Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 42
Filtrar
1.
Adv Radiat Oncol ; 9(6): 101489, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38681892

RESUMEN

Purpose: We retrospectively investigated spatial pattern associations between primary and recurrent tumor sites after definitive external-beam radiation therapy (EBRT) for prostate cancer, using positron emission tomography/computed tomography (PET/CT) with a prostate-specific membrane antigen (PSMA)-targeted probe, 18F-FSU-880. Methods and Materials: We used data from our prior phase 2 trial involving patients who received PET/CT with 18F-FSU-880, which was designed to evaluate the tumor detection efficacy of PSMA-PET/CT for recurrent prostate cancer. Data from patients with local intraprostatic recurrence detected by PSMA-PET/CT after definitive EBRT were retrospectively analyzed. The prostate and seminal vesicles were divided into 14 sections. Two diagnostic radiologists separately re-evaluated the intraprostatic location of the primary tumor on magnetic-resonance imaging and that of the recurrent tumor on PSMA-PET/CT, respectively, and the rate of overlap between primary and recurrent tumors was calculated. The overlap rate was defined as "the number of sections that overlapped between the primary tumor and recurrent tumor" divided by "the total number of sections of recurrent tumor". A recurrent tumor was considered to be at the same location as the primary tumor when the overlap rate was equal to or greater than 75%, and a partial overlap was defined as an overlap rate between 25 and 74%. Results: Twelve patients had local recurrence detected by PSMA-PET/CT. The median time to diagnosis of local recurrence was 9.1 (range, 2.2-12.3) years after definitive EBRT. The recurrent tumor was detected at the same location in 25.0%, and a partial overlap was noted in 41.7%. Conclusions: Local intraprostatic recurrence after definitive EBRT often occurs at the same site or at a partially overlapping site adjacent to the primary intraprostatic dominant lesion. Our results support the merit of focal dose-escalation for intraprostatic dominant lesions in definitive EBRT.

2.
Int J Urol ; 2024 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-38551314

RESUMEN

Liquid biopsy has emerged as a valuable and minimally invasive tool for real-time detection of clinically actionable abnormalities across various cancer types. Its applicability is particularly compelling in the realm of prostate cancer, where novel therapeutic agents, including those targeting DNA repair systems, are under development. Despite these advancements, challenges persist in effectively screening for prostate cancer, enhancing risk stratification, and determining optimal approaches for treating advanced disease. Consequently, there is a pressing need for improved biomarkers to aid clinicians in decision-making within these contexts. Cell-free DNA and extracellular vesicle analysis have demonstrated promise in diagnosis, prognostication, assessment of treatment responses, and identification of emerging mechanisms of resistance. Nevertheless, obstacles must be addressed before liquid biopsies can be integrated into routine clinical practice. These challenges encompass preanalytical considerations such as sample collection and storage, methods of extracellular vesicle isolation and enrichment, and the need for enhanced interpretation of generated sequencing data. This review provides a comprehensive overview of current clinical opportunities in managing prostate cancer through blood-based liquid biopsy, highlighting the progress made, and acknowledging the challenges that remain. Additionally, we discuss the next steps required for the effective implementation of liquid biopsies in guiding personalized treatment strategies for prostate cancer.

3.
Sci Rep ; 14(1): 5847, 2024 03 11.
Artículo en Inglés | MEDLINE | ID: mdl-38462660

RESUMEN

This study aimed to assess the effects of thienopyridine-class antiplatelet agents (including ticlopidine, clopidogrel, and prasugrel) on bleeding complications in patients who underwent robot-assisted radical prostatectomy. This cohort study used a database for robot-assisted radical prostatectomy at 23 tertiary centers nationwide between 2011 and 2022. Patients who received thienopyridines (thienopyridine group) were compared with those who received aspirin monotherapy (aspirin group). The primary outcome was the incidence of bleeding complications. High-grade complications were defined as Clavien-Dindo grade III or higher. The risks of these outcomes were evaluated using inverse probability of treatment weighted regression models. The study results demonstrated that thienopyridine therapy was associated with a higher risk of overall bleeding complications (OR: 3.62, 95%CI 1.54-8.49). The increased risks of the thienopyridine group were detected for low-grade bleeding complications (OR: 3.20, 95%CI 1.23-8.30) but not for high-grade bleeding complications (OR: 5.23, 95%CI 0.78-34.9). The increased risk of bleeding complications was not observed when thienopyridine was discontinued (OR: 2.52, 95%CI 0.83-7.70); however, it became apparent when it was continued perioperatively (OR: 4.35, 95%CI 1.14-16.61). In conclusion, thienopyridine increased the incidence of bleeding complications, particularly low-grade bleeding complications, following robot-assisted radical prostatectomy. These bleeding effects emerged when thienopyridine was continued perioperatively.


Asunto(s)
Inhibidores de Agregación Plaquetaria , Piridinas , Robótica , Masculino , Humanos , Inhibidores de Agregación Plaquetaria/efectos adversos , Estudios de Cohortes , Hemorragia/inducido químicamente , Aspirina/efectos adversos , Tienopiridinas , Prostatectomía/efectos adversos
4.
Nat Commun ; 15(1): 1828, 2024 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-38418825

RESUMEN

No consensus strategies exist for prognosticating metastatic castration-resistant prostate cancer (mCRPC). Circulating tumor DNA fraction (ctDNA%) is increasingly reported by commercial and laboratory tests but its utility for risk stratification is unclear. Here, we intersect ctDNA%, treatment outcomes, and clinical characteristics across 738 plasma samples from 491 male mCRPC patients from two randomized multicentre phase II trials and a prospective province-wide blood biobanking program. ctDNA% correlates with serum and radiographic metrics of disease burden and is highest in patients with liver metastases. ctDNA% strongly predicts overall survival, progression-free survival, and treatment response independent of therapeutic context and outperformed established prognostic clinical factors. Recognizing that ctDNA-based biomarker genotyping is limited by low ctDNA% in some patients, we leverage the relationship between clinical prognostic factors and ctDNA% to develop a clinically-interpretable machine-learning tool that predicts whether a patient has sufficient ctDNA% for informative ctDNA genotyping (available online: https://www.ctDNA.org ). Our results affirm ctDNA% as an actionable tool for patient risk stratification and provide a practical framework for optimized biomarker testing.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Pronóstico , Estudios Prospectivos , Bancos de Muestras Biológicas , Biomarcadores de Tumor/genética , Biopsia Líquida , Mutación
5.
Int J Clin Oncol ; 29(3): 325-332, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38191958

RESUMEN

BACKGROUND/PURPOSE: The long-term clinical impact of prostate position-based image-guided radiotherapy (IGRT) for localized prostate cancer remains unclear. MATERIALS AND METHODS: We retrospectively compared clinical outcomes following intensity-modulated radiation therapy (IMRT) with cone-beam computed tomography-based prostate position-based IGRT (P-IGRT) or without P-IGRT (non-P-IGRT). From June 2011, we applied P-IGRT in IMRT for intermediate-risk (IR) prostate cancer (PCa) (D'Amico risk classification) (76 Gy in 38 fractions, with smaller margins). Clinical outcomes of patients who received P-IGRT between June 2011 and June 2019 were retrospectively compared with those of patients with IR PCa who received IMRT without P-IGRT between October 2002 and May 2011 in our institution (74 Gy in 37 fractions). RESULTS: A total of 222 consecutive patients were analyzed: 114 in the P-IGRT cohort and 108 in the non-P-IGRT cohort. The median follow-up period after IMRT was 7.1 years for the P-IGRT cohort and 10.8 years for the non-P-IGRT cohort. The biochemical failure-free rate was significantly better in the P-IGRT cohort (94.9% for the P-IGRT cohort vs 82.7% for the non-P-IGRT cohort at 10 years, p = 0.041). The rate of rectal bleeding which needs intervention including the use of suppositories was significantly lower in the P-IGRT cohort (p < 0.001). CONCLUSIONS: The use of P-IGRT with higher doses and smaller margins was correlated with significantly better biochemical control, and a lower incidence of rectal bleeding in IMRT for intermediate-risk prostate cancer. The enhanced accuracy using P-IGRT has the potential to independently improve disease control and reduce late rectal bleeding.


Asunto(s)
Neoplasias de la Próstata , Radioterapia Guiada por Imagen , Radioterapia de Intensidad Modulada , Masculino , Humanos , Próstata , Radioterapia de Intensidad Modulada/efectos adversos , Estudios Retrospectivos , Neoplasias de la Próstata/radioterapia , Radioterapia Guiada por Imagen/efectos adversos
6.
J Natl Cancer Inst ; 116(1): 115-126, 2024 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-37676819

RESUMEN

BACKGROUND: The phase 3 CALGB 90203 (Alliance) trial evaluated neoadjuvant chemohormonal therapy for high-risk localized prostate cancer before radical prostatectomy. We dissected the molecular features of post-treated tumors with long-term clinical outcomes to explore mechanisms of response and resistance to chemohormonal therapy. METHODS: We evaluated 471 radical prostatectomy tumors, including 294 samples from 166 patients treated with 6 cycles of docetaxel plus androgen deprivation therapy before radical prostatectomy and 177 samples from 97 patients in the control arm (radical prostatectomy alone). Targeted DNA sequencing and RNA expression of tumor foci and adjacent noncancer regions were analyzed in conjunction with pathologic changes and clinical outcomes. RESULTS: Tumor fraction estimated from DNA sequencing was significantly lower in post-treated tumor tissues after chemohormonal therapy compared with controls. Higher tumor fraction after chemohormonal therapy was associated with aggressive pathologic features and poor outcomes, including prostate-specific antigen-progression-free survival. SPOP alterations were infrequently detected after chemohormonal therapy, while TP53 alterations were enriched and associated with shorter overall survival. Residual tumor fraction after chemohormonal therapy was linked to higher expression of androgen receptor-regulated genes, cell cycle genes, and neuroendocrine genes, suggesting persistent populations of active prostate cancer cells. Supervised clustering of post-treated high-tumor-fraction tissues identified a group of patients with elevated cell cycle-related gene expression and poor clinical outcomes. CONCLUSIONS: Distinct recurrent prostate cancer genomic and transcriptomic features are observed after exposure to docetaxel and androgen deprivation therapy. Tumor fraction assessed by DNA sequencing quantifies pathologic response and could be a useful trial endpoint or prognostic biomarker. TP53 alterations and high cell cycle transcriptomic activity are linked to aggressive residual disease, despite potent chemohormonal therapy.


Asunto(s)
Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/cirugía , Terapia Neoadyuvante , Docetaxel , Antagonistas de Andrógenos/uso terapéutico , Andrógenos/uso terapéutico , Resultado del Tratamiento , Recurrencia Local de Neoplasia/cirugía , Antígeno Prostático Específico , Prostatectomía , Proteínas Nucleares , Proteínas Represoras
7.
Br J Cancer ; 130(1): 53-62, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37980367

RESUMEN

BACKGROUND: CC-115, a dual mTORC1/2 and DNA-PK inhibitor, has promising antitumour activity when combined with androgen receptor (AR) inhibition in pre-clinical models. METHODS: Phase 1b multicentre trial evaluating enzalutamide with escalating doses of CC-115 in AR inhibitor-naive mCRPC patients (n = 41). Primary endpoints were safety and RP2D. Secondary endpoints included PSA response, time-to-PSA progression, and radiographic progression. RESULTS: Common adverse effects included rash (31.7% Grades 1-2 (Gr); 31.7% Gr 3), pruritis (43.9% Gr 1-2), diarrhoea (37% Gr 1-2), and hypertension (17% Gr 1-2; 9.8% Gr 3). CC-115 RP2D was 5 mg twice a day. In 40 evaluable patients, 80% achieved ≥50% reduction in PSA (PSA50), and 58% achieved ≥90% reduction in PSA (PSA90) by 12 weeks. Median time-to-PSA progression was 14.7 months and median rPFS was 22.1 months. Stratification by PI3K alterations demonstrated a non-statistically significant trend towards improved PSA50 response (PSA50 of 94% vs. 67%, p = 0.08). Exploratory pre-clinical analysis suggested CC-115 inhibited mTOR pathway strongly, but may be insufficient to inhibit DNA-PK at RP2D. CONCLUSIONS: The combination of enzalutamide and CC-115 was well tolerated. A non-statistically significant trend towards improved PSA response was observed in patients harbouring PI3K pathway alterations, suggesting potential predictive biomarkers of response to a PI3K/AKT/mTOR pathway inhibitor. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02833883.


Asunto(s)
Benzamidas , Feniltiohidantoína , Neoplasias de la Próstata Resistentes a la Castración , Pirazinas , Triazoles , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/patología , Antígeno Prostático Específico/uso terapéutico , Diana Mecanicista del Complejo 1 de la Rapamicina , Fosfatidilinositol 3-Quinasas , Nitrilos/uso terapéutico , ADN/uso terapéutico
8.
Cancer Sci ; 115(1): 283-297, 2024 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-37923364

RESUMEN

Androgen-deprivation therapy is a standard treatment for advanced prostate cancer. However, most patients eventually acquire resistance and progress to castration-resistant prostate cancer (CRPC). In this study, we established new CRPC cell lines, AILNCaP14 and AILNCaP15, from LNCaP cells under androgen-deprived conditions. Unlike most pre-existing CRPC cell lines, both cell lines expressed higher levels of androgen receptor (AR) and prostate-specific antigen (PSA) than parental LNCaP cells. Moreover, these cells exhibited primary resistance to enzalutamide. Since AR signaling plays a significant role in the development of CRPC, PSA promoter sequences fused with GFP were introduced into AILNCaP14 cells to conduct GFP fluorescence-based chemical screening. We identified flavopiridol, a broad-spectrum CDK inhibitor, as a candidate drug that could repress AR transactivation of CRPC cells, presumably through the inhibition of phosphorylation of AR on the serine 81 residue (pARSer81 ). Importantly, this broad-spectrum CDK inhibitor inhibited the proliferation of AILNCaP14 cells both in vitro and in vivo. Moreover, a newly developed liver metastatic model using AILNCaP15 cells revealed that the compound attenuated tumor growth of CRPC harboring highly metastatic properties. Finally, we developed a patient-derived xenograft (PDX) model of CRPC and DCaP CR from a patient presenting therapeutic resistance to enzalutamide, abiraterone, and docetaxel. Flavopiridol successfully suppressed the tumor growth of CRPC in this PDX model. Since ARSer81 was found to be phosphorylated in clinical CRPC samples, our data suggested that broad-spectrum CDK inhibitors might be a potent candidate drug for the treatment of CRPC, including those exhibiting primary resistance to enzalutamide.


Asunto(s)
Benzamidas , Feniltiohidantoína , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Antígeno Prostático Específico , Antagonistas de Andrógenos/uso terapéutico , Andrógenos , Resistencia a Antineoplásicos , Receptores Androgénicos/metabolismo , Nitrilos/uso terapéutico , Línea Celular Tumoral
10.
Front Oncol ; 13: 1139049, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37064121

RESUMEN

Introduction: Bone is a major metastatic site of renal cell carcinoma (RCC). Recently, it is well recognized that bone metastatic tumor cells remodel bone marrow vasculature. However, the precise mechanism underlying cell-cell communication between bone metastatic RCC and the cells in bone marrow remains unknown. Extracellular vesicles (EVs) reportedly play crucial roles in intercellular communication between metastatic tumor cells and bone marrow. Therefore, we conducted the current study to clarify the histological alteration in vascular endothelium in bone marrow induced by EVs secreted from bone metastatic RCC cells as well as association between angiogenesis in bone marrow and bone metastasis formation. Materials and methods: We established a bone metastatic RCC cell line (786-O BM) by in vivo selection and observed phenotypic changes in tissues when EVs were intravenously injected into immunodeficient mice. Proteomic analysis was performed to identify the protein cargo of EVs that could contribute to histological changes in bone. Tissue exudative EVs (Te-EVs) from cancer tissues of patients with bone metastatic RCC (BM-EV) and those with locally advanced disease (LA-EV) were compared for in vitro function and protein cargo. Results: Treatment of mice with EVs from 786-O BM promoted angiogenesis in the bone marrow in a time-dependent manner and increased the gaps of capillary endothelium. 786-O BM EVs also promoted tube formation in vitro. Proteomic analysis of EVs identified aminopeptidase N (APN) as a candidate protein that enhances angiogenesis. APN knockdown in 786-O BM resulted in reduced angiogenesis in vitro and in vivo. When parental 786-O cells were intracardially injected 12 weeks after treatment with786-O BM EVs, more bone metastasis developed compared to those treated with EVs from parental 786-O cells. In patient samples, BM-EVs contained higher APN compared to LA-EV. In addition, BM-EVs promoted tube formation in vitro compared to LA-EVs. Conclusion: EVs from bone metastatic RCC promote angiogenesis and gap formation in capillary endothelium in bone marrow in a time-dependent manner.

11.
Asian J Endosc Surg ; 16(3): 558-562, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36882944

RESUMEN

A 47-year-old man underwent low anterior resection for rectal cancer and was surveilled for 5 years without metastasis. Twenty-four years later, the patient developed an implantation cyst at the anastomotic site. Two years after the diagnosis, colonoscopy revealed a disintegrated area in the lesion, and pathological examination of the biopsy specimen revealed adenocarcinoma. Due to the suspicion of invasion into the surrounding organs, the patient underwent laparoscopic total pelvic exenteration after neoadjuvant chemoradiotherapy. A transabdominal and transperineal endoscopic approach was used for safe en bloc excision of the tumor. Pathological examination of the specimen confirmed mucinous adenocarcinoma arising from the implantation cyst. Although an implantation cyst is considered benign, it is important to suspect malignant transformation when its appearance changes. For the accurate diagnosis of implantation cysts, surgeons, endoscopists, and radiologists should be aware of this disease.


Asunto(s)
Adenocarcinoma Mucinoso , Adenocarcinoma , Quistes , Exenteración Pélvica , Neoplasias del Recto , Masculino , Humanos , Persona de Mediana Edad , Exenteración Pélvica/métodos , Neoplasias del Recto/cirugía , Neoplasias del Recto/patología , Adenocarcinoma/cirugía , Adenocarcinoma/patología , Quistes/cirugía , Adenocarcinoma Mucinoso/cirugía
12.
Clin Cancer Res ; 29(15): 2835-2844, 2023 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-36996325

RESUMEN

PURPOSE: Androgen receptor pathway inhibitors (ARPI) are standard of care for treatment-naïve metastatic castration-resistant prostate cancer (mCRPC), but rapid resistance is common. Early identification of resistance will improve management strategies. We investigated whether changes in circulating tumor DNA (ctDNA) fraction during ARPI treatment are linked with mCRPC clinical outcomes. EXPERIMENTAL DESIGN: Plasma cell-free DNA was collected from 81 patients with mCRPC at baseline and after 4 weeks of first-line ARPI treatment during two prospective multicenter observational studies (NCT02426333; NCT02471469). ctDNA fraction was calculated from somatic mutations in targeted sequencing and genome copy-number profiles. Samples were classified into detected versus undetected ctDNA. Outcome measurements were progression-free survival (PFS) and overall survival (OS). Nondurable treatment response was defined as PFS ≤6 months. RESULTS: ctDNA was detected in 48/81 (59%) baseline and 29/81 (36%) 4-week samples. ctDNA fraction for samples with detected ctDNA was lower at 4 weeks versus baseline (median 5.0% versus 14.5%, P = 0.017). PFS and OS were shortest for patients with persistent ctDNA at 4 weeks (univariate HR, 4.79; 95% CI, 2.62-8.77 and univariate HR, 5.49; 95% CI, 2.76-10.91, respectively), independent of clinical prognostic factors. For patients exhibiting change from detected to undetected ctDNA by 4 weeks, there was no significant PFS difference versus patients with baseline undetected ctDNA. ctDNA change had a positive predictive value of 88% and negative predictive value of 92% for identifying nondurable responses. CONCLUSIONS: Early changes in ctDNA fraction are strongly linked to duration of first-line ARPI treatment benefit and survival in mCRPC and may inform early therapy switches or treatment intensification. See related commentary by Sartor, p. 2745.


Asunto(s)
ADN Tumoral Circulante , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , ADN Tumoral Circulante/genética , ADN Tumoral Circulante/sangre , Estudios Prospectivos , Nitrilos/uso terapéutico , Antagonistas de Receptores Androgénicos/uso terapéutico
13.
Asian J Endosc Surg ; 16(3): 441-446, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-36974637

RESUMEN

INTRODUCTION: This study was performed to investigate the preoperative factors associated with difficulty achieving trifecta in robot-assisted partial nephrectomy for clinical T1b renal cell carcinoma. METHODS: Among 187 patients who underwent robot-assisted partial nephrectomy at our hospital from March 2012 to February 2022, we retrospectively examined 30 patients with unilateral single clinical T1b renal cell carcinoma with at least 6 months of postoperative follow-up, excluding patients with hereditary disease. The following factors were examined in detail: patient-related factors, perioperative factors, surgical techniques, tumor factors, and R.E.N.A.L. nephrometry scores. We examined the preoperative factors associated with difficulty achieving trifecta. A positive surgical margin was pathologically defined as the presence of tumor cells at the margin of the resected specimen or visually defined as intraoperative tumor incision or pseudocapsular damage. RESULTS: Of the 30 patients in this study, 12 achieved trifecta and 18 did not. The reasons for not achieving trifecta were a warm ischemia time of >25 min (66.7%), positive surgical margin (23.3%), and Clavien-Dindo grade ≥3 complications (13.3%) (with overlapping factors). No patients had a pathologically positive surgical margin. Visually positive surgical margins were confirmed by the surgical records and surgical videos. Achieving trifecta was challenging in the multivariate analysis when the "L" component of the R.E.N.A.L. nephrometry score was ≥2 points. CONCLUSION: A preoperative "L" component of ≥2 points in the R.E.N.A.L. nephrometry score was associated with difficulty achieving trifecta.


Asunto(s)
Carcinoma de Células Renales , Neoplasias Renales , Procedimientos Quirúrgicos Robotizados , Robótica , Humanos , Carcinoma de Células Renales/cirugía , Estudios Retrospectivos , Márgenes de Escisión , Resultado del Tratamiento , Neoplasias Renales/cirugía , Procedimientos Quirúrgicos Robotizados/métodos , Nefrectomía/métodos
15.
Cancer Med ; 12(3): 3328-3342, 2023 02.
Artículo en Inglés | MEDLINE | ID: mdl-36812122

RESUMEN

Using new castration-resistant prostate cancer (CRPC) cell lines developed from LNCaP cells as a model for CRPC, we searched for novel biomarkers by analyzing the proteins secreted in culture supernatants. The results showed that the levels of secretory leukocyte protease inhibitor (SLPI) in these cell lines were 4.7-6.7 times higher than those secreted in parental LNCaP. Patients with localized prostate cancer (PC) and who expressed SLPI had a significantly lower prostate-specific antigen (PSA) progression-free survival rate than those who did not. Multivariate analysis revealed that SLPI expression was an independent risk factor for PSA recurrence. By contrast, when immunostaining of SLPI was performed on consecutive prostate tissue samples obtained from 11 patients, both in hormone naive (HN) and castration resistant (CR) conditions, only one patient expressed SLPI in the HNPC state; however, four of the 11 patients expressed SLPI in the CRPC state. In addition, two of these four patients were resistant to enzalutamide, and there was a discrepancy between their serum PSA levels and radiographic progression of the disease. These results suggest that SLPI can be a predictor of prognosis in patients with localized PC and disease progression in CRPC patients.


Asunto(s)
Antígeno Prostático Específico , Neoplasias de la Próstata Resistentes a la Castración , Masculino , Humanos , Próstata , Inhibidor Secretorio de Peptidasas Leucocitarias , Regulación hacia Arriba , Recurrencia Local de Neoplasia
16.
Br J Cancer ; 127(9): 1680-1690, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-35986085

RESUMEN

BACKGROUND: The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial. METHODS: Germline DNA from 549 Japanese men with metastatic and/or castration-resistant PCa was sequenced for 27 cancer-predisposing genes. The associations between pathogenic variants and clinical outcomes were examined. Further, for comparison, DNA from prostate biopsy tissue samples from 80 independent patients with metastatic PCa were analysed. RESULTS: Forty-four (8%) patients carried germline pathogenic variants in one of the analysed genes. BRCA2 was most frequently altered (n = 19), followed by HOXB13 (n = 9), PALB2 (n = 5) and ATM (n = 5). Further, the BRCA1, BRCA2, PALB2 and ATM variants showed significant association with a short time to castration resistance and overall survival (hazard ratio = 1.99 and 2.36; 95% CI, 1.15-3.44 and 1.23-4.51, respectively), independent of other clinical variables. Based on log-rank tests, the time to castration resistance was also significantly short in patients with BRCA1, BRCA2, PALB2 or ATM somatic mutations and TP53 mutations. CONCLUSIONS: Germline variants in BRCA1, BRCA2, PALB2 or ATM are independent prognostic factors of the short duration of response to hormonal therapy in advanced PCa.


Asunto(s)
Mutación de Línea Germinal , Neoplasias de la Próstata , Masculino , Humanos , Pronóstico , Proteína BRCA2/genética , Genes BRCA2 , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Mutación , Predisposición Genética a la Enfermedad , Proteína BRCA1/genética , Proteína del Grupo de Complementación N de la Anemia de Fanconi/genética , Proteínas de la Ataxia Telangiectasia Mutada/genética
17.
Gan To Kagaku Ryoho ; 48(10): 1203-1208, 2021 Oct.
Artículo en Japonés | MEDLINE | ID: mdl-34657048

RESUMEN

With increasing treatment options for metastatic prostate cancer(mPC), there is a growing attention to circulating tumor cells(CTC)and circulating tumor DNA(ctDNA)as minimally invasive biomarkers to facilitate precision medicine. CTC count and ctDNA abundance have been reported to be prognostic factors. In addition, on-treatment changes in these values might also be associated with the treatment response. Androgen receptor gene alterations, including ligand-binding domain mutations, copy number amplification, or structural rearrangements, are identified in most metastatic castration-resistant prostate cancer(mCRPC)and associated with treatment response to androgen receptor pathway inhibitors. Alterations in different DNA damage repair genes, including BRCA2, ATM, CDK12, or mismatch repair genes, are linked to favorable response to targeted therapies such as poly(adenosine diphosphate-ribose)polymerase(PARP)inhibitors or immune checkpoint inhibitors. Overactivation of the PI3K signaling pathway is mainly caused by PTEN loss, and several clinical trials are underway to assess the treatment effect of the targeted therapies such as Akt inhibitors. To disseminate treatment strategies using CTC and ctDNA in clinical practice, we will require prospective biomarker-driven clinical trials, development of novel targeted therapies, and exploration of other molecular characteristics such as epigenome.


Asunto(s)
Neoplasias de la Próstata Resistentes a la Castración , Biomarcadores , Biomarcadores de Tumor/genética , Humanos , Biopsia Líquida , Masculino , Fosfatidilinositol 3-Quinasas , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética
18.
Clin Cancer Res ; 27(22): 6164-6173, 2021 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-34526361

RESUMEN

PURPOSE: Although cell-free DNA (cfDNA) testing is expected to drive cancer precision medicine, little is known about the significance of detecting low-frequency variants in circulating cell-free tumor DNA (ctDNA) in castration-resistant prostate cancer (CRPC). We aimed to identify genomic profile including low-frequency variants in ctDNA from patients with CRPC and investigate the clinical utility of detecting variants with variant allele frequency (VAF) below 1%. EXPERIMENTAL DESIGN: This prospective, multicenter cohort study enrolled patients with CRPC eligible for treatment with abiraterone or enzalutamide. We performed targeted sequencing of pretreatment cfDNA and paired leukocyte DNA with molecular barcodes, and ctDNA variants with a VAF ≥0.1% were detected using an in-house pipeline. We investigated progression-free survival (PFS) and overall survival (OS) after different ctDNA fraction cutoffs were applied. RESULTS: One hundred patients were analyzed (median follow-up 10.7 months). We detected deleterious ATM, BRCA2, and TP53 variants even in samples with ctDNA fraction below 2%. When the ctDNA fraction cutoff value of 0.4% was applied, significant differences in PFS and OS were found between patients with and without defects in ATM or BRCA2 [HR, 2.52; 95% confidence interval (CI), 1.24-5.11; P = 0.0091] and TP53 (HR, 3.74; 95% CI, 1.60-8.71; P = 0.0014). However, these differences were no longer observed when the ctDNA fraction cutoff value of 2% was applied, and approximately 50% of the samples were classified as ctDNA unquantifiable. CONCLUSIONS: Detecting low-frequency ctDNA variants with a VAF <1% is important to identify clinically informative genomic alterations in CRPC.


Asunto(s)
Ácidos Nucleicos Libres de Células , Neoplasias de la Próstata Resistentes a la Castración , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/uso terapéutico , Ácidos Nucleicos Libres de Células/genética , Estudios de Cohortes , Humanos , Masculino , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética
19.
Cancer Sci ; 112(7): 2781-2791, 2021 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-33960594

RESUMEN

The prevalence of neuroendocrine prostate cancer (NEPC) arising from adenocarcinoma (AC) upon potent androgen receptor (AR) pathway inhibition is increasing. Deeper understanding of NEPC biology and development of novel therapeutic agents are needed. However, research is hindered by the paucity of research models, especially cell lines developed from NEPC patients. We established a novel NEPC cell line, KUCaP13, from tissue of a patient initially diagnosed with AC which later recurred as NEPC. The cell line has been maintained permanently in vitro under regular cell culture conditions and is amenable to gene engineering with lentivirus. KUCaP13 cells lack the expression of AR and overexpress NEPC-associated genes, including SOX2, EZH2, AURKA, PEG10, POU3F2, ENO2, and FOXA2. Importantly, the cell line maintains the homozygous deletion of CHD1, which was confirmed in the primary AC of the index patient. Loss of heterozygosity of TP53 and PTEN, and an allelic loss of RB1 with a transcriptomic signature compatible with Rb pathway aberration were revealed. Knockdown of PEG10 using shRNA significantly suppressed growth in vivo. Introduction of luciferase allowed serial monitoring of cells implanted orthotopically or in the renal subcapsule. Although H3K27me was reduced by EZH2 inhibition, reversion to AC was not observed. KUCaP13 is the first patient-derived, treatment-related NEPC cell line with triple loss of tumor suppressors critical for NEPC development through lineage plasticity. It could be valuable in research to deepen the understanding of NEPC.


Asunto(s)
Adenocarcinoma/patología , Carcinoma Neuroendocrino/patología , Línea Celular Tumoral/patología , Neoplasias de la Próstata/patología , Animales , Proteínas Reguladoras de la Apoptosis/genética , Carcinoma Neuroendocrino/genética , Carcinoma Neuroendocrino/secundario , Línea Celular Tumoral/metabolismo , ADN Helicasas/genética , Proteínas de Unión al ADN/genética , Ensayos de Selección de Medicamentos Antitumorales , Proteína Potenciadora del Homólogo Zeste 2/antagonistas & inhibidores , Eliminación de Gen , Expresión Génica , Genes Relacionados con las Neoplasias , Genes de Retinoblastoma , Genes Supresores de Tumor , Genes p53 , Ingeniería Genética , Xenoinjertos , Homocigoto , Humanos , Cariotipificación , Pérdida de Heterocigocidad , Masculino , Ratones SCID , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Trasplante de Neoplasias , Fosfohidrolasa PTEN/genética , Neoplasias del Pene/genética , Neoplasias del Pene/secundario , Neoplasias de la Próstata/genética , Proteínas de Unión al ARN/genética , Receptores Androgénicos
20.
Cancer Sci ; 112(8): 3363-3374, 2021 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-34009695

RESUMEN

The therapeutic landscape of metastatic clear cell renal cell carcinoma (ccRCC) has rapidly expanded, and there is an urgent need to develop noninvasive biomarkers that can select an optimal therapy or evaluate the response in real time. To evaluate the clinical utility of circulating tumor DNA (ctDNA) analysis in ccRCC, we established a highly sensitive assay to detect mutations in von Hippel-Lindau gene (VHL) using a combination of digital PCR and multiplex PCR-based targeted sequencing. The unique assay could detect VHL mutations with a variant allele frequency (VAF) <1.0%. Further, we profiled the mutation status of VHL in 76 cell-free DNA (cfDNA) and 50 tumor tissues from 56 patients with ccRCC using the assay. Thirteen VHL mutations were identified in cfDNA from 12 (21.4%) patients with a median VAF of 0.78% (range, 0.13%-4.20%). Of the 28 patients with VHL mutations in matched tumor tissues, eight (28.6%) also had VHL mutation in cfDNA with a median VAF of 0.47% (range, 0.13%-2.88%). In serial ctDNA analysis from one patient, we confirmed that the VAF of VHL mutation changed consistent with tumor size by radiographic imaging during systemic treatment. In conclusion, VHL mutation in cfDNA was detected only in a small number of patients even using the highly sensitive assay; nevertheless, we showed the potential of ctDNA analysis as a novel biomarker in ccRCC.


Asunto(s)
Carcinoma de Células Renales/genética , Mutación , Proteína Supresora de Tumores del Síndrome de Von Hippel-Lindau/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Línea Celular Tumoral , Ácidos Nucleicos Libres de Células/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Análisis de Secuencia de ADN
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...