The testosterone (TT)/androgen receptor axis plays a crucial role in the initiation and progression of prostate cancer (PCa). We aimed to investigate the predictive value of serum TT levels on metastatic PCa progression. A total of 219 patients with metastatic PCa were included in this study. Analyses performed included Pearson’s correlation test, Wilcoxon rank test, Chi-square test, Cox regression, and Kaplan-Meier analysis. High serum TT levels (> 405 ng/dL) before ADT treatment, deep testosterone reduction (DTR) within the first year of ADT, rapid DTR within 3 months of ADT, and sustained DTR in the first year of ADT are associated with longer CRPC progression-free time. Low serum TT levels before abiraterone treatment are a risk factor for early PSA progression. We constructed a nomogram model based on the DTR within the first year of ADT. Calibration curve and decision curve analyses suggest the model has a high predictive ability for 1-, 1.5-, and 2-year CRPC progression and well clinical utility. Serum TT levels before and during ADT, as well as before abiraterone treatment, can predict metastatic PCa progression. Monitoring serum TT levels throughout the entire course of treatment is crucial for patient follow-up and prognosis.

Molecular targeted therapies have shown considerable efficacy in treating metastatic renal cell carcinoma (mRCC). However, many patients still experience tumor recurrence or metastasis due to drug resistance. Despite extensive research on resistance mechanisms, there is a lack of comprehensive bibliometric studies examining the overall characteristics of targeted therapy resistance in renal cell carcinoma. Publications on resistance to targeted therapy in renal cell carcinoma were identified from the Web of Science Core Collection (WoSCC) from June 2004 to November 2024. The English-language literature was analyzed using bibliometric tools, including VOSviewer and CiteSpace, to examine publication trends, active countries/regions, key authors, and institutions. Keyword analysis, co-citation mapping, and gene identification were conducted to uncover research trends and focal points. A total of 1081 publications were identified, with the United States, China, and Italy as the top contributing countries. Prominent institutions included the Cleveland Clinic, the Sloan Kettering Cancer Center, the MD Anderson Cancer Center, Fudan University, and Huazhong University of Science and Technology. Camillo Porta was a prolific author, and Brian I. Rini was among the most highly cited. The journal Cancers published the most papers in this field, and the Journal of Clinical Oncology was the most co-cited. Key research topics included the “tumor microenvironment” and “combination therapy”. A comprehensive analysis of publications related to "the tumor microenvironment" reveals that "renal cancer stem cells" and "epithelial-mesenchymal transition" have been identified as key terms strongly associated with therapeutic resistance mechanisms in targeted cancer treatments. In-depth analysis of the regulatory molecules and molecular mechanisms in the literature highlighted the roles of microRNA and the synergistic effects between anti-PD-L1/PD-1 and targeted drugs. Bibliometric analysis of research on molecular targeted therapy resistance in renal cell carcinoma revealed a clear trajectory and rapidly increasing trend in this field. The impact of the tumor microenvironment, particularly the roles of renal cancer stem cells and epithelial-mesenchymal transition, has garnered significant attention. Additionally, the combination of anti-PD-L1/PD-1 and targeted drugs, as well as the involvement of miRNA, have emerged as key areas of focus. As understanding of this field deepens, future research is expected to uncover novel therapeutic targets and more effectively overcome the challenges of targeted therapy resistance in renal cell carcinoma, ultimately improving patient outcomes.

PURPOSE:Upper tract urothelial carcinoma (UTUC) and urothelial carcinoma of the bladder (UCB) share histomorphological and therapeutic features but distinct epidemiologic and clinicopathologic characteristics. We examined alterations of chromatin regulatory genes in molecular subtypes, clonal relatedness, and T-cell receptor (TCR) diversity in UTUC and UCB. MATERIALS AND METHODS:Targeted next-generation sequencing or whole-exome DNA sequencing and TCR sequencing were conducted with 34 UTUC and 49 UCB specimens from 63 patients. Tumors were subtyped based on the expression of CK5 and GATA3. Results of tissue microarray of 78 muscle-invasive bladder cancer (MIBC) samples were used as prognostic factors of different subtypes of MIBC. RESULTS:Chromatin regulatory genes were frequently mutated in both UTUC and UCB. Rapid relapse and progression of non-MIBC are correlated with alterations of KMT2C and EP300. Frequency of alterations in chromatin regulatory genes is higher in UTUC patients with SBS22 and SBS2 signatures and lower in UCB patients with SBS2 and SBS6 signatures. GATA3 and CK5 double-positive patients with higher frequencies of SMARCA4, ARID1A, and EP300 mutations have better prognoses than patients with basal subtypes. Although UTUC and UCB in the same patient can be either clonally related or developed independently, mutated genes in chromatin pathway were enriched in the related clones. Compared to UTUC, UCB had more deleterious mutations in DNA damage repair (DDR) genes, higher levels of tumor mutation burden (TMB) and copy number variations (CNVs), as well as higher TCR clonality and lower TCR diversity. CONCLUSIONS:Since genetic alterations of the chromatin pathway genes are important in both UTUC and UCB, they could serve as potential biomarkers for predicting disease progression and therapeutic targets. Differences in mutation frequencies of DDR pathway, TMB, CNV, and TCR might be the contributing factors for the distinct responses to immune checkpoint inhibitor (ICI) between UTUC and UCB.

Metastasis is the primary culprit behind cancer-related fatalities in multiple cancer types, including prostate cancer. Despite great advances, the precise mechanisms underlying prostate cancer metastasis are far from complete. By using a transgenic mouse prostate cancer model (TRAMP) with and without Phf8 knockout, we have identified a crucial role of PHF8 in prostate cancer metastasis. By complexing with E2F1, PHF8 transcriptionally upregulates SNAI1 in a demethylation-dependent manner. The upregulated SNAI1 subsequently enhances epithelial-to-mesenchymal transition (EMT) and metastasis. Given the role of the abnormally activated PHF8/E2F1-SNAI1 axis in prostate cancer metastasis and poor prognosis, the levels of PHF8 or the activity of this axis could serve as biomarkers for prostate cancer metastasis. Moreover, targeting this axis could become a potential therapeutic strategy for prostate cancer treatment. (c) 2024 The Pathological Society of Great Britain and Ireland.

[This corrects the article DOI: 10.3389/fonc.2022.826778.].

Introduction21-hydroxylase deficiency (21OHD) is the most common cause of congenital adrenal hyperplasia (CAH). However, patients with 21OHD manifest various phenotypes due to a wide-spectrum residual enzyme activity of different CYP21A2 mutations.MethodsA total of 15 individuals from three unrelated families were included in this study. Target Capture-Based Deep Sequencing and Restriction Fragment Length Polymorphism was conducted on peripheral blood DNA of the three probands to identify potential mutations/deletions in CYP21A2; Sanger sequencing was conducted with the DNA from the family members of the probands.ResultsDramatically different phenotypes were seen in the three probands of CAH with different compound heterozygous mutations in CYP21A2. Proband 1 manifested simple virilizing with mutations of 30-kb deletion/c.[188A>T;518T>A], the latter is a novel double mutants classified as SV associated mutation. Although both probands carry the same compound mutations [293-13C>G]:[518T>A], gonadal dysfunction and giant bilateral adrenal myelolipoma were diagnosed for proband 2 and proband 3, respectively.ConclusionBoth gender and mutations contribute to the phenotypes, and patients with the same compound mutations and gender could present with different phenotypes. Genetic analysis could help the etiologic diagnosis, especially for atypical 21OHD patients.

For clear cell renal cell carcinoma (ccRCC), lipid deposition plays important roles in the development, metastasis, and drug resistance. However, the molecular mechanisms underlying lipid deposition in ccRCC remain largely unknown. By conducting an unbiased CRISPR-Cas9 screening, we identified the epigenetic regulator plant homeodomain finger protein 8 (PHF8) as an important regulator in ccRCC lipid deposition. Moreover, PHF8 is regulated by von Hippel–Lindau (VHL)/hypoxia-inducible factor (HIF) axis and essential for VHL deficiency–induced lipid deposition. PHF8 transcriptionally up-regulates glutamate-ammonia ligase (GLUL), which promotes the lipid deposition and ccRCC progression. Mechanistically, by forming a complex with c-MYC, PHF8 up-regulates TEA domain transcription factor 1 (TEAD1) in a histone demethylation–dependent manner. Subsequently, TEAD1 up-regulates GLUL transcriptionally. Pharmacological inhibition of GLUL by l -methionine sulfoximine not only repressed ccRCC lipid deposition and tumor growth but also enhanced the anticancer effects of everolimus. Thus, the PHF8-GLUL axis represents a potential therapeutic target for ccRCC treatment.

Objective To analyze the risk factors for biochemical recurrence in prostate cancer patients after radical prostatectomy (RP) and establish a risk prediction model for the recurrence. Methods A retrospective cohort study was conducted on 279 patients who underwent RP surgery in our hospital from September 2007 to March 2022. There were 21 clinical indicators collected and analyzed. After time factors were included, Lasso regression was applied to screen the indicators, Kaplan-Meier method was used to draw survival curve, univariate and multivariate Cox proportional risk regression models were employed to analyze the risk factors and establish a prediction model. Then receiver operating characteristic (ROC) curve were plotted to evaluate the discriminative performance of the model. Then a nomogram was draw based on the obtained risk factors. Calibration curve was used to evaluate the accuracy of prediction, and decision curve was employed to assess the clinical benefit. Results During a median follow-up time of 37.10 (17.60, 61.30) months, 86 cases (30.8%), at a median age of 68.00 (65.00, 72.00) years, experienced biochemical recurrence. Univariate analysis showed that 12 indicators were strongly associated with biochemical recurrence after RP (P < 0.05), and Lasso regression screening indicated 7 representative indicator sets, including nutritional risk index (NRI), clinical T-stage, pathological Gleason score, pathological T-stage, positive surgical margin, lymph node invasion, and seminal vesicle invasion. Further multifactorial analysis revealed that pathological high stage (≥pT3 stage) (HR=1.895, 95%CI: 1.045~3.435, P=0.035), positive surgical margin (HR=1.808, 95%CI: 1.006~3.25, P=0.048), lymph node invasion (HR=2.161, 95% CI: 1.118~4.175, P=0.022) and NRI ≤106.9 (HR=0.598, 95% CI: 0.378~0.946, P=0.028) were independent risk factors for biochemical recurrence. The predictive equation was established with an AUC of 0.743 (95% CI: 0.677~0.810, P < 0.001), a sensitivity of 0.826 and a specificity of 0.534. And the established nomogram has a C-index of 0.741 (95%CI: 0.677~0.805; P < 0.001), with good agreement indicated by calibration curve. Clinical decision curve displayed that there was a net benefit when the threshold probability was 15%~85%. Conclusion High pathological stage (≥pT3 stage), positive surgical margin, lymph node invasion, and NRI ≤106.9 are independent risk factors for biochemical recurrence of prostate cancer after RP. Our prediction model can make effective judgments and provide references for clinical decision making.

Introduction and importance:The feasibility of combined tislelizumab with gemcitabine and cisplatin as a neoadjuvant regimen for muscle-invasive bladder cancer (MIBC) remains to be investigated.Case presentation:The neoadjuvant treatment not only shrunk tumours significantly but also lowered their stages from T4bN1M0, T3N0M0, and T3bN0M0 to pT1, pT0 and pTis, respectively. The treatment suppressed tumour cell proliferation and promoted luminal-to-basal transition.Clinical discussion:MIBC is an aggressive bladder cancer with poor prognosis. All three patients with MIBC benefited greatly from the neoadjuvant regimen (tislelizumab + gemcitabine + cisplatin). It appears that the effect of the treatment is independent of the levels of programmed death-ligand 1 nor the subtype of urothelial bladder cancer.Conclusion:Combination of tislelizumab with gemcitabine and cisplatin appeared to be a safe and efficacious neoadjuvant therapy for MIBC.

Background Genetic profiling of patients with prostate cancer could potentially identify mutations prone to castration-resistant prostate cancer (CRPC). Here, we aimed to identify the differences in genetic profiles of patients with hormone-sensitive prostate cancer (HSPC) and CRPC and stratify HSPC patients to identify mutations associated with CRPC progression. Methods A total of 103 samples were collected, including 62 DNA samples from the tumor tissues of 59 HSPC patients and 41 cell-free DNA (cfDNA) samples from prostate cancer patients at different cancer stages. Targeted sequence was conducted on both the tissue DNA and cfDNA. The associations between mutations and clinical outcomes (CRPC-free time) were analyzed using χ 2 test, logistic regression analysis, Kaplan–Meier analysis, and Cox regression analysis. Results By comparing to that of cfDNA sequencing, the results from DNA sequencing of 1-needle (80%) and mixed 12-needle (77.8%) biopsies are highly comparable. FOXA1 (30.5%), CDK12 (23.7%), and TP53 (22.0%) were the top 3 most frequently mutated genes in HSPC patients; 50.8% (30/59) and 44.1% (26/59) HSPC patients had mutations in DDR and HRR pathway, respectively. Mutations in AR and APC as well as the members involved in the regulation of stem cell pluripotency and EMT pathway were often observed in CRPC samples. We established a panel of four genetic mutations (MSH2, CDK12, TP53, and RB1) to predict the risk of CRPC early progression with concordance index = 0.609 and the area under curve of the ROC curve as 0.838. Conclusions In this study, we demonstrated that the cfDNA can be used in genetic profiling in prostate cancer and our newly established panel is capable of predicting which mHSPC patient has a high risk of early CRPC progression.

Objective To investigate the inherited mutations and their association with clinical features and treatment response in young-onset prostate cancer patients. Method Targeted gene sequencing on 139 tumor susceptibility genes was conducted with a total of 24 patients diagnosed with PCa under the age of 63 years old. Meanwhile, the related clinical information of those patients is collected and analyzed. Results Sixty-two germline mutations in 45 genes were verified in 22 patients. BRCA2 (20.8%) and GJB2 (20.8%) were found to be the most frequently mutated, followed by CHEK2, BRCA1, PALB2, CDKN2A, HOXB13, PPM1D, and RECQL (8.3% of each, 2/24). Of note, 58.3% (14/24) patients carry germline mutations in DNA repair genes (DRGs). Four families with HRR (homologous recombination repair)-related gene mutations were described and analyzed in detail. Two patients with BRCA2 mutation responded well to the combined treatment of androgen deprivation therapy (ADT) and radiotherapy/chemotherapy. Conclusion Mutations in DRGs are more prevalent in early-onset PCa with advanced clinical stages, and these patients had shorter progression-free survival. ADT Combined with either radiotherapy or chemotherapy may be effective in treating PCa caused by HRR-related gene mutations.

The TMPRSS2-ERG fusion gene has frequently been found in prostate cancer and is associated with malignancy. Identifying novel fusions will help to stratify patients and establish patient-tailored therapies. A 78-year-old man presented to our hospital with severe symptoms of urinary urgency and frequency for 2 years, as well as severe bone pain for 1 year. He was diagnosed with metastatic prostate cancer with a Gleason score of 5 + 5. Three gene fusions, ERG_VEGFA, TMPRSS2_ERG, and VEGFA_TMPRSS2, were identified in the patient's prostate cancer tissue. Notably, administration of the tyrosine kinase inhibitor, anlotinib, in combination with a gonadotropin-releasing hormone agonist (GnRHa) and abiraterone, reduced the patient's bone pain and also stabilized his prostate cancer for more than 2 years. This is the first report of somatic fusions among the VEGFA, ERG, and TMPRSS2 genes in cancer tissues from a patient with prostate cancer who responded well to antiangiogenic treatment combined with a GnRHa and abiraterone.