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Bladder cancer is a prevalent malignancy with high morbidity and mortality, particularly when diagnosed at an advanced stage. Early detection is critical, as it significantly improves prognosis and the patient’s outcomes. Bladder cancer also has a high recurrence rate, necessitating long-term surveillance. While cystoscopy remains the gold standard for diagnosis and monitoring, it is invasive and costly. Urine cytology, though widely used, has high specificity for detecting high-grade urothelial carcinoma but suffers from low sensitivity and limited effectiveness as a stand-alone diagnostic tool. Urinary biomarkers offer a promising, noninvasive alternative for early detection and disease surveillance. This review examines FDA-approved urinary biomarker tests, including NMP 22, UroVysion, and BTA, highlighting their clinical utility and limitations. Additionally, we explore emerging biomarkers such as DNA methylation assays, genomic alterations, and proteomic signatures as well as advanced technologies like next-generation sequencing and machine learning-based platforms. These innovations have the potential to enhance diagnostic accuracy, risk stratification, and recurrent monitoring, ultimately improving early detection and long-term disease management. By evaluating both established and emerging urinary biomarkers, this review aims to provide clinicians and researchers with insights into evolving tools for bladder cancer diagnosis and surveillance.

BackgroundHepatic arterial infusion chemotherapy (HAIC) with fluorouracil, leucovorin, and oxaliplatin (FOLFOX), lenvatinib and programmed death receptor-1 signaling inhibitors (PD1s) all alone have been proven effective in treating advanced hepatocellular carcinoma (HCC), yet the efficacy and safety of the tri-combination therapy in treating HCC patients with portal vein tumor thrombosis (PVTT) remains unknown.MethodsIn this retrospective study, HCC patients with PVTT received either induction therapy of HAIC and lenvatinib plus PD1s in the initial period of treatment and then dual maintenance therapy of lenvatinib and PD1s (HAIC-Len-PD1) or continuous lenvatinib combined with PD1s (Len-PD1).ResultsIn total, 53 and 89 patients were enrolled into the Len-PD1 group and HAIC-Len-PD1 group, respectively. The median overall survival times were 13.8 months in the Len-PD1 group and 26.3 months in the HAIC-Len-PD1 group (hazard ratio (HR) = 0.43, P < 0.001). The median progression-free survival (PFS) time was significantly longer in the HAIC-Len-PD1 group than in the Len-PD1 group (11.5 months versus 5.5 months, HR = 0.43, P < 0.001). Induction therapy showed an objective response rate (ORR) 3 times higher than lenvatinib combined with PD1s therapy (61.8% versus 20.8%, P < 0.001), and exhibited inspiring intra- and extra-hepatic tumor control ability. Induction therapy led to more adverse events than lenvatinib combined with PD1s therapy, most of which were tolerable and controllable.ConclusionThe induction therapy of FOLFOX-HAIC and lenvatinib plus PD1s is an effective and safe treatment for HCC patients with PVTT. The concept of induction therapy could be applied to other local–regional treatments and drugs combinations in HCC management.

Peritumoral hepatocytes are critical components of the liver cancer microenvironment, However, the role of peritumoral hepatocytes in the local tumor immune interface and the underlying molecular mechanisms have not been elucidated. YTHDF2, an RNA N 6 -methyladenosine (m 6 A) reader, is critical for liver tumor progression. The function and regulatory roles of YTHDF2 in peritumoral hepatocytes are unknown. This study demonstrated that oxaliplatin (OXA) upregulated m 6 A modification and YTHDF2 expression in hepatocytes. Studies using tumor-bearing liver-specific Ythdf2 knockout mice revealed that hepatocyte YTHDF2 suppresses liver tumor growth through CD8 + T cell recruitment and activation. Additionally, YTHDF2 mediated the response to immunotherapy. Mechanistically, OXA upregulated YTHDF2 expression by activating the cGAS-STING signaling pathway and consequently enhanced the therapeutic outcomes of immunotherapeutic interventions. Ythdf2 stabilized Cx3cl1 transcripts in an m 6 A-dependent manner, regulating the interplay between CD8 + T cells and the progression of liver malignancies. Thus, this study elucidated the novel role of hepatocyte YTHDF2, which promotes therapy-induced antitumor immune responses in the liver. The findings of this study provide valuable insights into the mechanism underlying the therapeutic benefits of targeting YTHDF2.

Background Tri-combination therapy based on hepatic arterial infusion chemotherapy (HAIC) of infusion fluorouracil, leucovorin, and oxaliplatin (FOLFOX-HAIC) plus immune checkpoint inhibitors (ICIs) and tyrosine kinase inhibitors (TKIs) for the locally advanced hepatocellular carcinoma (HCC) patients have been proven effective. However, whether it was best for these HCC patients to start with the most potent therapeutic pattern was still under debate. This retrospective study evaluated the efficacy and safety of FOLFOX-HAIC combined with systemic therapies in the patterns of sequential and concurrent schedules. Methods This real-world study included 117 unresectable HCC patients who initially received either FOLFOX-HAIC monotherapy (HAIC group, n  = 44) or concurrent ICIs and TKIs (ConHAIC group, n  = 73) from March 2020 and June 2022, during the period of FOLFOX-HAIC monotherapy in HAIC group, patients in the HAIC group ( n  = 30) experienced progressive disease (PD) would have their treatment pattern converted from the FOLFOX-HAIC monotherapy to the combination of FOLFOX-HAIC plus ICIs and TKIs sequentially (SeqHAIC group). The progression-free survival (PFS) and overall survival (OS), as primary outcomes, were compared between patients in the SeqHAIC and ConHAIC groups. Results The median follow-up time of the SeqHAIC group was 24.92 months (95% CI, 12.74–37.09 months) and of the ConHAIC group was 17.87 months (95% CI, 16.85–18.89 months) and no significant difference was observed in both PFS (HR, 1.572; 95% CI, 0.848–2.916; p  = 0.151) and OS (HR, 1.212; 95% CI, 0.574–2.561; p  = 0.614) between the SeqHAIC and the ConHAIC groups. As for the tumor responses, there was no significant difference between the two groups regarding tumor responses, overall response rates ( p  = 0.658) and disease control rates ( p  = 0.641) were 50.0%, 45.2%, and 83.3%, 89.0% for the SeqHAIC and the ConHAIC groups, respectively. Conclusion Our study revealed that sequential systemic ICIs and TKIs in combination with FOLFOX-HAIC provides similar long-term prognosis and better tolerability compared to concurrent therapy for locally advanced HCC patients. Prospective studies with a larger sample size and longer follow-up are required to validate these findings.

BackgroundTransarterial therapy (TAT), bevacizumab (Bev), and immune checkpoint inhibitors (ICIs) have individually exhibited efficacy in treating advanced-stage hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of the combination of these three treatments as a neoadjuvant modality in patients with locally advanced HCC.MethodsThe primary endpoint is overall survival (OS). The second endpoint is progression free survival (PFS), objective response rate (ORR), pathological response rate and safety.ResultsA total of 54 patients received standard systemic therapy comprising Bev combined with ICIs (Bev-ICIs group), 113 patients received direct surgery (Surgery group), and 273 patients received neoadjuvant therapy of TAT combined Bev plus ICIs, among which 79 patients (28.9%) underwent surgical resection after successful tumor downstaging (Neo-surgery group) while the remaining 194 patients (71.1%) received maintenance systemic therapies (Neo-maintenance group). Neoadjuvant following surgery demonstrated a prolonged OS in contrast to direct surgery, with a median OS time not reached in the Neo-surgery group and 30.6 (95% CI: 26.4-34.7) months in the Surgery group (hazard ratio (HR)=0.29, P=0.0058). The median PFS time in the Neo-surgery and Surgery groups stood at 19.2 (95% CI: 16.1-22.2) and 6.3 (95% CI:4.7-8) months, respectively (HR=0.25, P<0.0001). In patients failed to receiving resection after neoadjuvant therapy, the median OS was 22.8 (95% CI: 22.3-23.1) months, whereas that for the standard care population was 19.7 (95% CI: 15.9-24) month (HR=0.53, P=0.023). The median PFS time in Neo-maintenance group and Bev-ICIs groups was 11.2 (95% CI: 10.4-11.9) and 6.4 (95% CI: 4.4-8.5) months (HR=0.60, P=0.024). The ORR and disease control rate (DCR) across all patients received TAT-Bev-ICIs were 38.8% and 89.4%, respectively. Additionally, the pathological complete response (pCR) rate and the major pathological response (MPR) rate were 22.8% and 48.1% in the Neo-surgery group. As for safety, neoadjuvant therapy did not increase the perioperative complications when compared to direct surgery, and demonstrated similar incidences and severity of AEs when compared to the standard systemic therapy.ConclusionThe triple therapy regimen comprising TAT-Bev-ICIs emerged as a promising therapeutic strategy for locally advanced hepatocellular carcinoma (HCC) as a neoadjuvant intervention.

Hepatitis B virus (HBV) reactivation is a common complication in hepatocellular carcinoma (HCC) patients treated with chemotherapy or immunotherapy. This study aimed to evaluate the risk of HBV reactivation and its effect on survival in HCC patients treated with HAIC and lenvatinib plus PD1s. We retrospectively collected the data of 213 HBV-related HCC patients who underwent HAIC and lenvatinib plus PD1s treatment between June 2019 to June 2022 at Sun Yat-sen University, China. The primary outcome was the risk of HBV reactivation. The secondary outcomes were overall survival (OS), progression-free survival (PFS), and treatment-related adverse events. Sixteen patients (7.5%) occurred HBV reactivation in our study. The incidence of HBV reactivation was 5% in patients with antiviral prophylaxis and 21.9% in patients without antiviral prophylaxis, respectively. The logistic regression model indicated that for HBV reactivation, lack of antiviral prophylaxis ( =0.003) and tumor diameter ( =0.036) were independent risk factors. The OS and PFS were significantly shorter in the HBV reactivation group than the non-reactivation group ( =0.0023 and =0.00073, respectively). The number of AEs was more in HBV reactivation group than the non-reactivation group, especially hepatic AEs. HBV reactivation may occur in HCC patients treated with HAIC and lenvatinib plus PD1s. Patients with HBV reactivation had shorter survival time compared with non-reactivation. Therefore, HBV-related HCC patients should undergo antiviral therapy and HBV-DNA monitoring before and during the combination treatment.

Levels of C-reactive protein (CRP) and alpha-fetoprotein (AFP) in immunotherapy (CRAFITY) scores are associated with the prognosis of patients with hepatocellular carcinoma (HCC). This study aimed to explore the efficacy of lenvatinib and pembrolizumab (Len-P) based on the CRAFITY score. In this study, 228 patients with HCC who received Len-P in Sun Yat-sen University Cancer Center were included. CRAFITY 0 score was defined as AFP level below 100 ng/ml, CRP level below 1 mg/dl, CRAFITY 1 score was defined as AFP level at least 100 ng/ml or CRP level at least 1 mg/dl. CRAFITY 2 scores were defined as AFP levels exceeding 100 ng/ml and CRP levels exceeding 100 ng/ml. The primary outcome was overall survival (OS). The second outcome was tumor response rate. The survival time of CRAFITY 0 is significantly longer than that of CRAFITY 1 and CRAFITY 2 (p =.044). Univariate analysis showed that largest tumor size (HR = 2.149; 95% CI 1.129 - 4.091; p =.02), lymph node metastasis (HR = 2.012; 95% CI 1.132- 3.579; p = .017), and CRAFITY (HR = 0.372; 95% CI 0.168-0.824; p = .015) were important risk determinants of OS in all patients. The results of multivariate analysis show that CRAFITY score is an independent risk factors for OS (HR = 0.719; 95% CI 0.377-1.374; p =.048). The ORR of CRAFITY 0, 1 and 2 scores were 36.4%, 32% and 27.4%, respectively ( = .556). The ORR of intrahepatic lesions by CRAFITY 0, 1 and 2 were 37.9%, 35%, 30.6% ( = .688). CRAFITY score is a good predictor of prognosis in HCC patients receiving Len-P.

Protein tyrosine phosphatases are often exploited and subverted by pathogenic bacteria to cause human diseases. The tyrosine phosphatase mPTPB from Mycobacterium tuberculosis is an essential virulence factor that is secreted by the bacterium into the cytoplasm of macrophages, where it mediates mycobacterial survival in the host. Consequently, there is considerable interest in understanding the mechanism by which mPTPB evades the host immune responses, and in developing potent and selective mPTPB inhibitors as unique antituberculosis (antiTB) agents. We uncovered that mPTPB subverts the innate immune responses by blocking the ERK1/2 and p38 mediated IL-6 production and promoting host cell survival by activating the Akt pathway. We identified a potent and selective mPTPB inhibitor I-A09 with highly efficacious cellular activity, from a combinatorial library of bidentate benzofuran salicylic acid derivatives assembled by click chemistry. We demonstrated that inhibition of mPTPB with I-A09 in macrophages reverses the altered host immune responses induced by the bacterial phosphatase and prevents TB growth in host cells. The results provide the necessary proof-of-principle data to support the notion that specific inhibitors of the mPTPB may serve as effective antiTB therapeutics.

Background/purpose: The prognosis of hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT) is generally poor and hepatectomy is optional for these patients. This study aims to explore the survival benefits of neoadjuvant hepatic arterial infusion chemotherapy (HAIC) for resectable HCC with PVTT. Methods: This retrospective study included 120 resectable HCC patients with PVTT who underwent hepatectomy, from January 2017 to January 2021 at Sun Yat-sen University Cancer Center. Of these patients, the overall survival (OS) and recurrence-free survival (RFS) of 55 patients who received hepatectomy alone (Surgery group) and 65 patients who received neoadjuvant HAIC followed by hepatectomy (HAIC-Surgery group) were compared. Logistic regression analysis was conducted to develop a model predicting the response to neoadjuvant HAIC. Results: The OS rates for the HAIC-Surgery group at 1, 3, and 5 years were 94.9%, 78%, and 66.4%, respectively, compared with 84.6%, 47.6%, and 37.2% in the Surgery group ( p < 0.001). The RFS rates were 88.7%, 56.2%, and 38.6% versus 84.9%, 38.3%, and 22.6% ( p = 0.002). The subgroup analysis revealed that the survival benefit of neoadjuvant HAIC was limited to patients who responded to it. The logistic model, consisting of AFP and CRP, that predicted the response to neoadjuvant HAIC performed well, with an area under the ROC curve (AUC) of 0.756. Conclusion: Neoadjuvant HAIC followed by hepatectomy is associated with a longer survival outcome than hepatectomy alone for HCC patients with PVTT and the survival benefit is limited to patients who respond to neoadjuvant FOLFOX-HAIC.

Background Laparoscopic liver resection (LLR) is now widely performed in treating primary liver cancer (PLC) and yields equal long-term and superior short-term outcomes to those of open liver resection (OLR). The optimal surgical approach for resectable PLC (rPLC) remains controversial. Herein, we aimed to develop a nomogram to determine the most appropriate resection approach for the individual patient. Methods Patients with rPLC who underwent hepatectomy from January 2013 to December 2018 were reviewed. Prediction model for risky surgery during LLR was constructed. Results A total of 900 patients in the LLR cohort and 423 patients in the OLR cohort were included. A history of previous antitumor treatment, tumor diameter, tumor location and resection extent were independently associated with risky surgery of LLR. The nomogram which was constructed based on these risk factors demonstrated good accuracy in predicting risky surgery with a C index of 0.83 in the development cohort and of 0.76 in the validation cohort. Patients were stratified into high-, medium- or low-risk levels for receiving LLR if the calculated score was more than 0.8, between 0.2 and 0.8 or less than 0.2, respectively. High-risk patients who underwent LLR had more blood loss (441 ml to 417 ml) and a longer surgery time (183 min to 150 min) than those who received OLR. Conclusions Patients classified into the high-risk level for LLR instead undergo OLR to reduce surgical risks and complications and patients classified into the low-risk level undergo LLR to maximize the advantages of minimally invasive surgery. Trial registration This study was registered in the Chinese Clinical Trial Registry (registration number: ChiCTR2100049446).