Introduction The classic way of diagnosing prostate cancer (PCa) is by conducting the 12-core systematic biopsy (SB). However, it has a low detection rate for clinically significant PCa (csPCa) and can lead to the detection of clinically insignificant PCa (cisPCa). Although MRI-transrectal ultrasound (MRI-TRUS) fusion targeted biopsy (TB) can effectively improve the detection rate of csPCa, it may still miss some cases. Therefore, we propose using a combination of TB and SB methods to enhance the detection rate of csPCa while minimising the detection rate of cisPCa.Methods and analysis This study is a prospective, single-centre investigation that aims to assess and compare the detection rate of csPCa using MRI-TRUS fusion TB combined with SB versus TRUS 12-core SB alone. Biopsy-naïve men with suspected PCa will be subjected to multiparametric MRI. Patients with Prostate Imaging Reporting and Data System (V.2.1) score ≥3 will be enrolled in the TB-SB combination group. The sample size is established as 660 participants, considering a 10% drop-out rate. The primary outcome is the detection rate of csPCa in men without prior biopsy using MRI-TRUS fusion TB combined with the standard TRUS-guided 12-core SB method. CsPCa will be defined as International Society of Urological Pathology Grade ≥2.Ethics and dissemination This study has been approved by the Ethics Committee at the Shanghai Tenth People’s Hospital, an affiliated hospital of Tongji University School of Medicine. The research results will be published in a peer-reviewed international journal.Trial registration number ChiCTR2000036089.

When a patient has two or more primary tumors, excluding the possibility of diffuse, recurrent, or metastatic, they can be defined as having multiple primary malignant neoplasms (MPMNs). Moreover, cases of three primary urinary tract tumors are very rare. Here, we reported a patient of MPMNs with four primary tumors, including three urinary tract cancers (renal cancer, prostate cancer, and bladder cancer) and lung cancer. The four tumors appeared over 13 years, and pathological results confirmed that they were all primary tumors after different surgeries. In addition, we established patient-derived organoids (PDOs) by collecting tumor specimens. Hematoxylin-eosin (H&E) staining of PDOs showed that the organoids were histopathological consistent with parental tumor. Immunohistochemistry showed that PDOs can also reflect the expression of pathological markers in patients. At the same time, PDOs may also serve as “avatars” of patients to predict sensitivity to different drugs. In summary, we reported a case of MPMNs with four primary tumors and established PDOs from its tumor specimens. A personalized treatment strategy was established based on the histopathological characteristics of the organoids.

Concordance of genomic alterations between proggressive tumor tissue and matched ctDNA from patients with AVPC. A, Concordance in SMs and CNVs. Data are shown for 63 patients. B, Rose diagram of concordance for SMs + CNVs, SMs only or CNVs only. C, Proportions of patients with high positive concordance, low positive concordance or negative concordance. D, Association between high positive concordance and clinical characteristics, including the ctDNA%, AVPC criteria, progressive status, and PSA ≥ 10 ng/mL at the time of DNA sequencing. Associations were assessed using Kendall tau test, and significance was defined as *, P < 0.05 or **, P < 0.01. Data are shown for 61 patients. E–G, Concordance of alterations involving the tumor suppressor genes TP53, RB1, or PTEN in 46 patients with AVPC. E, Concordance of SMs or CNVs. F, Rose diagram of concordance for SMs + CNVs, SMs only or CNVs only. G, Proportions of patients with positive or negative concordance. ALP, alkaline phosphatase.

Univariate and multivariate logistic regression to identify associations between high positive concordance and clinical characteristics

Copy Number Variants Detected in Progressive Tumor Tissue and Matched Circulating Tumor DNA for Each AVPC Patient.

Clinical Characteristics of AVPC Patients, Stratified by Systemic Therapy with or without Local Therapy

Ability of alterations affecting signaling pathways in progressive tumor tissue or matched ctDNA to predict OS of patients with AVPC.

Univariate and multivariate Cox analysis of PFS and OS in patients with AVPC who received systemic therapy without local therapy

Comparing Survival Outcomes in AVPC Subgroups: Additional Platinum-Based Chemo vs. Docetaxel-Only. Survival outcomes of PFS (A) and OS (B) for additional Platinum-based chemotherapy or Docetaxel only in the AVPC subgroups without any alteration involving the tumor suppressor genes TP53, RB1, or PTEN. Survival outcomes of PFS (C) and OS (D) for additional Platinum-based chemotherapy or Docetaxel only in the AVPC subgroups with low concentration of ctDNA (ctDNA% < 13.5%).

Abstract Sequencing of circulating tumor DNA (ctDNA) is a minimally invasive approach to reveal the genomic alterations of cancer; however, its comparison with sequencing of tumor tissue has not been well documented in real-world patients with aggressive-variant prostate cancer (AVPC). Concordance of genomic alterations was assessed between progressive tumor tissue and matched ctDNA by next-generation sequencing for 63 patients with AVPC. Associations of genomic alterations with progression-free survival (PFS) and overall survival (OS) were investigated using Kaplan–Meier and Cox regression analyses. A total of 161 somatic mutations (SMs) and 84 copy-number variants (CNVs) were detected in tumors, of which 97 were also found in ctDNA, giving concordance of 39.6% (97/245) across all SMs and CNVs, 49.7% for SMs only and 20.2% for CNVs only. Across all patients with AVPC, chemotherapy was associated with significantly longer median PFS (6 vs. 0.75 months, P = 0.001) and OS (11 vs. 8 months, P < 0.001) than next-generation hormonal therapy (NHT). Among types of chemotherapy, additional platinum-based chemotherapy was associated with significantly longer median PFS and OS than docetaxel only in patients with TP53, RB1, or PTEN alterations, and in those with ctDNA% ≥ 13.5%. The concordance analysis first provides evidence for combining the sequencing of ctDNA and tumor tissue in real-world patients with AVPC. Chemotherapy is associated with significantly better survival than NHT, and the benefit of additional platinum-based chemotherapy may depend on the presence of alterations in TP53, RB1, or PTEN and on a sufficiently high proportion of ctDNA in patients with AVPC. Significance: AVPC is a highly malignant and heterogeneous disease. Sequencing of ctDNA is a minimally invasive approach to reveal genomic alterations. On the basis of the current real-world study, we found ctDNA does not fully recapitulate the landscape of genomic alterations from progressive tumor tissue in AVPC. We also revealed AVPC can benefit from chemotherapy, especially platinum-based regimens. TP53/RB1/PTEN alterations in ctDNA or tumor tissue could be biomarkers for platinum-based chemotherapy in this setting.

BackgroundUpper tract urothelial carcinoma (UTUC) is a rare malignancy. The management of metastatic or unresectable UTUC is mainly based on evidence extrapolated from histologically homologous bladder cancer, including platinum-based chemotherapy and immune checkpoint inhibitor alone, whereas UTUC exhibits more invasiveness, worse prognosis, and comparatively inferior response to treatments. First-line immunochemotherapy regimens have been attempted in clinical trials for unselected naïve-treated cases, but their efficacies relative to standard chemo- or immuno-monotherapy still remain controversial. Here, we present a case of highly aggressive UTUC for whom comprehensive genetic and phenotypic signatures predicted sustained complete response to first-line immunochemotherapy.Case presentationA 50-year-old man received retroperitoneoscopic nephroureterectomy and regional lymphadenectomy for high-risk locally advanced UTUC. Postoperatively, he developed rapid progression of residual unresectable metastatic lymph nodes. Pathologic analysis and next-generation sequencing classified the tumor as highly aggressive TP53/MDM2-mutated subtype with features more than expression of programmed death ligand-1, including ERBB2 mutations, luminal immune-infiltrated contexture, and non-mesenchymal state. Immunochemotherapy combining gemcitabine, carboplatin, and off-label programmed death-1 inhibitor sintilimab was initiated, and sintilimab monotherapy was maintained up to 1 year. Retroperitoneal lymphatic metastases gradually regressed to complete response. Blood-based analyses were performed longitudinally for serum tumor markers, inflammatory parameters, peripheral immune cells, and circulating tumor DNA (ctDNA) profiling. The ctDNA kinetics of tumor mutation burden and mean variant allele frequency accurately predicted postoperative progression and sustained response to the following immunochemotherapy, which were mirrored by dynamic changes in abundances of ctDNA mutations from UTUC-typical variant genes. The patient remained free of recurrence or metastasis as of this publishing, over 2 years after the initial surgical treatment.ConclusionImmunochemotherapy may be a promising first-line option for advanced or metastatic UTUC selected with specific genomic or phenotypic signatures, and blood-based analyses incorporating ctDNA profiling provide precise longitudinal monitoring.

Supplementary Figure 1. Characteristics of the study cohort at the patient level. (A) The presence of diagnostic criteria for AVPC in each patient. Criteria have been described in Materials and Methods. (B) Deleterious genomic alterations. (C) Treatment method. (D) Changes in PSA after treatment. (E) PFS and OS after treatment. #, truncated; *, level of PSA could not be evaluated.

Background: Bladder cancer (BLCA) is highly heterogeneous with distinct molecular subtypes. This research aimed to investigate the heterogeneity of different molecular subtypes from a tumor microenvironment perspective and develop a molecular-subtype-associated immune prognostic signature that can be recognized by MRI radiomics features. Methods: Individuals with BLCA in The Cancer Genome Atlas (TCGA) and IMvigor210 were classified into luminal and basal subtypes according to the UNC classification. The proportions of tumor-infiltrating immune cells (TIICs) were examined using The Cell Type Identification by Estimating Relative Subsets of RNA Transcripts algorithm. Immune-linked genes that were expressed differentially between luminal and basal subtypes and associated with prognosis were selected to develop the immune prognostic signature (IPS) and utilized for the classification of the selected individuals into low- and high-risk groups. Functional enrichment analysis (GSEA) was performed on the IPS. The data from RNA-sequencing and MRI images of 111 BLCA samples in our center were utilized to construct a least absolute shrinkage and selection operator (LASSO) model for the prediction of patients' IPSs. Results: Half of the TIICs showed differential distributions between the luminal and basal subtypes. IPS was highly associated with molecular subtypes, critical immune checkpoint gene expression, prognoses, and immunotherapy response. The prognostic value of the IPS was further verified through several validation data sets (GSE32894, GSE31684, GSE13507, and GSE48277) and meta-analysis. GSEA revealed that some oncogenic pathways were co-enriched in the group at high risk. A novel performance of a LASSO model developed as per ten radiomics features was achieved in terms of IPS prediction in both the validation (area under the curve (AUC): 0.810) and the training (AUC: 0.839) sets. Conclusions: Dysregulation of TIICs contributed to the heterogeneity between the luminal and basal subtypes. The IPS can facilitate molecular subtyping, prognostic evaluation, and personalized immunotherapy. A LASSO model developed as per the MRI radiomics features can predict the IPSs of affected individuals.

An additional calculation by using the selected patients (patients who have alteration detections in both tumor tissue and ctDNA in terms of the same alteration type) was developed for concordance.

Clinical Characteristics of Patients with AVPC

Patient-level concordance of genomic alterations involving the tumor suppressor genes TP53, RB1 or PTEN between progressive tumor tissue and matched ctDNA in patients with AVPC.

Study design and integrative landscape of SMs, CNVs, and deleterious GMs in patients with AVPC. A, Flow diagram of patients according to treatment history. Tumor tissue and matched ctDNA from 63 patients with clinically defined AVPC. All of them underwent systemic treatment. Among them, 14 patients received local treatment, while 59 patients did not. The systemic treatment methods included NHT (enzalutamide, abiraterone, and apalutamine), Chemotherapy (additional platinum-based chemotherapy or docetaxel only), and other therapies (inhibitors of tyrosine kinases, PD-1 or PARP inhibitor). B, Landscape of alterations involving 30 selected genes in progressive tumor tissues and matched ctDNA from patients with AVPC. C, Landscape of alterations involving signaling pathways in progressive tumor tissues and matched ctDNA from patients with AVPC. Significance was determined using χ2 and Fisher exact tests. ***, P < 0.001.

Objective To investigate the effect and mechanism of PRMT7 on migration and invasion of prostate cancer cells. Methods Transcriptome data of PRMT7 in normal prostate and prostate cancer tissues were obtained from TCGA and GTEx databases using R software. The expression levels of PRMT7 protein in cells were detected by Western blot. Migration and invasion of PRMT7 cells were assessed using wound healing assay and Transwell assay. Transcripts and proteins levels were evaluated using transcriptome sequencing analysis and label-free quantitative protein sequencing analysis. KISS1R was knockdown by siRNA transfection. Results The expression of PRMT7 was lower in prostate cancer tissues than that in normal prostate tissues as analyzed in TCGA and GTEx datasets. The expression of PRMT7 was downregulated in prostate cancer cell lines LNCaP and PC3 and the overexpression of PRMT7 suppressed migration and invasion in the prostate cancer cells, as determined by wound healing assay, Transwell assays. The whole-genome transcriptome, proteome sequencing analysis and Western blotting showed that the metastasis suppressor gene KISS1R was up-regulated both at the transcriptional and translational level by upregulating PRMT7 expression. Knockdown of KISS1R reversed the tumor-suppressive phenotype. Conclusion The study demonstrates that PRMT7 plays an anti-oncogenic role in prostate cancer cells and KISS1R is a downstream effector molecule of PRMT7 in modulating tumor cell migration and invasion, suggesting that PRMT7 may be a potential target for the clinical treatment of prostate cancer.