Ultrasonic Microbubble Cavitation Enhanced Tissue Permeability and Drug Diffusion in Solid Tumor Therapy.

Chemotherapy has an essential role not only in advanced solid tumor therapy intervention but also in society's health at large. Chemoresistance, however, seriously restricts the efficiency and sensitivity of chemotherapeutic agents, representing a significant threat to patients' quality of life and life expectancy. How to reverse chemoresistance, improve efficacy sensitization response, and reduce adverse side effects need to be tackled urgently. Recently, studies on the effect of ultrasonic microbubble cavitation on enhanced tissue permeability and retention (EPR) have attracted the attention of researchers. Compared with the traditional targeted drug delivery regimen, the microbubble cavitation effect, which can be used to enhance the EPR effect, has the advantages of less trauma, low cost, and good sensitization effect, and has significant application prospects. This article reviews the research progress of ultrasound-mediated microbubble cavitation in the treatment of solid tumors and discusses its mechanism of action to provide new ideas for better treatment strategies.

Prognostic Value of Tumor Size in Patients with Upper Tract Urothelial Carcinoma: A Systematic Review and Meta-analysis.

Context: The role of tumor size in predicting prognosis in upper tract urothelial carcinoma (UTUC) patients remains poorly defined. Objective: To assess the prognostic value of tumor size in patients with UTUC through a systematic review and meta-analysis. Evidence acquisition: A comprehensive literature search of the PubMed and Embase databases were performed to identify all relevant articles published up to December 2021 according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Available hazard ratios (HRs) and corresponding 95% confidence intervals (95% CIs) were analyzed to evaluate the association between tumor size and survival outcomes. Evidence synthesis: A total of 35 articles representing 32 292 patients met the eligibility criteria and were finally included for the meta-analysis. Tumor size was significantly associated with poor outcomes in terms of overall survival (HR = 1.42, 95% CI = 1.28-1.58), cancer-specific survival (HR = 1.66, 95% CI = 1.47-1.88), recurrence-free survival (HR = 1.25, 95% CI = 1.13-1.38), and intravesical recurrence (HR = 1.12, 95% CI = 1.04-1.20). There was between-study heterogeneity in the effect of tumor size on all these meta-analyses, with p < 0.10 and I2 generally >50%. Subgroup analyses illustrated that the association of tumor size with adverse prognosis in UTUC patients is not affected by treatment modalities. Segmental resection of ureter, whether receiving lymph node dissection, cutoff of tumor size, and region of population were potential sources of heterogeneity. The funnel plot test indicated no significant publication bias in the meta-analysis of survival outcomes. Conclusions: This study shows that larger tumor size is associated with an increased risk of overall and cancer-specific mortality, and disease recurrence in UTUC. Integration of tumor size with other prognostic indicators may help in risk stratification and individualized treatment of UTUC. Patient summary: Through a systematic review and meta-analysis, this study found that larger tumor size is associated with an increased risk of overall and cancer-specific mortality, and disease recurrence in patients with upper tract urothelial carcinoma.

Establishment of an Ex Vivo Tissue Culture Model for Evaluation of Antitumor Efficacy in Clear Cell Renal Cell Carcinoma.

There are many potential immunotherapeutic targets for cancer immunotherapy, which should be assessed for efficacy before they enter clinical trials. Here we established an ex vivo cultured patient-derived tumor tissue model to evaluate antitumor effectiveness of one VISTA inhibitor, given that our previous study showed that VISTA was selectively highly expressed in human clear cell renal cell carcinoma (ccRCC) tumors. We observed that all the tested patients responded to the anti-VISTA monoclonal antibody as manifested by TNF-α production, but only a small fraction were responders to the anti-PD-1 antibody. Co-blockade of VISTA and PD-1 resulted in a synergistic effect in 20% of RCC patients. Taken together, these findings indicate that this ex vivo tumor slice culture model represents a viable tool to evaluate antitumor efficacies for the inhibitors of immune checkpoints and further supports that VISTA could serve as a promising target for immunotherapy in ccRCC.

Deep Learning with Quantitative Features of Magnetic Resonance Images to Predict Biochemical Recurrence of Radical Prostatectomy: A Multi-Center Study.

Biochemical recurrence (BCR) occurs in up to 27% of patients after radical prostatectomy (RP) and often compromises oncologic survival. To determine whether imaging signatures on clinical prostate magnetic resonance imaging (MRI) could noninvasively characterize biochemical recurrence and optimize treatment. We retrospectively enrolled 485 patients underwent RP from 2010 to 2017 in three institutions. Quantitative and interpretable features were extracted from T2 delineated tumors. Deep learning-based survival analysis was then applied to develop the deep-radiomic signature (DRS-BCR). The model's performance was further evaluated, in comparison with conventional clinical models. The model achieved C-index of 0.802 in both primary and validating cohorts, outweighed the CAPRA-S score (0.677), NCCN model (0.586) and Gleason grade group systems (0.583). With application analysis, DRS-BCR model can significantly reduce false-positive predictions, so that nearly one-third of patients could benefit from the model by avoiding overtreatments. The deep learning-based survival analysis assisted quantitative image features from MRI performed well in prediction for BCR and has significant potential in optimizing systemic neoadjuvant or adjuvant therapies for prostate cancer patients.

Ultrasound-mediated microbubbles cavitation enhanced chemotherapy of advanced prostate cancer by increasing the permeability of blood-prostate barrier.

Although chemotherapy is an important treatment for advanced prostate cancer, its efficacy is relatively limited. Ultrasound-induced cavitation plays an important role in drug delivery and gene transfection. However, whether cavitation can improve the efficacy of chemotherapy for prostate cancer remains unclear. In this study, we treated RM-1 mouse prostate carcinoma cells with a combination of ultrasound-mediated microbubble cavitation and paclitaxel. Our results showed that combination therapy led to a more pronounced inhibition of cell viability and increased cell apoptosis. The enhanced efficacy of chemotherapy was attributed to the increased cell permeability induced by cavitation. Importantly, compared with chemotherapy alone (nab-paclitaxel), chemotherapy combined with ultrasound-mediated microbubble cavitation significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice in an orthotopic mouse model of RM-1 prostate carcinoma, indicating the synergistic effects of combined therapy on tumor reduction. Furthermore, we analyzed tumor-infiltrating lymphocytes and found that during chemotherapy, the proportions of CTLA4+ cells and PD-1+/CTLA4+ cells in CD8+ T cells slightly increased after cavitation treatment.

A novel nomogram provides improved accuracy for predicting biochemical recurrence after radical prostatectomy.

BACKGROUND: Various prediction tools have been developed to predict biochemical recurrence (BCR) after radical prostatectomy (RP); however, few of the previous prediction tools used serum prostate-specific antigen (PSA) nadir after RP and maximum tumor diameter (MTD) at the same time. In this study, a nomogram incorporating MTD and PSA nadir was developed to predict BCR-free survival (BCRFS). METHODS: A total of 337 patients who underwent RP between January 2010 and March 2017 were retrospectively enrolled in this study. The maximum diameter of the index lesion was measured on magnetic resonance imaging (MRI). Cox regression analysis was performed to evaluate independent predictors of BCR. A nomogram was subsequently developed for the prediction of BCRFS at 3 and 5 years after RP. Time-dependent receiver operating characteristic (ROC) curve and decision curve analyses were performed to identify the advantage of the new nomogram in comparison with the cancer of the prostate risk assessment post-surgical (CAPRA-S) score. RESULTS: A novel nomogram was developed to predict BCR by including PSA nadir, MTD, Gleason score, surgical margin (SM), and seminal vesicle invasion (SVI), considering these variables were significantly associated with BCR in both univariate and multivariate analyses (P < 0.05). In addition, a basic model including Gleason score, SM, and SVI was developed and used as a control to assess the incremental predictive power of the new model. The concordance index of our model was slightly higher than CAPRA-S model (0.76 vs. 0.70, P = 0.02) and it was significantly higher than that of the basic model (0.76 vs. 0.66, P = 0.001). Time-dependent ROC curve and decision curve analyses also demonstrated the advantages of the new nomogram. CONCLUSIONS: PSA nadir after RP and MTD based on MRI before surgery are independent predictors of BCR. By incorporating PSA nadir and MTD into the conventional predictive model, our newly developed nomogram significantly improved the accuracy in predicting BCRFS after RP.

Patient-Level Prediction of Multi-Classification Task at Prostate MRI Based on End-to-End Framework Learning From Diagnostic Logic of Radiologists.

The grade groups (GGs) of Gleason scores (Gs) is the most critical indicator in the clinical diagnosis and treatment system of prostate cancer. End-to-end method for stratifying the patient-level pathological appearance of prostate cancer (PCa) in magnetic resonance (MRI) are of high demand for clinical decision. Existing methods typically employ a statistical method for integrating slice-level results to a patient-level result, which ignores the asymmetric use of ground truth (GT) and overall optimization. Therefore, more domain knowledge (e.g., diagnostic logic of radiologists) needs to be incorporated into the design of the framework. The patient-level GT is necessary to be logically assigned to each slice of a MRI to achieve joint optimization between slice-level analysis and patient-level decision-making. In this paper, we propose a framework (PCa-GGNet-v2) that learns from radiologists to capture signs in a separate two-dimensional (2-D) space of MRI and further associate them for the overall decision, where all steps are optimized jointly in an end-to-end trainable way. In the training phase, patient-level prediction is transferred from weak supervision to supervision with GT. An association route records the attentional slice for reweighting loss of MRI slices and interpretability. We evaluate our method in an in-house multi-center dataset (N = 570) and PROSTATEx (N = 204), which yields five-classification accuracy over 80% and AUC of 0.804 at patient-level respectively. Our method reveals the state-of-the-art performance for patient-level multi-classification task to personalized medicine.

A Diagnostic Nomogram of Pathologic Grade for Preoperative Risk Stratification in Upper Tract Urothelial Carcinoma.

BACKGROUND: To develop a novel nomogram to improve the preoperative diagnosis of pathological grade of upper tract urothelial carcinoma (UTUC). METHODS: Retrospective study was conducted with 245 patients with UTUC treated by radical nephroureterectomy from 2002 to 2016. Of the cohort, 57.6% received ureteroscopic (URS) biopsy and 35.9% received urine cytology examination. Preoperative clinical characteristics and examination results were collected. Final pathological grade was diagnosed by postoperative pathology. Univariable and multivariable binary logistic regressions were applied to establish a preoperative predictive model for tumor grade, and significant factors were included in the nomogram. The area under curve (AUC) was used to show the predictive efficacy, and the calibration plot was drawn for validation. RESULTS: Of the 245 patients, 72.7% were diagnosed with pathological high-grade disease. Age (odds ratio [OR] = 1.03, P = .039), sessile (OR = 3.86, P = .021), positive urinary cytology (OR = 6.87, P = .035), and biopsy high-grade result (OR = 10.85, P < .001) were independent predictors for pathological high-grade disease. The predictive nomogram containing these factors achieved an AUC of 0.78, which was significantly better than URS biopsy alone (AUC = 0.62, P = .003) in the whole cohort. In the URS biopsy subgroup, the nomogram achieved an AUC of 0.79, better than biopsy alone (AUC = 0.76), but was not statistically significant (P = .431). When the cutoff value of the nomogram was set at 0.64, the sensitivity of detecting a high-grade lesion versus low-grade lesion was 80.3%, better than that of URS biopsy alone (sensitivity = 65.7%). CONCLUSIONS: Advanced age, sessile, positive urinary cytology, and biopsy high-grade were independent predictors of pathological high-grade disease in patients with UTUC. A nomogram containing these factors can improve diagnostic accuracy, potentially reducing the risk of "undergrading" by URS biopsy.

Radiologist-like artificial intelligence for grade group prediction of radical prostatectomy for reducing upgrading and downgrading from biopsy.

Rationale: To reduce upgrading and downgrading between needle biopsy (NB) and radical prostatectomy (RP) by predicting patient-level Gleason grade groups (GGs) of RP to avoid over- and under-treatment. Methods: In this study, we retrospectively enrolled 575 patients from two medical institutions. All patients received prebiopsy magnetic resonance (MR) examinations, and pathological evaluations of NB and RP were available. A total of 12,708 slices of original male pelvic MR images (T2-weighted sequences with fat suppression, T2WI-FS) containing 5405 slices of prostate tissue, and 2,753 tumor annotations (only T2WI-FS were annotated using RP pathological sections as ground truth) were analyzed for the prediction of patient-level RP GGs. We present a prostate cancer (PCa) framework, PCa-GGNet, that mimics radiologist behavior based on deep reinforcement learning (DRL). We developed and validated it using a multi-center format. Results: Accuracy (ACC) of our model outweighed NB results (0.815 [95% confidence interval (CI): 0.773-0.857] vs. 0.437 [95% CI: 0.335-0.539]). The PCa-GGNet scored higher (kappa value: 0.761) than NB (kappa value: 0.289). Our model significantly reduced the upgrading rate by 27.9% (P < 0.001) and downgrading rate by 6.4% (P = 0.029). Conclusions: DRL using MRI can be applied to the prediction of patient-level RP GGs to reduce upgrading and downgrading from biopsy, potentially improving the clinical benefits of prostate cancer oncologic controls.

A novel nephrometry scoring system for predicting peri-operative outcomes of retroperitoneal laparoscopic partial nephrectomy.

BACKGROUND: Although the impact of tumor complexity on peri-operative outcomes has been well established using several nephrometry scoring systems, the impact of adherent perirenal fat remains poorly defined. This study aimed to develop a novel nephrometry scoring system for predicting the peri-operative outcomes of laparoscopic partial nephrectomy (LPN) by integrating and optimizing the RENAL score (RNS) and Mayo adhesive probability (MAP) score. METHODS: We retrospectively evaluated 159 patients treated with retroperitoneal LPN. The patients' demographic parameters, RNSs, and MAP scores were evaluated as potential predictors of perioperative outcomes, including operation time, estimated blood loss (EBL), and margin, ischemia, and complication (MIC) achievement rate. The independent predictors were used to develop a novel nephrometry scoring system. The predictive value and inter-observer agreement for the novel nephrometry scoring system were evaluated. RESULTS: Tumor radius (R score), nearness to the renal sinus or collecting system (N score), and posterior perinephric fat thickness were independent predictors of peri-operative outcomes and were used to develop the RNP score. The univariate analysis revealed that the RNP score was significantly associated with operation time, EBL, and MIC achievement rate (P < 0.050). The RNP score was an independent predictor of operation time (P < 0.001), EBL (P = 0.018), and MIC achievement rate (P = 0.023) in the multivariate analysis. The RNP score was not inferior to RNS in the area under the curve for predicting peri-operative outcomes and performed better in inter-observer agreement (76.7% vs. 57.8%) and kappa value (0.804 vs. 0.726). CONCLUSION: The RNP score, combining the advantages of the RNS and MAP score, demonstrated a good predictive value for the peri-operative outcomes of retroperitoneal LPN and better inter-observer agreement.

Impact of sarcomatoid differentiation and rhabdoid differentiation on prognosis for renal cell carcinoma with vena caval tumour thrombus treated surgically.

BACKGROUND: Sarcomatoid differentiation in renal cell carcinoma (RCC) with vena caval tumour thrombus has been shown to be associated with aggressive behaviours and poor prognosis; however, evidence of the impact of rhabdoid differentiation on prognosis is lacking. This study evaluated the impact of sarcomatoid differentiation and rhabdoid differentiation on oncological outcomes for RCC with vena caval tumour thrombus treated surgically. METHODS: We retrospectively analysed patients treated surgically for RCC with vena caval tumour thrombus at our institute from Jan 2015 to Nov 2018. Prognostic variables were evaluated for associations with progression-free survival (PFS) and cancer-specific survival (CSS) by Kaplan-Meier survival analysis and log-rank test. Univariate and multivariate analyses were performed to determine independent prognostic variables. RESULTS: We identified 125 patients with RCC and vena caval tumour thrombus, including 17 (13.6%) with sarcomatoid differentiation alone, 8 (6.4%) with rhabdoid differentiation alone and 3 (2.4%) with both sarcomatoid and rhabdoid differentiation. Compared to pure RCC, patients with sarcomatoid differentiation but not rhabdoid differentiation have worse PFS (p = 0.018 and p = 0.095, respectively). The univariate and multivariate analyses both showed sarcomatoid differentiation as a significant predictor of PFS. Compared to pure RCC, patients with sarcomatoid differentiation (p = 0.002) and rhabdoid differentiation (p = 0.001) both had significantly worse CSS. The univariate analysis showed sarcomatoid differentiation, rhabdoid differentiation, metastasis and blood transfusion as significant predictors of CSS (All, p < 0.05). In the multivariate analysis, sarcomatoid differentiation (HR 3.90, p = 0.008), rhabdoid differentiation (HR 3.01, p = 0.042), metastasis (HR 3.87, p = 0.004) and blood transfusion (HR 1.34, p = 0.041) all remained independent predictors of CSS. CONCLUSIONS: Sarcomatoid differentiation and rhabdoid differentiation are both independent predictors of poor prognosis in RCC with vena caval tumour thrombus treated surgically.

[Influence of holmium laser and thulium laser enucleation of the prostate on erectile function].

In recent years, holmium laser enucleation of the prostate (HoLEP) and thulium laser enucleation of the prostate (ThuLEP) have been widely used in the treatment of benign prostatic hyperplasia (BPH) because of their significant clinical effects, high safety, and low incidence of complications. With the improvement of living standards, BPH patients care about not only the improvement of lower-urinary-tract symptoms (LUTS) secondary to BPH but also that of sexual function, especially erectile function, after treatment. However, there are comparatively few studies about the effects of HoLEP and ThuLEP on erectile function and relevant opinions are quite controversial. Most studies reported that HoLEP and ThuLEP did not impair erectile function, but some showed that a few patients experienced a decrease of erectile function after operation. Before surgery, urologists should explain clearly to the patients the potential impact on sexual function, as mental factors may also induce erectile dysfunction. This study presents an overview of recent studies about the infuence of HoLEP and ThuLEP on erectile function.