Assessment of PD-L1 Expression in Non-Small Cell Lung Cancers Using [68Ga]Ga-DOTA-WL12 PET/CT.

Assessing programmed death ligand-1 (PD-L1) expression in non-small cell lung cancer (NSCLC), particularly in metastatic cases, remains challenging. In this study, surface plasmon resonance (SPR) analysis and [68Ga]Ga-DOTA-WL12 micro-PET/CT imaging are performed. [68Ga]Ga-DOTA-WL12 PET/CT and [18F]FDG PET/CT are performed on a cohort of 20 patients with NSCLC. Semi-quantitative assessments include SUVmax, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and target-to-background ratio (TBR). DOTA-WL12 exhibits robust PD-L1 binding with a KD value of 0.2 nM. Subsequent human studies reveal significant correlations between PD-L1 expression and the [68Ga]Ga-DOTA-WL12 SUVmax in primary and metastatic lesions, surpassing the [18F]FDG results (r = 0.8889, p <0.0001 vs r = 0.0469, p = 0.8127). Notably, [68Ga]Ga-DOTA-WL12 imaging discerned SUVmax and TBR differences between PD-L1 TPS ≤1% and PD-L1 TPS > 1% groups (p all <0.001). In an NSCLC patient with brain metastases, [68Ga]Ga-DOTA-WL12 shows a SUVmean of 0.04 in the brain background, with TBR values of 17 and 23, underscoring its potential for detecting brain metastases. The study provides initial evidence for the clinical utility of [68Ga]Ga-DOTA-WL12 PET/CT for lesion detection, immunotherapy selection, and therapeutic efficacy evaluation in PD-L1-expressing NSCLC, demonstrating its potential as a valuable tool in NSCLC research and management.

Category Switching Test: A Brief Amyloid-ß-Sensitive Assessment Tool for Mild Cognitive Impairment.

The Category Switching Test (CaST) is a verbal fluency test with active semantic category switching. This study aimed to explore the association between CaST performance and brain amyloid-ß (Aß) burden in patients with mild cognitive impairment (MCI) and the neurofunctional mechanisms. A total of 112 participants with MCI underwent Florbetapir positron emission tomography, resting-state functional magnetic resonance imaging, and a neuropsychological test battery. The high Aß burden group had worse CaST performance than the low-burden group. CaST score and left middle temporal gyrus fractional amplitude of low-frequency fluctuations (fALFF) related inversely to the global Florbetapir standardized uptake value rate. Functional connectivity between the left middle temporal gyrus and frontal lobe decreased widely and correlated with CaST score in the high Aß burden group. Thus, CaST score and left middle temporal gyrus fALFF were valuable in discriminating high Aß burden. CaST might be useful in screening for MCI with high Aß burden.

Chronic cauda equina syndrome decompression surgery recovery is very "bad"? Based on patient self-assessment.

BACKGROUND: Symptoms of cauda equina syndrome (CES) secondary to degenerative lumbar spine diseases are sometimes mild and tend to be ignored by patients, resulting in delayed treatment. In addition, the long-term efficacy of surgery is unclear. OBJECTIVE: To determine the predictive factors of CES and post-operative recovery in patients with symptoms lasting > 3 months. METHODS: From January 2011 to December 2020, data of 45 patients with CES secondary to lumbar disk herniation/lumbar spinal stenosis were collected from a single center. The patients had bladder, bowel or sexual dysfunction and decreased perineal sensation that lasted for > 3 months. A 2-year post-operative follow-up was conducted to evaluate recovery outcomes, which were measured by validated self-assessment questionnaires conducted by telephone and online. RESULTS: Overall, 45 CES patients (57.8% female; mean age, 56 years) were included. The duration of pre-operative CES symptoms was 79.6 weeks (range, 13-730 weeks). The incidence of saddle anesthesia before decompression was 71.1% (n = 32), bladder dysfunction 84.4% (n = 38), bowel dysfunction 62.2% (n = 28) and sexual dysfunction 64.4% (n = 29). The overall recovery rate of CES after a 2-year follow-up was 64.4%. The rates of the residual symptoms at the last follow-up were as follows: saddle anesthesia 22.2%, bladder dysfunction 33.3%, bowel dysfunction 24.4% and sexual dysfunction 48.9%. Pre-operative saddle anesthesia, overactive bladder and sexual dysfunction were risk factors for poor prognosis after decompression. CONCLUSION: CES patients with symptoms lasting > 3 months may recover after surgery. Sexual dysfunction has a high residual rate and should not be ignored during diagnosis and treatment.

Differential diagnosis and feature visualization for thyroid nodules using computer-aided ultrasonic diagnosis system: initial clinical assessment.

BACKGROUND: To assess the diagnostic efficacy of the computer-aided ultrasonic diagnosis system (CAD system) in differentiating benign and malignant thyroid nodules. METHODS: The images of 296 thyroid nodules were included in validation sets. The diagnostic efficacy of the CAD system was compared with that of junior physicians and senior physicians, as well as that of the combination diagnosis of the CAD system with junior physicians. The diagnostic efficacy of the CAD system for different sizes of thyroid nodules was compared. RESULTS: The diagnostic sensitivity and accuracy of the CAD system were higher than those of junior physicians (83.4% vs. 72.2%, 73.0% vs. 69.6%), but the diagnostic specificity of the CAD system was lower than that of junior physicians (62.1% vs. 66.9%). The diagnostic accuracy of the CAD system was lower than that of senior physicians (73.0% vs. 83.8%). However, the combination diagnosis of the CAD system with junior physicians had higher accuracy (81.8%) and AUC (0.842) than those of either the CAD system or junior physicians alone, and comparable diagnostic performance with those of senior physicians. The Kappa was 0.635 in the combination diagnosis of the CAD system with junior physicians, showing good consistency with the pathological results. The accuracy (76.4%) of the CAD system was the highest for nodules of 1-2 cm. CONCLUSION: The CAD system can effectively assist physicians to identify malignant and benign thyroid nodules, reduce the overdiagnosis and overtreatment of thyroid nodules, avoid unnecessary invasive fine needle aspiration, and improve the diagnostic accuracy of junior physicians.

Automation of Monte Carlo-based treatment plan verification for proton therapy.

PURPOSE: Independent calculations of proton therapy plans are an important quality control procedure in treatment planning. When using custom Monte Carlo (MC) models of the beamline, deploying the calculations can be laborious, time consuming, and require in-depth knowledge of the computational environment. We developed an automated framework to remove these barriers and integrate our MC model into the clinical workflow. MATERIALS AND METHODS: The Eclipse Scripting Application Programming Interface was used to initiate the automation process. A series of MATLAB scripts were then used for preprocessing of input data and postprocessing of results. Additional scripts were used to monitor the calculation process and appropriately deploy calculations to an institutional high-performance computing facility. The automated framework and beamline models were validated against 160 patient specific QA measurements from an ionization chamber array and using a ±3%/3 mm gamma criteria. RESULTS: The automation reduced the human-hours required to initiate and run a calculation to 1-2 min without leaving the treatment planning system environment. Validation comparisons had an average passing rate of 99.4% and were performed at depths ranging from 1 to 15 cm. CONCLUSION: An automated framework for running MC calculations was developed which enables the calculation of dose and linear energy transfer within a clinically relevant workflow and timeline. The models and framework were validated against patient specific QA measurements and exhibited excellent agreement. Before this implementation, execution was prohibitively complex for an untrained individual and its use restricted to a research environment.

Real-time shear wave elastography (SWE) assessment of short- and long-term treatment outcome in Budd-Chiari syndrome: A pilot study.

PURPOSE: The first aim of this study was to analyze the relationships between liver stiffness measurement, hepatic venous pressure and liver fibrosis. The second aim was to demonstrate the utility of real-time shear wave elastography for evaluation of Budd-Chiari syndrome patients before and after balloon hepatic venous angioplasty. MATERIALS AND METHODS: A total of 32 patients with Budd-Chiari syndrome slated for successful balloon angioplasty met the inclusion and exclusion criteria. Shear wave elastography was used to generate dynamic liver stiffness measurement 2 days before angioplasty and 2 days, 3 months, and 6 months after angioplasty. Hepatic venous pressures were measured during balloon angioplasty. Correlations among liver stiffness, hepatic venous pressure, and fibrosis were assessed. RESULT: Mean liver stiffness was 35.17 ± 10.60 kPa, 20.15 ± 5.47 kPa, 15.36 ± 4.34 kPa and 15.68 ± 5.58 kPa at baseline and 2 days, 3 months, and 6 months after angioplasty, respectively. Liver stiffness measured at 2 days and 3 months after angioplasty was significantly decreased (P < 0.001); liver stiffness measured at 6 months after angioplasty was not significantly different from that measured at 3 months after angioplasty (P = 0.636). Analysis of liver stiffness measurement and hepatic venous pressure before balloon angioplasty yielded a coefficient of correlation r = 0.701 (P < 0.001). Before and 2d after angioplasty, liver stiffness measurement did not correlated with fibrosis (r = - 0.170, P = 0.22), (r = 0.223, P = 0.220), respectively, while the LSM difference before and 2 days after angioplasty negatively correlated with stiffness severity (r = - 0.502, P = 0.003). Liver stiffness measured at 2 days and 3 months after angioplasty was significantly decreased (P < 0.001), remaining stable at 3 months, though still in the cirrhotic range. CONCLUSIONS: The liver stiffness of Budd-Chiari syndrome patients, measured by shear wave elastography, decreased considerably after hepatic venous recanalization, and significantly correlated with hepatic venous pressure though not with degree of fibrosis. Shear wave elastography may be effective in monitoring short- and long-term treatment outcomes in Budd-Chiari syndrome.

Repeatability of the "flash-replenishment" method in contrast-enhanced ultrasound for the quantitative assessment of hepatic microvascular perfusion.

This study aimed to evaluate the feasibility and repeatability of the flash-replenishment method in contrast-enhanced ultrasound (CEUS) perfusion imaging and assess quantitatively microvascular perfusion in the liver. Twenty healthy New Zealand rabbits were submitted to CEUS perfusion imaging with continuous intravenous infusion. Using flash-replenishment kinetics, the dynamic process of depletion and refilling of microbubble contrast agent was recorded. The hepatic microvascular perfusion parameters were calculated, including region of interest, peak intensity (PI), area under the curve (AUC), and hepatic artery to vein transit time (HA-HVTT). A consistency test was performed for multiple measurements by the same operator and blind measurements by two different operators. The hepatic perfusion imaging of 3×108 bubbles/min had minimal error and the best imaging effect and repeatability. The variability of the perfusion parameter measured at 3 cm depth under the liver capsule was at a minimum with coefficient of variation of 3.9%. The interclass correlation coefficient (ICC) of measurements taken by the same operator was 0.985, (95% confidence interval, CI=0.927-0.998). Measurements taken by two operators had good consistency and reliability, with the ICC of 0.948 (95%CI=0.853-0.982). The PI and AUC of liver parenchyma after reperfusion were lower than before blocking; and HA-HVTT was significantly longer than before blocking (P<0.05). The flash-replenishment method in CEUS perfusion imaging showed good stability and repeatability, which provide a valuable experimental basis for the quantitative assessment of hepatic microvascular perfusion in clinical practice.

Repeatability of the "flash-replenishment" method in contrast-enhanced ultrasound for the quantitative assessment of hepatic microvascular perfusion

This study aimed to evaluate the feasibility and repeatability of the flash-replenishment method in contrast-enhanced ultrasound (CEUS) perfusion imaging and assess quantitatively microvascular perfusion in the liver. Twenty healthy New Zealand rabbits were submitted to CEUS perfusion imaging with continuous intravenous infusion. Using flash-replenishment kinetics, the dynamic process of depletion and refilling of microbubble contrast agent was recorded. The hepatic microvascular perfusion parameters were calculated, including region of interest, peak intensity (PI), area under the curve (AUC), and hepatic artery to vein transit time (HA-HVTT). A consistency test was performed for multiple measurements by the same operator and blind measurements by two different operators. The hepatic perfusion imaging of 3×108 bubbles/min had minimal error and the best imaging effect and repeatability. The variability of the perfusion parameter measured at 3 cm depth under the liver capsule was at a minimum with coefficient of variation of 3.9%. The interclass correlation coefficient (ICC) of measurements taken by the same operator was 0.985, (95% confidence interval, CI=0.927-0.998). Measurements taken by two operators had good consistency and reliability, with the ICC of 0.948 (95%CI=0.853-0.982). The PI and AUC of liver parenchyma after reperfusion were lower than before blocking; and HA-HVTT was significantly longer than before blocking (P<0.05). The flash-replenishment method in CEUS perfusion imaging showed good stability and repeatability, which provide a valuable experimental basis for the quantitative assessment of hepatic microvascular perfusion in clinical practice.

Radiopharmaceuticals for Assessment of Altered Metabolism and Biometal Fluxes in Brain Aging and Alzheimer's Disease with Positron Emission Tomography.

Aging is a risk factor for Alzheimer's disease (AD). There are changes of brain metabolism and biometal fluxes due to brain aging, which may play a role in pathogenesis of AD. Positron emission tomography (PET) is a versatile tool for tracking alteration of metabolism and biometal fluxes due to brain aging and AD. Age-dependent changes in cerebral glucose metabolism can be tracked with PET using 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG), a radiolabeled glucose analogue, as a radiotracer. Based on different patterns of altered cerebral glucose metabolism, 18F-FDG PET was clinically used for differential diagnosis of AD and Frontotemporal dementia (FTD). There are continued efforts to develop additional radiopharmaceuticals or radiotracers for assessment of age-dependent changes of various metabolic pathways and biometal fluxes due to brain aging and AD with PET. Elucidation of age-dependent changes of brain metabolism and altered biometal fluxes is not only significant for a better mechanistic understanding of brain aging and the pathophysiology of AD, but also significant for identification of new targets for the prevention, early diagnosis, and treatment of AD.

Risk assessment models to evaluate the necessity of prostate biopsies in North Chinese patients with 4-50 ng/mL PSA.

BACKGROUND: Prostate-specific antigen (PSA) is widely used for prostate cancer screening, but low specificity results in high false positive rates of prostate biopsies. OBJECTIVE: To develop new risk assessment models to overcome the diagnostic limitation of PSA and reduce unnecessary prostate biopsies in North Chinese patients with 4-50 ng/mL PSA. METHODS: A total of 702 patients in seven hospitals with 4-10 and 10-50 ng/mL PSA, respectively, who had undergone transrectal ultrasound-guided prostate biopsies, were assessed. Analysis-modeling stage for several clinical indexes related to prostate cancer and renal function was carried out. Multiple logistic regression analyses were used to develop new risk assessment models of prostate cancer for both PSA level ranges 4-10 and 10-50 ng/mL. External validation stage of the new models was performed to assess the necessity of biopsy. RESULTS: The new models for both PSA ranges performed significantly better than PSA for detecting prostate cancers. Both models showed higher areas under the curves (0.937 and 0.873, respectively) compared with PSA alone (0.624 and 0.595), at pre-determined cut-off values of 0.1067 and 0.6183, respectively. Patients above the cut-off values were recommended for immediate biopsy, while the others were actively observed. External validation of the models showed significantly increased detection rates for prostate cancer (4-10 ng/mL group, 39.29% vs 17.79%, p=0.006; 10-50 ng/mL group, 71.83% vs 50.0%, p=0.015). CONCLUSIONS: We developed risk assessment models for North Chinese patients with 4-50 ng/mL PSA to reduce unnecessary prostate biopsies and increase the detection rate of prostate cancer.

Electroencephalogram assessment of mental fatigue in visual search.

Mental fatigue is considered to be a contributing factor responsible for numerous road accidents and various medical conditions and the efficiency and performance could be impaired during fatigue. Hence, determining how to evaluate mental fatigue is very important. In the present study, ten subjects performed a long-term visual search task with electroencephalogram recorded, and self-assessment and reaction time (RT) were combined to verify if mental fatigue had been induced and were also used as confirmatory tests for the proposed measures. The changes in relative energy in four wavebands (δ,θ,α, and ß), four ratio formulas [(α+θ)/ß,α/ß,(α+θ)/(α+ß), and θ/ß], and Shannon's entropy (SE) were compared and analyzed between the beginning and end of the task. The results showed that a significant increase occurred in alpha activity in the frontal, central, posterior temporal, parietal, and occipital lobes, and a dip occurred in the beta activity in the pre-frontal, inferior frontal, posterior temporal, and occipital lobes. The ratio formulas clearly increased in all of these brain regions except the temporal region, where only α/ß changed obviously after finishing the 60-min visual search task. SE significantly increased in the posterior temporal, parietal, and occipital lobes. These results demonstrate some potential indicators for mental fatigue detection and evaluation, which can be applied in the future development of countermeasures to fatigue.

Bioactivation of the nasal toxicant 2,6-dichlorobenzonitrile: an assessment of metabolic activity in human nasal mucosa and identification of indicators of exposure and potential toxicity.

The herbicide 2,6-dichlorobenzonitrile (DCBN) is a potent nasal toxicant in rodents; however, it is not known whether DCBN causes similar nasal toxicity in humans. The tissue-selective toxicity of DCBN in mouse nasal mucosa is largely dependent on target tissue bioactivation by CYP2A5. The human orthologues of CYP2A5, CYP2A6 and CYP2A13, are both expressed in nasal mucosa and are capable of activating DCBN. In this study, we directly determined the ability of human nasal mucosa to bioactivate DCBN. We also tested the suitability of a glutathione conjugate of DCBN (GS-DCBN) or its derivatives as biomarkers of DCBN exposure and nasal toxicity in mouse models. We found that human fetal nasal mucosa microsomes catalyze the formation of GS-DCBN, with a Km value comparable to that of adult mouse nasal mucosa microsomes. The activity of the human nasal mucosa microsomes was inhibited by 8-methoxypsoralen, a known CYP2A inhibitor. GS-DCBN and its metabolites were detected in the nasal mucosa and nasal-wash fluid obtained from DCBN-treated mice, in amounts that increased with escalations in DCBN dose, and they were all still detectable at 24 h after a DCBN treatment (at 10 mg/kg). Further studies in Cyp2a5-null mice indicated that GS-DCBN and its metabolites in nasal-wash fluid were generated in the nasal mucosa, rather than in other organs. Thus, our data indicate for the first time that the human nasal mucosa is capable of bioactivating DCBN and that GS-DCBN and its metabolites in nasal-wash fluid may collectively serve as indicators of DCBN exposure and potential nasal toxicity in humans.

Assessment of the relative potency of fentanyl buccal tablet to intravenous morphine in healthy volunteers using a thermally induced hyperalgesia pain model.

This exploratory randomized, double-blind, placebo-controlled, 5-treatment, 5-period crossover study was conducted using a thermally induced hyperalgesia pain model in 51 healthy volunteers (33 evaluable) to characterize the relative potency of fentanyl buccal tablet (FBT) versus intravenous morphine. Relative potency was assessed using the sum of pain intensity differences over 60 minutes after the application of a 43°C, 46°C, and 49°C painful stimulus following thermally induced hyperalgesia. Relative potency was also assessed by pupil diameter and responses to subjective questionnaires. The relative potency of FBT was 46.2 times that of intravenous morphine (95% confidence interval [CI], 17.6-575.3) based on the 49°C stimulus. The relative potency of FBT based on opiate-induced miosis was 44.6 (95% CI, 29.7-77.0) at 60 minutes. These results are an initial relative potency assessment and should not be considered guidance for dose-equivalent switching between agents in clinical practice.

A mathematical model for peptide inhibitor design.

This article presents a mathematical model on the design of peptide inhibitors for proteins. This model is a combination of the two rules on protein-ligand interaction, Miyazawa-Jernigan (M-J) matrix and hidden Markov model (HMM). The model is applied to predict peptide inhibitors for the protein cyclophilin A (CypA) and FKBP12, and then validated by the highest occupied molecular orbital calculation, dock process between protein and inhibitor, and biological experiments. The results are encouraging and suggest that we have taken a step forward towards building a mathematical theory on the design of peptide inhibitors for proteins. The mathematical model is rough at present, but if it represents a correct direction of the theoretical trends of biology as we believe, then this theory can be further developed and become more and more precise.

A clinical evaluation committee assessment of recombinant human tissue factor pathway inhibitor (tifacogin) in patients with severe community-acquired pneumonia.

INTRODUCTION: The purpose of this analysis was to determine the potential efficacy of recombinant human tissue factor pathway inhibitor (tifacogin) in a subpopulation of patients with community-acquired pneumonia (CAP) from a phase III study of severe sepsis. METHODS: A retrospective review of patients with suspected pneumonia was conducted by an independent clinical evaluation committee (CEC) blinded to treatment assignment. The CEC reanalyzed data from patients enrolled in an international multicenter clinical trial of sepsis who had a diagnosis of pneumonia as the probable source of sepsis. The primary efficacy measure was all-cause 28-day mortality. RESULTS: Of 847 patients identified on case report forms with a clinical diagnosis of pneumonia, 780 (92%) were confirmed by the CEC to have pneumonia. Of confirmed pneumonia cases, 496 (63.6%) met the definition for CAP. In the CEC CAP population, the mortality rates of the tifacogin and placebo groups were 70/251 (27.9%) and 80/245 (32.7%), respectively. The strongest signals were seen in patients with CAP not receiving concomitant heparin, having microbiologically confirmed infection, or having the combination of documented infection and no heparin. The reduction in mortality in this narrowly defined subgroup when treated with tifacogin compared with placebo was statistically significant (17/58 [29.3%] with tifacogin and 28/54 [51.9%] with placebo; unadjusted P value of less than 0.02). CONCLUSIONS: Tifacogin administration did not significantly reduce mortality in any severe CAP patient. Exploratory analyses showed an improved survival in patients who did not receive concomitant heparin with microbiologically confirmed infections. These data support the rationale of an ongoing phase III study exploring the potential benefit of tifacogin in severe CAP. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00084071.