Comparison of Micro-flow Imaging and Contrast-Enhanced Ultrasound in Ultrasound-Guided Microwave Ablation of Benign Thyroid Nodules.

OBJECTIVE: The study described here was aimed at ascertaining the utility of micro-flow imaging (MFI) during ultrasound (US)-guided microwave ablation (MWA) of thyroid nodules by contrasting its effectiveness with that of contrast-enhanced ultrasound (CEUS). METHODS: Seventy-three patients with eighty-eight thyroid nodules who underwent US-guided MWA were included in our study from January 2020 to June 2023. Thirty-five patients underwent CEUS during the MWA process, and thirty-eight patients underwent MFI during the MWA process. We compared the two groups' baseline characteristics, tumor volume (V), volume reduction rate (VRR), complications and clinical characteristics. RESULTS: Both groups exhibited similar outcomes with respect to V and VRR at 1, 3, 6, 12 and 18 mo after MWA (p > 0.05). Consistency was observed with respect to post-operative complications, supplementary ablation times and surgical duration (p > 0.05). It is worth noting that the MFI group had lower treatment costs compared with the CEUS group (11,337.64 ± 80.93 yuan for the MFI group versus 12,971.23 ± 254.89 yuan for the CEUS group, p < 0.05). CONCLUSION: In the MWA procedure for thyroid nodules, MFI is similar to CEUS with respect to safety and efficacy. Simultaneously, it offers the advantage of reducing surgical expenses, which lessens the economic burden for patients.

Ultrasound-guided percutaneous thermal ablation of parotid tumors: experience from two-centers.

Objective: To evaluate the efficacy and feasibility of ultrasound-guided percutaneous thermal ablation (TA) for treating benign parotid tumors.Methods: Patients with benign parotid tumors who underwent ultrasound-guided microwave ablation (MWA) or radiofrequency ablation (RFA) between January 2020 and March 2023 were included in this retrospective study. Change in tumor size (maximum diameter, tumor volume(V), volume reduction rate (VRR)) and cosmetic score (CS) were evaluated during a one-year follow-up period. We also recorded the incidence of any complications associated with TA.Results: A total of 23 patients (13 males and 10 females; median age 65 years, range 5-91 years) were included. The mean VRR at 1, 3, 6, and 12 months after TA was 37.03%±10.23%, 56.52%±8.76%, 82.28%±7.89%, and 89.39%±6.45%, respectively. Mean CS also changed from 3.39 ± 0.66 to 1.75 ± 0.93 (p < 0.001) by the end of follow-up time. Subgroup analysis showed that tumors with smaller initial maximum diameter had a faster CS reduction rate than those with larger initial diameter. The incidence of facial nerve dysfunction was 8.70%.Conclusion: Ultrasound-guided percutaneous TA is an effective and safe treatment option for patients with benign parotid tumors.

Preclinical Evaluation of a New Series of Albumin-Binding 177Lu-Labeled PSMA-Based Low-Molecular-Weight Radiotherapeutics.

Prostate-specific membrane antigen (PSMA)-based low-molecular-weight agents using beta(ß)-particle-emitting radiopharmaceuticals is a new treatment paradigm for patients with metastatic castration-resistant prostate cancer. Although results have been encouraging, there is a need to improve the tumor residence time of current PSMA-based radiotherapeutics. Albumin-binding moieties have been used strategically to enhance the tumor uptake and retention of existing PSMA-based investigational agents. Previously, we developed a series of PSMA-based, ß-particle-emitting, low-molecular-weight compounds. From this series, 177Lu-L1 was selected as the lead agent because of its reduced off-target radiotoxicity in preclinical studies. The ligand L1 contains a PSMA-targeting Lys-Glu urea moiety with an N-bromobenzyl substituent in the ε-amino group of Lys. Here, we structurally modified 177Lu-L1 to improve tumor targeting using two known albumin-binding moieties, 4-(p-iodophenyl) butyric acid moiety (IPBA) and ibuprofen (IBU), and evaluated the effects of linker length and composition. Six structurally related PSMA-targeting ligands (Alb-L1-Alb-L6) were synthesized based on the structure of 177Lu-L1. The ligands were assessed for in vitro binding affinity and were radiolabeled with 177Lu following standard protocols. All 177Lu-labeled analogs were studied in cell uptake and selected cell efficacy studies. In vivo pharmacokinetics were investigated by conducting tissue biodistribution studies for 177Lu-Alb-L2-177Lu-Alb-L6 (2 h, 24 h, 72 h, and 192 h) in male NSG mice bearing human PSMA+ PC3 PIP and PSMA- PC3 flu xenografts. Preliminary therapeutic ratios of the agents were estimated from the area under the curve (AUC0-192h) of the tumors, blood, and kidney uptake values. Compounds were obtained in >98% radiochemical yields and >99% purity. PSMA inhibition constants (Kis) of the ligands were in the ≤10 nM range. The long-linker-based agents, 177Lu-Alb-L4 and 177Lu-Alb-L5, displayed significantly higher tumor uptake and retention (p < 0.001) than the short-linker-bearing 177Lu-Alb-L2 and 177Lu-Alb-L3 and a long polyethylene glycol (PEG) linker-bearing agent, 177Lu-Alb-L6. The area under the curve (AUC0-192h) of the PSMA+ PC3 PIP tumor uptake of 177Lu-Alb-L4 and 177Lu-Alb-L5 were >4-fold higher than 177Lu-Alb-L2, 177Lu-Alb-L3, and 177Lu-Alb-L6, respectively. Also, the PSMA+ PIP tumor uptake (AUC0-192h) of 177Lu-Alb-L2 and 177Lu-Alb-L3 was ~1.5-fold higher than 177Lu-Alb-L6. However, the lowest blood AUC0-192h and kidney AUC0-192h were associated with 177Lu-Alb-L6 from the series. Consequently, 177Lu-Alb-L6 displayed the highest ratios of AUC(tumor)-to-AUC(blood) and AUC(tumor)-to-AUC(kidney) values from the series. Among the other agents, 177Lu-Alb-L4 demonstrated a nearly similar ratio of AUC(tumor)-to-AUC(blood) as 177Lu-Alb-L6. The tumor-to-blood ratio was the dose-limiting therapeutic ratio for all of the compounds. Conclusions: 177Lu-Alb-L4 and 177Lu-Alb-L6 showed high tumor uptake in PSMA+ tumors and tumor-to-blood ratios. The data suggest that linker length and composition can be modulated to generate an optimized therapeutic agent.

Hetero-bivalent agents targeting FAP and PSMA.

PURPOSE: We developed a theranostic radiopharmaceutical that engages two key cell surface proteases, fibroblast activation protein alpha (FAP) and prostate-specific membrane antigen (PSMA), each frequently overexpressed within the tumor microenvironment (TME). The latter is also expressed in most prostate tumor epithelium. To engage a broader spectrum of cancers for imaging and therapy, we conjugated small-molecule FAP and PSMA-targeting moieties using an optimized linker to provide 64Cu-labeled compounds. METHODS: We synthesized FP-L1 and FP-L2 using two linker constructs attaching the FAP and PSMA-binding pharmacophores. We determined in vitro inhibition constants (Ki) for FAP and PSMA. Cell uptake assays and flow cytometry were conducted in human glioma (U87), melanoma (SK-MEL-24), prostate cancer (PSMA + PC3 PIP and PSMA - PC3 flu), and clear cell renal cell carcinoma lines (PSMA + /PSMA - 786-O). Quantitative positron emission tomography/computed tomography (PET/CT) and tissue biodistribution studies were performed using U87, SK-MEL-24, PSMA + PC3 PIP, and PSMA + 786-O experimental xenograft models and the KPC genetically engineered mouse model of pancreatic cancer. RESULTS: 64Cu-FP-L1 and 64Cu-FP-L2 were produced in high radiochemical yields (> 98%) and molar activities (> 19 MBq/nmol). Ki values were in the nanomolar range for both FAP and PSMA. PET imaging and biodistribution studies revealed high and specific targeting of 64Cu-FP-L1 and 64Cu-FP-L2 for FAP and PSMA. 64Cu-FP-L1 displayed more favorable pharmacokinetics than 64Cu-FP-L2. In the U87 tumor model at 2 h post-injection, tumor uptake of 64Cu-FP-L1 (10.83 ± 1.02%ID/g) was comparable to 64Cu-FAPI-04 (9.53 ± 2.55%ID/g). 64Cu-FP-L1 demonstrated high retention 5.34 ± 0.29%ID/g at 48 h in U87 tumor. Additionally, 64Cu-FP-L1 showed high retention in PSMA + PC3 PIP tumor (12.06 ± 0.78%ID/g at 2 h and 10.51 ± 1.82%ID/g at 24 h). CONCLUSIONS: 64Cu-FP-L1 demonstrated high and specific tumor targeting of FAP and PSMA. This compound should enable imaging of lesions expressing FAP, PSMA, or both on the tumor cell surface or within the TME. FP-L1 can readily be converted into a theranostic for the management of heterogeneous tumors.

A Unique Core-Shell Structured, Glycol Chitosan-Based Nanoparticle Achieves Cancer-Selective Gene Delivery with Reduced Off-Target Effects.

The inherent instability of nucleic acids within serum and the tumor microenvironment necessitates a suitable vehicle for non-viral gene delivery to malignant lesions. A specificity-conferring mechanism is also often needed to mitigate off-target toxicity. In the present study, we report a stable and efficient redox-sensitive nanoparticle system with a unique core-shell structure as a DNA carrier for cancer theranostics. Thiolated polyethylenimine (PEI-SH) is complexed with DNA through electrostatic interactions to form the core, and glycol chitosan-modified with succinimidyl 3-(2-pyridyldithio)propionate (GCS-PDP) is grafted on the surface through a thiolate-disulfide interchange reaction to form the shell. The resulting nanoparticles, GCS-PDP/PEI-SH/DNA nanoparticles (GNPs), exhibit high colloid stability in a simulated physiological environment and redox-responsive DNA release. GNPs not only show a high and redox-responsive cellular uptake, high transfection efficiency, and low cytotoxicity in vitro, but also exhibit selective tumor targeting, with minimal toxicity, in vivo, upon systemic administration. Such a performance positions GNPs as viable candidates for molecular-genetic imaging and theranostic applications.

Imaging of Fibroblast Activation Protein in Cancer Xenografts Using Novel (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine-Based Small Molecules.

Fibroblast activation protein (FAP) has become a favored target for imaging and therapy of malignancy. We have synthesized and characterized two new (4-quinolinoyl)-glycyl-2-cyanopyrrolidine-based small molecules for imaging of FAP, QCP01 and [111In]QCP02, using optical and single-photon computed tomography/CT, respectively. Binding of imaging agents to FAP was assessed in six human cancer cell lines of different cancer types: glioblastoma (U87), melanoma (SKMEL24), prostate (PC3), NSCLC (NCIH2228), colorectal carcinoma (HCT116), and lung squamous cell carcinoma (NCIH226). Mouse xenograft models were developed with FAP-positive U87 and FAP-negative PC3 cells to test pharmacokinetics and binding specificity in vivo. QCP01 and [111In]QCP02 demonstrated nanomolar inhibition of FAP at Ki values of 1.26 and 16.20 nM, respectively. Both were selective for FAP over DPP-IV, a related serine protease. Both enabled imaging of FAP-expressing tumors specifically in vivo. [111In]QCP02 showed high uptake at 18.2 percent injected dose per gram in the U87 tumor at 30 min post-administration.

Contrast-Enhanced Ultrasound Guided Transoral Core Needle Biopsy: A Novel, Safe and Well-Tolerated Procedure for Obtaining High-Quality Tissue in Patients with Oral Cancer.

The aim of the prospective study described here was to compare the tolerability, safety and diagnostic value of contrast-enhanced ultrasound-guided transoral core needle biopsy (CEUS-CNB) with that of conventional US-guided transoral CNB (US-CNB) and standard incisional biopsy in patients with oral masses. Between June 2017 and November 2019, consecutive patients with oral masses referred for biopsy were randomly assigned to undergo incisional biopsy, US-CNB or CEUS-CNB. Procedure time, intra­operative blood loss volume, diagnostic performance and pain level before and after the procedure assessed by visual analogue score (VAS) were recorded and compared among the three procedures. Finally, 238 patients with pathology confirmation were analyzed: 80 patients underwent incisional biopsy, 78 patients US-CNB and 80 patients CEUS-CNB. In this study, no significant difference was found in biopsy time between CEUS-CNB, US-CNB and incisional biopsy (75 ± 11 s vs. 73.6 ± 12 s vs. 77 ± 13 s, p = 0.24). CEUS-CNB achieved the highest sensitivity (CEUS-CNB: 100%, US-CNB: 88.5%, incisional biopsy: 84.3%), negative predictive value (CEUS-CNB: 100%, US-CNB: 81.3%, incisional biopsy: 78.4%) and accuracy (CEUS-CNB: 100%, US-CNB: 92.3%, incisional biopsy: 90%). The VAS score for incision biopsy was higher (p = 0.01) and the amount of bleeding was larger (p < 0.001), yet there was no significant difference between CEUS-CNB and US-CNB. Our results indicate CEUS-guided transoral CNB is an efficient, safe and well-tolerated procedure, with biopsy time comparable to and diagnostic performance better than those of conventional US-guided transoral CNB and incisional biopsy.

Computer-aided diagnosis system of thyroid nodules ultrasonography: Diagnostic performance difference between computer-aided diagnosis and 111 radiologists.

To evaluate the diagnostic efficiency of computer-aided diagnosis (CAD) system and 111 radiologists with different experience in identifying benign and malignant thyroid nodules, and to summarize the ultrasound features that may affect the diagnostic of CAD and radiologists.Fifty thyroid nodules and 111 radiologists were enrolled in this study. All the 50 nodules were diagnosed by the 111 radiologists and the CAD system simultaneously. The diagnostic performance of the CAD system, senior and junior radiologists with the maximum accuracy were calculated and compared. Interobserver agreement for different ultrasound characteristics between the CAD and senior radiologist were analyzed.CAD system showed a higher specificity than junior radiologist (87.5% vs 70.4%, P = .03), and a lower sensitivity than the senior radiologist and junior radiologist but the statistics were not significant (76.9% vs 86.9%, P > .5; 76.9% vs 82.6%, P > .5). The CAD system and senior radiologist got larger AUC than junior radiologist but the differences were not statistically significant (0.82 vs 0.76, respectively; P = .5). The interobserver agreement for the US characteristics between the CAD system and senior radiologist were: substantial agreement for hypoechoic and taller than wide (kappa value = 0.66, 0.78), and moderate agreement for irregular margin and micro-calcifications (kappa value = 0.52, 0.42).The CAD system achieved equal diagnostic accuracy to the senior radiologists and higher accuracy than the junior radiologists. The interobserver agreements in the US features between the CAD system and senior radiologist were substantial agreement for hypoechoic and taller than wide; moderate agreement for irregular margin and micro-calcifications. The location of a thyroid nodule and the feature of macrocalcification with wide acoustic shadow may influence the analysis of the CAD system.

Contrast-enhanced ultrasound-guided celiac plexus neurolysis in patients with upper abdominal cancer pain: initial experience.

OBJECTIVES: The purpose of this study was to determine the efficacy and safety of contrast-enhanced ultrasound (CEUS)-guided celiac plexus neurolysis (CPN) in patients with upper abdominal cancer pain. METHODS: Thirty-five patients with upper abdominal cancers tortured by intractable upper abdominal pain underwent CEUS-guided CPN with ethanol. The pain alleviation and opioid intake were observed and evaluated during a 3-month follow-up after CPN. The dispersion of alcohol around the aorta was evaluated on 3D-CEUS. Complications were assessed during CPN and at follow-up. RESULTS: All of the 35 patients' CPN was successfully achieved. Pain relief was observed in 28 (80%), 20 (57.1%), 27 (77.1%), 20 (57.1%), and 10 (29.4%) patients immediately, 1 day, 1 month, 2 months, and 3 months after CPN, respectively. The agent dispersion around the aorta on CEUS images of 28 patients who showed pain relief was at least 90° of the circumference around the aorta. The median duration of pain alleviation was 2.7 months (95% confidence interval [CI], 2.5-2.9). Less than half of the patients had minor complications including irritant pain at the puncture site (8 of 35; 22.9%), diarrhea (4 of 35; 11.4%), nausea and vomiting (3 of 35; 8.6%), and post-procedural hypotension (1 of 35; 2.9%). CONCLUSIONS: CEUS-guided CPN is a safe and effective method to alleviate refractory upper abdominal pain in patients with upper abdominal cancers. CEUS image allows the visualization of puncture path and observation of drug dispersion. The pain relief is relevant to the dispersion of neurolytic agent around the aorta. KEY POINTS: • CEUS-guided celiac plexus neurolysis (CPN) is feasible and easy. • It allows direct visualization of the diffusion of the neurolytic agent in the retroperitoneal anatomic space. • CEUS-guided CPN improves safety of CPN by clearly delineating the needle path.

Preliminary study of real-time three-dimensional contrast-enhanced ultrasound of sentinel lymph nodes in breast cancer.

PURPOSE: To investigate the clinical value of real-time three-dimensional contrast-enhanced ultrasound (3D-CEUS) in the detection of sentinel lymph nodes (SLNs) and drainage lymphatics in breast cancer patients. METHOD: The prospective study was performed in women with pathology-confirmed T1/2 breast cancer between June 2016 and December 2017 who underwent sentinel lymph node biopsy and 3D-CEUS. The number, size, location, enhancement pattern of SLNs, and the lymphatic drainage patterns were reviewed. The routes, location of SLNs, and lymph channels (LCs) on the surface were marked. All patients underwent blue dye-guided sentinel lymph node biopsy (SLNB) finally. RESULTS: According to the postoperative pathology findings and the blue dye staining of the lymphatic drainage routes, there are six patterns of lymphatic drainage routes and the coincidence rate of the 3D-CEUS was 97.4%; the sensitivity, specificity, positive predictive value, negative predictive value, the LN detection rate, and the correct diagnosis rate of the 3D-CEUS were 75%, 93.0%, 81.8%, 89.9%, 95.3%, and 87.7%, respectively. CONCLUSION: 3D-CEUS is a new feasible and useful approach to detect the SLNs and LCs. 3D-CEUS can accurately localize the LCs and SLNs and estimate the presence of metastatic lymph nodes. KEY POINTS: • The three-dimensional contrast-enhanced ultrasound can detect the sentinel lymph nodes. • The three-dimensional contrast-enhanced ultrasound can show the stereo direction of sentinel lymph nodes and lymph drainage routes. • The three-dimensional contrast-enhanced ultrasound can accurately localize the LCs and SLNs and estimate the presence of metastatic lymph nodes.

Evaluation of a machine learning algorithm for up to 48-hour advance prediction of sepsis using six vital signs.

OBJECTIVE: Sepsis remains a costly and prevalent syndrome in hospitals; however, machine learning systems can increase timely sepsis detection using electronic health records. This study validates a gradient boosted ensemble machine learning tool for sepsis detection and prediction, and compares its performance to existing methods. MATERIALS AND METHODS: Retrospective data was drawn from databases at the University of California, San Francisco (UCSF) Medical Center and the Beth Israel Deaconess Medical Center (BIDMC). Adult patient encounters without sepsis on admission, and with at least one recording of each of six vital signs (SpO2, heart rate, respiratory rate, temperature, systolic and diastolic blood pressure) were included. We compared the performance of the machine learning algorithm (MLA) to that of commonly used scoring systems. Area under the receiver operating characteristic (AUROC) curve was our primary measure of accuracy. MLA performance was measured at sepsis onset, and at 24 and 48 h prior to sepsis onset. RESULTS: The MLA achieved an AUROC of 0.88, 0.84, and 0.83 for sepsis onset and 24 and 48 h prior to onset, respectively. These values were superior to those of SIRS (0.66), MEWS (0.61), SOFA (0.72), and qSOFA (0.60) at time of onset. When trained on UCSF data and tested on BIDMC data, sepsis onset AUROC was 0.89. DISCUSSION AND CONCLUSION: The MLA predicts sepsis up to 48 h in advance and identifies sepsis onset more accurately than commonly used tools, maintaining high performance for sepsis detection when trained and tested on separate datasets.

Follow-up evaluation with ultrasonography of peripheral nerve injuries after an earthquake.

Published data on earthquake-associated peripheral nerve injury is very limited. Ultrasonography has been proven to be efficient in the clinic to diagnose peripheral nerve injury. The aim of this study was to assess the role of ultrasound in the evaluation of persistent peripheral nerve injuries 1 year after the Wenchuan earthquake. Thirty-four patients with persistent clinical symptoms and neurologic signs of impaired nerve function were evaluated with sonography prior to surgical repair. Among 34 patients, ultrasonography showed that 48 peripheral nerves were entrapped, and 11 peripheral nerves were disrupted. There was one case of misdiagnosis on ultrasonography. The concordance rate of ultrasonographic findings with those of surgical findings was 98%. A total of 48 involved nerves underwent neurolysis and the symptoms resolved. Only five nerves had scar tissue entrapment. Preoperative and postoperative clinical and ultrasonographic results were concordant, which verified that ultrasonography is useful for preoperative diagnosis and postoperative evaluation of injured peripheral nerves.