to a lethal castrate-resistant metastatic disease. The ongoing unraveling of the complex tumor biology of prostate cancer uniquely positions molecular imaging with PET to contribute significantly to every clinical phase of prostate cancer evaluation. The purpose of this article was to provide a concise review of the current state of affairs and potential future developments in the diagnostic utility of PET in prostate cancer.

  11. Ureteral metastasis from prostate cancer.

    Science.gov (United States)

    Hongo, Hiroshi; Kosaka, Takeo; Yoshimine, Shunsuke; Oya, Mototsugu

    2014-08-28

    A 59-year-old man had an elevated prostate-specific antigen (PSA) concentration (439 ng/mL) in December 2008. We diagnosed prostatic adenocarcinoma by prostate needle biopsy. CT and MRI showed a prostatic tumour with bone and lymph node metastases. Combined androgen blockade therapy reduced the PSA level temporarily. After the PSA level gradually started to increase again and reached 27.27 ng/mL in October 2010, the patient was diagnosed with castration-resistant prostate cancer and treated with docetaxel chemotherapy. Radiological examination detected left hydronephrosis and a tumour in the left lower ureter in March 2011. Retrograde pyelography and urine cytology of class 3 from the left ureter indicated that the ureteral mass was a urothelial carcinoma. A left nephroureterectomy was performed. After the operation, the pathological examination showed a metastatic prostate carcinoma, accompanied by a decrease in the serum PSA level from 59.56 to 45.33 ng/mL.

  12. Sipuleucel-T (APC8015) for prostate cancer.

    Science.gov (United States)

    So-Rosillo, Rosendo; Small, Eric J

    2006-09-01

    Sipuleucel-T (Provenge; APC8015; Dendreon Corp, WA, USA) is a novel immunotherapeutic cellular product, which includes autologous dendritic cells pulsed ex vivo with a recombinant fusion protein (PA2024) consisting of granulocyte macrophage colony-stimulating factor and prostatic acid phosphatase. Two Phase II trials in men with androgen-dependent biochemically relapsed prostate cancer have demonstrated a decrease in prostate-specific antigen and prolongation in prostate-specific antigen doubling time. In men with hormone-refractory prostate cancer, clinical trials have demonstrated both biological activity and clinical response to sipuleucel-T. Data from two Phase III trials in men with asymptomatic, metastatic hormone-refractory prostate cancer demonstrated an improved median overall survival in men who received sipuleucel-T compared with placebo. Clinical trials are ongoing or are being developed to evaluate sipuleucel-T in various prostate cancer disease states and in combination with other treatment modalities.

  13. Denosumab Reduces Risk of Bone Side Effects in Advanced Prostate Cancer

    Science.gov (United States)

    The biological agent denosumab (Xgeva) is more effective than zoledronic acid at decreasing the risk of bone fractures and other skeletal-related events (SRE) in men with castration-resistant metastatic prostate cancer, according to results from a randomi

  14. [Metastatic bronchial carcinoid tumors].

    Science.gov (United States)

    Bouledrak, K; Walter, T; Souquet, P J; Lombard-Bohas, C

    2016-02-01

    Bronchial carcinoids are uncommon pulmonary neoplasms and represent 1 to 2 % of all lung tumors. In early stage of disease, the mainstay and only curative treatment is surgery. Bronchial carcinoids are generally regarded as low-grade carcinomas and metastatic dissemination is unusual. The management of the metastatic stage is not currently standardized due to a lack of relevant studies. As bronchial carcinoids and in particular their metastatic forms are rare, we apply treatment strategies that have been evaluated in gastrointestinal and pancreatic neuroendocrine tumors. However, bronchial carcinoids have their own characteristic. A specific therapeutic feature of these metastatic tumors is that they require a dual approach: both anti-secretory for the carcinoid syndrome, and anti-tumoral.

  15. Loss of SOX9 Expression Is Associated with PSA Recurrence in ERG-Positive and PTEN Deleted Prostate Cancers.

    Directory of Open Access Journals (Sweden)

    Christoph Burdelski

    Full Text Available The transcription factor SOX9 plays a crucial role in normal prostate development and has been suggested to drive prostate carcinogenesis in concert with PTEN inactivation. To evaluate the clinical impact of SOX9 and its relationship with key genomic alterations in prostate cancer, SOX9 expression was analyzed by immunohistochemistry on a tissue microarray containing 11,152 prostate cancers. Data on ERG status and deletions of PTEN, 3p13, 5q21 and 6q15 were available from earlier studies. SOX9 expression levels were comparable in luminal cells of normal prostate glands (50% SOX9 positive and 3,671 cancers lacking TMPRSS2:ERG fusion (55% SOX9 positive, but was markedly increased in 3,116 ERG-fusion positive cancers (81% SOX9 positive, p<0.0001. While no unequivocal changes in the SOX9 expression levels were found in different stages of ERG-negative cancers, a gradual decrease of SOX9 paralleled progression to advanced stage, high Gleason grade, metastatic growth, and presence of PTEN deletions in ERG-positive cancers (p<0.0001 each. SOX9 levels were unrelated to deletions of 3p, 5q, and 6q. Down-regulation of SOX9 expression was particularly strongly associated with PSA recurrence in ERG-positive tumors harboring PTEN deletions (p=0.001, but had no significant effect in ERG-negative cancers or in tumors with normal PTEN copy numbers. In summary, the results of our study argue against a tumor-promoting role of SOX9 in prostate cancer, but demonstrate that loss of SOX9 expression characterizes a particularly aggressive subset of ERG positive cancers harboring PTEN deletions.

  16. Molecular Imaging of Prostate Cancer: A Concise Synopsis

    Directory of Open Access Journals (Sweden)

    Hossein Jadvar

    2009-03-01

    Full Text Available Prostate cancer is the most common malignancy in men and continues to be a major public health problem. Imaging of prostate cancer remains particularly challenging owing to disease heterogeneity. Molecular imaging can provide unprecedented opportunities for deciphering the molecular mechanisms that are involved in the development and natural progression of prostate cancer from a localized process to the hormone-refractory metastatic disease. Such understanding will be the key for targeted imaging and therapy and for predicting and evaluating treatment response and prognosis. In this article, we review briefly the contribution of multimodality molecular imaging methods for the in vivo characterization of the pathophysiology of prostate cancer.

  17. Drive Stands

    Data.gov (United States)

    Federal Laboratory Consortium — The Electrical Systems Laboratory (ESL)houses numerous electrically driven drive stands. A drive stand consists of an electric motor driving a gearbox and a mounting...

  18. Overcoming docetaxel resistance in prostate cancer: a perspective review

    Science.gov (United States)

    2012-01-01

    The treatment of metastatic castrate-resistant prostate cancer has been historically challenging, with few therapeutic successes. Docetaxel was the first cytotoxic therapy associated with a survival benefit in castrate-resistant prostate cancer. Toxicity is typical of other cytotoxic agents, with myelosuppression being the dose-limiting toxicity and neurotoxicity also a notable side effect for some patients. Unfortunately, a significant proportion of men with castrate-resistant prostate cancer will not respond to docetaxel-based therapy and all patients will ultimately develop resistance. Because it is an effective therapy, docetaxel is likely to remain an important part of the treatment arsenal against metastatic prostate cancer for the foreseeable future, despite its toxicities and limitations. Overcoming docetaxel resistance has been a challenge since docetaxel was first established as front-line therapy for metastatic castrate-resistant prostate cancer. Recent studies have shown that several new drugs, including cabazitaxel and abiraterone, are effective after docetaxel failure, dramatically changing the therapeutic landscape for these patients. In addition, a greater understanding of the mechanisms underlying docetaxel resistance has led to several new treatment approaches which hold promise for the future. This review will discuss recent therapeutic advances in metastatic castrate-resistant prostate cancer as well as ongoing clinical trials. PMID:23118808

  19. Prostate Cancer

    Science.gov (United States)

    ... man's bladder that produces fluid for semen. Prostate cancer is common among older men. It is rare ... younger than 40. Risk factors for developing prostate cancer include being over 65 years of age, family ...

  20. Prostate Ultrasound

    Medline Plus

    Full Text Available ... uses sound waves to produce pictures of a man’s prostate gland and to help diagnose symptoms such ... also called transrectal ultrasound, provides images of a man's prostate gland and surrounding tissue. The exam typically ...

  1. Prostate Ultrasound

    Medline Plus

    Full Text Available ... of page How is the procedure performed? In men, the prostate gland is located directly in front ... What are the limitations of Prostate Ultrasound Imaging? Men who have had the tail end of their ...

  2. Prostate Ultrasound

    Science.gov (United States)

    ... prostate. help diagnose the cause of a man's infertility. A transrectal ultrasound of the prostate gland is ... the transducer is pressed against the skin, it directs small pulses of inaudible, high-frequency sound waves ...

  3. Prostate Ultrasound

    Medline Plus

    Full Text Available ... prostate. help diagnose the cause of a man's infertility. A transrectal ultrasound of the prostate gland is ... the transducer is pressed against the skin, it directs small pulses of inaudible, high-frequency sound waves ...

  4. Prostate Ultrasound

    Medline Plus

    Full Text Available ... nodule felt by a physician during a routine physical exam or prostate cancer screening exam. an elevated ... page Additional Information and Resources RTAnswers.org Radiation Therapy for Prostate Cancer top of page This page ...

  5. Prostatitis - nonbacterial

    Science.gov (United States)

    NBP; Prostatodynia; Pelvic pain syndrome; CPPS; Chronic nonbacterial prostatitis; Chronic genitourinary pain ... Possible causes of nonbacterial prostatitis include: A past ... common types of bacteria Irritation caused by a backup of urine ...

  6. Prostate Ultrasound

    Medline Plus

    Full Text Available ... uses sound waves to produce pictures of a man’s prostate gland and to help diagnose symptoms such ... also called transrectal ultrasound, provides images of a man's prostate gland and surrounding tissue. The exam typically ...

  7. 人前列腺癌细胞转移潜能与环氧化酶-2的表达及患者预后的相关性%Expression of cyclooxygenase-2 in human prostate cancer cell with different metastatic potential

    Institute of Scientific and Technical Information of China (English)

    陈臻; 秦大山; 岳中瑾; 王志平; 傅生军

    2003-01-01

    目的: 探讨人前列腺癌细胞转移潜能与其环氧化酶-2( COX-2)表达之间的关系,及环氧化酶-2与前列腺癌患者预后的关系. 方法 : 用运免疫组化及反转录聚合酶链式反应( RT-PCR)检测两种不同转移潜能人前列腺癌细胞 PC3及 PC3M中 COX-2 mRNA及其蛋白的表达以及在肿瘤坏死因子-α( TNF-α)刺激下两者的表达是否有所变化. 结果 : PC3细胞在无 TNF-α刺激时,检测不到 COX-2 mRNA 的表达,其蛋白表达也为阴性,而在 TNF-α刺激 4 h后, COX-2 mRNA及其蛋白的表达均为阳性.而在 PC3M细胞中无 TNF-α刺激时, COX-2 mRNA及其蛋白的表达已为阳性,在 TNF-α刺激 4 h后, COX-2 mRNA及其蛋白的表达均有增强. 结论 : COX-2可能在前列腺癌的发生发展中起着重要的作用,抑制 COX-2的表达,或许能够降低前列腺癌的恶性程度甚至能够阻止其发生.这对前列腺癌患者生存期内创造良好的生活质量及前列腺癌的防治提供有力的理论依据.%AIM:To investigate the relationship between human prostate cancer cells with different metastatic potential and expression of COX-2. METHODS: Expression of cyclooxygenase-2 and it's regulation by tumor necrosis factor-α in PC3 and PC3M were detected by reverse transcription-PCR and immunohistochemistry. RESULTS:We observed that the COX-2 mRNA level and COX-2 protein were undetectable in PC3 cells but it was positive at 4 h after stimulation with TNF-α .In PC3M, there were a gradual increase in COX-2 expression up to 4 h after stimulation with TNF-α compared with the beginning. CONCLUSION: The result of the current study demonstrate that the human prostate carcinoma cells generated COX-2 and regulated by TNF-α ,and that COX-2 might play an important role in the proliferation of prostate carcinoma cells.These findings suggest that inhibition of COX-2 development may lead to inhibition of the proliferation and metastasis of prostate carcinoma but also to the

  8. Chronic prostatitis

    OpenAIRE

    Le, Brian; Schaeffer, Anthony J.

    2011-01-01

    Chronic prostatitis can cause pain and urinary symptoms, and usually occurs without positive bacterial cultures from prostatic secretions (known as chronic abacterial prostatitis or chronic pelvic pain syndrome [CP/CPPS]). Bacterial infection can result from urinary tract instrumentation, but the cause and natural history of CP/CPPS are unknown.

  9. Chronic prostatitis

    OpenAIRE

    Erickson, Bradley A.; Schaeffer, Anthony J.; Le, Brian

    2008-01-01

    Chronic prostatitis can cause pain and urinary symptoms, and usually occurs without positive bacterial cultures from prostatic secretions (known as chronic abacterial prostatitis or chronic pelvic pain syndrome, CP/CPPS). Bacterial infection can result from urinary tract instrumentation, but the cause and natural history of CP/CPPS are unknown.

  10. Enlarged prostate

    Science.gov (United States)

    ... prostate URL of this page: //medlineplus.gov/ency/article/000381.htm Enlarged prostate To use the sharing ... sperm during ejaculation. The prostate gland surrounds the urethra, the tube ... hyperplasia (BPH). It is not cancer, and it does not raise your risk for ...

  11. Cellular traction stresses increase with increasing metastatic potential.

    Directory of Open Access Journals (Sweden)

    Casey M Kraning-Rush

    Full Text Available Cancer cells exist in a mechanically and chemically heterogeneous microenvironment which undergoes dynamic changes throughout neoplastic progression. During metastasis, cells from a primary tumor acquire characteristics that enable them to escape from the primary tumor and migrate through the heterogeneous stromal environment to establish secondary tumors. Despite being linked to poor prognosis, there are no direct clinical tests available to diagnose the likelihood of metastasis. Moreover, the physical mechanisms employed by metastatic cancer cells to migrate are poorly understood. Because metastasis of most solid tumors requires cells to exert force to reorganize and navigate through dense stroma, we investigated differences in cellular force generation between metastatic and non-metastatic cells. Using traction force microscopy, we found that in human metastatic breast, prostate and lung cancer cell lines, traction stresses were significantly increased compared to non-metastatic counterparts. This trend was recapitulated in the isogenic MCF10AT series of breast cancer cells. Our data also indicate that increased matrix stiffness and collagen density promote increased traction forces, and that metastatic cells generate higher forces than non-metastatic cells across all matrix properties studied. Additionally, we found that cell spreading for these cell lines has a direct relationship with collagen density, but a biphasic relationship with substrate stiffness, indicating that cell area alone does not dictate the magnitude of traction stress generation. Together, these data suggest that cellular contractile force may play an important role in metastasis, and that the physical properties of the stromal environment may regulate cellular force generation. These findings are critical for understanding the physical mechanisms of metastasis and the role of the extracellular microenvironment in metastatic progression.

  12. Stem cell and neurogenic gene-expression profiles link prostate basal cells to aggressive prostate cancer.

    Science.gov (United States)

    Zhang, Dingxiao; Park, Daechan; Zhong, Yi; Lu, Yue; Rycaj, Kiera; Gong, Shuai; Chen, Xin; Liu, Xin; Chao, Hsueh-Ping; Whitney, Pamela; Calhoun-Davis, Tammy; Takata, Yoko; Shen, Jianjun; Iyer, Vishwanath R; Tang, Dean G

    2016-02-29

    The prostate gland mainly contains basal and luminal cells constructed as a pseudostratified epithelium. Annotation of prostate epithelial transcriptomes provides a foundation for discoveries that can impact disease understanding and treatment. Here we describe a genome-wide transcriptome analysis of human benign prostatic basal and luminal epithelial populations using deep RNA sequencing. Through molecular and biological characterizations, we show that the differential gene-expression profiles account for their distinct functional properties. Strikingly, basal cells preferentially express gene categories associated with stem cells, neurogenesis and ribosomal RNA (rRNA) biogenesis. Consistent with this profile, basal cells functionally exhibit intrinsic stem-like and neurogenic properties with enhanced rRNA transcription activity. Of clinical relevance, the basal cell gene-expression profile is enriched in advanced, anaplastic, castration-resistant and metastatic prostate cancers. Therefore, we link the cell-type-specific gene signatures to aggressive subtypes of prostate cancer and identify gene signatures associated with adverse clinical features.

  13. Definition of molecular determinants of prostate cancer cell bone extravasation.

    Science.gov (United States)

    Barthel, Steven R; Hays, Danielle L; Yazawa, Erika M; Opperman, Matthew; Walley, Kempland C; Nimrichter, Leonardo; Burdick, Monica M; Gillard, Bryan M; Moser, Michael T; Pantel, Klaus; Foster, Barbara A; Pienta, Kenneth J; Dimitroff, Charles J

    2013-01-15

    Advanced prostate cancer commonly metastasizes to bone, but transit of malignant cells across the bone marrow endothelium (BMEC) remains a poorly understood step in metastasis. Prostate cancer cells roll on E-selectin(+) BMEC through E-selectin ligand-binding interactions under shear flow, and prostate cancer cells exhibit firm adhesion to BMEC via β1, β4, and αVβ3 integrins in static assays. However, whether these discrete prostate cancer cell-BMEC adhesive contacts culminate in cooperative, step-wise transendothelial migration into bone is not known. Here, we describe how metastatic prostate cancer cells breach BMEC monolayers in a step-wise fashion under physiologic hemodynamic flow. Prostate cancer cells tethered and rolled on BMEC and then firmly adhered to and traversed BMEC via sequential dependence on E-selectin ligands and β1 and αVβ3 integrins. Expression analysis in human metastatic prostate cancer tissue revealed that β1 was markedly upregulated compared with expression of other β subunits. Prostate cancer cell breaching was regulated by Rac1 and Rap1 GTPases and, notably, did not require exogenous chemokines as β1, αVβ3, Rac1, and Rap1 were constitutively active. In homing studies, prostate cancer cell trafficking to murine femurs was dependent on E-selectin ligand, β1 integrin, and Rac1. Moreover, eliminating E-selectin ligand-synthesizing α1,3 fucosyltransferases in transgenic adenoma of mouse prostate mice dramatically reduced prostate cancer incidence. These results unify the requirement for E-selectin ligands, α1,3 fucosyltransferases, β1 and αVβ3 integrins, and Rac/Rap1 GTPases in mediating prostate cancer cell homing and entry into bone and offer new insight into the role of α1,3 fucosylation in prostate cancer development.

  14. Human RecQL4 helicase plays critical roles in prostate carcinogenesis

    DEFF Research Database (Denmark)

    Su, Yanrong; Meador, Jarah A; Calaf, Gloria M

    2010-01-01

    Prostate cancer is the second leading cause of cancer-associated deaths among men in the western countries. Here, we report that human RecQL4 helicase, which is implicated in the pathogenesis of a subset of cancer-prone Rothmund-Thomson syndrome, is highly elevated in metastatic prostate cancer c...

  15. Imaging for Prostate Cancer Recurrence.

    Science.gov (United States)

    Maurer, Tobias; Eiber, Matthias; Fanti, Stefano; Budäus, Lars; Panebianco, Valeria

    2016-06-01

    Correct identification of metastatic sites in recurrent prostate cancer (PCa) is of crucial importance because it leads to further treatment decisions. To provide an overview on current imaging procedures and their performance in recurrent PCa. Medline search via PubMed was performed with the keywords imaging, recurrent, and prostate cancer as well as more detailed searches including the keywords bone scan, bone scintigraphy, computed tomography, magnetic resonance imaging, positron emission tomography, PET, choline, FDG, prostate-specific membrane antigen, and PSMA, with emphasis on recent literature from 2010 to the present. Non-English published literature was excluded. Abstracts and full-text articles were reviewed and assessed for relevant content. In diagnostic imaging and particularly with newer technologies like positron emission tomography (PET), a profound lack of prospectively designed studies in recurrent PCa has to be noted. In most studies histologic validation has only been performed in a subset of patient cohorts. Heterogeneity of included patient cohorts, lack of standardized assessment, as well as diverging end points, hamper systematic comparison of different image modalities. Thus evidence for currently used imaging in recurrent PCa is only presented descriptively. Computed tomography and magnetic resonance imaging (MRI) as well as bone scintigraphy still represent the standard imaging for recurrent PCa; however, particularly for detection of local recurrence, multiparametric MRI is a valuable imaging modality. PET using choline and particularly tracers against prostate-specific membrane antigen might improve visualization of metastatic lesions. These findings need to be validated in prospective trials. Imaging of recurrent prostate cancer (PCa) is important to guide further treatment. Computed tomography, magnetic resonance imaging, and bone scintigraphy represent the current standard. Positron emission tomography, especially with cancer

  16. Overexpression of vimentin in canine prostatic carcinoma

    DEFF Research Database (Denmark)

    Rodrigues, M M P; Rema, A; Gärtner, F

    2011-01-01

    Canine prostatic tumours exhibit similarities to those of man and may represent a useful model system to explore the mechanisms of cancer progression. Tumour progression to malignancy requires a change from an epithelial phenotype to a fibroblastic or mesenchymal phenotype. Vimentin expression...... is associated with the invasive phenotype of human prostate cancer cells. The aim of the present study was to characterize immunohistochemically the expression of vimentin by canine prostatic carcinomas. Primary carcinomas and metastatic tumour foci both showed vimentin expression. This finding suggests...... that the acquisition of the epithelial-mesenchymal transition phenotype in canine prostatic carcinoma may be characterized by the presence of mesenchymal intermediate filament (vimentin) that could lead to a higher likelihood of metastasis....

  17. Redefining Hormone Sensitive Disease in Advanced Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Xiaoyu Hou

    2012-01-01

    Full Text Available Prostate cancer is the most common cancer among men in the United States. For decades, the cornerstone of medical treatment for advanced prostate cancer has been hormonal therapy, intended to lower testosterone levels, known as Androgen Deprivation Therapy (ADT. The development of hormone-resistant prostate cancer (now termed castration-resistant prostate cancer:CRPC remains the key roadblock in successful long-term management of prostate cancer. New advancements in medical therapy for prostate cancer have added to the hormonal therapy armamentarium. These new therapeutic agents not only provide a survival benefit but also show potential for reversing hormonal resistance in metastatic CRPC, and thus redefining hormonally sensitive disease.

  18. Pre-clinical Orthotopic Murine Model of Human Prostate Cancer.

    Science.gov (United States)

    Shahryari, Varahram; Nip, Hannah; Saini, Sharanjot; Dar, Altaf A; Yamamura, Soichiro; Mitsui, Yozo; Colden, Melissa; Bucay, Nathan; Tabatabai, Laura Z; Greene, Kirsten; Deng, Guoren; Tanaka, Yuichiro; Dahiya, Rajvir; Majid, Shahana

    2016-08-29

    To study the multifaceted biology of prostate cancer, pre-clinical in vivo models offer a range of options to uncover critical biological information about this disease. The human orthotopic prostate cancer xenograft mouse model provides a useful alternative approach for understanding the specific interactions between genetically and molecularly altered tumor cells, their organ microenvironment, and for evaluation of efficacy of therapeutic regimens. This is a well characterized model designed to study the molecular events of primary tumor development and it recapitulates the early events in the metastatic cascade prior to embolism and entry of tumor cells into the circulation. Thus it allows elucidation of molecular mechanisms underlying the initial phase of metastatic disease. In addition, this model can annotate drug targets of clinical relevance and is a valuable tool to study prostate cancer progression. In this manuscript we describe a detailed procedure to establish a human orthotopic prostate cancer xenograft mouse model.

  19. Gene-modified bone marrow cell therapy for prostate cancer.

    Science.gov (United States)

    Wang, H; Thompson, T C

    2008-05-01

    There is a critical need to develop new and effective cancer therapies that target bone, the primary metastatic site for prostate cancer and other malignancies. Among the various therapeutic approaches being considered for this application, gene-modified cell-based therapies may have specific advantages. Gene-modified cell therapy uses gene transfer and cell-based technologies in a complementary fashion to chaperone appropriate gene expression cassettes to active sites of tumor growth. In this paper, we briefly review potential cell vehicles for this approach and discuss relevant gene therapy strategies for prostate cancer. We further discuss selected studies that led to the conceptual development and preclinical testing of IL-12 gene-modified bone marrow cell therapy for prostate cancer. Finally, we discuss future directions in the development of gene-modified cell therapy for metastatic prostate cancer, including the need to identify and test novel therapeutic genes such as GLIPR1.

  20. Positron emission tomography/computed tomography and radioimmunotherapy of prostate cancer

    DEFF Research Database (Denmark)

    Bouchelouche, Kirsten; Capala, Jacek; Oehr, Peter

    2009-01-01

    further. However, F-choline and C-choline PET/CT have been demonstrated to be useful for detection of recurrence. F-choline and F-fluoride PET/CT are useful for detection of bone metastases. Prostate tumor antigens may be used as targets for RIT. Prostate-specific membrane antigen is currently under focus....../CT in prostate cancer has proven to play a significant role, in particular for detection of prostate cancer recurrence and bone metastases. RIT of metastatic prostate cancer warrants further investigations....

  1. Dynamics of notch expression during murine prostate development and tumorigenesis.

    Science.gov (United States)

    Shou, J; Ross, S; Koeppen, H; de Sauvage, F J; Gao, W Q

    2001-10-01

    Notch signaling has been widely demonstrated to be responsible for cell fate determination during normal development and implicated in human T-cell leukemia and mouse mammary carcinomas. Here we show that Notch signaling may be involved in prostatic development and cancer cell growth. In situ hybridization and reverse transcription-PCR analyses revealed that Notch1 was expressed in prostate epithelial cells during normal development and in prostate cancer cells. Characterization of Notch1-green fluorescent protein transgenic mice, in which the expression of reporter green fluorescent protein is under the control of the Notch1 promoter, indicated that Notch1-expressing cells were associated with the basal epithelial cell population in the prostate. Examination of the transgenic adenocarcinoma of the mouse prostate showed that expression of Notch1 was elevated in malignant prostatic epithelial cells of primary and metastatic tumors. Expression of Notch ligands, however, was low or undetectable in cultured prostate cancer cells or in malignant prostatic epithelial cells in transgenic adenocarcinoma of the mouse prostate. Furthermore, overexpression of a constitutively active form of Notch1 inhibited the proliferation of various prostate cancer cells, including DU145, LNCaP, and PC3 cells. Taken together, our data indicate for the first time that Notch signaling may play a role in murine prostatic development and tumorigenesis.

  2. Predictive effect of androgen receptor splice variant 7 expression on time to castration resistance in patients with metastatic prostate cancer%前列腺癌组织中雄激素受体剪接变异体7表达对转移性前列腺癌患者激素敏感时间的预测作用

    Institute of Scientific and Technical Information of China (English)

    瞿元元; 叶定伟; 戴波; 孔蕴毅; 蔡旭; 常坤; 孙自捷; 张海梁; 朱耀

    2014-01-01

    receptor splice variant 7 (AR-V7) expression on time to castration resistance in patients with metastatic prostate cancer.Methods The data of 113 cases of advanced metastatic prostate cancer diagnosed by prostate biopsy in our institute from Jan.2002 to Jun.2010 were collected retrospectively.The median age at diagnosis was 70 years,ranged from 43 to 84 years.The median tPSA was 120.0 μg/L,ranged from 3.0 to 6 006.2 μg/L.There were 5 patients in M1a(4.4%),94 patients in M1b(83.2%) and 14 patients in M1c(12.4%).All patients received hormonal therapy.1mmunohistochemical staining and AR-V7 specific antibody were used to detect the expression of AR-V7 in prostate cancer tissues.Cox regression models were used to analyze the predictive role of patient characteristics including patient's age at diagnosis,tPSA level at diagnosis,Gleason score,clinical stage,PSA nadir during hormonal therapy,the time to PSA nadir and PSA half-life.The effect of AR-V7 expression on time to castration resistance was analyzed using Kaplan-Meier curves,and the differences were assessed using the log-rank test.Results The PSA nadir ranged from 0.0 to 143.0 μg/L and the median value was 0.7 μg/L.The time to PSA nadir ranged from 0.9 to 71.0 months and the median value was 8.1 months.The median PSA half life was 1.0 month,which ranged from 0.1 to 41.0 months.Followed up for a median time of 27 months,100 patients progressed to castration-resistant prostate cancer (CRPC) and the median time to castration resistance was 24 months.The expression of AR-V7 was positive in 23 out of 113 patients.Multivariate analysis showed that the expression of AR-V7 in prostate cancer (P=0.004,HR =2.223) and PSA nadir during hormonal therapy (P =0.035,HR =1.011) were independent predictive factors of time to castration resistance.The median time to castration resistance for patients with and without AR-V7 expression were (16.04±3.4) months and (30.04-6.0) months,respectively (P=0.001).Conclusions The expression

  3. Targeting Prostate Cancer for Gene Therapy Utilizing Lentivirus and Oncolytic VSV Virus

    Science.gov (United States)

    2010-04-01

    not yet published. 13. SUPPLEMENTARY NOTES 14. ABSTRACT Prostate cancer is the most commonly diagnosed non- skin carcinoma and o ne o f the...surgery or radiotherapy . Presently there are no therapies available for advanced and metastatic prostate cancer, thus the emergence of new targeted...aque a ssay w hich s howed a hi gher concentration of replicating vi rus in prostates of PTEN -/- mice while sparing normal cells in control mice

  4. Drugged Driving

    Science.gov (United States)

    ... Parents & Educators Children & Teens Search Connect with NIDA : Google Plus Facebook LinkedIn Twitter YouTube Flickr RSS Menu ... misuse of prescription drugs can make driving a car unsafe—just like driving after drinking alcohol. Drugged ...

  5. Review of Animal Models of Prostate Cancer Bone Metastasis

    Directory of Open Access Journals (Sweden)

    Jessica K. Simmons

    2014-06-01

    Full Text Available Prostate cancer bone metastases are associated with a poor prognosis and are considered incurable. Insight into the formation and growth of prostate cancer bone metastasis is required for development of new imaging and therapeutic strategies to combat this devastating disease. Animal models are indispensable in investigating cancer pathogenesis and evaluating therapeutics. Multiple animal models of prostate cancer bone metastasis have been developed, but few effectively model prostatic neoplasms and osteoblastic bone metastases as they occur in men. This review discusses the animal models that have been developed to investigate prostate cancer bone metastasis, with a focus on canine models and also includes human xenograft and rodent models. Adult dogs spontaneously develop benign prostatic hyperplasia and prostate cancer with osteoblastic bone metastases. Large animal models, such as dogs, are needed to develop new molecular imaging tools and effective focal intraprostatic therapy. None of the available models fully reflect the metastatic disease seen in men, although the various models have provided important insight into the metastatic process. As additional models are developed and knowledge from the different models is combined, the molecular mechanisms of prostate cancer bone metastasis can be deciphered and targeted for development of novel therapies and molecular diagnostic imaging.

  6. Prostate adenocarcinoma with negative immunohistochemical stain of prostate-specific antigen presenting with cervical mass: A case report

    Directory of Open Access Journals (Sweden)

    Liming Zhu

    2013-01-01

    Full Text Available Cervical regional nodal involvement, as the first manifestation of prostatic cancer, has been rarely reported. Prostate cancer metastasis to the supraclavicular lymph nodes with negative immunohistochemical stain of PSA is even rarer. We report a case of prostate cancer with negative immunohistochemical stain of prostate-specific antigen presenting with left supraclavicular node enlargement. A 63-year-old man was referred to our hospital for a left supraclavicular mass. He had a family history of gastric cancer (two brothers had died of gastric cancer. Enhanced computed tomography of the abdomen revealed retroperitoneal lymph node enlargement. Gastroscopy revealed no evidence of any gastric tumor. Biopsy of the left-sided supraclavicular lymph nodes revealed metastatic adenocarcinoma with a negative prostate-specific antigen (PSA stain. The serum tumor markers were examined, revealing PSA levels of 21.820 ng/ml. Biopsy of the prostate disclosed poorly-to-moderately differentiated adenocarcinoma (Gleason 4 + 4 = 8. Although rare, prostate cancer should be considered in the differential diagnoses of elderly men with undetermined original adenocarcinoma, metastatic to the supraclavicular lymph nodes. Rectal examination, serum PSA and pelvic image can be helpful to lead the diagnosis. PSA stain may be weak or negative in some poorly differentiated patients, however, it is still a sensitive and specific marker of prostatic differentiation and must be routinely applied.

  7. Prostate Ultrasound

    Medline Plus

    Full Text Available ... through blood vessels. Ultrasound imaging is a noninvasive medical test that helps physicians diagnose and treat medical conditions. Prostate ultrasound, also called transrectal ultrasound, provides ...

  8. Prostate Cancer Stem Cells: Research Advances

    Directory of Open Access Journals (Sweden)

    Dagmara Jaworska

    2015-11-01

    Full Text Available Cancer stem cells have been defined as cells within a tumor that possesses the capacity to self-renew and to cause the heterogeneous lineages of cancer cells that comprise the tumor. Experimental evidence showed that these highly tumorigenic cells might be responsible for initiation and progression of cancer into invasive and metastatic disease. Eradicating prostate cancer stem cells, the root of the problem, has been considered as a promising target in prostate cancer treatment to improve the prognosis for patients with advanced stages of the disease.

  9. Electric drives

    CERN Document Server

    Boldea, Ion

    2005-01-01

    ENERGY CONVERSION IN ELECTRIC DRIVESElectric Drives: A DefinitionApplication Range of Electric DrivesEnergy Savings Pay Off RapidlyGlobal Energy Savings Through PEC DrivesMotor/Mechanical Load MatchMotion/Time Profile MatchLoad Dynamics and StabilityMultiquadrant OperationPerformance IndexesProblemsELECTRIC MOTORS FOR DRIVESElectric Drives: A Typical ConfigurationElectric Motors for DrivesDC Brush MotorsConventional AC MotorsPower Electronic Converter Dependent MotorsEnergy Conversion in Electric Motors/GeneratorsPOWER ELECTRONIC CONVERTERS (PECs) FOR DRIVESPower Electronic Switches (PESs)The

  10. Prostate specific membrane antigen- a target for imaging and therapy with radionuclides

    DEFF Research Database (Denmark)

    Bouchelouche, Kirsten; Choyke, Peter L; Capala, Jacek

    2010-01-01

    Prostate cancer continues to represent a major health problem, and yet there is no effective treatment available for advanced metastatic disease. Thus, there is an urgent need for the development of more effective treatment modalities that could improve the outcome. Because prostate specific...... membrane antigen (PSMA), a transmembrane protein, is expressed by virtually all prostate cancers, and its expression is further increased in poorly differentiated, metastatic, and hormone-refractory carcinomas, it is a very attractive target. Molecules targeting PSMA can be labelled with radionuclides...... to become both diagnostic and/or therapeutic agents. The use of PSMA binding agents, labelled with diagnostic and therapeutic radio-isotopes, opens up the potential for a new era of personalized management of metastatic prostate cancer....

  11. Pancreatic Metastasis from Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Julian Jacob

    2010-01-01

    Full Text Available The pancreas is an unusual location for metastases from other primary cancers. Rarely, pancreatic metastases from kidney or colorectal cancers have been reported. However, a variety of other cancers may also spread to the pancreas. We report an exceptional case of pancreatic metastasis from prostate cancer. Differences in management between primary and secondary pancreatic tumors make recognition of metastases to the pancreas an objective of first importance. Knowledge of unusual locations for metastatic spread will reduce diagnostic delay and lead to a timely delivery of an appropriate treatment.

  12. Prostate Ultrasound

    Medline Plus

    Full Text Available ... Español More Info Images/Videos About Us News Physician Resources Professions Site Index A-Z Ultrasound - Prostate ... imaging is a noninvasive medical test that helps physicians diagnose and treat medical conditions. Prostate ultrasound, also ...

  13. Expression of Clostridium perfringens enterotoxin receptors claudin-3 and claudin-4 in prostate cancer epithelium.

    Science.gov (United States)

    Long, H; Crean, C D; Lee, W H; Cummings, O W; Gabig, T G

    2001-11-01

    The mRNA for Rvp.1 (rat ventral prostate) increases in abundance before gland involution after androgen deprivation. Rvp.1 is homologous to CPE-R, the high-affinity intestinal epithelial receptor for Clostridium perfringens enterotoxin (CPE), and is sufficient to mediate CPE binding and trigger subsequent toxin-mediated cytolysis. Rvp.1 (claudin-3) and CPE-R (claudin-4) are members of a larger family of transmembrane tissue-specific claudin proteins that are essential components of intercellular tight junction structures regulating paracellular ion flux. However, claudin-3 and claudin-4 are the only family members capable of mediating CPE binding and cytolysis. The present study was designed to study the expression of claudin-3 and claudin-4 in human prostate tissue as potential targets for CPE toxin-mediated therapy for prostate cancer. On human multiple-tissue Northern blot analysis, mRNAs for both claudin-3 and claudin-4 were expressed at high levels in prostate tissue. In normal prostate tissue, expression of claudin-3 was localized exclusively within acinar epithelial cells by in situ mRNA hybridization. Compared with expression within prostate epithelial cells in surrounding normal glandular tissue, expression of claudin-3 mRNA remained high in the epithelium of prostate adenocarcinoma (10 of 10) and prostatic intraepithelial neoplasia (five of five). Prostate adenocarcinoma cells metastatic to bone were obtained from a patient with disease progression during antiandrogen therapy. These metastatic cells were prostate-specific antigen-positive by immunohistochemical staining and also expressed functional CPE receptors as measured by sensitivity to CPE-induced cell lysis. The persistent high level of claudin-3 expression in prostate adenocarcinoma and functional cytotoxicity of CPE in metastatic androgen-independent prostate adenocarcinoma suggests a new potential therapeutic strategy for prostate cancer.

  14. Detection of Lipid-Rich Prostate Circulating Tumour Cells with Coherent Anti-Stokes Raman Scattering Microscopy

    Directory of Open Access Journals (Sweden)

    Mitra Ranjana

    2012-11-01

    Full Text Available Abstract Background Circulating tumour cells (CTC are an important indicator of metastasis and associated with a poor prognosis. Detection sensitivity and specificity of CTC in the peripheral blood of metastatic cancer patient remain a technical challenge. Methods Coherent anti-Stokes Raman scattering (CARS microscopy was employed to examine the lipid content of CTC isolated from the peripheral blood of metastatic prostate cancer patients. CARS microscopy was also employed to evaluate lipid uptake and mobilization kinetics of a metastatic human prostate cancer cell line. Results One hundred CTC from eight metastatic prostate cancer patients exhibited strong CARS signal which arose from intracellular lipid. In contrast, leukocytes exhibited weak CARS signal which arose mostly from cellular membrane. On average, CARS signal intensity of prostate CTC was 7-fold higher than that of leukocytes (P Conclusions Intracellular lipid could serve as a biomarker for prostate CTC which could be sensitively detected with CARS microscopy in a label-free manner. Strong affinity for lipid by metastatic prostate cancer cells could be used to improve detection sensitivity and therapeutic targeting of prostate CTC.

  15. MRI of the Prostate

    Science.gov (United States)

    ... News Physician Resources Professions Site Index A-Z Magnetic Resonance Imaging (MRI) - Prostate Magnetic resonance imaging (MRI) of the prostate ... limitations of MRI of the Prostate? What is MRI of the Prostate? Magnetic resonance imaging (MRI) is ...

  16. Pile Driving

    Science.gov (United States)

    1987-01-01

    Machine-oriented structural engineering firm TERA, Inc. is engaged in a project to evaluate the reliability of offshore pile driving prediction methods to eventually predict the best pile driving technique for each new offshore oil platform. Phase I Pile driving records of 48 offshore platforms including such information as blow counts, soil composition and pertinent construction details were digitized. In Phase II, pile driving records were statistically compared with current methods of prediction. Result was development of modular software, the CRIPS80 Software Design Analyzer System, that companies can use to evaluate other prediction procedures or other data bases.

  17. Phase I/II trials of {sup 186}Re-HEDP in metastatic castration-resistant prostate cancer: post-hoc analysis of the impact of administered activity and dosimetry on survival

    Energy Technology Data Exchange (ETDEWEB)

    Denis-Bacelar, Ana M.; Chittenden, Sarah J.; Divoli, Antigoni; Flux, Glenn D. [The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, Joint Department of Physics, London (United Kingdom); Dearnaley, David P.; Johnson, Bernadette [The Institute of Cancer Research and The Royal Marsden Hospital NHS Foundation Trust, Division of Radiotherapy and Imaging, London (United Kingdom); O' Sullivan, Joe M. [Queen' s University Belfast, Centre for Cancer Research and Cell Biology, Belfast (United Kingdom); McCready, V.R. [Brighton and Sussex University Hospitals NHS Trust, Department of Nuclear Medicine, Brighton (United Kingdom); Du, Yong [The Royal Marsden Hospital NHS Foundation Trust, Department of Nuclear Medicine and PET/CT, London (United Kingdom)

    2017-04-15

    To investigate the role of patient-specific dosimetry as a predictive marker of survival and as a potential tool for individualised molecular radiotherapy treatment planning of bone metastases from castration-resistant prostate cancer, and to assess whether higher administered levels of activity are associated with a survival benefit. Clinical data from 57 patients who received 2.5-5.1 GBq of {sup 186}Re-HEDP as part of NIH-funded phase I/II clinical trials were analysed. Whole-body and SPECT-based absorbed doses to the whole body and bone lesions were calculated for 22 patients receiving 5 GBq. The patient mean absorbed dose was defined as the mean of all bone lesion-absorbed doses in any given patient. Kaplan-Meier curves, log-rank tests, Cox's proportional hazards model and Pearson's correlation coefficients were used for overall survival (OS) and correlation analyses. A statistically significantly longer OS was associated with administered activities above 3.5 GBq in the 57 patients (20.1 vs 7.1 months, hazard ratio: 0.39, 95 % CI: 0.10-0.58, P = 0.002). A total of 379 bone lesions were identified in 22 patients. The mean of the patient mean absorbed dose was 19 (±6) Gy and the mean of the whole-body absorbed dose was 0.33 (±0.11) Gy for the 22 patients. The patient mean absorbed dose (r = 0.65, P = 0.001) and the whole-body absorbed dose (r = 0.63, P = 0.002) showed a positive correlation with disease volume. Significant differences in OS were observed for the univariate group analyses according to disease volume as measured from SPECT imaging of {sup 186}Re-HEDP (P = 0.03) and patient mean absorbed dose (P = 0.01), whilst only the disease volume remained significant in a multivariable analysis (P = 0.004). This study demonstrated that higher administered activities led to prolonged survival and that for a fixed administered activity, the whole-body and patient mean absorbed doses correlated with the extent of disease, which, in turn, correlated

  18. Imaging of Spinal Metastatic Disease

    Directory of Open Access Journals (Sweden)

    Lubdha M. Shah

    2011-01-01

    Full Text Available Metastases to the spine can involve the bone, epidural space, leptomeninges, and spinal cord. The spine is the third most common site for metastatic disease, following the lung and the liver. Approximately 60–70% of patients with systemic cancer will have spinal metastasis. Materials/Methods. This is a review of the imaging techniques and typical imaging appearances of spinal metastatic disease. Conclusions. Awareness of the different manifestations of spinal metastatic disease is essential as the spine is the most common site of osseous metastatic disease. Imaging modalities have complimentary roles in the evaluation of spinal metastatic disease. CT best delineates osseous integrity, while MRI is better at assessing soft tissue involvement. Physiologic properties, particularly in treated disease, can be evaluated with other imaging modalities such as FDG PET and advanced MRI sequences. Imaging plays a fundamental role in not only diagnosis but also treatment planning of spinal metastatic disease.

  19. Is there a role for {sup 11}C-choline PET/CT in the early detection of metastatic disease in surgically treated prostate cancer patients with a mild PSA increase <1.5 ng/ml?

    Energy Technology Data Exchange (ETDEWEB)

    Castellucci, Paolo [University of Bologna, Service of Nuclear Medicine, Department of Haematology-Oncology and Laboratory Medicine, Azienda Ospedaliero-Universitaria di Bologna, Policlinico Sant' Orsola-Malpighi, Bologna (Italy); Azienda Ospedaliero-Unversitaria di Bologna Policlinico Sant' Orsola-Malpighi, UO di Medicina Nucleare, PAD. 30, Bologna (Italy); Fuccio, Chiara; Santi, Ivan; Nanni, Cristina; Allegri, Vincenzo; Montini, Gian Carlo; Ambrosini, Valentina; Boschi, Stefano; Fanti, Stefano [University of Bologna, Service of Nuclear Medicine, Department of Haematology-Oncology and Laboratory Medicine, Azienda Ospedaliero-Universitaria di Bologna, Policlinico Sant' Orsola-Malpighi, Bologna (Italy); Rubello, Domenico; Marzola, Maria Cristina [Sanata Maria della Misericordia Hospital, Department of Nuclear Medicine, Medical Physics, Radiology, Service of Nuclear Medicine, PET/CT Centre, Rovigo (Italy); Schiavina, Riccardo; Martorana, Giuseppe [University of Bologna, Service of Urology, Department of Specialist Surgery and Anaesthesiology, Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant' Orsola-Malpighi, Bologna (Italy)

    2011-01-15

    The aim of this study was to evaluate the potential usefulness of whole-body {sup 11}C-choline PET/CT in the re-staging of prostate cancer (PC) patients previously treated with radical prostatectomy (RP), who presented a mild increase of prostate-specific antigen (PSA) <1.5 ng/ml (early biochemical relapse) during follow-up (FU). We evaluated 102 consecutive patients (mean age = 68 years, range = 54-82 years) previously treated with RP and who presented during FU a mild increase of trigger PSA serum levels <1.5 ng/ml: mean 0.86 {+-} 0.40 ng/ml (range 0.2-1.5) and median 0.93 ng/ml (range 0.67-1.10). In this patient series {sup 11}C-choline PET/CT was used as the first imaging examination at the time of the detection of a mild serum PSA increase <1.5 ng/ml. {sup 11}C-Choline PET/CT was performed following standard procedures in our centre. At the time of PET/CT, 86 patients were not receiving any pharmacologic treatment, while 16 were under anti-androgenic therapy. Positive PET findings were validated by: (a) transrectal ultrasound (TRUS)-guided biopsy in cases of local recurrence, (b) surgical lymphadenectomy, (c) other imaging procedures or (d) FU lasting for at least 12 months. Univariate and multivariate analyses were used to evaluate the following variables: age, TNM staging, Gleason score, time from RP to the biochemical relapse, anti-androgen therapy at the time of {sup 11}C-choline PET/CT scan, trigger PSA value and PSA kinetics, i.e. PSA doubling time (PSAdt) and PSA velocity (PSAvel), in order to assess the significant predictive factors related to the findings of a positive {sup 11}C-choline PET/CT scan. Overall, {sup 11}C-choline PET/CT showed positive findings in 29 of 102 patients (28% of cases). In detail, {sup 11}C-choline PET/CT detected: local relapse in 7 patients, bone metastases in 13 patients (4 single and 9 multiple) and lymph node metastases in 9 patients (6 single and 3 multiple). Positive PET findings were validated by: (a) TRUS

  20. The evolving role of immunotherapy in prostate cancer

    NARCIS (Netherlands)

    Gerritsen, W.R.

    2012-01-01

    The prognosis for men with metastatic, castration-resistant prostate cancer (CRPC) is limited, and patients have very few treatment options, particularly if the treatment failed with docetaxel (Taxotere). As a result, there is a requirement for novel approaches to therapy. Using immunotherapy to ind

  1. Urethral metastases of prostate cancer; A case report

    Energy Technology Data Exchange (ETDEWEB)

    Porre, P. de (Onze Lieve Vrouwziekenhuis, Aalst (Belgium). Dept. of Radiation Oncology)

    1993-04-01

    A patient presented with local pain and voiding difficulties due to a bulky prostatic cancer and diffuse metastatic lesions throughout the pars spongiosa of the urethra. This rare event prompted us to review the literature. Lacking a specific palliative therapy, we developed a technique of intraurethral brachytherapy. With this treatment, we were able to reach a life-lasting palliation. (orig.)

  2. Method for detecting the presence of prostate cancer

    Science.gov (United States)

    Karin, Michael; Luo, Jun-Li; Tan, Wei

    2010-04-13

    The present invention relates to compositions and methods for cancer diagnosis, treatment and drug screening. In particular, the present invention provides compositions and methods for targeting the nuclear translocation of IkB kinase-.alpha. (IKK.alpha.) and the IKK.alpha.-mediated suppression of Maspin expression observed in metastatic prostate cancer cells.

  3. The Function of Neuroendocrine Cells in Prostate Cancer

    Science.gov (United States)

    2015-06-20

    collaborations among urologists, pathologists, Pathologist Assistants, technical staff from UCLA’s Translational Pathology Core Laboratory (TPCL) and basic... Sud , S., Titz, B., Huang, J., Pienta, K. J., Graeber, T. G., and Witte, O. N. (2013) Metastatic castration-resistant prostate cancer reveals...Genitourinary Tumors. Adicon Clinical Laboratories Inc., Hangzhou, China, November 1, 2011 7. Medical Education in the United States, Anhui Medical

  4. Prostate Cancer Genetics in African Americans

    Science.gov (United States)

    2013-09-01

    questionnaire ;  Completion of an epidemiologic questionnaire ;  For those who have another family member with prostate cancer, drawing of blood and...victim in drive-by shooting in southeast Houston Houston closer to regional crime lab Houston mom charged in pre-teen·s abortion LATEST NEWS http...Prostate Cancer Study Creighton - Jackson State Questionnaire Database Notes Overview Two identical Microsoft Access databases are used to

  5. Immunotherapy in Metastatic Renal Cell Carcinoma: A Comprehensive Review

    Directory of Open Access Journals (Sweden)

    Rachna Raman

    2015-01-01

    Full Text Available Localized renal cell carcinoma (RCC is often curable by surgery alone. However, metastatic RCC is generally incurable. In the 1990s, immunotherapy in the form of cytokines was the mainstay of treatment for metastatic RCC. However, responses were seen in only a minority of highly selected patients with substantial treatment-related toxicities. The advent of targeted agents such as vascular endothelial growth factor tyrosine kinase inhibitors VEGF-TKIs and mammalian target of rapamycin (mTOR inhibitors led to a change in this paradigm due to improved response rates and progression-free survival, a better safety profile, and the convenience of oral administration. However, most patients ultimately progress with about 12% being alive at 5 years. In contrast, durable responses lasting 10 years or more are noted in a minority of those treated with cytokines. More recently, an improved overall survival with newer forms of immunotherapy in other malignancies (such as melanoma and prostate cancer has led to a resurgence of interest in immune therapies in metastatic RCC. In this review we discuss the rationale for immunotherapy and recent developments in immunotherapeutic strategies for treating metastatic RCC.

  6. Matrix metalloproteinase 9 expression in primary human prostatic adenocarcinoma and benign prostatic hyperplasia.

    Science.gov (United States)

    Hamdy, F. C.; Fadlon, E. J.; Cottam, D.; Lawry, J.; Thurrell, W.; Silcocks, P. B.; Anderson, J. B.; Williams, J. L.; Rees, R. C.

    1994-01-01

    Matrix metalloproteinase (MMP) expression was investigated in patients with prostatic adenocarcinoma and benign prostatic hyperplasia (BPH). Forty-one men were studied: 26 had histologically proven prostate cancer, with 14 (54%) showing metastatic disease; 15 patients had BPH. Prostatic tissue was obtained from transurethral resection and needle core biopsies; gelatinolytic activity was determined by zymography. Seven gelatinolytic bands were detected, with molecular weights ranging from > 100 kilodalton (kDa) to 29 kDa. Nine of 14 patients (64%) with skeletal metastases had 92 kDa activity, present in only two of 12 patients (17%) with a negative bone scan, and absent in BPH. The 92 kDa gelatinolytic activity was expressed in 73% of aneuploid tumours compared with 20% of diploid tumours. A 97 kDa gelatinase was expressed in 80% of BPH samples and 23% of carcinoma patients. Enzyme bands of 72, 66 and 45 kDa were equally expressed in malignant tissue, irrespective of metastatic status, but were expressed in fewer BPH patients. The 97, 92, 66 and 45 kDa enzymes were identified as being pro-MMP-9 sequences by Western blotting, using a specific antibody directed against the pro sequence of the mature protein. MMP activity appeared to be increased in malignant prostatic tissue compared with BPH. Pro-MMP-9, in its 92 kDa form, was shown to be exclusively expressed by malignant prostatic tissue, and in particular by tumours that exhibited the aggressive and metastatic phenotype. Images Figure 1 Figure 2 PMID:7506923

  7. SFMBT2 (Scm-like with four mbt domains 2) negatively regulates cell migration and invasion in prostate cancer cells.

    Science.gov (United States)

    Gwak, Jungsug; Shin, Jee Yoon; Lee, Kwanghyun; Hong, Soon Ki; Oh, Sangtaek; Goh, Sung-Ho; Kim, Won Sun; Ju, Bong Gun

    2016-07-26

    Metastatic prostate cancer is the leading cause of morbidity and mortality in men. In this study, we found that expression level of SFMBT2 is altered during prostate cancer progression and has been associated with the migration and invasion of prostate cancer cells. The expression level of SFMBT2 is high in poorly metastatic prostate cancer cells compared to highly metastatic prostate cancer cells. We also found that SFMBT2 knockdown elevates MMP-2, MMP-3, MMP-9, and MMP-26 expression, leading to increased cell migration and invasion in LNCaP and VCaP cells. SFMBT2 interacts with YY1, RNF2, N-CoR and HDAC1/3, as well as repressive histone marks such as H3K9me2, H4K20me2, and H2AK119Ub which are associated with transcriptional repression. In addition, SFMBT2 knockdown decreased KAI1 gene expression through up-regulation of N-CoR gene expression. Expression of SFMBT2 in prostate cancer was strongly associated with clinicopathological features. Patients having higher Gleason score (≥ 8) had substantially lower SFMBT2 expression than patients with lower Gleason score. Moreover, tail vein or intraprostatic injection of SFMBT2 knockdown LNCaP cells induced metastasis. Taken together, our findings suggest that regulation of SFMBT2 may provide a new therapeutic strategy to control prostate cancer metastasis as well as being a potential biomarker of metastatic prostate cancer.

  8. Benign prostate hyperplasia (BPH) - resources

    Science.gov (United States)

    Resources - benign prostatic hyperplasia (BPH); Prostate enlargement resources; BPH resources ... The following organizations provide information on benign prostatic hyperplasia ( prostate enlargement ... Urology Care Foundation -- www. ...

  9. Immune Response to Sipuleucel-T in Prostate Cancer

    Directory of Open Access Journals (Sweden)

    David I. Quinn

    2012-04-01

    Full Text Available Historically, chemotherapy has remained the most commonly utilized therapy in patients with metastatic cancers. In prostate cancer, chemotherapy has been reserved for patients whose metastatic disease becomes resistant to first line castration or androgen deprivation. While chemotherapy palliates, decreases serum prostate specific antigen and improves survival, it is associated with significant side effects and is only suitable for approximately 60% of patients with castrate-resistant prostate cancer. On that basis, exploration of other therapeutic options such as active secondary hormone therapy, bone targeted treatments and immunotherapy are important. Until recently, immunotherapy has had no role in the treatment of solid malignancies aside from renal cancer and melanoma. The FDA-approved autologous cellular immunotherapy sipuleucel-T has demonstrated efficacy in improving overall survival in patients with metastatic castrate-resistant prostate cancer in randomized clinical trials. The proposed mechanism of action is reliant on activating the patients’ own antigen presenting cells (APCs to prostatic acid phosphatase (PAP fused with granulocyte-macrophage colony stimulating factor (GM-CSF and subsequent triggered T-cell response to PAP on the surface of prostate cancer cells in the patients body. Despite significant prolongation of survival in Phase III trials, the challenge to health care providers remains the dissociation between objective changes in serum PSA or on imaging studies after sipleucel-T and survival benefit. On that basis there is an unmet need for markers of outcome and a quest to identify immunologic or clinical surrogates to fill this role. This review focuses on the impact of sipuleucel-T on the immune system, the T and B cells, and their responses to relevant antigens and prostate cancer. Other therapeutic modalities such as chemotherapy, corticosteroids and GM-CSF and host factors can also affect immune response. The

  10. Immune response to sipuleucel-T in prostate cancer.

    Science.gov (United States)

    Thara, Eddie; Dorff, Tanya B; Averia-Suboc, Monica; Luther, Michael; Reed, Mary E; Pinski, Jacek K; Quinn, David I

    2012-04-18

    Historically, chemotherapy has remained the most commonly utilized therapy in patients with metastatic cancers. In prostate cancer, chemotherapy has been reserved for patients whose metastatic disease becomes resistant to first line castration or androgen deprivation. While chemotherapy palliates, decreases serum prostate specific antigen and improves survival, it is associated with significant side effects and is only suitable for approximately 60% of patients with castrate-resistant prostate cancer. On that basis, exploration of other therapeutic options such as active secondary hormone therapy, bone targeted treatments and immunotherapy are important. Until recently, immunotherapy has had no role in the treatment of solid malignancies aside from renal cancer and melanoma. The FDA-approved autologous cellular immunotherapy sipuleucel-T has demonstrated efficacy in improving overall survival in patients with metastatic castrate-resistant prostate cancer in randomized clinical trials. The proposed mechanism of action is reliant on activating the patients' own antigen presenting cells (APCs) to prostatic acid phosphatase (PAP) fused with granulocyte-macrophage colony stimulating factor (GM-CSF) and subsequent triggered T-cell response to PAP on the surface of prostate cancer cells in the patients body. Despite significant prolongation of survival in Phase III trials, the challenge to health care providers remains the dissociation between objective changes in serum PSA or on imaging studies after sipleucel-T and survival benefit. On that basis there is an unmet need for markers of outcome and a quest to identify immunologic or clinical surrogates to fill this role. This review focuses on the impact of sipuleucel-T on the immune system, the T and B cells, and their responses to relevant antigens and prostate cancer. Other therapeutic modalities such as chemotherapy, corticosteroids and GM-CSF and host factors can also affect immune response. The optimal timing for

  11. [Obesity and prostate cancer. Role of adipocytokines and clinical implications].

    Science.gov (United States)

    Hoda, M R; Mohammed, N; Theil, G; Fischer, K; Fornara, P

    2012-09-01

    Obesity is proposed as a possible risk factor for many tumors. The present review discusses the current knowledge on the clinical and biological impact of obesity on the development and progression of prostate cancer, the role of adipocyte-derived hormones (adipocytokines) in this scenario and the resulting clinical implications. In addition, the results of own experimental and clinical studies on the involvement of adipocytokines (e.g. leptin, adiponectin) in the pathophysiology of prostate cancer are presented. It was found that patients who were diagnosed with prostate cancer at this clinic had higher serum leptin and lower serum adiponectin concentrations. These investigations and other studies have further shown that higher serum levels of the adipocytokine leptin were associated with larger prostate cancer volumes, high-grade classification, biochemical recurrence, metastasis and progression of metastatic prostate tumors, as well as increased mortality. Moreover, there was a strong correlation between the serum level of leptin and serum levels of prostate specific antigen (PSA). Leptin stimulated in vitro the proliferation and inhibited the apoptosis of prostate cancer cells in a dose and time-dependent manner, however, androgen-resistant cell lines responded more strongly. At the molecular level, adipocytokines require the network of tyrosine kinases to accomplish the mitogenic and antiapoptotic effects in prostate cancer cells. Prominent members of the most important signal transduction cascades, such as MAPK, PI3-K and JAK/STAT are activated upon binding of leptin to its receptor on the cell membrane of prostate cancer cells. Adipocytokines such as leptin may serve as additional prognostic parameters for the evaluation of specific therapies for metastatic hormone refractory prostate cancer. The findings presented here are intended as a basis for further studies.

  12. Metastatic Brain Tumors

    Directory of Open Access Journals (Sweden)

    Ersin Haciyakupoglu

    2014-04-01

    Full Text Available Metastatic tumor is secondary spread to the central nervous system of primer systemic cancers originating from tissues other than the central nervous system. In adults; there are metastases respectively from lungs, breasts, malign melanoma, renal cell carcinoma, colon and thyroid cancers. 30-60% of lung cancers metastasis to the brain. In children there are quite a few cerebral metastases. Most commonly leukemia, lymphoma, osteogenic sarcoma, rhabdomyosarcoma and germ cell tumors metastasis to the brain. %50 of malign melanoma, lung, breast and colon cancers intend to make multipl metastases but renal cell cancers intend to make solitary metastasis.While lung cancers metastasis to brain in 6-9 months after the definitive diagnosis, renal cancers in 1 year, colon cancers in 2 years, breast cancers and malign melanoma in 3 years metastasis to brain. In 6% of cases there are cerebral metastasis while there isn’t a symptom of a primary tumor. For treatment corticosteroids, surgery, Radiotherapy(RT, Chemotherapy(CT and Stereotactic Radiosurgery(SRS can be implemented. Small cell lung cancers, lymphoma, germ cell tumors are sensitive to RT and CT. Non small cell lung cancers, renal, colon cancers and malign melanoma are radioresistant. The purposes in the surgery of the metastatic brain tumors are; total resection of tumors without neurologic deficits, decreasing the intracranial pressure and decreasing the dose of postoperative radiotherapy. Key Words: Metastatic brain tumors, Stereotactic radiosurgery, Malign melanoma, Lung cancers, Renal cell carcinoma, Radiotherapy, Chemotherapy [Cukurova Med J 2014; 39(2.000: 191-202

  13. Xanthogranulomatous Prostatitis, a Rare Prostatic Entity

    Directory of Open Access Journals (Sweden)

    Alejandro Noyola

    2017-01-01

    Full Text Available There are several benign prostatic pathologies that can clinically mimic a prostate adenocarcinoma. Xanthogranulomatous prostatitis is a benign inflammatory condition of the prostate and a rare entity. A 47-year old male, with 3 years of lower urinary tract symptoms, with a palpable hypogastric tumor, digital rectal examination: solid prostate, of approximately 60 g. Initial PSA was 0.90 ng/mL. He underwent surgical excision of the lower abdominal nodule and prostatectomy. Histopathology showed xanthogranulomatous prostatitis, without malignancy. Xanthogranulomatous prostatitis is an extremely rare entity that can simulate prostate adenocarcinoma, therefore having a correct histopathological diagnosis is essential.

  14. Xanthogranulomatous Prostatitis, a Rare Prostatic Entity.

    Science.gov (United States)

    Noyola, Alejandro; Gil, José Fernando; Lujano, Heriberto; Piñon, Omar; Muñoz, Gabriel; Michel, José Manuel; Garcia, Jorge; Valdez, Jorge; Morales, Omar

    2017-01-01

    There are several benign prostatic pathologies that can clinically mimic a prostate adenocarcinoma. Xanthogranulomatous prostatitis is a benign inflammatory condition of the prostate and a rare entity. A 47-year old male, with 3 years of lower urinary tract symptoms, with a palpable hypogastric tumor, digital rectal examination: solid prostate, of approximately 60 g. Initial PSA was 0.90 ng/mL. He underwent surgical excision of the lower abdominal nodule and prostatectomy. Histopathology showed xanthogranulomatous prostatitis, without malignancy. Xanthogranulomatous prostatitis is an extremely rare entity that can simulate prostate adenocarcinoma, therefore having a correct histopathological diagnosis is essential.

  15. PROSTVAC® targeted immunotherapy candidate for prostate cancer.

    Science.gov (United States)

    Shore, Neal D

    2014-01-01

    Targeted immunotherapies represent a valid strategy for the treatment of metastatic castrate-resistant prostate cancer. A randomized, double-blind, Phase II clinical trial of PROSTVAC® demonstrated a statistically significant improvement in overall survival and a large, global, Phase III trial with overall survival as the primary end point is ongoing. PROSTVAC immunotherapy contains the transgenes for prostate-specific antigen and three costimulatory molecules (designated TRICOM). Research suggests that PROSTVAC not only targets prostate-specific antigen, but also other tumor antigens via antigen cascade. PROSTVAC is well tolerated and has been safely combined with other cancer therapies, including hormonal therapy, radiotherapy, another immunotherapy and chemotherapy. Even greater benefits of PROSTVAC may be recognized in earlier-stage disease and low-disease burden settings where immunotherapy can trigger a long-lasting immune response.

  16. Significance of pretreatment cardiovascular morbidity as a risk factor during treatment with parenteral oestrogen or combined androgen deprivation of 915 patients with metastasized prostate cancer

    DEFF Research Database (Denmark)

    Johansson, Robert; Damber, Jan Erik; Hagerman, Inger

    2011-01-01

    This study aimed to evaluate prognostic risk factors for cardiovascular events during treatment of metastatic prostate cancer patients with high-dose parenteral polyoestradiol phosphate (PEP, Estradurin®) or combined androgen deprivation (CAD) with special emphasis on pretreatment cardiovascular...

  17. Prostate Ultrasound

    Medline Plus

    Full Text Available ... physician during a routine physical exam or prostate cancer screening exam. an elevated blood test result. difficulty ... if a patient is at high risk for cancer. In this case, a biopsy is performed and ...

  18. Prostate Ultrasound

    Medline Plus

    Full Text Available ... physician during a routine physical exam or prostate cancer screening exam. an elevated blood test result. difficulty ... if a patient is at high risk for cancer. In this case, a biopsy is performed and ...

  19. Prostate Ultrasound

    Medline Plus

    Full Text Available ... physician during a routine physical exam or prostate cancer screening exam. an elevated blood test result. difficulty ... vessels or to detect abnormal masses, such as tumors. In an ultrasound examination, a transducer both sends ...

  20. Prostate Problems

    Science.gov (United States)

    ... do to help diagnose your prostate problem. Physical Exam A physical exam may help diagnose the cause ... sleep avoid or drink fewer liquids that have caffeine or alcohol in them avoid medicines that may ...

  1. Prostate Cancer

    Science.gov (United States)

    ... may help you cope with your distress, including: Art therapy Dance or movement therapy Exercise Meditation Music ... www.mayoclinic.org/diseases-conditions/prostate-cancer/basics/definition/CON-20029597 . Mayo Clinic Footer Legal Conditions and ...

  2. Prostate brachytherapy

    Science.gov (United States)

    ... the prostate. The doctor may use a computerized robot to do this. The radioactive material is removed ... M. is also a founding member of Hi-Ethics and subscribes to the principles of the Health ...

  3. Prostate Ultrasound

    Medline Plus

    Full Text Available ... rectum into the prostate gland which is situated right in front of the rectum. top of page ... prescribed procedure with your doctor, the medical facility staff and/or your insurance provider to get a ...

  4. Prostate Ultrasound

    Medline Plus

    Full Text Available ... abnormal area in the prostate gland for later laboratory testing. top of page How should I prepare? ... the returning sound waves), as well as the type of body structure and composition of body tissue ...

  5. Prostate Ultrasound

    Medline Plus

    Full Text Available ... are obtained from different angles to get the best view of the prostate gland. If a suspicious ... over time. Follow-up examinations are sometimes the best way to see if treatment is working or ...

  6. Prostatitis - bacterial

    Science.gov (United States)

    ... infection in or around the testicles ( epididymitis or orchitis ), you may also have symptoms of that condition. ... In: Wein AJ, ed. Prostatitis and related conditions, orchitis, and epididymitis. Campbell-Walsh Urology . 10th ed. Philadelphia, ...

  7. Prostate Ultrasound

    Medline Plus

    Full Text Available ... physician during a routine physical exam or prostate cancer screening exam. an elevated blood test result. difficulty urinating. Because ultrasound provides real-time images, it also can be used to guide ...

  8. Prostate Ultrasound

    Medline Plus

    Full Text Available ... information you were looking for? Yes No Please type your comment or suggestion into the following text box: Comment: E-mail: ... Images related to Ultrasound - Prostate Sponsored by Please ...

  9. Prostate Ultrasound

    Medline Plus

    Full Text Available ... area in the prostate gland for later laboratory testing. top of page How should I prepare? You ... computer or television monitor. The image is created based on the amplitude (loudness), frequency (pitch) and time ...

  10. Prostate Ultrasound

    Medline Plus

    Full Text Available ... abnormal area in the prostate gland for later laboratory testing. top of page How should I prepare? ... The transducer sends out inaudible, high—frequency sound waves into the body and then listens for the ...

  11. Prostate Ultrasound

    Medline Plus

    Full Text Available ... also known as benign prostatic hyperplasia (BPH) , with measurements acquired as needed for any treatment planning. detect ... Rarely, a small amount of blood may be present in the sperm or urine following the procedure. ...

  12. Prostate Ultrasound

    Medline Plus

    Full Text Available ... also known as benign prostatic hyperplasia (BPH) , with measurements acquired as needed for any treatment planning. detect ... accredited facilities database . This website does not provide cost information. The costs for specific medical imaging tests, ...

  13. Mechanical Entrapment Is Insufficient and Intercellular Adhesion Is Essential for Metastatic Cell Arrest in Distant Organs

    Directory of Open Access Journals (Sweden)

    Olga V. Glinskii

    2005-05-01

    Full Text Available In this report, we challenge a common perception that tumor embolism is a size-limited event of mechanical arrest, occurring in the first capillary bed encountered by blood-borne metastatic cells. We tested the hypothesis that mechanical entrapment alone, in the absence of tumor cell adhesion to blood vessel walls, is not sufficient for metastatic cell arrest in target organ microvasculature. The in vivo metastatic deposit formation assay was used to assess the number and location of fluorescently labeled tumor cells lodged in selected organs and tissues following intravenous inoculation. We report that a significant fraction of breast and prostate cancer cells escapes arrest in a lung capillary bed and lodges successfully in other organs and tissues. Monoclonal antibodies and carbohydrate-based compounds (anti-Thomsen-Friedenreich antigen antibody, anti-galectin-3 antibody, modified citrus pectin, and lactulosyl-L-leucine, targeting specifically β-galactoside-mediated tumor-endothelial cell adhesive interactions, inhibited by >90% the in vivo formation of breast and prostate carcinoma metastatic deposits in mouse lung and bones. Our results indicate that metastatic cell arrest in target organ microvessels is not a consequence of mechanical trapping, but is supported predominantly by intercellular adhesive interactions mediated by cancer-associated Thomsen-Friedenreich glycoantigen and β-galactoside-binding lectin galectin-3. Efficient blocking of β-galactoside-mediated adhesion precludes malignant cell lodging in target organs.

  14. Prostate cancer

    DEFF Research Database (Denmark)

    Chabanova, Elizaveta; Balslev, Ingegerd; Logager, Vibeke

    2011-01-01

    To investigate diagnostic accuracy of detection of prostate cancer by magnetic resonance: to evaluate the performance of T2WI, DCEMRI and CSI and to correlate the results with biopsy and radical prostatectomy histopathological data.......To investigate diagnostic accuracy of detection of prostate cancer by magnetic resonance: to evaluate the performance of T2WI, DCEMRI and CSI and to correlate the results with biopsy and radical prostatectomy histopathological data....

  15. 全雄激素阻断治疗后老年前列腺癌患者认知功能的变化特点%Cognitive changes in men undergoing complete androgen blockade for non-metastatic prostate cancer

    Institute of Scientific and Technical Information of China (English)

    张志强; 于德新; 谢栋栋; 杨琳琳; 施浩强; 李光远; 张芳芳; 王毅; 张涛

    2014-01-01

    Objective To observe and assess the cognitive changes in older men undergoing complete androgen blockade for non-metastatic prostate cancer.Methods A prospective study was conducted among 38 patients (74.5 ± 4.3) years with non-metastatic prostate cancer undergoing complete androgen blockade and 37 controls (71.9±5.1) years with non-metastatic prostate cancer undergoing radical prostatectomy.Montreal cognitive assessment (MoCA) were performed in all subjects at tbe beginning and 6,12months after the study,and the differences were analyzed statistically.There was no statistically significant difference between CAB group and control (27.92±1.05 vs 27.97±0.80,P=0.81) in the overall scores of MoCA at the onset of the study.Results There were no significant differences between two groups in the baseline of testosterone [(12.07±3.68 nmol/L) vs (12.51±3.91 nmolL),P=0.62].Six months later,the scores of visuospatial and executive function,attention,memories in the items of MoCA and total MoCA scores between CAB group and control were (4.26±0.59 vs 4.70±0.46,P=0.001),(4.87±0.66 vs 5.38±0.56,P=0.001),(4.08±0.70 vs 4.62±0.64,P=0.001) and (26.63±0.91 vs 27.78±0.82,P<0.001),and there were significant differences between two groups.There were no significant differences between CAB group and control in the items of MoCA score,including language (2.81±0.39 vs 2.78±0.42,P=0.73),abstract thinking (1.92±0.27 vs 1.92±0.28,P =0.97),orientation (5.84± 0.36 vs 5.65± 0.36,P =0.18)and naming (2.89±0.30 vs 2.73±0.44,P=0.07).Twelve months later,the scores of visuospatial and executive function,attention,memories and total MoCA scores between CAB group and control were (4.29±0.61vs4.70±0.46,P=0.002),(5.02±0.67 vs 5.49±0.56,P=0.002),(3.84±0.64 vs4.68±0.53,P<0.001)and (26.31±0.94 vs 27.87±0.84,P<0.001),and tbere were significant differences between two groups.There were no significant differences between CAB group and control in the items of MoCA score

  16. New serum biomarkers for prostate cancer diagnosis

    Science.gov (United States)

    Chadha, Kailash C.; Miller, Austin; Nair, Bindukumar B.; Schwartz, Stanley A.; Trump, Donald L.; Underwood, Willie

    2014-01-01

    Background Prostate-specific antigen (PSA) is currently used as a biomarker for diagnosis and management of prostate cancer (CaP). However, PSA typically lacks the sensitivity and specificity desired of a diagnostic marker. Objective The goal of this study was to identify an additional biomarker or a panel of biomarkers that is more sensitive and specific than PSA in differentiating benign versus malignant prostate disease and/or localized CaP versus metastatic CaP. Methods Concurrent measurements of circulating interleukin-8 (IL-8), Tumor necrosis factor-α (TNF-α) and soluble tumor necrosis factor-α receptors 1 (sTNFR1) were obtained from four groups of men: (1) Controls (2) with elevated prostate-specific antigen with a negative prostate biopsy (elPSA_negBx) (3) with clinically localized CaP and (4) with castration resistant prostate cancer. Results TNF-α Area under the receiver operating characteristic curve (AUC = 0.93) and sTNFR1 (AUC = 0.97) were strong predictors of elPSA_negBx (vs. CaP). The best predictor of elPSA_negBx vs CaP was sTNFR1 and IL-8 combined (AUC = 0.997). The strongest single predictors of localized versus metastatic CaP were TNF-α (AUC = 0.992) and PSA (AUC = 0.963) levels. Conclusions The specificity and sensitivity of a PSA-based CaP diagnosis can be significantly enhanced by concurrent serum measurements of IL-8, TNF-α and sTNFR1. In view of the concerns about the ability of PSA to distinguish clinically relevant CaP from indolent disease, assessment of these biomarkers in the larger cohort is warranted. PMID:25593898

  17. New serum biomarkers for prostate cancer diagnosis

    Directory of Open Access Journals (Sweden)

    Kailash C Chadha

    2014-01-01

    Full Text Available Background: Prostate-specific antigen (PSA is currently used as a biomarker for diagnosis and management of prostate cancer (CaP. However, PSA typically lacks the sensitivity and specificity desired of a diagnostic marker. Objective: The goal of this study was to identify an additional biomarker or a panel of biomarkers that is more sensitive and specific than PSA in differentiating benign versus malignant prostate disease and/or localized CaP versus metastatic CaP. Methods: Concurrent measurements of circulating interleukin-8 (IL-8, Tumor necrosis factor-α (TNF-α and soluble tumor necrosis factor-α receptors 1 (sTNFR1 were obtained from four groups of men: (1 Controls (2 with elevated prostate-specific antigen with a negative prostate biopsy (elPSA_negBx (3 with clinically localized CaP and (4 with castration resistant prostate cancer. Results: TNF-α Area under the receiver operating characteristic curve (AUC = 0.93 and sTNFR1 (AUC = 0.97 were strong predictors of elPSA_negBx (vs. CaP. The best predictor of elPSA_negBx vs CaP was sTNFR1 and IL-8 combined (AUC = 0.997. The strongest single predictors of localized versus metastatic CaP were TNF-α (AUC = 0.992 and PSA (AUC = 0.963 levels. Conclusions: The specificity and sensitivity of a PSA-based CaP diagnosis can be significantly enhanced by concurrent serum measurements of IL-8, TNF-α and sTNFR1. In view of the concerns about the ability of PSA to distinguish clinically relevant CaP from indolent disease, assessment of these biomarkers in the larger cohort is warranted.

  18. Cdc6 and Cyclin E2 Are PTEN-Regulated Genes Associated with Human Prostate Cancer Metastasis

    Directory of Open Access Journals (Sweden)

    Zhong Wu

    2009-01-01

    Full Text Available Phosphatase and tensin homolog deleted on chromosome 10 (PTEN is frequently inactivated in metastatic prostate cancer, yet the molecular consequences of this and their association with the metastatic phenotype are incompletely understood. We performed transcriptomic analysis and identified genes altered by conditional PTEN reexpression in C4-2, a human metastatic prostate cancer cell line with inactive PTEN. PTEN-regulated genes were disproportionately represented among genes altered in human prostate cancer progression and metastasis but not among those associated with tumorigenesis. From the former set, we identified two novel putative PTEN targets, cdc6 and cyclin E2, which were overexpressed in metastatic human prostate cancer and up-regulated as a function of PTEN depletion in poorly metastatic DU145 human prostate cancer cells harboring a wild type PTEN. Inhibition of cdc6 and cyclin E2 levels as a consequence of PTEN expression was associated with cell cycle G1 arrest, whereas use of PTEN activity mutants revealed that regulation of these genes was dependent on PTEN lipid phosphatase activity. Computational and promoter-reporter evaluations implicated the E2F transcription factor in PTEN regulation of cdc6 and cyclin E2 expression. Our results suggest a hypothetical model whereby PTEN loss upregulates cell cycle genes such as cdc6 and cyclin E2 that in turn promote metastatic colonization at distant sites.

  19. Widespread telomere instability in prostatic lesions.

    Science.gov (United States)

    Tu, LiRen; Huda, Nazmul; Grimes, Brenda R; Slee, Roger B; Bates, Alison M; Cheng, Liang; Gilley, David

    2016-05-01

    A critical function of the telomere is to disguise chromosome ends from cellular recognition as double strand breaks, thereby preventing aberrant chromosome fusion events. Such chromosome end-to-end fusions are known to initiate genomic instability via breakage-fusion-bridge cycles. Telomere dysfunction and other forms of genomic assault likely result in misregulation of genes involved in growth control, cell death, and senescence pathways, lowering the threshold to malignancy and likely drive disease progression. Shortened telomeres and anaphase bridges have been reported in a wide variety of early precursor and malignant cancer lesions including those of the prostate. These findings are being extended using methods for the analysis of telomere fusions (decisive genetic markers for telomere dysfunction) specifically within human tissue DNA. Here we report that benign prostatic hyperplasia (BPH), high-grade prostatic intraepithelial neoplasia (PIN), and prostate cancer (PCa) prostate lesions all contain similarly high frequencies of telomere fusions and anaphase bridges. Tumor-adjacent, histologically normal prostate tissue generally did not contain telomere fusions or anaphase bridges as compared to matched PCa tissues. However, we found relatively high levels of telomerase activity in this histologically normal tumor-adjacent tissue that was reduced but closely correlated with telomerase levels in corresponding PCa samples. Thus, we present evidence of high levels of telomere dysfunction in BPH, an established early precursor (PIN) and prostate cancer lesions but not generally in tumor adjacent normal tissue. Our results suggest that telomere dysfunction may be a common gateway event leading to genomic instability in prostate tumorigenesis. .

  20. Gene therapy for prostate cancer.

    LENUS (Irish Health Repository)

    Tangney, Mark

    2012-01-31

    Cancer remains a leading cause of morbidity and mortality. Despite advances in understanding, detection, and treatment, it accounts for almost one-fourth of all deaths per year in Western countries. Prostate cancer is currently the most commonly diagnosed noncutaneous cancer in men in Europe and the United States, accounting for 15% of all cancers in men. As life expectancy of individuals increases, it is expected that there will also be an increase in the incidence and mortality of prostate cancer. Prostate cancer may be inoperable at initial presentation, unresponsive to chemotherapy and radiotherapy, or recur following appropriate treatment. At the time of presentation, patients may already have metastases in their tissues. Preventing tumor recurrence requires systemic therapy; however, current modalities are limited by toxicity or lack of efficacy. For patients with such metastatic cancers, the development of alternative therapies is essential. Gene therapy is a realistic prospect for the treatment of prostate and other cancers, and involves the delivery of genetic information to the patient to facilitate the production of therapeutic proteins. Therapeutics can act directly (eg, by inducing tumor cells to produce cytotoxic agents) or indirectly by upregulating the immune system to efficiently target tumor cells or by destroying the tumor\\'s vasculature. However, technological difficulties must be addressed before an efficient and safe gene medicine is achieved (primarily by developing a means of delivering genes to the target cells or tissue safely and efficiently). A wealth of research has been carried out over the past 20 years, involving various strategies for the treatment of prostate cancer at preclinical and clinical trial levels. The therapeutic efficacy observed with many of these approaches in patients indicates that these treatment modalities will serve as an important component of urological malignancy treatment in the clinic, either in isolation or