Fumarate inhibits PTEN to promote tumorigenesis and therapeutic resistance of type2 papillary renal cell carcinoma.

Fumarate is an oncometabolite. However, the mechanism underlying fumarate-exerted tumorigenesis remains unclear. Here, utilizing human type2 papillary renal cell carcinoma (PRCC2) as a model, we show that fumarate accumulates in cells deficient in fumarate hydratase (FH) and inhibits PTEN to activate PI3K/AKT signaling. Mechanistically, fumarate directly reacts with PTEN at cysteine 211 (C211) to form S-(2-succino)-cysteine. Succinated C211 occludes tethering of PTEN with the cellular membrane, thereby diminishing its inhibitory effect on the PI3K/AKT pathway. Functionally, re-expressing wild-type FH or PTEN C211S phenocopies an AKT inhibitor in suppressing tumor growth and sensitizing PRCC2 to sunitinib. Analysis of clinical specimens indicates that PTEN C211 succination levels are positively correlated with AKT activation in PRCC2. Collectively, these findings elucidate a non-metabolic, oncogenic role of fumarate in PRCC2 via direct post-translational modification of PTEN and further reveal potential stratification strategies for patients with FH loss by combinatorial AKTi and sunitinib therapy.

Multi-cohort validation of Ascore: an anoikis-based prognostic signature for predicting disease progression and immunotherapy response in bladder cancer.

Bladder cancer ranks as the 10th most common cancer worldwide, with deteriorating prognosis as the disease advances. While immune checkpoint inhibitors (ICIs) have shown promise in clinical therapy in both operable and advanced bladder cancer, identifying patients who will respond is challenging. Anoikis, a specialized form of cell death that occurs when cells detach from the extracellular matrix, is closely linked to tumor progression. Here, we aimed to explore the anoikis-based biomarkers for bladder cancer prognosis and immunotherapeutic decisions. Through consensus clustering, we categorized patients from the TCGA-BLCA cohort into two clusters based on anoikis-related genes (ARGs). Significant differences in survival outcome, clinical features, tumor immune environment (TIME), and potential ICIs response were observed between clusters. We then formulated a four-gene signature, termed "Ascore", to encapsulate this gene expression pattern. The Ascore was found to be closely associated with survival outcome and served as an independent prognosticator in both the TCGA-BLCA cohort and the IMvigor210 cohort. It also demonstrated superior predictive capacity (AUC = 0.717) for bladder cancer immunotherapy response compared to biomarkers like TMB and PD-L1. Finally, we evaluated Ascore's independent prognostic performance as a non-invasive biomarker in our clinical cohort (Gulou-Cohort1) using circulating tumor cells detection, achieving an AUC of 0.803. Another clinical cohort (Gulou-Cohort2) consisted of 40 patients undergoing neoadjuvant anti-PD-1 treatment was also examined. Immunohistochemistry of Ascore in these patients revealed its correlation with the pathological response to bladder cancer immunotherapy (P = 0.004). Impressively, Ascore (AUC = 0.913) surpassed PD-L1 (AUC = 0.662) in forecasting immunotherapy response and indicated better net benefit. In conclusion, our study introduces Ascore as a novel, robust prognostic biomarker for bladder cancer, offering a new tool for enhancing immunotherapy decisions and contributing to the tailored treatment approaches in this field.

Highly accurate and effective deep neural networks in pathological diagnosis of prostate cancer.

PURPOSE: To established an AI system to make the pathological diagnosis of prostate cancer. METHODS: Prostate histopathological whole mount (WM) sections from patients underwent robot-assisted laparoscopic prostatectomy were prepared. All the prostate WM pathological sections were converted to digital image data and marked with different colors on the basis of the ISUP Gleason grade group. The image was then fed into a segmentation algorithm. We chose modified U-Net as our fundamental network architecture. RESULTS: 172 patients were involved in this study. 896 pieces of prostate WM pathological sections from 160 patients, in which 826 pieces of WM sections from 148 patients were assigned to the training set randomly. After image segmentation there were totally 2,138,895 patches, of which 1,646,535 patches were valid for training. The other WM section was arranged for testing. Based on the whole image testing, AI and pathologists presented the same answers among 21 of 22 pieces of sections. To evaluate the diagnostic results at the pixel level, we anticipated correct cancer or non-cancer diagnose from this AI system. The area under the ROC curve as 96.8%. The value of pixel accuracy of three methods (binary analysis, clinically oriented analysis and analysis for different ISUP Gleason grade) were 96.93%, 95.43% and 93.88%, respectively. The value of frequency weighted IoU were 94.32%, 92.13% and 90.21%, respectively. CONCLUSIONS: This AI system is able to assist pathologists to make a final diagnosis, indicating the great potential and a wide-range of applications of AI in the medical field.

Modified Retzius-sparing robot-assisted radical prostatectomy for cases with anterior tumor: a propensity score-matched analysis.

OBJECTIVE: To compare the outcomes between a modified Retzius-sparing robot-assisted radical prostatectomy (mRS-RARP) technique and conventional robot-assisted radical prostatectomy (Con-RARP) technique for cases with anterior prostate cancer (PCa), especially positive surgical margin (PSM) rates and urinary continence (UC). PATIENTS AND METHODS: We retrospectively included 193 mRS-RARP and 473 Con-RARP consecutively performed by a single surgeon for anterior PCa. Perioperative complications, pathology, and continence were compared after propensity score matching using 9 variables. RESULTS: After matching (n = 193 per group), PSM were not significantly different in the two groups (16.1% in mRS-RARP group vs. 15.0% in Con-RARP group, p = 0.779). The UC at catheter removal and at 1-month was significantly higher in the mRS-RARP (24.9% vs. 9.8%, p < 0.001; 29.0% vs. 13.5%, p < 0.001, respectively), but not at 3-, 6-, and 12-month follow-ups (p = 0.261, 0.832, and 0.683, respectively). CONCLUSION: mRS-RARP seems to be an oncologically safe approach for patients with anterior PCa. Compared with the conventional approach, mRS-RARP approach shows benefits in the short-term postoperative UC recovery.

A PSMA PET/CT-based risk model for prediction of concordance between targeted biopsy and combined biopsy in detecting prostate cancer.

PURPOSE: This study is to investigate the diagnostic value of 68Ga-PSMA-11 in improving the concordance between mpMRI-TB and combined biopsy (CB) in detecting PCa. METHODS: 115 consecutive men with 68Ga-PSMA-11 PET/CT prior to prostate biopsy were included for analysis. PSMA intensity, quantified as maximum standard uptake value (SUVmax), minimum apparent diffusion coefficient (ADCmin) and other clinical characteristics were evaluated relative to biopsy concordance using univariate and multivariate logistic regression analyses. A prediction model was developed based on the identified parameters, and a dynamic online diagnostic nomogram was constructed, with its discrimination evaluated through the area under the ROC curve (AUC) and consistency assessed using calibration plots. To assess its clinical applicability, a decision curve analysis (DCA) was performed, while internal validation was conducted using bootstrapping methods. RESULTS: Concordance between mpMRI-TB and CB occurred in 76.5% (88/115) of the patients. Multivariate logistic regression analyses performed that SUVmax (OR= 0.952; 95% CI 0.917-0.988; P= 0.010) and ADCmin (OR= 1.006; 95% CI 1.003-1.010; P= 0.001) were independent risk factors for biopsy concordance. The developed model showed a sensitivity, specificity, accuracy and AUC of 0.67, 0.78, 0.81 and 0.78 in the full sample. The calibration curve demonstrated that the nomogram's predicted outcomes closely resembled the ideal curve, indicating consistency between predicted and actual outcomes. Furthermore, the decision curve analysis (DCA) highlighted the clinical net benefit achievable across various risk thresholds. These findings were reinforced by internal validation. CONCLUSIONS: The developed prediction model based on SUVmax and ADCmin showed practical value in guiding the optimization of prostate biopsy pattern. Lower SUVmax and Higher ADCmin values are associated with greater confidence in implementing mono-TB and safely avoiding SB, effectively balancing benefits and risks.

Prediction of false-positive PI-RADS 5 lesions on prostate multiparametric MRI: development and internal validation of a clinical-radiological characteristics based nomogram.

BACKGROUND: To develop a risk model including clinical and radiological characteristics to predict false-positive The Prostate Imaging Reporting and Data System (PI-RADS) 5 lesions. METHODS: Data of 612 biopsy-naïve patients who had undergone multiparametric magnetic resonance imaging (mpMRI) before prostate biopsy were collected. Clinical variables and radiological variables on mpMRI were adopted. Lesions were divided into the training and validation cohort randomly. Stepwise multivariate logistic regression analysis with backward elimination was performed to screen out variables with significant difference. A diagnostic nomogram was developed in the training cohort and further validated in the validation cohort. Calibration curve and receiver operating characteristic (ROC) analysis were also performed. RESULTS: 296 PI-RADS 5 lesions in 294 patients were randomly divided into the training and validation cohort (208 : 88). 132 and 56 lesions were confirmed to be clinically significant prostate cancer in the training and validation cohort respectively. The diagnostic nomogram was developed based on prostate specific antigen density, the maximum diameter of lesion, zonality of lesion, apparent diffusion coefficient minimum value and apparent diffusion coefficient minimum value ratio. The C-index of the model was 0.821 in the training cohort and 0.871 in the validation cohort. The calibration curve showed good agreement between the estimation and observation in the two cohorts. When the optimal cutoff values of ROC were 0.288 in the validation cohort, the sensitivity, specificity, PPV, and NPV were 90.6%, 67.9%, 61.7%, and 92.7% in the validation cohort, potentially avoiding 9.7% unnecessary prostate biopsies. CONCLUSIONS: We developed and validated a diagnostic nomogram by including 5 factors. False positive PI-RADS 5 lesions could be distinguished from clinically significant ones, thus avoiding unnecessary prostate biopsy.

Diagnostic performance of magnetic resonance imaging features to differentiate adrenal pheochromocytoma from adrenal tumors with positive biochemical testing results.

BACKGROUND: It is extremely essential to accurately differentiate pheochromocytoma from Adrenal incidentalomas (AIs) before operation, especially biochemical tests were inconclusive. We aimed to evaluate the value of magnetic resonance imaging (MRI) features to differentiate pheochromocytomas among adrenal tumors, among which the consequences of biochemical screening tests of catecholamines and/or catecholamine metabolites are positive. METHODS: With institutional review board approval, this study retrospectively compared 35 pheochromocytoma (PHEO) patients with 27 non-pheochromocytoma(non-PHEO) patients between January 2022 to September 2023, among which the consequences of biochemical screening tests of catecholamines and/or catecholamine metabolites are positive. T test was used for the independent continuous data and the chi-square test was used for categorical variables. Univariate and multivariate logistic regression were applied to find the independent variate of the features to differentiate PHEO from non-PHEO and ROC analysis was applied to evaluate the diagnostic value of the independent variate. RESULTS: We found that the T2-weighted (T2W) signal intensity in patients with pheochromocytoma was higher than other adrenal tumors, with greatly significant (p < 0.001). T2W signal intensity ratio (T2W nodule-to-muscle SI ratio) was an independent risk factor for the differential diagnosis of adrenal PHEOs from non-PHEOs. This feature alone had 91.4% sensitivity and 81.5% specificity to rule out pheochromocytoma based on optimal threshold, with an area under the receiver operating characteristics curve (AUC­ROC) of 0.910(95% C I: 0.833-0.987). CONCLUSION: Our study confirms that T2W signal intensity ratio can differentiate PHEO from non-PHEO, among which the consequences of biochemical screening tests of catecholamines and/or catecholamine metabolites are positive.

Clinical study on laparoscopic minimally invasive surgery and transumbilical single-port laparoscopic surgery in the treatment of benign ovarian tumours and its influence on ovarian functions.

OBJECTIVE: The objective of this study was to explore the influence of traditional laparoscopic surgery and transumbilical single-port laparoscopic surgery on ovarian function in patients with benign ovarian tumours. MATERIALS AND METHODS: Forty-four patients with benign ovarian tumours who were treated in our hospital from January 2020 to June 2021 were selected and randomly divided into two groups, with 22 cases in each group according to random number table. The conventional group was treated with conventional laparoscopic surgery, while the modified group was treated with transumbilical single-port laparoscopic surgery. The measurement method was t -test, and the enumeration method was two tests. The clinical operation-related indicators, ovarian function (follicle-stimulating hormone, E 2 and luteinising hormone), complication incidence, Visual Analogue Scale (VAS) and landscaping satisfaction scores of the two groups were compared. RESULTS: There were no significant differences in complications and operation duration between the two groups ( P > 0.05). After treatment, the ovarian function indexes and beautification satisfaction scores of the modified group were significantly superior to those of the conventional group ( P < 0.05). Besides, the intraoperative bleeding volume, post-operative exhaust time, hospital stay and three-dimensional VAS scores on day 1 and day 3 after surgery of the modified group were lower than those of the conventional group ( P < 0.05). CONCLUSION: Transumbilical single-port laparoscopic surgery for benign ovarian tumours has a significant clinical effect, which can effectively reduce bleeding during the operation, improve ovarian function, relieve surgical pain, promote rapid post-operative recovery and improve patients' satisfaction with landscaping. It is worthy of clinical application.

Cancer Cell-Selective PD-L1 Inhibition via a DNA Safety Catch to Enhance Immunotherapy Specificity.

Immune checkpoint protein blockade (ICB) has emerged as a powerful immunotherapy approach, but suppressing immune-related adverse events (irAEs) for noncancerous cells and normal tissues remains challenging. Activatable ICB has been developed with tumor microenvironment highly-expressed molecules as stimuli, but they still lack precision and efficiency considering the diffusion of stimuli molecules in whole tumor tissue. Here we assemble PD-L1 with a duplex DNA strand, termed as "safety catch", to regulate its accessibility for ICB. The safety catch remains at "on" status for noncancerous cells to prevent ICB binding to PD-L1. Cancer cell membrane protein c-Met acts as a trigger protein to react with safety catch, which selectively exposes its hybridization region for ICB reagent. The ICB reagent is a retractable DNA nanostring with repeating hairpin-structural units, whose contraction drives PD-L1 clustering with endocytosis-guided degradation. The safety catch, even remained at "safety on" status, is removed from the cell membrane via a DNA strand displacement reaction to minimize its influence on noncancerous cells. This strategy demonstrates selective and potent immunotherapeutic capabilities only against cancer cells both in vitro and in vivo, and shows effective suppression of irAEs in normal tissues, therefore would become a promising approach for precise immunotherapy in mice.

Patient-derived Immunocompetent Tumor Organoids: A Platform for Chemotherapy Evaluation in the Context of T-cell Recognition.

Most of the anticancer compounds synthesized by chemists are primarily evaluated for their direct cytotoxic effects at the cellular level, often overlooking the critical role of the immune system. In this study, we developed a patient-derived, T-cell-retaining tumor organoid model that allows us to evaluate the anticancer efficacy of chemical drugs under the synergistic paradigm of antigen-specific T-cell-dependent killing, which may reveal the missed drug hits in the simple cytotoxic assay. We evaluated clinically approved platinum (Pt) drugs and a custom library of twenty-eight PtIV compounds. We observed low direct cytotoxicity of Pt drugs, but variable synergistic effects in combination with immune checkpoint inhibitors (ICIs). In contrast, the majority of PtIV compounds exhibited potent tumor-killing capabilities. Interestingly, several PtIV compounds went beyond direct tumor killing and showed significant immunosynergistic effects with ICIs, outstanding at sub-micromolar concentrations. Among these, Pt-19, PtIV compounds with cinnamate axial ligands, emerged as the most therapeutically potent, demonstrating pronounced immunosynergistic effects by promoting the release of cytotoxic cytokines, activating immune-related pathways and enhancing T cell receptor (TCR) clonal expansion. Overall, this initiative marks the first use of patient-derived immunocompetent tumor organoids to explore and study chemotherapy, advancing their path toward more effective small molecule drug discovery.

Cancer Cell-Selective Membrane Receptor Clustering Driven by VEGF Secretion for In Vivo Therapy.

Clustering of cell membrane receptors regulates cell behaviors. Although receptor clustering plans have achieved wide applications in cancer therapy, it still remains challenging to manipulate receptor clustering selectively for cancer cells with little influence on normal cells. Here, we design a Raji cell Selective MAnipulation of Receptor Clustering (SMARC) strategy for CD20, which is driven by endogenous secretion of Raji cells. Retractable DNA nanostrings with repeating hairpin-structured units are anchored to the cell membrane CD20, which contract in response to Raji cell-secreted vascular endothelial growth factor (VEGF) with corresponding CD20 clustering. The contraction of DNA nanostrings is intensified via a VEGF amplifier including DNA cyclic reactions to continuously trigger the foldings of hairpin-structured units in DNA nanostrings. The SMARC strategy shows selective and efficient apoptosis of Raji cells with little interference to normal B cells and demonstrates good in vivo therapeutic efficacy, which provides a promising tool for precise cancer therapy.

Targeting MHC-I molecules for cancer: function, mechanism, and therapeutic prospects.

The molecules of Major histocompatibility class I (MHC-I) load peptides and present them on the cell surface, which provided the immune system with the signal to detect and eliminate the infected or cancerous cells. In the context of cancer, owing to the crucial immune-regulatory roles played by MHC-I molecules, the abnormal modulation of MHC-I expression and function could be hijacked by tumor cells to escape the immune surveillance and attack, thereby promoting tumoral progression and impairing the efficacy of cancer immunotherapy. Here we reviewed and discussed the recent studies and discoveries related to the MHC-I molecules and their multidirectional functions in the development of cancer, mainly focusing on the interactions between MHC-I and the multiple participators in the tumor microenvironment and highlighting the significance of targeting MHC-I for optimizing the efficacy of cancer immunotherapy and a deeper understanding of the dynamic nature and functioning mechanism of MHC-I in cancer.

Safety, Tolerability, and Pharmacokinetics of Senaparib, a Novel PARP1/2 Inhibitor, in Chinese Patients With Advanced Solid Tumors: A Phase I Trial.

BACKGROUND: Senaparib, a novel poly(ADP-ribose) polymerase 1/2 inhibitor, demonstrated antitumor activity in preclinical studies. This phase I, first-in-human, dose-escalation/-expansion study explored the pharmacokinetics, safety and tolerability, and preliminary antitumor activity of senaparib in Chinese patients with advanced solid tumors. PATIENTS AND METHODS: Adults with advanced solid tumors who had failed ³1 line of prior systemic treatment were enrolled. Senaparib (once daily [QD]) dose was escalated from 2 mg until the maximum tolerated dose (MTD)/recommended phase II dose (RP2D) using a modified 3 + 3 design. Dose expansion included: dose groups with ≥1 objective response and one dose higher, as well as those at the MTD/RP2D. Primary objectives were to evaluate the safety and tolerability, and determine the MTD and/or RP2D of senaparib. RESULTS: Fifty-seven patients were enrolled across 10 dose groups (2-120 mg QD, and 50 mg twice daily). No dose-limiting toxicities were observed. The most common senaparib-related adverse events were anemia (80.9%), white blood cell count decreased (43.9%), platelet count decreased (28.1%), and asthenia (26.3%). Senaparib exposure increased dose proportionately at 2-80 mg; absorption saturated at 80-120 mg. Senaparib accumulation was minimal after repeated QD administration (accumulation ratio=1.1-1.5). The objective response rate was 22.7% (n=10/44) overall (all partial responses) and 26.9% (n=7/26) for patients harboring BRCA1/BRCA2 mutations. Disease control rates were 63.6% and 73.1%, respectively. CONCLUSIONS: Senaparib was well tolerated and demonstrated promising antitumor activity in Chinese patients with advanced solid tumors. The RP2D for this clinical study in China was identified as 100 mg QD. CLINICALTRIALS.GOV IDENTIFIER: NCT03508011.

Impact of operator expertise on transperineal free-hand mpMRI-fusion-targeted biopsies under local anaesthesia for prostate cancer diagnosis: a multicenter prospective learning curve.

PURPOSE: Transperineal mpMRI-targeted fusion prostate biopsies (TPFBx) are recommended for prostate cancer diagnosis, but little is known about their learning curve (LC), especially when performed under local anaesthesia (LA). We investigated how operators' and institutions' experience might affect biopsy results. METHODS: Baseline, procedure and pathology data of consecutive TPFBx under LA were prospectively collected at two academic Institutions, from Sep 2016 to May 2019. Main inclusion criterion was a positive MRI. Endpoints were biopsy duration, clinically significant prostate cancer detection rate on targeted cores (csCDR-T), complications, pain and urinary function. Data were analysed per-centre and per-operator (with ≥ 50 procedures), comparing groups of consecutive patient, and subsequently through regression and CUSUM analyses. Learning curves were plotted using an adjusted lowess smoothing function. RESULTS: We included 1014 patients, with 27.3% csCDR-T and a median duration was 15 min (IQR 12-18). A LC for biopsy duration was detected, with the steeper phase ending after around 50 procedures, in most operators. No reproducible evidence in favour of an impact of experience on csPCa detection was found at operator's level, whilst a possible gentle LC of limited clinical relevance emerged at Institutional level; complications, pain and IPSS variations were not related to operator experience. CONCLUSION: The implementation of TPFBx under LA was feasible, safe and efficient since early phases with a relatively short learning curve for procedure time.

The impact of a second MRI and re-biopsy in patients with initial negative mpMRI-targeted and systematic biopsy for PIRADS ≥ 3 lesions.

OBJECTIVE: To evaluate the proportions of detected prostate cancer (PCa) and clinically significant PCa (csPCa), as well as identify clinical predictors of PCa, in patients with PI-RADS > = 3 lesion at mpMRI and initial negative targeted and systematic biopsy (initial biopsy) who underwent a second MRI and a re-biopsy. METHODS: A total of 290 patients from 10 tertiary referral centers were included. The primary outcome measures were the presence of PCa and csPCa at re-biopsy. Logistic regression analyses were performed to evaluate predictors of PCa and csPCa, adjusting for relevant covariates. RESULTS: Forty-two percentage of patients exhibited the presence of a new lesion. Furthermore, at the second MRI, patients showed stable, upgrading, and downgrading PI-RADS lesions in 42%, 39%, and 19%, respectively. The interval from the initial to repeated mpMRI and from the initial to repeated biopsy was 16 mo (IQR 12-20) and 18 mo (IQR 12-21), respectively. One hundred and eight patients (37.2%) were diagnosed with PCa and 74 (25.5%) with csPCa at re-biopsy. The presence of ASAP on the initial biopsy strongly predicted the presence of PCa and csPCa at re-biopsy. Furthermore, PI-RADS scores at the first and second MRI and a higher number of systematic biopsy cores at first and second biopsy were independent predictors of the presence of PCa and csPCa. Selection bias cannot be ruled out. CONCLUSIONS: Persistent PI-RADS ≥ 3 at the second MRI is suggestive of the presence of a not negligible proportion of csPca. These findings contribute to the refinement of risk stratification for men with initial negative MRI-TBx.

Combination of robot-assisted laparoscopy and ureteroscopy for the management of complex ureteral strictures.

BACKGROUND: To summarize the efficacy of combined robot-assisted laparoscopy and ureteroscopy in treating complex ureteral strictures. METHODS: Eleven patients underwent combined robot-assisted laparoscopy and ureteroscopy for ureteral strictures between January 2020 and August 2022. Preoperative B-ultrasound, glomerular filtration rate measurement, and intravenous pyelography showed different degrees of hydronephrosis in the affected kidney and moderate to severe stenosis in the corresponding part of the ureter. During the operation, stricture segment resection and end-to-end anastomosis were performed using the da Vinci robot to find the stricture point under the guidance of a ureteroscopic light source in the lateral or supine lithotomy position. RESULTS: All the patients underwent robot-assisted laparoscopy and ureteroscopy combined with end-to-end ureterostenosis. There were no conversions to open surgery or intraoperative complications. Significant ureteral stricture segments were found in all patients intraoperatively; however, stricture length was not significantly different from the imaging findings. Patients were followed up for 3-27 months. Two months postoperatively, the double-J stent was removed, a ureteroscopy was performed, the ureteral mucosa at the end-to-end anastomosis grew well, and the lumen was patent in all patients. Furthermore, imaging examination showed that hydronephrosis was significantly improved in all patients, with grade I hydronephrosis in three cases and grade 0 hydronephrosis in eight cases. No recurrence of ureteral stricture was observed in patients followed up for > 1 year. CONCLUSION: Robot-assisted laparoscopy combined with ureteroscopy is an effective method for treating complex ureteral strictures and can achieve accurate localization of the structured segment.

Prediction of T staging in PI-RADS 4-5 prostate cancer by combination of multiparametric MRI and 68Ga-PSMA-11 PET/CT.

BACKGROUND: In this study, we explored the diagnostic performances of multiparametric magnetic resonance imaging (mpMRI), 68 Ga-PSMA-11 PET/CT and combination of 68 Ga-PSMA-11 PET/CT and mpMRI (mpMRI + PET/CT) for extracapsular extension (ECE). Based on the analyses above, we tested the feasibility of using mpMRI + PET/CT results to predict T staging in prostate cancer patients. METHODS: By enrolling 75 patients of prostate cancer with mpMRI and 68 Ga-PSMA-11 PET/CT before radical prostatectomy, we analyzed the detection performances of ECE in mpMRI, 68 Ga-PSMA-11 PET/CT and mpMRI + PET/CT on their lesion images matched with their pathological sample images layer by layer through receiver operating characteristics (ROC) analysis. By inputting the lesion data into Prostate Imaging Reporting and Data System (PI-RADS), we divided the lesions into different PI-RADS scores. The improvement of detecting ECE was analyzed by net reclassification improvement (NRI). The predictors for T staging were evaluated by using univariate and multivariable analysis. The Kappa test was used to evaluate the prediction ability. RESULTS: One hundred three regions of lesion were identified from 75 patients. 50 of 103 regions were positive for ECE. The ECE diagnosis AUC of mpMRI + PET/CT is higher than that of mpMRI alone (ΔAUC = 0.101; 95% CI, 0.0148 to 0.1860; p < 0.05, respectively). Compared to mpMRI, mpMRI + PET/CT has a significant improvement in detecting ECE in PI-RADS 4-5 (NRI 36.1%, p < 0.01). The diagnosis power of mpMRI + PET/CT was an independent predictor for T staging (p < 0.001) in logistic regression analysis. In patients with PI-RADS 4-5 lesions, 40 of 46 (87.0%) patients have correct T staging prediction from mpMRI + PET/CT (κ 0.70, p < 0.01). CONCLUSION: The prediction of T staging in PI-RADS 4-5 prostate cancer patients by mpMRI + PET/CT had a quite good performance.

Negative Pressure Wound Therapy for Patients With Complicated Mucocutaneous Separation Following Ileal Conduit Urinary Diversion: A Case Series.

BACKGROUND: Mucocutaneous separation (MCS) is one of the early stomal complications of ileal conduit diversion after radical cystectomy. It can result in abdominal infection and sepsis, prolonging patient recovery. Negative pressure wound therapy (NPWT) has been widely used for abdominal wounds after orthopedic and burn surgery. This case series describes its use in complicated MCS and ostomy retraction after ileal conduit diversion. CASES: We describe a case series of 3 patients with moderate to severe MCS with and without infection after robot-assisted radical cystectomy with ileal conduit diversion. Our patients were treated with NPWT to avoid infection and create a satisfactory environment for healing MCS. After 2 to 4 weeks of NPWT, all 3 patients had normal micturition function with no additional peristomal wounds or complications. CONCLUSION: Negative pressure wound therapy may be used in the management of complicated MCS after ileal conduit diversion.

Environmental microcystin exposure triggers the poor prognosis of prostate cancer: Evidence from case-control, animal, and in vitro studies.

Microcystin-leucine-arginine (MC-LR) is positively linked with multiple cancers in humans. However, the association between MC-LR and the risk and prognosis of prostate cancer has not been conducted in epidemiological studies. No reported studies have linked MC-LR exposure to the poor prognosis of prostate cancer by conducting experimental studies. The content of MC-LR was detected in most of the aquatic food in wet markets and supermarkets in Nanjing and posed a health risk for consumers. MC-LR levels in both prostate cancer tissues and serum were significantly higher than controls. The adjusted odds ratio (OR) for prostate cancer risk by serum MC-LR was 1.75 (95%CI: 1.21-2.52) in the whole subjects, and a positive correlation between MC-LR and advanced tumor stage was observed. Survival curve analysis indicated patients with higher MC-LR levels in tissues exhibited poorer overall survival. Human, animal, and cell studies confirmed that MC-LR exposure increases the expression of estrogen receptor-α (ERα) and promotes epithelial-mesenchymal transition (EMT) in prostate cancer. Moreover, MC-LR-induced decreased E-cadherin levels, increased vimentin levels, and increased migratory and invasive capacities of prostate cancer cells were markedly suppressed upon ERα knockdown. MC-LR-induced xenograft tumor growth and lung metastasis in BALB/c nude mice can be effectively alleviated with ERα knockdown. Our data demonstrated that MC-LR upregulated vimentin and downregulated E-cadherin through activating ERα, promoting migration and invasion of prostate cancer cells. Our findings highlight the role of MC-LR in prostate cancer, providing new perspectives to understand MC-LR-induced prostatic toxicity.

NIR-II Light Powered Asymmetric Hydrogel Nanomotors for Enhanced Immunochemotherapy.

Nanomotors are appealing drug carriers, and the strength of the propelling force is important for their motion capability. Though high motion efficiency has been achieved with 808 nm light driven Janus-structured noble metal nanomotors, the NIR-I light penetration depth and material biocompatibility limit their broad application. Herein, we develop a 1064 nm NIR-II light driven asymmetric hydrogel nanomotor (AHNM) with high motion capability and load it with doxorubicin for enhanced immunochemotherapy. Magnetic field assisted photopolymerization generates an asymmetric distribution of Fe3 O4 @Cu9 S8 nanoparticles in the AHNM, producing self-thermophoresis as driving force under NIR-II irradiation. The AHNM is also functionalized with dopamine for the capture and retention of tumor-associated antigens to boost immune activation. The as-obtained NIR-II light driven AHNM has a high tumor tissue penetration capability and enhances immunochemotherapy, providing a promising strategy for cancer therapy.