24 results on '"Bilen, Mehmet A."'
Search Results
2. Current Landscape of Immunotherapy in Genitourinary Malignancies
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Alhalabi, Omar, Rafei, Hind, Bilen, Mehmet Asim, Shah, Amishi Yogesh, Crusio, Wim E., Series Editor, Lambris, John D., Series Editor, Radeke, Heinfried H., Series Editor, Rezaei, Nima, Series Editor, Naing, Aung, editor, and Hajjar, Joud, editor
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- 2020
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3. Circulating Tumor DNA in Genitourinary Cancers: Detection, Prognostics, and Therapeutic Implications.
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Gerke, Margo B., Jansen, Caroline S., and Bilen, Mehmet A.
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BLOOD testing ,DNA analysis ,NUCLEIC acid analysis ,GENOMICS ,EARLY detection of cancer ,TUMOR markers ,BODY fluid examination ,DNA ,GENITOURINARY organ tumors ,ONCOGENES ,NUCLEIC acids ,EXTRACELLULAR space ,GENETIC mutation ,BLOOD - Abstract
Simple Summary: Circulating tumor DNA (ctDNA) is a non-invasive method of identifying and monitoring genitourinary cancers, including prostate, bladder, and renal cell carcinoma, via blood or urine samples. CtDNA introduces a potential method for cancer screening. If detected, ctDNA may reveal genetic alterations that have prognostic value. As treatment options for genitourinary cancers progress towards accounting for tumor genetic profiles, ctDNA may predict which patients have improved responses to therapeutic targets. CtDNA may play an important role in surveillance after tumor resection and may be used to reveal mechanisms of treatment resistance. The clinical utility of ctDNA has yet to be established. Significantly more research is needed to understand the utility ctDNA has in clinical practice. CtDNA is emerging as a non-invasive clinical detection method for several cancers, including genitourinary (GU) cancers such as prostate cancer, bladder cancer, and renal cell carcinoma (RCC). CtDNA assays have shown promise in early detection of GU cancers, providing prognostic information, assessing real-time treatment response, and detecting residual disease and relapse. The ease of obtaining a "liquid biopsy" from blood or urine in GU cancers enhances its potential to be used as a biomarker. Interrogating these "liquid biopsies" for ctDNA can then be used to detect common cancer mutations, novel genomic alterations, or epigenetic modifications. CtDNA has undergone investigation in numerous clinical trials, which could address clinical needs in GU cancers, for instance, earlier detection in RCC, therapeutic response prediction in castration-resistant prostate cancer, and monitoring for recurrence in bladder cancers. The utilization of liquid biopsy for ctDNA analysis provides a promising method of advancing precision medicine within the field of GU cancers. [ABSTRACT FROM AUTHOR]
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- 2024
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4. Prostate Cancer Skeletal Metastasis: A Spontaneous Evolution from Osteolytic to Osteoblastic Morphology without Treatment.
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Lawal, Ismaheel O., Bilen, Mehmet A., Halkar, Raghuveer K., Jani, Ashesh B., and Schuster, David M.
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BONE metastasis , *PROSTATE cancer , *METASTASIS , *POSITRON emission tomography , *PROSTATE-specific antigen , *PROSTATE - Abstract
Skeletal metastases due to prostate cancer (PCa) are more commonly osteoblastic than osteolytic. In the rarer cases of osteolytic skeletal metastasis of PCa, transition to osteoblastic phenotype occurs following treatment, which indicates successful healing. In this report, we present a case of spontaneous osteolytic to osteoblastic evolution of PCa skeletal metastasis without treatment in a patient with recurrence of PCa. Our patient is a 59-year-old male who had a robotic radical prostatectomy in July 2014 for a T2c adenocarcinoma of the prostate gland (Gleason score = 4 + 3). He had adjuvant pelvic radiotherapy in January 2015 due to prostate-specific antigen (PSA) persistence. PSA began to rise in October 2015. An 18 F-fluciclovine positron emission tomography/computed tomography (PET/CT) scan obtained in June 2017 at a PSA of 0.5 ng/mL was negative. Repeat 18 F-fluciclovine PET/CT of February 2020 at PSA of 3.72 ng/mL showed prostate bed recurrence and a nonavid osteolytic left inferior pubic ramus lesion. 18F radiohybrid prostate-specific membrane antigen (18 F-rhPSMA) PET/CT scan of August 2020 performed as part of an ongoing clinical trial confirmed local prostate bed recurrence with a low-grade radiotracer uptake in the osteolytic left inferior pubic ramus bone lesion. Without salvage therapy, 18 F-fluciclovine PET/CT of October 2020 and March 2022 shows progressive sclerosis in the left pubic ramus lesion. An osteolytic to osteoblastic transition of a bone lesion as shown in this patient calls for a rethink in our understanding of untreated PCa skeletal metastasis progression. This case provides novel insight into the understanding of the temporal evolution of skeletal metastasis and calls for further research. [ABSTRACT FROM AUTHOR]
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- 2023
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5. Clinical predictors of survival in patients with castration-resistant prostate cancer receiving sipuleucel-T cellular immunotherapy
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Bilen, Mehmet Asim, Hess, Kenneth R., Subudhi, Sumit K., Aparicio, Ana, Kim, Jeri, Zurita-Saavedra, Amado J., Araujo, John C., Corn, Paul G., Stover, Jessica, Lin, Sue-Hwa, Logothetis, Christopher J., and Tu, Shi-Ming
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- 2017
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6. Olaparib in Patients With Metastatic Prostate Cancer With BRCA1 / 2 Mutation: Results From the TAPUR Study.
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Yang, Eddy S., Halabi, Susan, Rothe, Michael, Garrett-Mayer, Elizabeth, Mangat, Pam K., Pisick, Evan, Dib, Elie, Burgess, Earle F., Zakem, Michael, Rohatgi, Nitin, Bilen, Mehmet A., O'Lone, Raegan, Grantham, Gina N., and Schilsky, Richard L.
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PROSTATE cancer patients ,PROSTATE cancer ,BRCA genes ,OLAPARIB ,CANCER patients ,PROGRESSION-free survival - Abstract
PURPOSE: The TAPUR Study is a phase II basket trial that aims to evaluate activity of approved targeted agents in patients with advanced cancers with potentially actionable genomic variants. Data from a cohort of patients with metastatic castrate-resistant prostate cancer (mCRPC) and BRCA1 / 2 mutations treated with olaparib are reported. METHODS: Eligible patients with measurable mCRPC were matched to treatment according to protocol-specified genomic matching rules. Patients had no remaining standard treatment options, Eastern Cooperative Oncology Group performance status 0-2, and adequate organ function. Simon's two-stage design was used with a primary end point of disease control, defined as objective response or stable disease of at least 16-week duration. Secondary end points include radiographic progression-free survival, overall survival, duration of response, duration of stable disease, and safety. RESULTS: Thirty patients with mCRPC with BRCA1 / 2 mutations were treated with olaparib. The disease control rate was 69% (95% CI, 51 to 81), and the objective response rate was 58% (95% CI, 37 to 77). The median radiographic progression-free survival and the median overall survival were 38.4 (95% CI, 16.3 to 52.1) weeks and 76.4 (95% CI, 49.3 to 106.0) weeks, respectively. Six of 30 (20%) patients experienced grade 3-4 adverse or serious adverse events including anemia, aspiration, decreased WBC count, and fatigue. CONCLUSION: Olaparib has antitumor activity in patients with mCRPC with BRCA1 / 2 mutations and warrants further study to determine how to best integrate it into the standard treatment of patients with BRCA1 / 2 -mutated prostate cancer. Olaparib showed a positive signal of activity in real-world patients w/prostate cancer w/BRCA1 or BRCA2 mutations @ASCO #TAPUR. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Prognostic Evaluation of Metastatic Castration Resistant Prostate Cancer and Neuroendocrine Prostate Cancer with [ 68 Ga]Ga DOTATATE PET-CT.
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Bilen, Mehmet Asim, Akintayo, Akinyemi, Liu, Yuan, Abiodun-Ojo, Olayinka, Kucuk, Omer, Carthon, Bradley C., Schuster, David M., and Parent, Ephraim E.
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MEN'S health , *METASTASIS , *QUANTITATIVE research , *NEUROENDOCRINE tumors , *SOMATOSTATIN , *SURVIVAL analysis (Biometry) , *DESCRIPTIVE statistics , *PROSTATE-specific antigen , *EMISSION-computed tomography - Abstract
Simple Summary: Prostate cancer is the most common cancer in men and, along with the aggressive neuroendocrine variant of prostate cancer, is known to express high levels of the somatostatin receptor. This study explored the feasibility of using the somatostatin binding radiopharmaceutical, [68Ga]Ga-DOTATATE PET/CT, to identify metastatic lesions in 17 men with known metastatic castrate resistant prostate cancer or neuroendocrine prostate cancer. All patients demonstrated [68Ga]Ga-DOTATATE avid lesions corresponding to sites of disease as identified by CT. Additionally, we retrospectively correlated the degree of [68Ga]Ga-DOTATATE to treatment response and found that men with marked [68Ga]Ga-DOTATATE uptake in their metastatic deposits had significantly worse outcomes compared to those with moderate or mild [68Ga]Ga-DOTATATE uptake. Conversely, men with only mild [68Ga]Ga-DOTATATE uptake in their metastatic deposits had a favorable prognostic outcome. Objectives: Prostate cancer is well known to express high levels of somatostatin receptors and preliminary data suggests that PET imaging with the somatostatin analog, [68Ga]Ga-DOTATATE, may allow for whole body staging of patients with metastatic castration resistant prostate cancer (mCRPC) and neuroendocrine prostate cancer (NePC). This study explores the utility of [68Ga]Ga-DOTATATE PET-CT to identify metastatic deposits in men with mCRPC and NePC and prognosticate disease progression. Methods: [68Ga]Ga-DOTATATE PET-CT was performed in 17 patients with mCRPC and of those, 2/17 had NePC. A semiquantitative analysis with standardized uptake values (SUV) (e.g., SUVmax, SUVmean) was performed for each metastatic lesion and reference background tissues. [68Ga]Ga-DOTATATE uptake in metastatic deposits was further classified as: mild (less than liver), moderate (up to liver average), or marked (greater than liver). Serial prostate-specific antigen measurements and patient survival were followed up to 3 years after PET imaging to assess response to standard of care treatment. Results: All patients had at least one metastatic lesion with identifiable [68Ga]Ga-DOTATATE uptake. Marked [68Ga]Ga-DOTATATE uptake was found in 7/17 patients, including both NePC patients, and all were non-responders to systemic therapy and died within the follow up period, with a mean time to death of 8.1 months. Three patients had mild [68Ga]Ga-DOTATATE uptake, and all were responders to systemic therapy and were alive 36 months after [68Ga]Ga-DOTATATE imaging. Conclusions: [68Ga]Ga-DOTATATE is able to identify mCRPC and NePC metastatic deposits, and lesions with [68Ga]Ga-DOTATATE uptake > liver may portend poor outcomes in patients with mCRPC. [ABSTRACT FROM AUTHOR]
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- 2022
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8. Genomic landscape of advanced prostate cancer patients with BRCA1 versus BRCA2 mutations as detected by comprehensive genomic profiling of cell-free DNA.
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Swami, Umang, Zimmerman, Raquel Mae, Nussenzveig, Roberto H., Hernandez, Edgar Javier, Yeonjung Jo, Sayegh, Nicolas, Wesolowski, Sergiusz, Kiedrowski, Lesli A., Barata, Pedro C., Lemmon, Gordon Howard, Bilen, Mehmet A., Heath, Elisabeth I., Nandagopal, Lakshminarayan, Babiker, Hani M., Pal, Sumanta K., Lilly, Michael, Maughan, Benjamin L., Haaland, Benjamin, Yandell, Mark, and Sartor, Oliver
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PROSTATE cancer ,PROSTATE cancer patients ,CELL-free DNA ,BRCA genes ,CANCER patients ,CIRCULATING tumor DNA ,FISHER exact test - Abstract
BRCA1-mutated prostate cancer has been shown to be less responsive to poly (ADP-ribose) polymerase (PARP) inhibitors as compared to BRCA2-mutated prostate cancer. The reason for this differential response is not clear. We hypothesized this differential sensitivity to PARP inhibitors may be explained by distinct genomic landscapes of BRCA1 versus BRCA2 co-segregating genes. In a large dataset of 7,707 men with advanced prostate cancer undergoing comprehensive genomic profiling (CGP) of cell-free DNA (cfDNA), 614 men harbored BRCA1 and/or BRCA2 alterations. Differences in the genomic landscape of co-segregating genes was investigated by Fisher's exact test and probabilistic graphical models (PGMs). Results demonstrated that BRCA1 was significantly associated with six other genes, while BRCA2 was not significantly associated with any gene. These findings suggest BRCA2 may be the main driver mutation, while BRCA1 mutations tend to co-segregate with mutations in other molecular pathways contributing to prostate cancer progression. These hypothesis-generating data may explain the differential response to PARP inhibition and guide towards the development of combinatorial drug regimens in those with BRCA1 mutation. [ABSTRACT FROM AUTHOR]
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- 2022
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9. Modulation of prostate cancer cell gene expression by cell-to-cell contact with bone marrow stromal cells or osteoblasts
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Zhang, Shuming, Wang, Jun, Bilen, Mehmet A., Lin, Sue-Hwa, Stupp, Samuel I., and Satcher, Robert L.
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- 2009
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10. Small-Cell Carcinoma of the Prostate: Report of Outcomes of Localized Disease Using the National Cancer Database.
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Xu, Karen M., Yuan Liu, Gillespie, Theresa W., Osunkoya, Adeboye O., Carthon, Bradley, Bilen, Mehmet A., Filson, Christopher P., Ogan, Kenneth, Patel, Pretesh R., Shelton, Joseph W., Kucuk, Omer, Joshi, Shreyas, and Jani, Ashesh B.
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SMALL cell carcinoma ,PROSTATE cancer ,CANCER radiotherapy ,CANCER chemotherapy ,PROSTATE-specific antigen - Abstract
We studied comparative outcomes of efficacy of radiotherapy (RT) versus surgery for small-cell carcinoma of the prostate (SCCP). The National Cancer Database (NCDB) was queried for patients with nonmetastatic disease diagnosed from 2004 to 2015. Overall survival for patients who received RT or surgery was similar among patients with either pure or mixed small-cell histology. Both RT and surgery yield comparable outcomes when provided as local therapy. Background: Small-cell carcinoma of the prostate (SCCP) is a rare but aggressive prostate cancer histology. We studied the reported comparative outcomes of the efficacy of radiotherapy (RT) versus surgery for nonmetastatic SCCP. Methods: The National Cancer Database (NCDB) was queried for nonmetastatic disease diagnosed from 2004 to 2015 as SCCP (defined as having a component of SCCP) receiving a single definitive local control modality (RT or surgery). Results: A total of 243 patients were included (177 RT and 66 surgery). A total of 142 patients received chemotherapy (CHT). Mean age was 68 years. One hundred forty patients had adenocarcinoma concurrently with the SCCP while 103 patients had pure histology. For pure histology, multivariable analysis (MVA) showed nonacademic facility, stage 4 disease, and poorly differentiated grade were associated with worse survival. On MVA, receipt of CHT (hazard ratio [HR] = 0.84, P = .644) or receipt of androgen deprivation therapy (HR = 0.88, P = .715) did not affect overall survival. Receipt of RT was nonsignificant compared to surgery (HR = 0.75, P = .475). For mixed histology, MVA showed receipt of CHT and prostate-specific antigen > 20 ng/mL were associated with worse survival. Receipt of androgen deprivation therapy (HR = 1.35, P = .414) did not affect overall survival. Receipt of RT was also nonsignificant compared to surgery (HR = 1.42, P = .344). Conclusion: RT and surgery for nonmetastatic SCCP yield comparable options as local therapies. [ABSTRACT FROM AUTHOR]
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- 2021
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11. Detection of Microsatellite Instability via Circulating Tumor DNA and Response to Immunotherapy in Metastatic Castration-Resistant Prostate Cancer: A Case Series.
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Ravindranathan, Deepak, Russler, Greta Anne, Yantorni, Lauren, Drusbosky, Leylah M., and Bilen, Mehmet Asim
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CIRCULATING tumor DNA ,CASTRATION-resistant prostate cancer ,PROSTATE cancer ,MICROSATELLITE repeats ,IMMUNOTHERAPY - Abstract
Pembrolizumab has been approved by the US Food and Drug Administration for the treatment of metastatic or unresectable solid tumors that are microsatellite instability-high (MSI-H) or mismatch repair deficient. Blood-based circulating tumor DNA (ctDNA) assays have been validated to identify tumors with MSI-H status without the need for tissue biopsy. We report 2 patients with metastatic castration-resistant prostate cancer (mCRPC) who had prior treatment with multiple lines of therapy and underwent ctDNA testing, which detected MSI-H status. Both patients were treated with pembrolizumab, resulting in an excellent clinical response measured with liquid biopsies before and after initiation of therapy, which demonstrated a significant reduction in somatic-variant allele frequency in addition to a decrease in prostate serum antigen levels. [ABSTRACT FROM AUTHOR]
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- 2021
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12. Circulating interleukin 6, androgen deprivation therapy, and fatigue in prostate cancer: Is inflammation the link?
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Nazha, Bassel and Bilen, Mehmet Asim
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ANDROGEN deprivation therapy , *PROSTATE cancer , *CANCER fatigue , *IMMUNE checkpoint inhibitors , *PROSTATE cancer patients - Abstract
Fatigue is a common symptom among patients with prostate cancer receiving androgen deprivation therapy. A proinflammatory state with elevated interleukin 6 levels likely mediates fatigue in this patient population, might contribute to prostate cancer's limited response to immune checkpoint inhibitors, and could be targeted with exercise and nutritional interventions to improve quality of life. [ABSTRACT FROM AUTHOR]
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- 2021
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13. Hybrid negative enrichment of circulating tumor cells from whole blood in a 3D-printed monolithic device.
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Chu, Chia-Heng, Liu, Ruxiu, Ozkaya-Ahmadov, Tevhide, Boya, Mert, Swain, Brandi E., Owens, Jacob M., Burentugs, Enerelt, Bilen, Mehmet Asim, McDonald, John F., and Sarioglu, A. Fatih
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BLOOD cells ,LEUCOCYTES ,MEMBRANE filters ,BLOOD ,CANCER cells ,PROSTATE cancer ,TISSUE scaffolds - Abstract
Isolation and analysis of circulating tumor cells (CTCs) from blood samples present exciting opportunities for basic cancer research and personalized treatment of the disease. While microchip-based negative CTC enrichment offers both sensitive microfluidic cell screening and unbiased selection, conventional microchips are inherently limited by their capacity to deplete a large number of normal blood cells. In this paper, we use 3D printing to create a monolithic device that combines immunoaffinity-based microfluidic cell capture and a commercial membrane filter for negative enrichment of CTCs directly from whole blood. In our device, stacked layers of chemically-functionalized microfluidic channels capture millions of white blood cells (WBCs) in parallel without getting saturated and the leuko-depleted blood is post-filtered with a 3 μm-pore size membrane filter to eliminate anucleated blood cells. This hybrid negative enrichment approach facilitated direct extraction of viable CTCs off the chip on a membrane filter for downstream analysis. Immunofluorescence imaging of enriched cells showed ∼90% tumor cell recovery rate from simulated samples spiked with prostate, breast or ovarian cancer cells. We also demonstrated the feasibility of our approach for processing clinical samples by isolating prostate cancer CTCs directly from a 10 mL whole blood sample. [ABSTRACT FROM AUTHOR]
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- 2019
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14. Circulating tumor DNA alterations in patients with metastatic castration-resistant prostate cancer.
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Sonpavde, Guru, Agarwal, Neeraj, Pond, Gregory Russell, Nagy, Rebecca J., Nussenzveig, Roberto H., Hahn, Andrew W., Sartor, Oliver, Gourdin, Theodore Stewart, Nandagopal, Lakshminarayanan, Ledet, Elisa M., Naik, Gurudatta, Armstrong, Andrew J., Wang, Jue, Bilen, Mehmet Asim, Gupta, Shilpa, Grivas, Petros, Pal, Sumanta K., Lanman, Richard B., Talasaz, AmirAli, and Lilly, Michael B.
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CASTRATION-resistant prostate cancer ,CELL-free DNA ,EPIDERMAL growth factor receptors ,ADENOMATOUS polyposis coli ,ANDROGEN receptors - Abstract
Background: Because cell-free DNA (cfDNA) analysis facilitates the noninvasive genomic profiling of metastatic castration-resistant prostate cancer (mCRPC), the authors evaluated the association between cfDNA alterations and outcomes and evolution with therapy.Methods: Patients with mCRPC underwent cfDNA genomic profiling using Guardant360, which examines major cancer-associated genes. Clinical factors, therapy information, failure-free survival, and overall survival (OS) were obtained for select patients. The association between genomic alterations and outcomes was investigated.Results: Of 514 men with mCRPC, 482 (94%) had ≥1 circulating tumor DNA (ctDNA) alteration. The most common recurrent somatic mutations were in TP53 (36%), androgen receptor (AR) (22%), adenomatous polyposis coli (APC) (10%), neurofibromin 1 (NF1) (9%), epidermal growth factor receptor (EGFR), catenin beta-1 (CTNNB1), and AT-rich interactive domain-containing protein 1A (ARID1A) (6% each); and BRCA1, BRCA2, and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) (5% each) The most common genes with increased copy numbers were AR (30%), MYC (20%), and BRAF (18%). Clinical outcomes were available for 163 patients, 46 of whom (28.8%) were untreated for mCRPC. A higher number of ctDNA alterations, AR alterations, and amplifications of MYC and BRAF were associated with worse failure-free survival and/or OS. On multivariable analysis, MYC amplification remained significantly associated with OS. Prior therapy and serial profiling demonstrated the evolution of alterations in AR and other genes.Conclusions: ctDNA frequently was detected in this large cohort of "real-world" patients with mCRPC, and the alterations appeared to be similar to previously reported tumor tissue alterations. A higher number of alterations, and AR and MYC alterations, appear to compromise clinical outcomes, suggesting a role for immune checkpoint inhibitors and novel AR and BET inhibitors in selected patients. [ABSTRACT FROM AUTHOR]- Published
- 2019
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15. Metastatic Prostate Cancer Manifesting as Cholestatic Jaundice: A Case Report and Review of the Literature.
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Ravindranathan, Deepak, Hitron, Emilie Elise, Russler, Greta Anne, Xue, Yue, and Bilen, Mehmet Asim
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JAUNDICE ,PARANEOPLASTIC syndromes ,PROSTATE cancer ,DIAGNOSIS ,DOCETAXEL - Abstract
A paraneoplastic syndrome can often present as the first manifestation of an underlying malignancy. We report a patient who presented with cholestatic jaundice as a paraneoplastic syndrome from his newly diagnosed metastatic prostate cancer. He received initial treatment with androgen deprivation therapy followed by six cycles of docetaxel resulting in resolution of his cholestatic process, normalization of liver enzyme levels, and excellent biochemical and radiographic response. To the best of our knowledge, this is the first reported case of metastatic prostate cancer with cholestatic jaundice as a paraneoplastic phenomenon to be safely treated with androgen deprivation therapy and upfront docetaxel, reflecting the latest shift in the treatment of metastatic prostate cancer. [ABSTRACT FROM AUTHOR]
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- 2018
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16. Cadherin-11 endocytosis through binding to clathrin promotes cadherin-11-mediated migration in prostate cancer cells.
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Satcher, Robert L., Tianhong Pan, Bilen, Mehmet A., Xiaoxia Li, Yu-Chen Lee, Ortiz, Angelica, Kowalczyk, Andrew P., Li-Yuan Yu-Lee, and Sue-Hwa Lin
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CADHERINS ,CLATHRIN ,ENDOCYTOSIS ,PROSTATE cancer ,CANCER cells - Abstract
Cadherin-11 (Cad11) cell adhesion molecule plays a role in prostate cancer cell migration. Because disassembly of adhesion complexes through endocytosis of adhesion proteins has been shown to play a role in cell migration, we examined whether Cad11 endocytosis plays a role in Cad11-mediated migration. The mechanism by which Cad11 is internalized is unknown. Using a GST pulldown assay, we found that clathrin binds to the Cad11 cytoplasmic domain but not to that of E-cadherin. Using deletion analysis, we identified a unique sequence motif, VFEEE, in the Cad11 membrane proximal region (amino acid residues 11--15) that binds to clathrin. Endocytosis assays using K[sup +]-depletion buffer showed that Cad11 internalization is clathrin dependent. Proximity ligation assays showed that Cad11 colocalizes with clathrin, and immunofluorescence assays showed that Cad11 localizes in vesicles that stain for the early endosomal marker Rab5. Deletion of the VFEEE sequence from the Cad11 cytoplasmic domain (Cad11-cla-Δ5) leads to inhibition of Cad11 internalization and reduces Cad11-mediated cell migration in C4-2B and PC3-mm2 prostate cancer cells. These observations suggest that clathrimmediated internalization of Cad11 regulates surface trafficking of Cad11 and that dynamic turnover of Cad11 regulates the migratory function of Cad11 in prostate cancer cells. [ABSTRACT FROM AUTHOR]
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- 2015
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17. Maintenance Therapy Containing Metformin and/or Zyflamend for Advanced Prostate Cancer: A Case Series.
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Bilen, Mehmet Asim, Lin, Sue-Hwa, Tang, Dean G., Parikh, Kinjal, Lee, Mong-Hong, Yeung, Sai-Ching J., and Tu, Shi-Ming
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METFORMIN , *PROSTATE cancer , *DIAGNOSIS , *INFLAMMATION , *CLINICAL trials , *OREGANO - Abstract
Metformin is derived from galegine, a natural ingredient, and recent studies have suggested that metformin could enhance the antitumor effects of hormone ablative therapy or chemotherapy and reduce prostate cancer-specific mortality. Zyflamend is a combination of herbal extracts that reduces inflammation and comprises turmeric, holy basil, green tea, oregano, ginger, rosemary, Chinese goldthread, hu zhang, barberry, and basil skullcap. We propose a maintenance regimen with metformin and/or Zyflamend that targets cancer stem cells and the tumor microenvironment to keep the cancer dormant and prevent it from activation from dormancy. Herein, we report the clinical course of four patients who experienced a clinical response after treatment with metformin and/or Zyflamend. [ABSTRACT FROM AUTHOR]
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- 2015
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18. Randomized phase 2 study of bone-targeted therapy containing strontium-89 in advanced castrate-sensitive prostate cancer.
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Bilen, Mehmet Asim, Johnson, Marcella M., Mathew, Paul, Pagliaro, Lance C., Araujo, John C., Aparicio, Ana, Corn, Paul G., Tannir, Nizar M., Wong, Franklin C., Fisch, Michael J., Logothetis, Christopher J., and Tu, Shi‐Ming
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RADIOPHARMACEUTICALS , *PROSTATE cancer patients , *BONE metastasis , *ANDROGEN drugs , *DOXORUBICIN , *ZOLEDRONIC acid , *PATIENTS , *THERAPEUTICS - Abstract
BACKGROUND Radiopharmaceutical use may improve the survival time of patients with castrate-resistant prostate cancer and bone metastases. Whether androgen-deprivation therapy (ADT) combined with bone-targeted therapy provides a clinical benefit to patients with advanced castrate-sensitive prostate cancer has not been investigated. METHODS Eighty male patients were enrolled, and 79 were randomized: 40 to the control arm and 39 to the strontium-89 (Sr-89) arm. After randomization, patients in both study arms received ADT, doxorubicin, and zoledronic acid. Kaplan-Meier methodology was used to evaluate the progression-free survival (PFS) time. Multivariate Cox proportional hazards regression was used to evaluate the effects of Sr-89 after controlling for the number of bone metastases. RESULTS The median follow-up time for the 29 patients alive at the last follow-up was 76.9 months (range, 0.07-103.4 months). The median PFS time was 18.5 months (95% confidence interval, 9.7-49.4 months) for the control arm and 12.9 months (95% confidence interval, 8.9-72.5 months) for the Sr-89 arm ( P = .86). No patient developed myelodysplastic syndrome or a hematologic malignancy. An unplanned subgroup analysis suggested increased efficacy of bone-targeted therapy with a greater extent of bone involvement (ie, >6 bone metastases vs ≤6 bone metastases on the bone scan). CONCLUSIONS The data showed that bone-targeted therapy using 1 dose of Sr-89 combined with chemohormonal ablation therapy did not favorably affect the PFS of patients with castrate-sensitive prostate cancer. The combined therapy was feasible and safe. Whether such bone-targeted therapy provides a favorable outcome for those patients with a greater tumor burden in the bone warrants further investigation. Cancer 2015;121:69-76. © 2014 American Cancer Society. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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19. Ductal Adenocarcinoma of the Prostate: Clinical Features and Implications After Local Therapy.
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Shi-Ming Tu, Lopez, Adriana, Leibovici, Dan, Bilen, Mehmet A., Evliyaoglu, Ferhat, Aparicio, Ana, Guo, Charles C., Kuban, Deborah A., Johnson, Marcy M., and Pisters, Louis L.
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PROSTATE cancer ,CANCER patients ,ADENOCARCINOMA ,PROSTATECTOMY ,RADIOTHERAPY - Abstract
The article presents a study that examines the clinical result of patients who had prostate ductal adenocarcinoma after main radiotherapy or radical prostatectomy. The study shows that patients with pure ductal prostate cancer have long survival rate compared to patients with mixed ductal prostate cancer. It reveals that the median time to local progression was smaller for patients having pure ductal adenocarcinoma than for patients with fused ductal adenocarcinoma of the prostate after surgery.
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- 2009
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20. Immunotherapies in Genitourinary Oncology: Where Are We Now? Where Are We Going?
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Jang, Albert, Adler, David M., Rauterkus, Grant P., Bilen, Mehmet A., and Barata, Pedro C.
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BLADDER tumors ,CYTOKINES ,IMMUNE checkpoint inhibitors ,GENITOURINARY organ tumors ,IMMUNE system ,KIDNEY tumors ,BCG vaccines ,IMMUNOTHERAPY - Abstract
Simple Summary: Genitourinary malignancies include cancers along the urinary tract and the male reproductive tract, encompassing the adrenal glands, kidneys, bladder, prostate, and testicles. Immunotherapy, which treats cancer by using the immune system to attack malignant cells, has historically been successful in treating some types of genitourinary cancers, especially of the bladder and kidney. In the past decade, a more precise method of immunotherapy, known as immune checkpoint inhibition, has gained popularity as it enhances the immune system's ability to recognize and destroy tumor cells. Several immune checkpoint inhibitors have achieved success in patients with advanced genitourinary cancers. This review provides a brief overview of traditional immunotherapies, focuses on how immune checkpoint inhibitors have achieved success in patients with advanced cancers, and investigates the role for immunotherapy in genitourinary malignancies in the future. For decades, limited options existed to treat metastatic genitourinary cancers, including treatment options that could be classified as immunotherapy. Historically, immunotherapy centered on systemic cytokines for the treatment of metastatic kidney cancer, which had several adverse effects, as well as the Bacillus Calmette–Guérin vaccine for non-metastatic bladder cancer. Within the past decade, advances in immunotherapy have led to several approvals from the United States Food and Drug Administration, particularly in the field of immune checkpoint inhibition. Immune checkpoint inhibitors (ICIs) are now being used extensively to treat multiple solid tumors, including kidney and bladder cancers, and they are also being tested in many other cancers. Despite encouraging data from phase 2/3 clinical trials, less is known about biomarkers that may predict better response to ICIs. The effect of ICIs in genitourinary cancers is heterogeneous, with some tumor types having little clinical data available, or ICIs having limited activity in other tumors. In this review, we briefly discuss approved immunotherapy agents prior to the time of ICIs. Then, given the emergence of this class of agents, we summarize the several important ICIs and the clinical trials that led to their approval. Finally, we mention ongoing and future clinical trials. [ABSTRACT FROM AUTHOR]
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- 2021
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21. Therapeutic Vaccines for Genitourinary Malignancies.
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Dutcher, Giselle M. A. and Bilen, Mehmet Asim
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CANCER vaccines ,GENITOURINARY diseases ,BCG vaccines ,DNA vaccines ,THERAPEUTIC use of cytokines ,VACCINATION ,THERAPEUTICS - Abstract
The field of genitourinary malignancies has been a showcase for therapeutic cancer vaccine success since the application of intravesicular Bacillus Calmette-Guerin (BCG) for bladder cancer in the 1970s and enjoyed a renaissance in 2010 with the US Food and Drug Administration (FDA) approval of sipuleucel-T for prostate cancer. Several vaccine strategies have emerged, such as autologous or allogeneic whole-tumor vaccines, DNA vaccines, use of viral vectors, and peptides as immunostimulatory adjuvants. Despite impressive early trials, vaccine monotherapy has achieved limited success in the clinical world; however, combinations of vaccine and immune checkpoint inhibition or vaccine and cytokine stimulation are expected to move the field forward. This article reviews pivotal trials of cancer vaccines in prostate, renal, and bladder cancer and ongoing trials combining vaccines with other immune therapy agents. [ABSTRACT FROM AUTHOR]
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- 2018
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22. BMP4 Promotes Prostate Tumor Growth in Bone through Osteogenesis.
- Author
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Yu-Chen Lee, Chien-Jui Cheng, Bilen, Mehmet A., Jing-Fang Lu, Satcher, Robert L., Li-Yuan Yu-Lee, Gallick, Gary E., Maity, Sankar N., and Sue-Hwa Lin
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PROSTATE cancer , *CANCER treatment , *TUMOR growth , *BONE metastasis , *BONE cancer , *BONE growth - Abstract
Induction of new bone formation is frequently seen in the bone lesions from prostate cancer. However, whether osteogenesis is necessary for prostate tumor growth in bone is unknown. Recently, 2 xenografts, MDA-PCa-118b and MDA-PCa-133, were generated from prostate cancer bone metastases. When implanted subcutaneously in severe combined immunodeficient (SCID) mice, MDA-PCa-118b induced strong ectopic bone formation whileMDA-PCa-133 did not. To identify the factors that are involved in bone formation, we compared the expression of secreted factors (secretome) from MDA-PCa-118b and MDA-PCa-133 by cytokine array. We found that the osteogenic MDA-PCa-118b xenograft expressed higher levels of bone morphogenetic protein BMP4 and several cytokines including interleukin-8, growth-related protein (GRO), and CCL2. We showed that BMP4 secreted from MDA-PCa-118b contributed to about a third of the osteogenic differentiation seen in MDA- PCa-118b tumors. The conditioned media from MDA-PCa-118b induced a higher level of osteoblast differentiation, which was significantly reduced by treatment with BMP4 neutralizing antibody or the small molecule BMP receptor 1 inhibitor LDN-193189. BMP4 did not elicit an autocrine effect on MDA-PCa-118b, which expressed low to undetectable levels of BMP receptors. Treatment of SCIDmice bearingMDA-PCa-118b tumors with LDN- 193189 significantly reduced tumor growth. Thus, these studies support a role of BMP4-mediated osteogenesis in the progression of prostate cancer in bone. Cancer Res; 71(15); 5194-203. ©2011 AACR. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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23. 18F-fluciclovine-PET/CT imaging versus conventional imaging alone to guide postprostatectomy salvage radiotherapy for prostate cancer (EMPIRE-1): a single centre, open-label, phase 2/3 randomised controlled trial.
- Author
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Jani, Ashesh B, Schreibmann, Eduard, Goyal, Subir, Halkar, Raghuveer, Hershatter, Bruce, Rossi, Peter J, Shelton, Joseph W, Patel, Pretesh R, Xu, Karen M, Goodman, Mark, Master, Viraj A, Joshi, Shreyas S, Kucuk, Omer, Carthon, Bradley C, Bilen, Mehmet A, Abiodun-Ojo, Olayinka A, Akintayo, Akinyemi A, Dhere, Vishal R, and Schuster, David M
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PROSTATE cancer , *ANDROGEN deprivation therapy , *CANCER radiotherapy , *PROSTATE cancer patients , *COMPUTED tomography , *RADIOACTIVE tracers - Abstract
Background: Molecular imaging is increasingly used to guide treatment decisions and planning in prostate cancer. We aimed to evaluate the role of 18F-fluciclovine-PET/CT in improving cancer control compared with conventional imaging (bone scan and either CT or MRI) alone for salvage postprostatectomy radiotherapy.Methods: In EMPIRE-1, a single-centre, open-label, phase 2/3 randomised controlled trial, patients with prostate cancer with detectable PSA after prostatectomy and negative conventional imaging (no extrapelvic or bone findings) were randomly assigned in a 1:1 ratio to radiotherapy directed by conventional imaging alone or to conventional imaging plus 18F-fluciclovine-PET/CT. Computer-generated randomisation was stratified by PSA concentration, adverse pathology indicators, and androgen deprivation therapy intent. In the 18F-fluciclovine-PET/CT group, radiotherapy decisions were rigidly determined by PET findings, which were also used for target delineation. The primary endpoint was 3 year event-free survival, with events defined as biochemical or clinical recurrence or progression, or initiation of systemic therapy, using univariate and multivariable analyses in patients who received radiotherapy. This trial is registered with ClinicalTrials.gov, NCT01666808 and is closed to new participants.Findings: From Sept 18, 2012, to March 4, 2019, 165 patients were randomly assigned, with median follow-up of 3·52 years (95% CI 2·98-3·95). PET findings resulted in four patients in the 18F-fluciclovine-PET/CT group having radiotherapy aborted; these patients were excluded from survival analyses. Median survival was not reached (95% CI 35·2-not reached; 33% of 81 patients had events) in the conventional imaging group compared with not reached (95% CI not reached-not reached; 20% of 76 patients) in the 18F-fluciclovine-PET/CT group, and 3 year event-free survival was 63·0% (95% CI 49·2-74·0) in the conventional imaging group versus 75·5% (95% CI 62·5-84·6) for 18F-fluciclovine-PET/CT (difference 12·5; 95% CI 4·3-20·8; p=0·0028). In adjusted analyses, study group (hazard ratio 2·04 [95% CI 1·06-3·93], p=0·0327) was significantly associated with event-free survival. Toxicity was similar in both study groups, with the most common adverse events being late urinary frequency or urgency (37 [46%] of 81 patients in the conventional imaging group and 31 [41%] of 76 in the PET group), and acute diarrhoea (11 [14%] in the conventional imaging group and 16 [21%] in the PET group).Interpretation: Inclusion of 18F-fluciclovine-PET into postprostatectomy radiotherapy decision making and planning significantly improved survival free from biochemical recurrence or persistence. Integration of novel PET radiotracers into radiotherapy decisions and planning for prostate cancer patients warrants further study.Funding: National Institutes of Health/National Cancer Institute, Blue Earth Diagnostics, and Winship Cancer Institute of Emory University. [ABSTRACT FROM AUTHOR]- Published
- 2021
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24. The addition of chemotherapy in the definitive management of high risk prostate cancer.
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Ferris, Matthew J., Liu, Yuan, Ao, Jingning, Zhong, Jim, Abugideiri, Mustafa, Gillespie, Theresa W., Carthon, Bradley C., Bilen, Mehmet A., Kucuk, Omer, and Jani, Ashesh B.
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PROSTATE cancer , *RADIOTHERAPY , *PROSTATECTOMY , *CANCER treatment , *IMMUNOLOGICAL adjuvants , *ANTINEOPLASTIC agents , *COMBINED modality therapy , *PROGNOSIS , *PROSTATE tumors , *RESEARCH funding , *IMPACT of Event Scale - Abstract
In attempt to improve long-term disease control outcomes for high-risk prostate cancer, numerous clinical trials have tested the addition of chemotherapy (CTX)-either adjuvant or neoadjuvant-to definitive local therapy, either radical prostatectomy (RP) or radiation therapy (RT). Neoadjuvant trials generally confirm safety, feasibility, and pre-RP PSA reduction, but rates of pathologic complete response are rare, and no indications for neoadjuvant CTX have been firmly established. Adjuvant regimens have included CTX alone or in combination with androgen deprivation therapy (ADT). Here we provide a review of the relevant literature, and also quantify utilization of CTX in the definitive management of localized high-risk prostate cancer by querying the National Cancer Data Base. Between 2004 and 2013, 177 patients (of 29,659 total) treated with definitive RT, and 995 (of 367,570 total) treated with RP had CTX incorporated into their treatment regimens. Low numbers of RT + CTX patients precluded further analysis of this population, but we investigated the impact of CTX on overall survival (OS) for patients treated with RP +/- CTX. Disease-free survival or biochemical-recurrence-free survival are not available through the National Cancer Data Base. Propensity-score matching was conducted as patients treated with CTX were a higher-risk group. For nonmatched groups, OS at 5-years was 89.6% for the CTX group vs. 95.6%, for the no-CTX group (P < 0.01). The difference in OS between CTX and no-CTX groups did not persist after propensity-score matching, with 5-year OS 89.6% vs. 90.9%, respectively (Hazard ratio 0.99; P = 0.88). In summary, CTX was not shown to improve OS in this retrospective study. Multimodal regimens-such as RP followed by ADT, RT, and CTX; or RT in conjunction with ADT followed by CTX-have shown promise, but long-term follow-up of randomized data is required. [ABSTRACT FROM AUTHOR]
- Published
- 2018
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