Platelet-Drug Conjugates Engineered via One-step Fusion Approach for Metastatic and Postoperative Cancer Treatment.

The exploration of cell-based drug delivery systems for cancer therapy has gained growing attention. Approaches to engineering therapeutic cells with multidrug loading in an effective, safe, and precise manner while preserving their inherent biological properties remain of great interest. Here, we report a strategy to simultaneously load multiple drugs in platelets in a one-step fusion process. We demonstrate doxorubicin (DOX)-encapsulated liposomes conjugated with interleukin-15 (IL-15) could fuse with platelets to achieve both cytoplasmic drug loading and surface cytokine modification with a loading efficiency of over 70 % within minutes. Due to their inherent targeting ability to metastatic cancers and postoperative bleeding sites, the engineered platelets demonstrated a synergistic therapeutic effect to suppress lung metastasis and postoperative recurrence in mouse B16F10 melanoma tumor models.

Disrupting glycolysis and DNA repair in anaplastic thyroid cancer with nucleus-targeting platinum nanoclusters.

Cancer cells rely on aerobic glycolysis and DNA repair signals to drive tumor growth and develop drug resistance. Yet, fine-tuning aerobic glycolysis with the assist of nanotechnology, for example, dampening lactate dehydrogenase (LDH) for cancer cell metabolic reprograming remains to be investigated. Here we focus on anaplastic thyroid cancer (ATC) as an extremely malignant cancer with the high expression of LDH, and develop a pH-responsive and nucleus-targeting platinum nanocluster (Pt@TAT/sPEG) to simultaneously targets LDH and exacerbates DNA damage. Pt@TAT/sPEG effectively disrupts LDH activity, reducing lactate production and ATP levels, and meanwhile induces ROS production, DNA damage, and apoptosis in ATC tumor cells. We found Pt@TAT/sPEG also blocks nucleotide excision repair pathway and achieves effective tumor cell killing. In an orthotopic ATC xenograft model, Pt@TAT/sPEG demonstrates superior tumor growth suppression compared to Pt@sPEG and cisplatin. This nanostrategy offers a feasible approach to simultaneously inhibit glycolysis and DNA repair for metabolic reprogramming and enhanced tumor chemotherapy.

MRI-Based Machine Learning Radiomics for Preoperative Assessment of Human Epidermal Growth Factor Receptor 2 Status in Urothelial Bladder Carcinoma.

BACKGROUND: The human epidermal growth factor receptor 2 (HER2) has recently emerged as hotspot in targeted therapy for urothelial bladder cancer (UBC). The HER2 status is mainly identified by immunohistochemistry (IHC), preoperative and noninvasive methods for determining HER2 status in UBC remain in searching. PURPOSES: To investigate whether radiomics features extracted from MRI using machine learning algorithms can noninvasively evaluate the HER2 status in UBC. STUDY TYPE: Retrospective. POPULATION: One hundred ninety-five patients (age: 68.7 ± 10.5 years) with 14.3% females from January 2019 to May 2023 were divided into training (N = 156) and validation (N = 39) cohorts, and 43 patients (age: 67.1 ± 13.1 years) with 13.9% females from June 2023 to January 2024 constituted the test cohort (N = 43). FIELD STRENGTH/SEQUENCE: 3 T, T2-weighted imaging (turbo spin-echo), diffusion-weighted imaging (breathing-free spin echo). ASSESSMENT: The HER2 status were assessed by IHC. Radiomics features were extracted from MRI images. Pearson correlation coefficient and the least absolute shrinkage and selection operator (LASSO) were applied for feature selection, and six machine learning models were established with optimal features to identify the HER2 status in UBC. STATISTICAL TESTS: Mann-Whitney U-test, chi-square test, LASSO algorithm, receiver operating characteristic analysis, and DeLong test. RESULTS: Three thousand forty-five radiomics features were extracted from each lesion, and 22 features were retained for analysis. The Support Vector Machine model demonstrated the best performance, with an AUC of 0.929 (95% CI: 0.888-0.970) and accuracy of 0.859 in the training cohort, AUC of 0.886 (95% CI: 0.780-0.993) and accuracy of 0.846 in the validation cohort, and AUC of 0.712 (95% CI: 0.535-0.889) and accuracy of 0.744 in the test cohort. DATA CONCLUSION: MRI-based radiomics features combining machine learning algorithm provide a promising approach to assess HER2 status in UBC noninvasively and preoperatively. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

A Nomogram of MRI Features to Assess Muscle Invasion in VI-RADS 2 Tumors With Stalk.

BACKGROUND: Vesical Imaging-Reporting and Data System (VI-RADS) is widely used to assess the muscle-invasive status of bladder cancer. However, the current classification efficacy of VI-RASD 2 tumors of stalk is unsatisfactory. PURPOSE: To develop a nomogram to assess muscle-invasive bladder cancer (MIBC) in VI-RADS 2 tumors with stalk. STUDY TYPE: Retrospective. POPULATION: A total of 186 patients (age: 67.8 ± 12.7 years) with 15.1% females, divided randomly into a training cohort (N = 130) and validation cohort (N = 56). FIELD STRENGTH/SEQUENCE: 3-T, T2-weighted imaging (turbo spin-echo), diffusion-weighted imaging (breathing-free spin-echo), and dynamic contrast-enhanced imaging (gradient-echo). ASSESSMENT: Twenty-one MRI features of tumors and stalks were developed from training cohort. The mean apparent diffusion coefficient (ADC) values of the tumor, stalk, and psoas muscles were calculated from the three circular regions of interest. The normalized T value = mean ADC tumor mean ADC muscle . The normalized ST value = mean ADC stalk mean ADC tumor . Three readers assessed the morphology of tumors and stalks. STATISTICAL TESTS: The final features of nomogram were selected by univariable logistic and the least absolute shrinkage and selection operator (LASSO) regression. The performance of the nomogram was assessed by the receiver operating characteristic (ROC) curve, calibration, and decision curve analysis. RESULTS: In VI-RADS 2 tumors with stalk, tumor size over 3 cm, increased stalk width, stalk morphology, decreased normalized T value, and increased normalized ST value were selected as the risk factors for MIBC. The AUC, accuracy, sensitivity, and specificity of the nomogram to assess MIBC were 0.969 (95% CI: 0.941-0.997), 92.3%, 94.1%, and 92.0% in training cohort and 0.940 (95% CI: 0.859-1.000), 89.3%, 75.0%, and 91.7% in validation cohort. DATA CONCLUSION: This study constructed a nomogram for preoperative assessment of MIBC and modifying the current VI-RADS. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Vesical imaging reporting and data system (VI-RADS) could predict the survival of bladder-cancer patients who received radical cystectomy.

Vesical Imaging Reporting and Data System (VI-RADS) shows good potential in determining muscle-invasive bladder cancer (MIBC) patients. However, whether VI-RADS could predict the prognosis of radical cystectomy (RC) patients has not been reported. Our purpose is to determine whether VI-RADS contributed to predict oncologic outcomes. In this retrospective study, we analysed the information of bladder cancer patients who admitted to our centre from June 2012 to June 2022. All patients who underwent multiparametric magnetic resonance imaging (mpMRI) and underwent RC were included. VI-RADS scoring was performed by two radiologists blinded to the clinical data. Patients' clinical features, pathology data, and imaging information were recorded. Kaplan-Meier method was used to estimate patients' overall survival (OS) and progression-free survival (PFS). Log-rank test was used to assess statistical differences. COX regression analysis was used to estimate risk factors. Ultimately, we included 219 patients, with 188 males and 31 females. The median age was 66 (IQR = 61-74.5) years. The VI-RADS scores were as follows: VI-RADS 1, 4 (1.8%); VI-RADS 2, 68 (31.1%); VI-RADS 3, 40 (18.3%); VI-RADS 4, 69 (31.5%); and VI-RADS 5, 38 (17.4%). Patients with VI-RADS ≥ 3 had poorer OS and PFS than those with VI-RADS < 3. The AUC of VI-RADS predicting 3-year OS was 0.804, with sensitivity of 0.824 and negative predictive value of 0.942. Multivariate COX analysis showed that VI-RADS ≥ 3 was risk factors for OS (HR = 3.517, P = 0.003) and PFS (HR = 4.175, P < 0.001). In the MIBC subgroup, patients with VI-RADS ≥ 4 had poorer OS and PFS. In the non-muscle invasive bladder cancer (NMIBC) subgroup, the prognosis of patients with VI-RADS ≥ 3 remained poorer. VI-RADS scores could effectively predict the survival of patients after RC.

Significance of Normalized Apparent Diffusion Coefficient in the Vesical Imaging-Reporting and Data System for Diagnosing Muscle-Invasive Bladder Cancer.

BACKGROUND: Vesical Imaging-Reporting and Data System (VI-RADS) has been developed for assessing bladder cancer from multiparametric (mp) MRI but its performance in diagnosing muscle-invasive bladder cancer (MIBC) is suboptimal. PURPOSE: To investigate associations between normalized apparent diffusion coefficient (NADC) and clinicopathological characteristics and to determine whether the inclusion of NADC can improve the performance of VI-RADS in diagnosing MIBC. STUDY TYPE: Retrospective. POPULATION: Two hundred seventy-five patients with pathologically confirmed bladder cancer (101 MIBC and 174 non-MIBC [NMIBC]) underwent preoperative mpMRI (233 male, 42 female). FIELD STRENGTH/SEQUENCE: 3-T, T2-weighted imaging (turbo spin-echo), diffusion-weighted imaging (free-breathing spin-echo), and dynamic contrast-enhanced imaging (gradient-echo). ASSESSMENT: NADC was the mean ADC of tumor divided by that of the iliopsoas muscles in trans caput femoris plane. Associations between NADC and clinicopathological characteristics were evaluated. Models were established for differentiating MIBC and NMIBC: VI-RADS model; VN model (VI-RADS and NADC), Images model (significant variables from imaging associated with MIBC), LN model (Images model without NADC), and Full model (all significant variables associated with MIBC). STATISTICAL TESTS: Variables for model development were based on logistic regression. Models were evaluated by receiver operating characteristic (ROC) curve. Comparison of the area under the curves (AUCs) for the models used DeLong's test. A P value <0.05 was considered statistically significant. RESULTS: NADC was significantly lower in lesions with diameter ≥ 3 cm, MIBC, histological high grade, lymph node metastasis, and lymphovascular invasion. Compared with VI-RADS model, the AUCs for VN model (VI-RADS score and NADC), Images model (VI-RADS score, NADC and tumor size) and Full model (VI-RADS score, NADC, tumor size and histological grade) were significantly higher. No significant differences were observed between the AUCs for VN model and Images model (P = 0.051). DATA CONCLUSION: NADC reflects information about the aggressiveness of bladder cancer. Combining VI-RADS with NADC can improve performance in diagnosing MIBC. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Development and Validation of an MRI-Based Nomogram for Preoperative Detection of Muscle Invasion in VI-RADS 3.

BACKGROUND: The relationship between tumor and muscle layer in the vesical imaging-reporting and data system (VI-RADS) 3 is ambiguous, and there is a lack of preoperative and non-invasive procedures to detect muscle invasion in VI-RADS 3. PURPOSE: To develop a nomogram based on MRI features for detecting muscle invasion in VI-RADS 3. STUDY TYPE: Retrospective. POPULATION: 235 cases (Age: 67.5 ± 11.5 years) with 11.9% females were randomly divided into a training cohort (n = 164) and a validation cohort (n = 71). FIELD STRENGTH/SEQUENCE: 3T, T2-weighted imaging (turbo spin-echo), diffusion-weighted imaging (breathing-free spin echo), and dynamic contrast-enhanced imaging (gradient echo). ASSESSMENT: 3 features were selected from the training cohort, including tumor contact length greater than maximum tumor diameter (TCL > Dmax), flat tumor morphology, and lower standard deviation of apparent diffusion coefficient (ADCSD ). Three readers assessed VI-RADS scores and the tumor morphology. STATISTICAL TESTS: Interobserver agreement was assessed by Kappa analysis. Features for final analysis were selected by logistic regression. The performance of the nomogram was evaluated by the receiver operating characteristic curve, decision curve analysis, and calibration curve. RESULTS: TCL > Dmax, flat morphology, and lower ADCSD were the independent risk factors for muscle invasive in VI-RADS 3. The AUCs, accuracy, sensitivity, and specificity of the nomogram 1 composed of three features for detecting muscle invasion were 0.852 (95% CI: 0.793-0.912), 0.756, 0.917, and 0.663 in the training cohort, and 0.885 (95% CI: 0.801-0.969), 0.817, 0.900, and 0.784 in the validation cohort. The nomogram 2 without ADCSD has nearly the same performance as the nomogram 1. DATA CONCLUSION: Nomogram can be an efficient tool for preoperative detection of muscle invasion in VI-RADS 3. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Insight into over Repair of Hot Carrier Degradation by GIDL Current in Si p-FinFETs Using Ultra-Fast Measurement Technique.

In this article, an experimental study on the gate-induced drain leakage (GIDL) current repairing worst hot carrier degradation (HCD) in Si p-FinFETs is investigated with the aid of an ultra-fast measurement (UFM) technique (~30 µs). It is found that increasing GIDL bias from 3 V to 4 V achieves a 114.7% VT recovery ratio from HCD. This over-repair phenomenon of HCD by UFM GIDL is deeply discussed through oxide trap behaviors. When the applied gate-to-drain GIDL bias reaches 4 V, a significant electron trapping and interface trap generation of the fresh device with GIDL repair is observed, which greatly contributes to the approximate 114.7% over-repair VT ratio of the device under worst HCD stress (-2.0 V, 200 s). Based on the TCAD simulation results, the increase in the vertical electric field on the surface of the channel oxide layer is the direct cause of an extraordinary electron trapping effect accompanied by the over-repair phenomenon. Under a high positive electric field, a part of channel electrons is captured by oxide traps in the gate dielectric, leading to further VT recovery. Through the discharge-based multi-pulse (DMP) technique, the energy distribution of oxide traps after GIDL recovery is obtained. It is found that over-repair results in a 34% increment in oxide traps around the conduction energy band (Ec) of silicon, which corresponds to a higher stabilized VT shift under multi-cycle HCD-GIDL tests. The results provide a trap-based understanding of the transistor repairing technique, which could provide guidance for the reliable long-term operation of ICs.

Renal Lipoma-Like Angiomyolipoma of Tumour Thrombus Extending to the Confluence of Inferior Vena Cava with Right Atrium: A Rare Case Report and Literature Review.

Angiomyolipoma (AML) complicated with tumour thrombus extending to the confluence of inferior vena cava (IVC) with right atrium is rarely observed. We report a female AML patient admitted to our centre on January 21, 2020, with complication of tumour thrombus extending to the confluence of IVC with right atrium and had no sign of difficult breathing. She underwent whole-abdominal enhanced CT for abdominal pain and was diagnosed with a possible renal AML with tumour thrombus. Open radical nephrectomy and thrombectomy of vena cava were performed. Intraoperative transoesophageal echocardiography indicated that the tumour thrombus has reached the confluence of IVC with right atrium. The operation took 255 min with an intraoperative haemorrhage of 800mL. The patient was discharged 7 days after surgery. Pathology revealed lipoma-like AML. Immunohistochemistry showed vimentin (+), EMA (-), HMB45 (+), S-100 (-), SMA (+), TFE-3 (-), melan A (+). After 2 years of follow-up, we found that the patient showed full recovery and had no recurrence. Therefore, lipoma-like AML should also be followed closely for recurrence and metastasis. When AML involves IVC tumour thrombus, open thrombectomy and radical nephrectomy are safe and effective methods.

HNRNPL induced circFAM13B increased bladder cancer immunotherapy sensitivity via inhibiting glycolysis through IGF2BP1/PKM2 pathway.

BACKGROUND: The response rate to immunotherapy in patients with bladder cancer (BCa) remains relatively low. Considering the stable existence and important functions in tumour metabolism, the role of circRNAs in regulating immune escape and immunotherapy sensitivity is receiving increasing attention. METHODS: Circular RNA (circRNA) sequencing was performed on five pairs of BCa samples, and circFAM13B (hsa_circ_0001535) was screened out because of its remarkably low expression in BCa. Further mRNA sequencing was conducted, and the association of circFAM13B with glycolysis process and CD8+ T cell activation was confirmed. The functions of circFAM13B were verified by proliferation assays, glycolysis assays, BCa cells-CD8+ T cell co-culture assays and tumorigenesis experiment among human immune reconstitution NOG mice. Bioinformatic analysis, RNA-protein pull down, mass spectrometry, RNA immunoprecipitation, luciferase reporter assay and fluorescence in situ hybridization were performed to validate the HNRNPL/circFAM13B/IGF2BP1/PKM2 cascade. RESULTS: Low expression of circFAM13B was observed in BCa, and it was positively associated with lower tumour stage and better prognosis among patients with BCa. The function of CD8+ T cells was promoted by circFAM13B, and it could attenuate the glycolysis of BCa cells and reverse the acidic tumour microenvironment (TME). The production of granzyme B and IFN-γ was improved, and the immunotherapy (PD-1 antibodies) sensitivity was facilitated by the inhibition of acidic TME. Mechanistically, circFAM13B was competitively bound to the KH3-4 domains of IGF2BP1 and subsequently reduced the binding of IGF2BP1 and PKM2 3'UTR. Thus, the stability of the PKM2 mRNA decreased, and glycolysis-induced acidic TME was inhibited. The generation of circFAM13B was explored by confirming whether heterogeneous nuclear ribonucleoprotein L (HNRNPL) could promote circFAM13B formation via pre-mRNA back-splicing. CONCLUSIONS: HNRNPL-induced circFAM13B could repress immune evasion and enhance immunotherapy sensitivity by inhibiting glycolysis and acidic TME in BCa through the novel circFAM13B/IGF2BP1/PKM2 cascade. Therefore, circFAM13B can be used as a biomarker for guiding the immunotherapy among patients with BCa.

Robot-Assisted Totally Intracorporeal Resection of Cutaneous Ureterostomy Tumor and Ileal Conduit Surgery: A Rare Case Report.

BACKGROUND: Radical cystectomy (RC) is the standard treatment for muscular invasive bladder cancer (MIBC) and some high-risk non-muscular invasive bladder cancer (NMIBC). Cutaneous ureterostomy is a common form of urinary diversion. However, after radical cystectomy, recurrence of upper urinary tract malignancies is possible. There is no relevant report on how to improve this situation's management. CASE PRESENTATION: This case is a 56-year-old male patient hospitalized due to the development of a new tumor in the ureteral cutaneous stoma following radical cystectomy for more than five years. A biopsy of the tumor revealed high-grade urothelial carcinoma. Computed tomography (CT) revealed that the local soft tissue around the cutaneous stoma was thickened, but no other lesions were visible. After evaluating the case, we chose robot-assisted completely intracorporeal resection of cutaneous ureterostomy tumor and ileal conduit surgery. The total time for the operation and the blood loss were 400 minutes and 150 ml, respectively. Following surgery, the patient got standard chemotherapy in combination with immunotherapy. Additionally, ten months following the surgery, the patient did not experience disease progression or complications. CONCLUSION: The robot-assisted operation is safe and feasible for upper urinary tract tumor recurrence following radical cystectomy with cutaneous ureterostomy.

BN nanospheres functionalized with mesoporous silica for enhancing CpG oligodeoxynucleotide-mediated cancer immunotherapy.

CpG oligodeoxynucleotides (CpG ODNs) possess strong immunostimulatory activity, which hold great promise in cancer immunotherapy. However, their therapeutic efficacy is largely limited due to nuclease degradation and poor cellular internalization. Efficiently delivering CpG ODNs into target cells is crucial to improve their therapeutic efficacy. Boron nitride nanospheres (BNNS) possess advantage as carriers for CpG ODNs. However, their poor aqueous dispersity and low CpG ODN loading capacity became a big obstacle for further applications. Herein, we develop amino group grafted, mesoporous silica (MS)-functionalized BNNS as novel nanovectors for CpG ODN delivery. Modification of BNNS with MS significantly improved the dispersity of BNNS and CpG ODN loading. BNNS@MS-NH2 exhibited no cytotoxicity and enhanced the delivery of CpG ODNs into macrophages. BNNS@MS-NH2/CpG ODN complexes triggered enhanced immunostimulation and induced higher amounts of cytokines. Most importantly, BNNS@MS-NH2/CpG ODN complexes induced bifurcated cytokines, which simultaneously simulated the secretion of IL-6, TNF-α and IFN-α. In contrast, CpG ODN and BNNS/CpG ODN complexes could not. The result of the Transwell plate assay suggested that BNNS@MS-NH2/CpG ODN complexes were more effective in inhibiting cancer cell growth. Taken together, our findings provide a promising strategy for enhancing CpG ODN-mediated cancer immunotherapy.