The prognostic nomogram including MRI for locally advanced prostate cancer treated by radical prostatectomy.

OBJECTIVE: To establish the prognostic nomogram for locally advanced prostate cancer (LAPC) patients treated by radical prostatectomy (RP) based on clinical and multiparametric-MRI (mp-MRI) metrics. METHODS: One hundred and twenty-one patients diagnosed with LAPC were included in this study. They were all examined by mp-MRI within one week before surgery and treated by RP (36 with RP alone, 48 with neoadjuvant hormonal therapy (NHT) and 37 with neoadjuvant chemohormonal therapy (NCHT)). The biochemical progression-free survival (bPFS) was analyzed by Kaplan-Meier method. Univariate and multivariate analysis were used to determine prognostic factors that were related with bPFS. The prognostic nomogram was established by factors that were significant in multivariate analyses. RESULTS: The median bPFS had significant difference in the subgroup of treatment (RP alone: 2 [0.00-5.04] vs. NHT: 9.3 [6.746-11.854] vs. NCHT: 11.17 [0.000-25.075] months [Log rank p < .001]), the subgroup of hyperintensity within prostate in DWI (negative: 15.97 [11.202-20.731] vs. positive: 5.2 [2.952-7.448] months [Log rank p < .001]) and the subgroup of pelvic lymph node metastasis (negative: 10.2 [8.404-11.996] vs. unilateral: 4.43 [0.000-11.086] vs. Bilateral: 1.83 [0.636~3.031] [Log rank p < .001]). The method of treatment (hazards ratio [HR], 0.566; 95% confidence interval [CI], 0.356-0.899; p = .016), hyperintensity within prostate in DWI (HR, 2.539; 95% CI, 1.349-4.779; p = .004) and the metastasis burden of pelvic lymph node (HR, 2.492; 95% CI, 1.645-3.777; p < .001) were identified as independent predictors with significance in multivariable Cox regression analysis. The nomogram was established based on these three factors. CONCLUSION: We established a nomogram based on three significant prognosis factors including the neoadjuvant therapeutic schedule, hyperintensity within prostate in DWI and the metastasis burden of pelvic lymph nodes, which were associated with the clinical outcomes in LAPC patients after surgery.

Targeted Next-Generation Sequencing Reveals Heterogenous Genomic Features in Viscerally Metastatic Prostate Cancer.

PURPOSE: We sought to explore the genomic features of bone-only metastasis, hepatic metastasis and pulmonary metastasis without liver involvement in prostate cancer using targeted next-generation sequencing. MATERIALS AND METHODS: A hybridization capture-based next-generation sequencing was performed to detected genomic alterations in 50 genes, including androgen receptor, DNA damage response and other clinical relevant drivers. RESULTS: We successfully sequenced circulating tumor DNA from 109 blood samples and 29 metastatic tissue samples from 129 patients with metastatic castration-resistant prostate cancer (metastatic castration-resistant prostate cancer). We observed distinct genomic profiles of metastatic castration-resistant prostate cancer across various metastatic sites. High prevalence of PTEN alteration was found in viscerally metastatic prostate cancer compared with bone-only metastatic prostate cancer (PTEN, 9.09% vs 2.08%, p=0.105). When comparing viscerally metastatic prostate cancer according to the metastatic sites, AR alteration rarely occurs in hepatically metastatic prostate cancer, which stood in great contrast to the high alteration frequency in hepatically metastatic prostate cancer (0.0% vs 42.1%, p=0.01). For overall DNA damage response alteration, the highest frequency was found in hepatically metastatic prostate cancer (63.2%). CONCLUSIONS: Through genomic profiling of prostate cancer across various metastatic sites, we identified an extremely low frequency of AR alterations in pulmonarily metastatic prostate cancer without liver involvement, high prevalence of DNA damage response pathway deficiency in hepatically metastatic prostate cancer and high PTEN alteration rates in viscerally metastatic prostate cancer. We discovered the genomic diversity among bone-only metastatic prostate cancer, hepatically metastatic prostate cancer and pulmonarily metastatic prostate cancer without liver involvement. Our findings shed new light on the heterogenous prognosis in visceral metastases and hint at potential therapeutic targets in both hepatically metastatic prostate cancer and pulmonarily metastatic prostate cancer without liver involvement.

Comparative Analysis of Genomic Alterations across Castration Sensitive and Castration Resistant Prostate Cancer via Circulating Tumor DNA Sequencing.

PURPOSE: To explore the genomic profiles of Chinese patients with castration sensitive prostate cancer and those with metastatic castration resistant prostate cancer via germline and circulating tumor DNA sequencing. MATERIALS AND METHODS: A hybridization capture based next-generation sequencing assay was used to identify germline and somatic alterations in 50 genes including androgen receptor pathway genes, DNA damage repair pathway genes, TP53 and RB1. RESULTS: We successfully sequenced DNA from 396 blood samples and 32 matched tumor tissue samples from 396 patients. We observed a similar frequency of deleterious germline alterations between patients with castration sensitive prostate cancer and metastatic castration resistant prostate cancer (8.9% vs 9.8%, p >0.05). There was a high consistency (90.9%) between metastatic tumor tissue and matched circulating tumor DNA. Among patients who were circulating tumor DNA positive we observed significantly higher alteration frequencies of CDK12 (27.2% vs 6.4%, p <0.001) and FOXA1 (36.8% vs 15.3%, p <0.001) in our metastatic castration resistant prostate cancer cohort compared with the SU2C-PCF (Stand Up to Cancer-Prostate Cancer Foundation) cohort. Alteration frequencies of DNA damage repair pathway genes (66.7% vs 41.5%, p=0.015) and androgen receptor pathway genes (71.9% vs 48.8%, p=0.018) in patients with metastatic castration resistant prostate cancer were higher than in patients with de novo metastatic castration sensitive prostate cancer. Androgen receptor alteration was selectively enriched in metastatic castration resistant prostate cancer. CONCLUSIONS: Through genomic profiling of prostate cancer across clinical states we identified a similar frequency of deleterious germline alterations between patients with castration sensitive prostate cancer and metastatic castration resistant prostate cancer. We explored the genomic diversity of androgen receptor and DNA damage repair pathway genes between patients with metastatic castration sensitive prostate cancer and metastatic castration resistant prostate cancer. Higher alteration frequencies of CDK12 and FOXA1 were observed in our metastatic castration resistant prostate cancer cohort than in the SU2C-PCF cohort. Our findings support the view that circulating tumor DNA sequencing could guide clinical treatment for metastatic prostate cancer.

Distinct Response to Platinum-Based Chemotherapy among Patients with Metastatic Castration-Resistant Prostate Cancer Harboring Alterations in Genes Involved in Homologous Recombination.

PURPOSE: We aimed to explore the association between genomic status and clinical outcome of platinum-based chemotherapy among patients with metastatic castration-resistant prostate cancer (mCRPC). MATERIALS AND METHODS: We conducted a retrospective study of 55 patients with mCRPC who received platinum-based chemotherapy after the progression to docetaxel chemotherapy and underwent genomic profiling of 14 homologous recombination (HR) pathway genes. Progression-free survival (PFS) was analyzed using the Kaplan-Meier method. RESULTS: Of 55 patients, 23 harbored genomic defects in HR pathway genes. Median prostate specific antigen (PSA)-PFS for the HR defect group was 6.7 months compared with 2.6 months for the no HR defect group (p=0.001). The patients harboring somatic HR defect displayed shorter PSA-PFS than those harboring germline HR defect (4.5 months vs not available; p=0.066). The PSA50 (patients who survived for 12 weeks and had a PSA decline over 50% from baseline) response rate displayed higher in patients harboring BRCA2 or ATM defect (6/8, 75.0%) than in those harboring CDK12 defect (2/9, 22.2%; p=0.06). Patients harboring BRCA2 or ATM defect displayed prolonged PSA-PFS, compared with those harboring CDK12 defect and those harboring other HR defect (p=0.038). In multivariate Cox regression analysis, HR defect and BRCA2 or ATM defect were independent significant factors associated with superior PAS-PFS to platinum-based chemotherapy. CONCLUSIONS: The patients with mCRPC harboring alterations in different HR genes displayed distinct response to platinum-based chemotherapy. Patients with mCRPC harboring genomic defects in crucial HR genes either in the germline or somatic, especially BRCA2 and ATM, might experience superior outcomes to platinum-based chemotherapy, compared with those harboring CDK12 defect.

Precise diagnosis and risk stratification of prostate cancer by comprehensive serum metabolic fingerprints: a prediction model study.

OBJECTIVES: Prostate cancer (PCa) is one of the most common malignancies in men worldwide and has caused increasing clinical morbidity and mortality, making timely diagnosis and accurate staging crucial. The authors introduced a novel approach based on mass spectrometry for precise diagnosis and stratification of PCa to facilitate clinical decision-making. METHODS: Matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry analysis of trace blood samples was combined with machine learning algorithms to construct diagnostic and stratification models. A total of 367 subjects, comprising 181 with PCa and 186 with non-PCa were enrolled. Additional 60 subjects, comprising 30 with PCa and 30 with non-PCa were enrolled as an external cohort for validation. Subsequent metabolomic analysis was carried out using Autoflex MALDI-TOF, and the mass spectra were introduced into various algorithms to construct different models. RESULTS: Serum metabolic fingerprints were successfully obtained from 181 patients with PCa and 186 patients with non-PCa. The diagnostic model based on the eight signals demonstrated a remarkable area under curve of 100% and was validated in the external cohort with the area under curve of 87.3%. Fifteen signals were selected for enrichment analysis, revealing the potential metabolic pathways that facilitate tumorigenesis. Furthermore, the stage prediction model with an overall accuracy of 85.9% precisely classified subjects with localized disease and those with metastasis. The risk stratification model, with an overall accuracy of 89.6%, precisely classified the subjects as low-risk and high-risk. CONCLUSIONS: Our study facilitated the timely diagnosis and risk stratification of PCa and provided new insights into the underlying mechanisms of metabolic alterations in PCa.

Advances of hafnium based nanomaterials for cancer theranostics.

Hafnium-based nanomaterials (Hf-NMs) have attracted the interest of numerous biomedical researchers by their unique properties. Recent years have witnessed significant advancements in the field of Hafnium-based nanomaterials, particularly in the context of cancer diagnosis and treatment. However, research in this area, especially concerning the clinical application of Hafnium-based nanomaterials, has not been thoroughly reviewed. This review will cover: 1) Classification and synthesis of Hafnium-based nanomaterials including Hafnium oxide nanomaterials, Hafnium Metal-Organic Frameworks/nanoscale coordination polymers (MOFs/NCPs); 2) Hafnium-based nanomaterials act as contrast enhancement agent for cancer imaging, and hafnium-based nanomaterials used for diagnosis in cancer liquid biopsy; 3) hafnium-based nanomaterials for cancer therapy, including hafnium-based nanomaterials for radiotherapy, hafnium-based nanomaterials for photodynamic therapy, hafnium-based nanomaterials for various combined therapy; and 4) Translation, toxicity, and safety for Hf-NMs in human and preclinical animal models. More attention will be given to the clinical translation of Hf-NMs in cancer.

Early Plasma Circulating Tumor DNA as a Potential Biomarker of Disease Recurrence in Non-metastatic Prostate Cancer.

PURPOSE: In non-metastatic prostate cancer (nmPCa) setting, it is important to early identify the patients at risk of biochemical recurrence (BCR) for immediate postoperative intervention. Our study aimed to evaluate the potential clinical utility of circulating tumor DNA (ctDNA) for predicting disease recurrence. Materials and Methods: This real-world observational study evaluated 161 cases of nmPCa undergoing next-generation sequencing at our institution. A total of 139 ctDNA samples and 31 biopsied tumor tissue underwent genomic profiling. The study endpoint was BCR after radical prostatectomy. Relationships between the ctDNA status and the biochemical progression-free survival (bPFS) were analyzed by log-rank test and multivariate Cox regression. RESULTS: Of 161 enrolled patients, 19 (11.8%) harbored deleterious alterations in NCOR2, followed by BRCA2 (3.7%), ATR (2.5%), and CDK12 (2.5%). Of available pre-operative blood samples (n=139), ctDNA was detectable in 91 (65.5%). Until last follow-up, 56 of 68 patients (85.3%) with detectable ctDNA had achieved BCR, whereas only eight of 39 patients (20.5%) with undetectable ctDNA had achieved BCR. Patients who had undetectable ctDNA experienced significantly longer bPFS compared with those who had detectable ctDNA (not available vs. 8.2 months; hazard ratio, 0.14; p < 0.01). Pre-operative ctDNA status was a significant prognostic factor of disease recurrence. CONCLUSION: Pre-operative ctDNA detection could identify patients at high risk of recurrence and has the potential to inform immediate postoperative interventions, but these approaches remain to be validated in prospective studies. ctDNA studies can provide insights into accurate monitoring and precise treatment rather than simply following routine clinical care.

Simultaneous subset tracing and miRNA profiling of tumor-derived exosomes via dual-surface-protein orthogonal barcoding.

The clinical potential of miRNA-based liquid biopsy has been largely limited by the heterogeneous sources in plasma and tedious assay processes. Here, we develop a precise and robust one-pot assay called dual-surface-protein-guided orthogonal recognition of tumor-derived exosomes and in situ profiling of microRNAs (SORTER) to detect tumor-derived exosomal miRNAs and enhance the diagnostic accuracy of prostate cancer (PCa). The SORTER uses two allosteric aptamers against exosomal marker CD63 and tumor marker EpCAM to create an orthogonal labeling barcode and achieve selective sorting of tumor-specific exosome subtypes. Furthermore, the labeled barcode on tumor-derived exosomes initiated targeted membrane fusion with liposome probes to import miRNA detection reagents, enabling in situ sensitive profiling of tumor-derived exosomal miRNAs. With a signature of six miRNAs, SORTER differentiated PCa and benign prostatic hyperplasia with an accuracy of 100%. Notably, the diagnostic accuracy reached 90.6% in the classification of metastatic and nonmetastatic PCa. We envision that the SORTER will promote the clinical adaptability of miRNA-based liquid biopsy.

Early serial circulating tumor DNA sequencing predicts the efficacy of chemohormonal therapy in patients with metastatic hormone-sensitive prostate cancer.

Chemohormonal therapy is a standard treatment for metastatic hormone-sensitive prostate cancer (mHSPC); however, there are no biomarkers to guide clinical decisions regarding therapeutic options. We aimed to evaluate the clinical utility of serial circulating tumor DNA (ctDNA) sequencing in early prediction of the efficacy of chemohormonal therapy in patients with mHSPC. We conducted a retrospective observational study of 66 patients with mHSPC receiving chemohormonal therapy who underwent serial targeted gene-panel ctDNA sequencing. Peripheral blood samples were collected before treatment and after one cycle of chemotherapy. Kaplan-Meier and log-rank analyses were used to analyze the association between ctDNA status and disease progression-free survival. Serial changes in the ctDNA fraction and genetic alterations were also observed. After one cycle of chemotherapy, 23 (34.8%) patients displayed elevated ctDNA levels, whereas the other patients (65.2%, n = 43) did not. The median time to castration resistance in the group with reduced ctDNA levels was significantly longer than that in the group with increased ctDNA levels (17.70 vs. 8.43 months [mo], p < 0.001). Interestingly, patients with de novo alterations in homologous recombination pathway genes after treatment experienced a shorter time to castration resistance than that experienced by the remaining patients (8.02 vs. 13.20 mo, p = 0.011). The increased ctDNA levels or de novo alterations detected in homologous recombination pathway genes are a harbinger of disease progression. Early serial ctDNA sequencing could aid clinicians in making accurate treatment decisions.

Engineering the MoS2 /MXene Heterostructure for Precise and Noninvasive Diagnosis of Prostate Cancer with Clinical Specimens.

High-throughput metabolic fingerprinting has been deemed one of the most promising strategies for addressing the high false positive rate of prostate cancer (PCa) diagnosis in the prostate-specific antigen (PSA) gray zone. However, the current metabolic fingerprinting remains challenging in achieving high-precision metabolite detection in complex biological samples (e.g., serum and urine). Herein, a novel self-assembly MoS2 /MXene heterostructure nanocomposite with a tailored doping ratio of 10% is presented as a matrix for laser desorption ionization mass spectrometry analysis in clinical biosamples. Notably, owing to the two-dimensional architecture and doping effect, MoS2 /MXene demonstrates favorable laser desorption ionization performance with low adsorption energy, which is evidenced by efficient urinary metabolic fingerprinting with an enhanced area under curve (AUC) diagnosis capability of 0.959 relative to that of serum metabolic fingerprinting (AUC = 0.902) for the diagnosis of PCa in the PSA gray zone. Thus, this MoS2 /MXene heterostructure is anticipated to offer a novel strategy to precisely and noninvasively diagnose PCa in the PSA gray zone.

PD-1 inhibitor plus anlotinib for metastatic castration-resistant prostate cancer: a real-world study.

Management and treatment of terminal metastatic castration-resistant prostate cancer (mCRPC) remains heavily debated. We sought to investigate the efficacy of programmed cell death 1 (PD-1) inhibitor plus anlotinib as a potential solution for terminal mCRPC and further evaluate the association of genomic characteristics with efficacy outcomes. We conducted a retrospective real-world study of 25 mCRPC patients who received PD-1 inhibitor plus anlotinib after the progression to standard treatments. The clinical information was extracted from the electronic medical records and 22 patients had targeted circulating tumor DNA (ctDNA) next-generation sequencing. Statistical analysis showed that 6 (24.0%) patients experienced prostate-specific antigen (PSA) response and 11 (44.0%) patients experienced PSA reduction. The relationship between ctDNA findings and outcomes was also analyzed. DNA-damage repair (DDR) pathways and homologous recombination repair (HRR) pathway defects indicated a comparatively longer PSA-progression-free survival (PSA-PFS; 2.5 months vs 1.2 months, P = 0.027; 3.3 months vs 1.2 months, P = 0.017; respectively). This study introduces the PD-1 inhibitor plus anlotinib as a late-line therapeutic strategy for terminal mCRPC. PD-1 inhibitor plus anlotinib may be a new treatment choice for terminal mCRPC patients with DDR or HRR pathway defects and requires further investigation.