Peng Du

Cancer cachexia is a multifactorial metabolic syndrome characterized by progressive skeletal muscle loss, affecting 30–60% of patients with advanced renal cell carcinoma (RCC). It significantly impacts treatment tolerance, quality of life, and prognosis, yet its diagnosis and management remain challenging due to fragmented RCC-specific evidence, particularly in the era of immune checkpoint inhibitor (ICI)-based therapy. The pathogenesis involves persistent systemic inflammation, metabolic reprogramming, and tumor–host interactions. The IL-6/STAT3 and TNF-α/NF-κB pathways are central to muscle catabolism, while tumor-derived mediators such as GDF15 and PTHrP, along with mitochondrial dysfunction, further drive cachexia progression. For prognostic assessment, CT-derived skeletal muscle mass evaluation combined with systemic inflammatory and nutritional biomarkers—including neutrophil-to-lymphocyte ratio (NLR), modified Glasgow Prognostic Score (mGPS), prognostic nutritional index (PNI), and cachexia index (CXI)—has improved risk stratification in advanced RCC. Preclinical and emerging clinical data suggest that targeted therapies may partially attenuate cachexia by modulating inflammatory signaling, while multimodal interventions integrating nutritional support and exercise rehabilitation remain the cornerstone of management. Novel strategies, such as inhibition of the GDF15/GFRAL axis, are under active investigation. Future research should prioritize identification of early biomarkers, standardization of cachexia assessment, and prospective evaluation of cachexia-directed interventions in the immunotherapy era. Integrating cachexia assessment into routine practice may ultimately enable personalized treatment and improve long-term outcomes for patients with advanced RCC.

Background/Objectives: This study evaluated neoadjuvant disitamab vedotin plus programmed cell death protein 1 (PD-1) blockade and associations of post-treatment neutrophil-to-lymphocyte ratio (NLR) and systemic immune-inflammation index (SII) with response and progression-free survival (PFS) in muscle-invasive bladder cancer. Methods: This single-center retrospective cohort included 71 patients with cT2–T3N0M0, human epidermal growth factor receptor 2 (HER2)-expressing disease treated between September 2021 and October 2025. Logistic regression and receiver operating characteristic analyses evaluated response endpoints; Kaplan–Meier and Cox methods evaluated PFS. Benjamini–Hochberg correction was applied separately to response analyses. Results: Complete response (CR), objective response, and disease control rates were 66.2%, 84.5%, and 88.7%. Of 47 CRs, 5 were cystectomy-confirmed pathological CR (pCR) and 42 were clinical CR (cCR). Response associations did not remain significant after correction (minimum q = 0.082). AUCs were 0.659–0.708. In a two-variable Cox model based on 14 PFS events, treatment cycles (HR 0.615, 95% CI 0.419–0.903; p = 0.013) and SII per 100 units (HR 1.205, 95% CI 1.073–1.355; p = 0.002) were associated with PFS, but these estimates require cautious interpretation. Two deaths occurred. Conclusions: Neoadjuvant disitamab vedotin plus PD-1 blockade showed promising antitumor activity. The pooled CR endpoint may overestimate pathological response and is not directly comparable with cystectomy-confirmed pCR. Without standardized pretreatment NLR and SII measurements, reverse causality cannot be excluded. Response associations and PFS findings based on 14 events require cautious interpretation and prospective validation.

Background/Objectives: The clinical management of bladder cancer is severely impeded by high recurrence rates and the rapid emergence of chemoresistance, necessitating the discovery of novel therapeutic agents with distinct mechanisms of action. Dehydrodiisoeugenol (DHE), a bioactive neolignan, exhibits potent anti-tumor efficacy, yet its direct molecular targets and mode of action remain elusive. Methods: To deconvolute the mechanism of DHE, we integrated a phenotypic screening approach using 2D cell lines and 3D patient-derived organoids with a chemoproteomics-based activity-based protein profiling (ABPP) strategy. We synthesized a functionalized photoaffinity probe to capture the specific interactome of DHE under physiological conditions and validated targets via cellular thermal shift assays (CETSA), quantitative mass spectrometry, and 100 ns molecular dynamics (MD) simulations. Results: DHE exhibited potent dose-dependent cytotoxicity in bladder cancer cells, with IC50 values of 39.23 μM in T24 and 34.58 μM in 5637 cells. In 3D patient-derived organoids, DHE significantly reduced viability (p < 0.0001). Using a dual-filtering ABPP strategy, we identified 65 high-confidence candidate targets, prioritizing PTPN1 (PTP1B) as the primary functional interactor. Comparative molecular docking and 100 ns MD analyses showed that multiple stereoisomers of DHE could adopt plausible PTPN1-binding modes. Mechanistically, organoid proteomics indicated that DHE engagement with PTPN1 disrupts ER membrane homeostasis, thereby modulating the PI3K-Akt signaling axes. Conclusions: These findings establish PTPN1 as a critical druggable vulnerability in bladder cancer and define the molecular basis for the therapeutic potential of DHE. This study highlights the power of combining chemoproteomics with physiological 3D models to accelerate the translation of natural products into precision cancer therapies.

Background: High-risk and locally advanced prostate cancer (HRPC/LAPC) continues to present significant therapeutic challenges. Although conventional neoadjuvant therapy combining androgen deprivation therapy (ADT) with first-generation antiandrogens [e.g., bicalutamide (BICA)] has been widely adopted, this approach’s limited efficacy in achieving durable pathological responses and improving long-term survival underscores the need for more effective strategies. The emergence of novel hormonal therapies (NHTs), such as abiraterone and next-generation androgen receptor inhibitors (e.g., darolutamide), has revolutionized the treatment for patients with advanced disease by enabling marked suppression of the androgen signaling pathway. However, evidence regarding the perioperative benefits of ADT plus NHT relative to those of conventional ADT + BICA remains scarce, particularly in terms of pathological outcomes [e.g., complete response and minimal residual disease (MRD)] and early efficacy indicators. This study thus aimed to compare these treatment approaches through a retrospective analysis of real-world data in order to better inform the optimization of neoadjuvant strategies for this high-risk population. The objective of this study was to compare the pathological and early oncological outcomes of neoadjuvant ADT plus NHT to those of conventional ADT plus BICA in patients with high-risk or LAPC undergoing radical prostatectomy (RP). Methods: A retrospective cohort study was conducted that included 87 patients who received neoadjuvant therapy followed by RP. Patients were stratified into two groups: an ADT + BICA group (n=35) and an ADT + NHT group (n=52). The primary endpoints included the pathological complete response (pCR) rate, incidence of MRD, the pathological downstaging rate (based on American Joint Committee on Cancer eighth edition staging), and positive surgical margin (PSM) rate. The secondary endpoints included the rate of ≥50% decline in prostate-specific antigen level (PSA50 response rate), PSA90 response rate, and biochemical recurrence (BCR) rate. Results: The ADT + NHT group, compared to the ADT + BICA group, demonstrated significantly higher rates of pCR (15.4% vs. 0%, P=0.04), MRD (30.8% vs. 8.6%; P=0.01), and pathological downstaging (44.2% vs. 22.9%; P=0.04). Although both groups achieved 100% PSA50 and high PSA90 response rates (97.1% vs. 94.2%), no significant differences were observed in PSM rates (32.7% vs. 48.6%; P=0.14) or BCR-free survival (log-rank P=0.90). Among NHT agents, darolutamide showed the most favorable performance. All regimens were well-tolerated, with no grade 3–4 adverse events being reported. Conclusions: Neoadjuvant ADT + NHT was associated with improved pathological responses compared to ADT + BICA, although this advantage did not translate into significant differences in surgical margins or short-term survival outcomes. These findings support the superior pathological efficacy of NHT-containing regimens and underscore the need for longer-term follow-up to evaluate their survival benefits.

Background: Results from a multinational Phase 3 study demonstrated high accuracy and a favorable safety and tolerability profile of [ ⁸⁹ Zr]Zr-girentuximab PET for detection and characterization of clear cell renal cell carcinoma (ccRCC). However, [ ⁸⁹ Zr]Zr-girentuximab has not been studied in Chinese patients. In this Phase 1 study, we aimed to evaluate safety and tolerability, radiation and tumor dosimetry, and pharmacokinetics of [ ⁸⁹ Zr]Zr-girentuximab PET in Chinese patients with suspected ccRCC. This study was approved by the Ethics Committee of Beijing Cancer Hospital (2022YW225) and was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent. Ten Chinese patients received 37 MBq (± 10%; 10mg mass dose) of [ ⁸⁹ Zr]Zr-girentuximab intravenously. Whole-body PET imaging was performed in the supine position at approximately 0.5, 4, 24, 72 hours, and 7 ± 1 days after administration, and low dose CT was used for attenuation correction. Adverse events were recorded from time of [ ⁸⁹ Zr]Zr-girentuximab administration through final visit. Blood samples were collected from patients approximately 1 hour before, and 0.5, 1, 2, 4, 24, 72 hours, and 5 ± 1 days after [ ⁸⁹ Zr]Zr-girentuximab administration. Biodistribution and normal organ dosimetry were performed based on PET images to determine significant differences in tumor-absorbed dose. Results: Of 10 adverse events reported, none were serious or considered related to [ ⁸⁹ Zr]Zr-girentuximab. The organs receiving the highest mean (SD) normalized absorbed doses were the liver (1.51 [0.23] mGy/MBq), kidneys (1.42 [0.35] mGy/MBq), and heart wall (1.22 [0.18] mGy/MBq), with a mean whole-body normalized effective dose of 0.49 (0.08) mSv/MBq. In 7 patients with histologically confirmed ccRCC, mean (SD) tumor normalized absorbed dose was 2.87 (1.54) mGy/MBq (range: 1.17 to 5.41 mGy/MBq). Conclusion: [ ⁸⁹ Zr]Zr-girentuximab has a favorable safety and tolerability profile in Chinese patients, with a dosimetry profile similar to previously studied non-Chinese populations. [ ⁸⁹ Zr]Zr-girentuximab is a promising novel PET agent for the detection and characterization of ccRCC in Chinese patients. Trial registration: ClinicalTrials.gov Identifier NCT05861778. Registered 17 May 2023.

Background/Objectives: The purpose of this study was to investigate the association between HER-2 expression and clinicopathological characteristics, biochemical recurrence (BCR) rate, and BCR-free survival in localized prostate cancer (PCa) patients after radical prostatectomy (RP). Methods: Between January 2018 and December 2019, 44 patients with pathologically confirmed localized PCa who underwent RP were included in this study. According to the expressed level of HER-2 protein, patients were divided into four cohorts: cohort-1 (HER-2 0), cohort-2 (HER-2 1+ or 2+), cohort-3 (HER-2 0 or 1+), and cohort-4 (HER-2 2+); the clinicopathological and clinical outcomes were analyzed and compared between cohort-1 and cohort-2, and cohort-3 and cohort-4, respectively. Univariable and multivariable COX regression models and Kaplan–Meier curves were used to determine the association between HER-2 expression and clinicopathological outcomes, including Gleason score (GS), pathological T (pT) stage, positive surgical margins (PSM), and BCR-free survival, respectively. Results: The median follow-up time was 43 months (IQR 35–49). Among the 44 patients, 20 (45.5%) exhibited HER-2 immuno-reactivity, including 14 (31.8%) with HER-2 1+, 6 (13.64%) with HER-2 2+, and 0 (0%) with HER-2 3+ staining. The proportion of patients with PSM was significantly lower in the HER-2 0 group than in those with HER-2 1+ or 2+ (25.0% vs. 65.0%, p = 0.008). Multivariable logistics regression models revealed that HER-2 1+ or 2+ was an independent risk factor that was strongly associated with a higher proportion of PSM (OR, 2.69; 95% CI, 0.62–11.71, p = 0.042). A total of 18 (40.9%) patients experienced BCR after surgery, including 6 (25%) in cohort-1 and 12 (60.0%) in cohort-2 (p = 0.019), as well as 13 (34.2%) in cohort-3 and 5 (83.3%) in cohort-4 (p = 0.023). Kaplan–Meier analysis showed that patients in cohort-1 (HER-2 0) had significantly longer BCR-free survival than those in cohort-2 (HER-2 1+ or 2+) (p < 0.001), and those in cohort-3 had longer BCR-free survival than those in cohort-4 (p < 0.001). Furthermore, patients with PSM showed significantly shorter BCR-free survival compared to those with patients with negative surgical margins (NSM) (p = 0.005). Multivariable Cox regression analysis revealed that HER-2 1+, 2+ (HR, 17.00; 95% CI, 1.38–210.22, p < 0.001), HER-2 2+ (HR, 2.85; 95% CI, 1.23–3.25, p = 0.004), and PSM (HR, 6.12; 95% CI, 3.08–11.72, p = 0.007) were all significant independent predictors of BCR following surgery. Conclusions: HER-2 expression is a common phenomenon in PCa; nearly half of the proportion of localized PCa had HER-2 1+ or 2+, but the cases that expressed HER-2 3+ were rare. Cases with HER-2 1+ or 2+ were more likely to develop BCR compared with HER-2 0. The HER-2 1+ or 2+ expression was closely associated with a higher incidence of PSM and was an independent predictor of shorter BCR-free survival in patients with localized prostate cancer after radical prostatectomy.

Cisplatin (CDDP) resistance has been established to significantly impact Bladder Cancer (BCa) therapy. On the other hand, the crucial regulatory involvement of SIRT7 and EZH2 in bladder cancer development is well known. Herein, the collaborative regulatory roles and underlying mechanisms of SIRT7 and EZH2 in CDDP resistance in bladder cancer were explored. Immunohistochemistry (IHC) and Western Blot (WB) analyses were used to assess the expression levels of SIRT7/EZH2 and RND3 in bladder cancer tissues, normal ureteral epithelial cells, and bladder cancer cell lines. Furthermore, the impact of various treatments on of UMUC3 cell proliferation and CDDP sensitivity was assessed using CCK-8 assays, plate cloning assays, and flow cytometry analysis. Additionally, the levels of H3K18ac and H3K27me³ at the promoter region of the RND3 gene, the binding abilities of SIRT7 and EZH2, and the succinylation level of the EZH2 protein were examined using ChIP-qPCR assays, CO-IP assays, and IP assays, respectively. Moreover, in vivo experiments were conducted using a bladder cancer mouse model created by subcutaneously injecting UMUC3 cells into Balb/c nude mice. According to the results, SIRT7 correlated with the sensitivity of bladder cancer cells to both the platinum-based chemotherapy and CDDP. Specifically, SIRT7 could bind to the RND3 promoter, downregulating H3K18ac and RND3, ultimately leading to an increased CDDP sensitivity in UMUC3 cells. Furthermore, EZH2 siRNA could decrease H3K27me³ levels in the RND3 promoter, upregulating RND3. Overall, in the promoter region of the RND3 gene, SIRT7 upregulated H3K27me³ and EZH2 downregulated H3K18ac, leading to a decline in RND3 expression and CDDP sensitivity in bladder cancer cells. Additionally, SIRT7 reduced the succinylation of the EZH2 protein resulting in an EZH2-mediated RND3 downregulation. Therefore, targeting SIRT7 and EZH2 could be a viable approach to enhancing CDDP efficacy in bladder cancer treatment.

Background/Objectives: Procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1 (PLOD1) is known as an enhancer of collagen fiber deposition and cross-linking stability. However, there is limited information on its function in tumors. In this study, we aimed to elucidate the function and potential mechanism of action of PLOD1 across cancers. Methods: We assessed the pan-cancer expression, mutation, methylation and prognostic value of PLOD1 through multiple online databases. In addition, we performed correlation analyses of its immunological features, as well as functional assessment analyses of PLOD1. Finally, we assessed the effect of PLOD1 knockdown on bladder tumor cells using in vitro experiments. Results: Our findings suggest that PLOD1 is aberrantly expressed in multiple cancer types, accompanied by a poor prognosis. Epigenetic alterations in PLOD1 are highly heterogeneous across a wide range of tumors, and aberrant methylation and copy number variants correlate with a poor prognosis. In the tumor microenvironment, PLOD1 expression correlated positively with the infiltration level of various immunosuppressive cells (e.g., monocytes, macrophages and tumor-associated fibroblasts) and negatively with immune-killing cells (e.g., CD8⁺ T cells, B cells and CD4⁺ T cells). In addition, PLOD1 expression was associated with immune checkpoints and immunomodulatory genes. Finally, in vitro experiments demonstrated that knockdown of PLOD1 reduced the proliferation, migration and antiapoptotic abilities of T24 cells. Conclusions: The results of this study demonstrate that PLOD1 is a potential oncogene and prognostic biomarker in pan-cancer; tumor tissues with high PLOD1 expression reveal a relatively immunosuppressive tumor microenvironment.

Background: Systemic immune-inflammation index (SII), a novel prognostic indicator, is being more commonly utilized in different types of cancer. This research project involved combining information from previously published studies to examine how pre-treatment SII can predict outcomes in individuals with upper tract urothelial carcinoma (UTUC). Further examination of the correlation between SII and clinical and pathological features in UTUC.Methods: We thoroughly chose pertinent articles from various databases including PubMed, Embase, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), WanFang database, and Chinese Scientific Journal Database (VIP) until March 10, 2022.The data collected was analyzed using Stata 17.0 software (Stat Corp, College Station, TX). Subsequently, the impact of SII on the survival outcomes of UTUC patients was evaluated by combining HRs with 95% confidence intervals.Results: Six included studies were finally confirmed, including 3911 UTUC patients in seven cohorts. The results showed that high SII before treatment predicted poor overall survival (HR =1.87, 95%CI 1.20-2.92, p=0.005), cancer specific survival (HR=2.70, 95%CI 1.47-4.96, P=0.001), and recurrence‐free survival (HR =1.52, 95%CI 1.12-2.07, P=0.007). And the elevated SII may be related to LVI (present vs. absent) (OR=0.83, 95% CI=0.71-0.97, p=0.018), pT stage (pT ≥3 vs. < 3) (OR=1.82, 95% CI=1.21-2.72, p=0.004), and pN stage (N+ vs. N0) (OR=3.27, 95% CI=1.60-6.71, p=0.001).Conclusion: A comprehensive analysis of all included articles in this study showed that higher pretreatment SII was related to poorer survival outcomes and adverse pathological features independently.Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022316333.

Angiotensin-converting enzyme 2 (ACE2) is the main molecular target for coronavirus SARS-CoV-2 to enter cells. Molecularly specific tracers that bind to ACE2 with high affinity can be used to determine the tissue distribution of this important receptor, noninvasively. A novel targeting PET imaging probe, [¹⁸F]AlF-DX600-BCH, was developed to detect the in vivo expression of ACE2 and monitor response to therapy. Preclinical experiments, including biodistribution, PET imaging, and tissue section analysis, were conducted after tests of in vitro and in vivo stability and pharmacokinetics. The agent was advanced to clinical evaluation in 10 volunteers who received [¹⁸F]AlF-DX600-BCH PET/CT at 1 and 2 h after injection (NCT04542863). Preclinical results of both biodistribution and PET demonstrated [¹⁸F]AlF-DX600-BCH accumulation in rat kidney (standardized uptake value; SUV_{kidney/normal} > 50), along with specific uptake in testes (SUV_{testis/normal} > 10) tissues. Kidney, gastrointestinal, and bronchial cell labeling were correlated to ACE2 positive by immunohistochemistry (IHC) staining. In clinical imaging, significant tracer accumulation was predominantly observed in the urinary and reproductive system (SUV_{renal cortex} = 32.00, SUV_testis = 4.56), and the conjunctiva and nasal mucosa saw elevated uptake in several cases. This work is the first report of a radioisotope probe, [¹⁸F]AlF-DX600-BCH, targeting ACE2 with promising preliminary preclinical and translational outlook, thereby demonstrating the potential of noninvasive mapping of ACE2.