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Article ; Online: Is It Time to Re-Examine the Prostate Cancer Treatment Paradigm by Targeting the Interaction Between the Prostate and Metastases?

Logothetis, Christopher J / Aparicio, Ana M

Journal of clinical oncology : official journal of the American Society of Clinical Oncology

2016 Volume 34, Issue 24, Page(s) 2810–2811

MeSH term(s)	Bone Neoplasms ; Humans ; Male ; Prostatic Neoplasms
Language	English
Publishing date	2016-07-18
Publishing country	United States
Document type	Editorial ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	604914-x
ISSN	1527-7755 ; 0732-183X
ISSN (online)	1527-7755
ISSN	0732-183X
DOI	10.1200/JCO.2016.68.4738
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Article ; Online: Integrative molecular analyses of the MD Anderson prostate cancer patient-derived xenograft (MDA PCa PDX) series.

Anselmino, Nicolas / Labanca, Estefania / Shepherd, Peter D A / Dong, Jiabin / Yang, Jun / Song, Xiaofei / Nandakumar, Subhiksha / Kundra, Ritika / Lee, Cindy J / Schultz, Nikolaus / Zhang, Jianhua / Araujo, John C / Aparicio, Ana M / Subudhi, Sumit K / Corn, Paul G / Pisters, Louis L / Ward, John F / Davis, John W / Vazquez, Elba S /

Gueron, Geraldine / Logothetis, Christopher J / Futreal, Andrew / Troncoso, Patricia / Chen, Yu / Navone, Nora M

Clinical cancer research : an official journal of the American Association for Cancer Research

2024

Abstract: Purpose: Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer (PCa) models. This initiative builds on the rich MD ... ...

Abstract	Purpose: Develop and deploy a robust discovery platform that encompasses heterogeneity, clinical annotation, and molecular characterization and overcomes the limited availability of prostate cancer (PCa) models. This initiative builds on the rich MD Anderson (MDA) PCa patient-derived xenograft (PDX) resource to complement existing publicly available databases by addressing gaps in clinically annotated models reflecting the heterogeneity of potentially lethal and lethal PCa. Experimental design: We performed whole-genome, targeted, and RNA sequencing in representative samples of the same tumor from 44 PDXs derived from 38 patients linked to donor tumor metadata and corresponding organoids. The cohort includes models derived from different morphologic groups, disease states, and involved organ sites (including circulating tumor cells), as well as paired samples representing heterogeneity or stages before and after therapy. Results: The cohort recapitulates clinically reported alterations in PCa genes, providing a data resource for clinical and molecular interrogation of suitable experimental models. Paired samples displayed conserved molecular alteration profiles, suggesting the relevance of other regulatory mechanisms (e.g., epigenomic) influenced by the microenvironment and/or treatment. Transcriptomically, models were grouped based on morphological classification. DNA damage response-associated mechanisms emerged as differentially regulated between adenocarcinoma and neuroendocrine PCa in a cross-interrogation of PDX/patient datasets. Conclusions: We addressed the gap in clinically relevant PCa models through comprehensive molecular characterization of MDA PCa PDXs, providing a discovery platform that integrates with patient data and benchmarked to therapeutically relevant consensus clinical groupings. This unique resource supports robust hypothesis generation and testing from basic, translational, and clinical perspectives.
Language	English
Publishing date	2024-03-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-2438
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Article ; Online: Pattern and Distribution of Distant Metastases in Anaplastic Prostate Carcinoma: A Single-Institute Experience With 101 Patients.

Ganeshan, Dhakshinamoorthy / Aparicio, Ana M / Morani, Ajay / Kundra, Vikas

AJR. American journal of roentgenology

2017 Volume 209, Issue 2, Page(s) 327–332

Abstract: Objective: The aim of this study was to evaluate the sites and frequencies of distant metastases in patients with anaplastic prostate carcinoma and to correlate those findings with prostate-specific antigen (PSA) levels.: Materials and methods: ... ...

Abstract	Objective: The aim of this study was to evaluate the sites and frequencies of distant metastases in patients with anaplastic prostate carcinoma and to correlate those findings with prostate-specific antigen (PSA) levels. Materials and methods: Patients with anaplastic prostate carcinoma (n = 101) underwent CT and bone scans before platinum-based chemotherapy. CT findings were retrospectively reviewed to identify the sites of metastases. CT findings were correlated with baseline PSA levels. The Wilcoxon rank sum test was used to correlate PSA levels between patients with metastases at osseous and nonosseous sites. The Wilcoxon rank sum test was also used to correlate the type of bone metastases (blastic vs lytic) and the PSA levels. Results: Eighty-three of 101 patients (82%) had osseous metastases. PSA levels were significantly higher in patients with bone metastases than in patients without osseous metastases. However, 23 of the 83 patients (28%) with bone metastases had PSA levels in the normal range (i.e., < 4 ng/mL). The type of bone metastases (blastic vs lytic) did not show any statistically significant correlation to the PSA levels. Overall, 63 of 101 patients (62%) had nonosseous distant metastases at one or more sites, including the liver (n = 34), lung (n = 24), mediastinum (n = 31), pleura (n = 7), brain (n = 9), adrenal glands (n = 6), peritoneum (n = 4), and spleen (n = 1). PSA levels were not significantly elevated in patients with nonosseous distant metastases. Twenty-six of the 63 patients (41%) with nonosseous metastases had PSA levels in the normal range (< 4 ng/mL). Conclusion: Patients with the anaplastic clinical variant of prostate cancer have a high frequency of typical and atypical sites of metastases. Common sites of nonosseous distant metastases include the liver, lung, mediastinum, pleura, brain, and adrenal glands. PSA levels are unreliable and may be disproportionately low, despite the presence of multifocal large-volume metastases. CT of the chest, abdomen, and pelvis should be considered in routine staging and follow-up of patients with anaplastic prostate carcinoma regardless of their PSA levels.
MeSH term(s)	Adult ; Aged ; Biopsy ; Humans ; Male ; Middle Aged ; Neoplasm Metastasis/diagnostic imaging ; Positron-Emission Tomography ; Prostate-Specific Antigen/blood ; Prostatic Neoplasms/pathology ; Retrospective Studies ; Tomography, X-Ray Computed
Chemical Substances	Prostate-Specific Antigen (EC 3.4.21.77)
Language	English
Publishing date	2017-06-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	82076-3
ISSN	1546-3141 ; 0361-803X ; 0092-5381
ISSN (online)	1546-3141
ISSN	0361-803X ; 0092-5381
DOI	10.2214/AJR.16.17214
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Article ; Online: Combined CTLA-4 and PD-L1 blockade in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer is associated with increased myeloid and neutrophil immune subsets in the bone microenvironment.

Subudhi, Sumit K / Siddiqui, Bilal A / Aparicio, Ana M / Yadav, Shalini S / Basu, Sreyashi / Chen, Hong / Jindal, Sonali / Tidwell, Rebecca S S / Varma, Ashwin / Logothetis, Christopher J / Allison, James P / Corn, Paul G / Sharma, Padmanee

Journal for immunotherapy of cancer

2022 Volume 9, Issue 10

Abstract: Background: Immune checkpoint therapy (ICT) has low response rates in patients with metastatic castration-resistant prostate cancer (mCRPC), in part due to few T cells in the tumor microenvironment (TME). Anti-cytotoxic T lymphocyte-associated protein 4 ...

Abstract	Background: Immune checkpoint therapy (ICT) has low response rates in patients with metastatic castration-resistant prostate cancer (mCRPC), in part due to few T cells in the tumor microenvironment (TME). Anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) promotes intratumoral T cell infiltration but induces upregulation of PD-1 and programmed death ligand-1 (PD-L1) within the prostate TME. Combined anti-CTLA-4 plus anti-PD-1 can partly overcome this adaptive resistance and was recently shown to augment responses in patients with mCRPC with measurable disease. Although bone is the most common site of metastasis in prostate cancer, patients with bone-predominant disease are frequently excluded from trials because they lack measurable disease, which limits assessment of disease progression and tissue sampling. We therefore designed this study to investigate combined ICT in mCRPC to bone. Hypothesis: Combined anti-CTLA-4 (tremelimumab) plus anti-PD-L1 (durvalumab) is safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone. Patients and methods: In this single-arm pilot study, men with chemotherapy-naïve mCRPC to bone received tremelimumab (75 mg intravenous) plus durvalumab (1500 mg intravenous) every 4 weeks (up to four doses), followed by durvalumab (1500 mg intravenous) maintenance every 4 weeks (up to nine doses). The primary endpoint was incidence of adverse events. Secondary endpoints included serum prostate-specific antigen (PSA), progression-free survival (PFS), radiographic PFS (rPFS), and maximal PSA decline. Results: Twenty-six patients were treated between August 8, 2017 and March 28, 2019. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 patients (42%), with no grade 4 or 5 events. TRAEs leading to discontinuation occurred in three patients (12%). PSA decline ≥50% occurred in three patients (12%). Six patients (24%) achieved stable disease for >6 months. At a median follow-up of 43.6 months, median rPFS was 3.7 months (95% CI: 1.9 to 5.7), and median overall survival was 28.1 months (95% CI: 14.5 to 37.3). Post-treatment evaluation of the bone microenvironment revealed transcriptional upregulation in myeloid and neutrophil immune subset signatures and increased expression of inhibitory immune checkpoints. Conclusions: Tremelimumab plus durvalumab was safe and well tolerated in patients with chemotherapy-naïve mCRPC to bone, with potential activity in a small number of patients as measured by rPFS. Combination of CTLA-4 and PD-L1 blockade with therapies targeting the myeloid compartment or other inhibitory immune receptors may be necessary to overcome mechanisms of resistance within prostate bone microenvironment. Trial registration number: NCT03204812.
MeSH term(s)	Aged ; Aged, 80 and over ; Antineoplastic Combined Chemotherapy Protocols/pharmacology ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; CTLA-4 Antigen/therapeutic use ; Humans ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Male ; Middle Aged ; Neutrophils/metabolism ; Pilot Projects ; Prostatic Neoplasms, Castration-Resistant/drug therapy ; Tumor Microenvironment
Chemical Substances	CTLA-4 Antigen ; Immune Checkpoint Inhibitors
Language	English
Publishing date	2022-02-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2021-002919
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Article ; Online: Development of a translational medicine protocol for an NCTN genitourinary clinical trial: Critical steps, common pitfalls and a basic guide to translational clinical research.

Meeks, Joshua J / Goldkorn, Amir / Aparicio, Ana M / McConkey, David J

Urologic oncology

2018 Volume 37, Issue 5, Page(s) 313–317

Abstract: Translational medicine (TM) components of prospective clinical trials provide an invaluable opportunity to test hypotheses that contribute to our knowledge of human disease biology and/or the mechanism of action of a given therapeutic intervention. Our ... ...

Abstract	Translational medicine (TM) components of prospective clinical trials provide an invaluable opportunity to test hypotheses that contribute to our knowledge of human disease biology and/or the mechanism of action of a given therapeutic intervention. Our ability to sample tumors and their microenvironment, and the depth and breadth of biological information that can be extracted from them, has increased exponentially in recent years. This information is critical to guide the next steps clinical research if we are to accelerate the pace of progress in cancer treatment. Thus, TM studies should be considered key components of any clinical trial. However, TM studies are costly and biologic sampling can impose significant morbidity on our patients. Therefore, TM investigators should be engaged early in the design process (similar to a statistician) to ensure that the most imperative research questions are rigourosly defined, that the obtained specimens can be used to answer them and that the results will serve as the foundation for additional studies. In this review, we focus on TM studies in the context of the National Cancer Institute's National Clinical Trials Network trials and offer a description of the genesis of TM components, methods in sample acquisition and biomarker research, and a guide to funding mechanisms, in order to provide a blueprint for future TM research protocols. While TM studies can take many forms, the research discussed primarily focusses on basic and translational research involving molecular, cellular, and immunobiology.
MeSH term(s)	Clinical Protocols ; Clinical Trials as Topic/methods ; Humans ; Research Design ; Translational Medical Research/methods ; United States ; Urogenital Neoplasms
Language	English
Publishing date	2018-08-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	1336505-8
ISSN	1873-2496 ; 1078-1439
ISSN (online)	1873-2496
ISSN	1078-1439
DOI	10.1016/j.urolonc.2018.06.008
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Article: Function of Tumor Suppressors in Resistance to Antiandrogen Therapy and Luminal Epithelial Plasticity of Aggressive Variant Neuroendocrine Prostate Cancers.

Soundararajan, Rama / Aparicio, Ana M / Logothetis, Christopher J / Mani, Sendurai A / Maity, Sankar N

Frontiers in oncology

2018 Volume 8, Page(s) 69

Abstract: Combined loss of tumor suppressors (TSPs), PTEN, TP53, and RB1, is highly associated with small cell carcinoma of prostate phenotype. Recent genomic studies of human tumors as well as analyses in mouse genetic models have revealed a unique role for these ...

Abstract	Combined loss of tumor suppressors (TSPs), PTEN, TP53, and RB1, is highly associated with small cell carcinoma of prostate phenotype. Recent genomic studies of human tumors as well as analyses in mouse genetic models have revealed a unique role for these TSPs in dictating epithelial lineage plasticity-a phenomenon that plays a critical role in the development of aggressive variant prostate cancer (PCa) and associated androgen therapy resistance. Here, we summarize recently published key observations on this topic and hypothesize a possible mechanism by which concurrent loss of TSPs could potentially regulate the PCa disease phenotype.
Language	English
Publishing date	2018-03-15
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2018.00069
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Article: Large Extracellular Vesicle Characterization and Association with Circulating Tumor Cells in Metastatic Castrate Resistant Prostate Cancer.

Gerdtsson, Anna S / Setayesh, Sonia M / Malihi, Paymaneh D / Ruiz, Carmen / Carlsson, Anders / Nevarez, Rafael / Matsumoto, Nicholas / Gerdtsson, Erik / Zurita, Amado / Logothetis, Christopher / Corn, Paul G / Aparicio, Ana M / Hicks, James / Kuhn, Peter

Cancers

2021 Volume 13, Issue 5

Abstract: Liquid biopsies hold potential as minimally invasive sources of tumor biomarkers for diagnosis, prognosis, therapy prediction or disease monitoring. We present an approach for parallel single-object identification of circulating tumor cells (CTCs) and ... ...

Abstract	Liquid biopsies hold potential as minimally invasive sources of tumor biomarkers for diagnosis, prognosis, therapy prediction or disease monitoring. We present an approach for parallel single-object identification of circulating tumor cells (CTCs) and tumor-derived large extracellular vesicles (LEVs) based on automated high-resolution immunofluorescence followed by downstream multiplexed protein profiling. Identification of LEVs >6 µm in size and CTC enumeration was highly correlated, with LEVs being 1.9 times as frequent as CTCs, and additional LEVs were identified in 73% of CTC-negative liquid biopsy samples from metastatic castrate resistant prostate cancer. Imaging mass cytometry (IMC) revealed that 49% of cytokeratin (CK)-positive LEVs and CTCs were EpCAM-negative, while frequently carrying prostate cancer tumor markers including AR, PSA, and PSMA. HSPD1 was shown to be a specific biomarker for tumor derived circulating cells and LEVs. CTCs and LEVs could be discriminated based on size, morphology, DNA load and protein score but not by protein signatures. Protein profiles were overall heterogeneous, and clusters could be identified across object classes. Parallel analysis of CTCs and LEVs confers increased sensitivity for liquid biopsies and expanded specificity with downstream characterization. Combined, it raises the possibility of a more comprehensive assessment of the disease state for precise diagnosis and monitoring.
Language	English
Publishing date	2021-03-02
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13051056
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Article ; Online: Phase II study of the histone deacetylase inhibitor vorinostat (Suberoylanilide Hydroxamic Acid; SAHA) in recurrent or metastatic transitional cell carcinoma of the urothelium - an NCI-CTEP sponsored: California Cancer Consortium trial, NCI 6879.

Quinn, David I / Tsao-Wei, Denice D / Twardowski, Przemyslaw / Aparicio, Ana M / Frankel, Paul / Chatta, Gurkamal / Wright, John J / Groshen, Susan G / Khoo, Stella / Lenz, Heinz-Josef / Lara, Primo N / Gandara, David R / Newman, Edward

Investigational new drugs

2021 Volume 39, Issue 3, Page(s) 812–820

Abstract: Background: Until the advent of T cell check point inhibitors standard second-line therapy for patients with metastatic urothelial cancer (mUC) was undefined. Histone deacetylase inhibitors (HDACi) have anti-cancer activity in a variety of tumor models ... ...

Abstract	Background: Until the advent of T cell check point inhibitors standard second-line therapy for patients with metastatic urothelial cancer (mUC) was undefined. Histone deacetylase inhibitors (HDACi) have anti-cancer activity in a variety of tumor models including modulation of apoptosis in bladder cancer cell lines. We evaluated the efficacy and toxicity of the HDACi vorinostat in patients with mUC failing first-line platinum-based therapy either in the adjuvant/neoadjuvant setting or for recurrent/advanced disease. Methods: Vorinostat was given orally 200 mg twice daily continuously until progression or unacceptable toxicity. The primary end point was RECIST response rate (RR); a RR > 20% was deemed interesting in a 2-stage design requiring one response in the first 12 patients to proceed to 2nd stage for a total of 37 subjects. CT or MRI scan imaging occurred every 6 weeks. Results: Fourteen patients were accrued characterized by: median age 66 years (43-84); Caucasian (79%); males (86%); and Karnofsky performance status ≥90 (50%). Accrual was terminated in the first stage as no responses were observed. Best response was stable disease (3 patients). Progression was observed in 8 patients. Two patients came off therapy prior to re-imaging and a 3rd patient died while on treatment and was not assessed for response. Median number of cycles was 2 (range 1-11). Median disease-free survival and overall survival times were 1.1 (0.8, 2.1) & 3.2 (2.1, 14.5) months, respectively. Toxicities were predominantly cytopenias and thrombocytopenic bleeding. Two pts. had grade 5 toxicity unlikely related to treatment. Two pts. had grade 4 and 6 had grade 3 toxicities observed. Two patients with stable disease remained on therapy for 6+ cycles. Conclusions: Vorinostat on this dose-schedule had limited efficacy and significant toxicity resulting in a unfavorable risk:benefit ratio in patients with mUC. NCT00363883.
MeSH term(s)	Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/adverse effects ; Carcinoma, Transitional Cell/drug therapy ; Carcinoma, Transitional Cell/mortality ; Carcinoma, Transitional Cell/pathology ; Female ; Histone Deacetylase Inhibitors/administration & dosage ; Histone Deacetylase Inhibitors/adverse effects ; Humans ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Neoplasm Recurrence, Local/drug therapy ; Neoplasm Recurrence, Local/mortality ; Neoplasm Recurrence, Local/pathology ; Treatment Outcome ; Urologic Neoplasms/drug therapy ; Urologic Neoplasms/mortality ; Urologic Neoplasms/pathology ; Urothelium/pathology ; Vorinostat/administration & dosage ; Vorinostat/adverse effects
Chemical Substances	Antineoplastic Agents ; Histone Deacetylase Inhibitors ; Vorinostat (58IFB293JI)
Language	English
Publishing date	2021-01-06
Publishing country	United States
Document type	Clinical Trial, Phase II ; Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	604895-x
ISSN	1573-0646 ; 0167-6997
ISSN (online)	1573-0646
ISSN	0167-6997
DOI	10.1007/s10637-020-01038-6
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Article ; Online: Role of radical prostatectomy in metastatic prostate cancer: A review.

Metcalfe, Michael J / Smaldone, Marc C / Lin, Daniel W / Aparicio, Ana M / Chapin, Brian F

Urologic oncology

2017 Volume 35, Issue 4, Page(s) 125–134

Abstract: Context: Recent demonstration of efficacy with the use of chemohormonal therapy for men with metastatic prostate cancer (mPCa) has expanded the therapeutic options for these patients. Furthermore, multimodal therapy to treat systemic disease in the ... ...

Abstract	Context: Recent demonstration of efficacy with the use of chemohormonal therapy for men with metastatic prostate cancer (mPCa) has expanded the therapeutic options for these patients. Furthermore, multimodal therapy to treat systemic disease in the context of locoregional control has gained increasing interest. Concomitantly, the role of radical prostatectomy (RP) in multimodal treatment for locally advanced prostate cancer is expanding. As a result, there is interest in investigating the potential benefit of cytoreductive RP in mPCa. Objective: To review the literature regarding the role of cytoreductive prostatectomy in the setting of mPCa. Evidence acquisition: MEDLINE and PubMed electronic databases were queried for English language articles related to patients with mPCa who underwent RP from January 1990 to June 2016. Key words used in our search included cytoreductive prostatectomy, radical prostatectomy, and metastatic prostate cancer. Preclinical, retrospective, and prospective studies were included. Evidence synthesis: There are no published randomized control trials examining the role of cytoreduction in mPCa. Local symptoms are high in mPCa and often provide a necessity for palliative procedures with the impact on oncologic outcomes being uncertain. Recently, preclinical and retrospective population-based data suggest a benefit from treatment of the primary tumor in metastatic disease. Potential mechanisms mediating this benefit include prevention of symptomatic local progression and modulation of disease biology, resulting in an improvement in progression-free and overall survival. Current literature supports the feasibility of cytoreductive prostatectomy as it is associated with acceptable side effects that are comparable to RP for high-risk localized disease. In aggregate, these data compel prospective evaluation of the hypothesis that cytoreductive prostatectomy improves the outcome of men with mPCa. Conclusions: Cytoreductive prostatectomy in mPCa is a feasible procedure that may improve outcomes for men when combined with multimodal management. Preclinical, translational, and retrospective evidence supports local therapy for metastatic disease. However, currently, evidence is limited and is subject to bias. The results of ongoing prospective randomized trials are required before incorporating this therapeutic strategy into clinical practice.
Language	English
Publishing date	2017-04
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	1336505-8
ISSN	1873-2496 ; 1078-1439
ISSN (online)	1873-2496
ISSN	1078-1439
DOI	10.1016/j.urolonc.2017.01.001
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Article ; Online: A Modular Trial of Androgen Signaling Inhibitor Combinations Testing a Risk-Adapted Strategy in Patients with Metastatic Castration-Resistant Prostate Cancer.

Aparicio, Ana M / Tidwell, Rebecca S S / Yadav, Shalini S / Chen, Jiun-Sheng / Zhang, Miao / Liu, Jingjing / Guo, Shuai / Pilie, Patrick G / Yu, Yao / Song, Xingzhi / Vundavilli, Haswanth / Jindal, Sonali / Zhu, Keyi / Viscuse, Paul V / Lebenthal, Justin M / Hahn, Andrew W / Soundararajan, Rama / Corn, Paul G / Zurita, Amado J /

Subudhi, Sumit K / Zhang, Jianhua / Wang, Wenyi / Huff, Chad / Troncoso, Patricia / Allison, James P / Sharma, Padmanee / Logothetis, Christopher J

Clinical cancer research : an official journal of the American Association for Cancer Research

2024

Abstract: Purpose: To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers (mCRPC).: Experimental design: In a modular, randomized ... ...

Abstract	Purpose: To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers (mCRPC). Experimental design: In a modular, randomized phase II trial, 192 men were treated with 8 weeks of abiraterone acetate, prednisone and apalutamide (AAPA; Module 1), then allocated to Modules 2 or 3 based on Satisfactory (≥50% PSA decline from baseline and <5 CTC/7.5 mL) versus Unsatisfactory status. Men in the former were randomized to continue AAPA alone (Module 2A) or with ipilimumab (Module 2B). Men in the latter had carboplatin+cabazitaxel added to AAPA (Module 3). Optional baseline biopsies were subject to correlative studies. Results: Median overall survival (from allocation) was 46.4 (95% CI 39.2, 68.2), 41.4 (95% CI 33.3, 49.9) and 18.7 (95% CI 14.3, 26.3) months in Modules 2A (n=64), 2B (n=64) and 3 (n=59) respectively. Toxicities were within expectations. Of 192 eligible patients, 154 (80.2%) underwent pre-treatment metastatic biopsies. The aggressive variant prostate cancer molecular profile (defects in ≥2 of p53, RB1, and PTEN) was associated with Unsatisfactory status. Exploratory analyses suggested SPP1+ and IGFBP2+ macrophages, druggable myeloid cell markers, and germline pathogenic mutations were enriched in the Unsatisfactory group. Conclusions: Adding ipilimumab to AAPA did not improve outcomes in men with androgen responsive mCRPC. Despite the addition of carboplatin+cabazitaxel, men in the Unsatisfactory group had shortened survivals. Adaptive designs can enrich for biologically and clinically relevant disease subgroups, to contribute to the development of marker-informed, risk-adapted therapy strategies in men with prostate cancer.
Language	English
Publishing date	2024-04-29
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-3740
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In stock of ZB MED Cologne/Königswinter

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In stock of ZB MED Cologne/Königswinter

Order via subito