Association of higher triglyceride-glucose index and triglyceride-to-high-density lipoprotein cholesterol ratio with early neurological deterioration after thrombolysis in acute ischemic stroke patients.

Background: Insulin resistance (IR) can predict the prognosis of patients suffering from cerebrovascular disorders. The triglyceride-glucose (TyG) index and triglyceride-to-high-density lipoprotein cholesterol (TG/HDL-C) ratio have been confirmed to be easy and reliable indicators of IR. However, the relationships between the TyG index or TG/HDL-C ratio and early neurological deterioration (END) after thrombolysis in patients with acute ischemic stroke (AIS) are uncertain. Methods: A retrospective analysis of 1,187 patients diagnosed with AIS who underwent intravenous thrombolysis between January 2018 and February 2024 was performed. Post-thrombolysis END was defined as an increase in the National Institutes of Health Stroke Scale (NIHSS) score of ≥4 within 24 h after thrombolysis. Logistic regression analysis was performed to explore the relationships of the TyG index and TG/HDL-C ratio with post-thrombolysis END. Receiver operating characteristic (ROC) analysis was used to assess the ability of the TyG index and TG/HDL-C ratio to discriminate post-thrombolysis END. Results: Among the 1,187 recruited patients, 179 (15.08%) were diagnosed with post-thrombolysis END, and 1,008 (84.92%) were diagnosed with non-END. A binary logistic regression model indicated that the TyG index (odds ratio [OR], 2.015; 95% confidence interval [CI] 1.964-2.414, p = 0.015) and TG/HDL-C ratio (OR, 1.542; 95% CI, 1.160-2.049, p = 0.004) were independent factors for post-thrombolysis END. The area under the curve (AUC) values for the TyG index, TG/HDL-C ratio, and TyG index combined with the TG/HDL-C ratio for post-thrombolysis END were 0.704, 0.674, and 0.755, respectively. Conclusion: This study indicates that the TyG index and TG/HDL-C ratio can be used as prognostic factors to predict post-thrombolysis END.

Higher homocysteine and fibrinogen are associated with early-onset post-stroke depression in patients with acute ischemic stroke.

Background: Post-stroke depression (PSD) is a well-established psychiatric complication following stroke. Nevertheless, the relationship between early-onset PSD and homocysteine (Hcy) or fibrinogen remains uncertain. Methods: Acute ischemic stroke (AIS) patients who met the established criteria were enrolled in this study. Early-onset PSD was diagnosed two weeks after the stroke. The severity of depressive symptoms was assessed by the Hamilton Depression Scale-17 items (HAMD-17), with patients scored ≥7 assigned to the early-onset PSD group. Spearman rank correlation analysis was employed to evaluate the associations between Hcy, fibrinogen, and HAMD scores across all patients. Logistic regression analysis was conducted to investigate the relationship between Hcy, fibrinogen, and early-onset PSD. Receiver operating characteristic curve (ROC) analysis was ASSDalso performed to detect the predictive ability of Hcy and fibrinogen for early-onset PSD. Results: Among the 380 recruited patients, a total of 106 (27.89%) patients were diagnosed with early-onset PSD. The univariate analysis suggested that patients in the PSD group had a higher admission National Institutes of Health Stroke Scale (NIHSS) score, modified Rankin Scale score (mRS), Hcy, and fibrinogen levels than patients in the non-PSD group (P<0.05). The logistic regression model indicated that Hcy (odds ratio [OR], 1.344; 95% confidence interval [CI] 1.209-1.494, P<0.001) and fibrinogen (OR, 1.57 6; 95% CI 1.302-1.985, P<0.001) were independently related to early-onset PSD. Area under curve (AUC) of Hcy, fibrinogen, and Hcy combined fibrinogen to predict early-onset PSD was 0.754, 0.698, and 0.803, respectively. Conclusion: This study indicates that Hcy and fibrinogen may be independent risk factors for early-onset PSD and can be used as predictive indicators for early-onset PSD.

Comparison of an Affibody-based Molecular Probe and 18F-FDG for Detecting HER2-Positive Breast Cancer at PET/CT.

Background Human epidermal growth factor receptor 2 (HER2) affibody-based tracers could be an alternative to nonspecific radiotracers for noninvasive detection of HER2 expression in breast cancer lesions at PET/CT. Purpose To compare an affibody-based tracer, Al18F-NOTA-HER2-BCH, and fluorine 18 (18F) fluorodeoxyglucose (FDG) for detecting HER2-positive breast cancer lesions on PET/CT images. Materials and Methods In this prospective study conducted from June 2020 to July 2023, participants with HER2-positive breast cancer underwent both Al18F-NOTA-HER2-BCH and 18F-FDG PET/CT. HER2 positivity was confirmed with pathologic assessment (immunohistochemistry test results of 3+, or 2+ followed by fluorescence in situ hybridization, indicated HER2 amplification). Two independent readers visually assessed the uptake of tracers on images. Lesion uptake was quantified using the maximum standardized uptake value (SUVmax) and target to background ratio (TBR) and compared using a general linear mixed model. Results A total of 42 participants (mean age, 56.3 years ± 10.1 [SD]; 41 female) with HER2-positive breast cancer were included; 42 (100%) had tumors that were detected with Al18F-NOTA-HER2-BCH PET/CT and 40 (95.2%) had tumors detected with 18F-FDG PET/CT. Primary tumors in two of 21 participants, lymph node metastases in four of 21 participants, bone metastases in four of 15 participants, and liver metastases in three of nine participants were visualized only with Al18F-NOTA-HER2-BCH. Lung metastasis in one of nine participants was visualized only with 18F-FDG. Al18F-NOTA-HER2-BCH enabled depiction of more suspected HER2-positive primary tumors (26 vs 21) and lymph node (170 vs 130), bone (92 vs 66), and liver (55 vs 27) metastases than 18F-FDG. The SUVmax and TBR values of primary tumors and lymph node, bone, and liver metastases were all higher on Al18F-NOTA-HER2-BCH images than on 18F-FDG images (median SUVmax range, 10.4-13.5 vs 3.4-6.2; P value range, <.001 to .02; median TBR range, 2.7-17.6 vs 1.2-7.8; P value range, <.001 to .001). No evidence of differences in the SUVmax and TBR for chest wall or lung metastases was observed between Al18F-NOTA-HER2-BCH and 18F-FDG (P value range, .06 to .53). Conclusion PET/CT with the affibody-based tracer Al18F-NOTA-HER2-BCH enabled detection of more primary lesions and lymph node, bone, and liver metastases than PET/CT using 18F-FDG. ClinicalTrials.gov Identifier: NCT04547309 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Ulaner in this issue.

Construction and Application of a PD-L1-Targeted Multimodal Diagnostic and Dual-Functional Theranostics Nanoprobe.

Background: In recent years, PD-L1 has been primarily utilized as an immune checkpoint marker in cancer immunotherapy. However, due to tumor heterogeneity, the response rate to such therapies often falls short of expectations. In addition to its role in immunotherapy, PD-L1 serves as a specific target on the surface of tumor cells for targeted diagnostic and therapeutic interventions. There is an absence of a fully developed PD-L1-targeted diagnostic and therapeutic probe for clinical use, which constrains the exploration and clinical exploitation of this target. Methods and Results: In this study, we engineered a PD-L1-targeted probe with multimodal imaging and dual therapeutic functionalities utilizing organic melanin nanoparticles. Functionalization with the WL12-SH peptide endowed the nanoprobe with specific targeting capabilities. Subsequent radiolabeling with 89Zr (half-life: 100.8 hours) and chelation of Mn2+ ions afforded the probe the capacity for simultaneous PET and MRI imaging modalities. Cellular uptake assays revealed pronounced specificity, with -positive cells exhibiting significantly higher uptake than -negative counterparts (p < 0.05). Dual-modal PET/MRI imaging delineated rapid and sustained accumulation at the neoplastic site, yielding tumor-to-non-tumor (T/NT) signal ratios at 24 hours post-injection of 16.67±3.45 for PET and 6.63±0.64 for MRI, respectively. We conjugated the therapeutic radionuclide 131I (half-life: 8.02 days) to the construct and combined low-dose radiotherapy and photothermal treatment (PTT), culminating in superior antitumor efficacy while preserving a high safety profile. The tumors in the cohort receiving the dual-modality therapy exhibited significantly reduced volume and weight compared to those in the control and monotherapy groups. Conclusion: We developed and applied a novel -targeted multimodal theranostic nanoprobe, characterized by its high specificity and superior imaging capabilities as demonstrated in PET/MRI modalities. Furthermore, this nanoprobe facilitates potent therapeutic efficacy at lower radionuclide doses when used in conjunction with PTT.

Preclinical Evaluation and Pilot Clinical Study of 18F-Labeled Inhibitor Peptide for Noninvasive Positron Emission Tomography Mapping of Angiotensin Converting Enzyme 2.

Angiotensin-converting enzyme 2 (ACE2) is the main molecular target for coronavirus SARS-CoV-2 to enter cells. Molecularly specific tracers that bind to ACE2 with high affinity can be used to determine the tissue distribution of this important receptor, noninvasively. A novel targeting PET imaging probe, [18F]AlF-DX600-BCH, was developed to detect the in vivo expression of ACE2 and monitor response to therapy. Preclinical experiments, including biodistribution, PET imaging, and tissue section analysis, were conducted after tests of in vitro and in vivo stability and pharmacokinetics. The agent was advanced to clinical evaluation in 10 volunteers who received [18F]AlF-DX600-BCH PET/CT at 1 and 2 h after injection (NCT04542863). Preclinical results of both biodistribution and PET demonstrated [18F]AlF-DX600-BCH accumulation in rat kidney (standardized uptake value; SUVkidney/normal > 50), along with specific uptake in testes (SUVtestis/normal > 10) tissues. Kidney, gastrointestinal, and bronchial cell labeling were correlated to ACE2 positive by immunohistochemistry (IHC) staining. In clinical imaging, significant tracer accumulation was predominantly observed in the urinary and reproductive system (SUVrenal cortex = 32.00, SUVtestis = 4.56), and the conjunctiva and nasal mucosa saw elevated uptake in several cases. This work is the first report of a radioisotope probe, [18F]AlF-DX600-BCH, targeting ACE2 with promising preliminary preclinical and translational outlook, thereby demonstrating the potential of noninvasive mapping of ACE2.

Comparison of renal clearance of [18F]AlF-RESCA-HER2-BCH and [18F]AlF-NOTA-HER2-BCH in mice and breast cancer patients.

PURPOSE: A novel HER2 affibody-based molecular probe, [18F]AlF-RESCA-HER2-BCH, was developed for reducing renal uptake, evaluated, and compared with [18F]AlF-NOTA-HER2-BCH. METHODS: In preclinical studies, micro-PET/CT was performed using HER2-positive gastric cancer patient-derived xenografts (PDX) model at 0.5-1 (dynamic), 2, 4, and 6 h post-injection. For blocking experiment, 0.5 mg cold affibody was co-injected with probes. Biodistribution were performed on HER2-positive PDX models at 2 h post-injection. For clinical study, PET/CT images were acquired at 2 h and 4 h after injection of 231.29 ± 17.77 MBq [18F]AlF-NOTA-HER2-BCH or [18F]AlF-RESCA-HER2-BCH in five breast cancer patients (4 HER2-positive and 1 HER2-low). Standardized uptake values (SUVs) were measured in tumors and source-organs for semi-quantitative analysis. The OLINDA/EXM software (version 1.2) was used to calculate the radiation doses. RESULTS: [18F]AlF-NOTA-HER2-BCH and [18F]AlF-RESCA-HER2-BCH were stably labeled with [18F]F, with high binding specificity and affinity to HER2. Micro-PET/CT of both tracers could clearly visualize HER2-positive PDX tumors with high uptake of 16.24 ± 1.74% ID/g and 14.39 ± 2.45% ID/g at 2 h post-injection. The renal accumulation of [18F]AlF-RESCA-HER2-BCH was significantly lower than that of [18F]AlF-NOTA-HER2-BCH (5.16 ± 0.22% ID/g vs. 158.73 ± 5.44% ID/g at 2 h, p < 0.0001). In the clinical study, both [18F]AlF-NOTA-HER2-BCH and [18F]AlF-RESCA-HER2-BCH demonstrated favorable tumor targeting and image contrast. [18F]AlF-RESCA-HER2-BCH showed a higher SUVmax in both primary tumor and metastases, and a significantly higher target-to-nontarget ratio in metastases than [18F]AlF-NOTA-HER2-BCH. Moreover, [18F]AlF-RESCA-HER2-BCH had lower renal accumulation (43.56 ± 7.88 vs. 79.81 ± 3.81 at 2 h, p < 0.0001; 33.23 ± 6.89 vs. 78.63 ± 4.00 at 4 h, p < 0.0001) as well as a significantly lower renal absorbed dose than [18F]AlF-NOTA-HER2-BCH (0.4450 ± 0.1117 mGy/MBq vs. 0.8030 ± 0.1604 mGy/MBq, p < 0.01). CONCLUSIONS: [18F]AlF-RESCA-HER2-BCH tended to provide better image contrast than [18F]AlF-NOTA-HER2-BCH with a higher target-to-nontarget ratio in detection of metastases. Notably, [18F]AlF-RESCA-HER2-BCH had lower renal accumulation than [18F]AlF-NOTA-HER2-BCH.

Diagnostic performance of integrated whole-body 18F-FDG PET/MRI for detecting bone marrow involvement in indolent lymphoma: Comparison with 18F-FDG PET or MRI alone.

Purpose: To investigate the diagnostic performance of integrated whole-body 18F-FDG PET/MRI for detecting bone marrow involvement (BMI) in indolent lymphoma compared with 18F-FDG PET or MRI alone. Methods: Patients with treatment-naive indolent lymphoma who underwent integrated whole-body 18F-FDG PET/MRI and bone marrow biopsy (BMB) were prospectively enrolled. Agreement between PET, MRI, PET/MRI, BMB, and the reference standard was assessed using kappa statistics. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) of each method were calculated. A receiver operating characteristic (ROC) curve was used to determine the area under the curve (AUC). AUCs of PET, MRI, PET/MRI, and BMB were compared using the DeLong test. Results: Fifty-five patients (24 males and 31 females; mean age: 51.1 ± 10.1 years) were included in this study. Of these 55 patients, 19 (34.5%) had BMI. Two patients were upstaged as extra bone marrow lesions were detected via PET/MRI. 97.1% (33/34) of participants were confirmed as BMB-negative in the PET-/MRI-group. PET/MRI (parallel test) and BMB showed excellent agreement with the reference standard (k = 0.843, 0.918), whereas PET and MRI showed moderate agreement (k = 0.554, 0.577). The sensitivity, specificity, accuracy, PPV, and NPV for identifying BMI in indolent lymphoma were 52.6%, 97.2%, 81.8%, 90.9%, and 79.5%, respectively, for PET; 63.2%, 91.7%, 81.8%, 80.0%, and 82.5%, respectively, for MRI; 89.5%, 100%, 96.4%, 100%, and 94.7%, respectively, for BMB; and 94.7%, 91.7%, 92.7%, 85.7%, and 97.1%, respectively, for PET/MRI (parallel test). According to ROC analysis, the AUCs of PET, MRI, BMB, and PET/MRI (parallel test) for detecting BMI in indolent lymphomas were 0.749, 0.774, 0.947, and 0.932, respectively. The DeLong test showed significant differences between the AUCs of PET/MRI (parallel test) and those of PET (P = 0.003) and MRI (P = 0.004). Regarding histologic subtypes, the diagnostic performance of PET/MRI for detecting BMI in small lymphocytic lymphoma was lower than that in follicular lymphoma, which was in turn lower than that in marginal zone lymphoma. Conclusion: Integrated whole-body 18F-FDG PET/MRI showed excellent sensitivity and accuracy for detecting BMI in indolent lymphoma compared with 18F-FDG PET or MRI alone, demonstrating that 18F-FDG PET/MRI is an optimal method and a reliable alternative to BMB. Trial registration: ClinicalTrials.gov (NCT05004961 and NCT05390632).

Predictive Value of 18 F-FDG PET/MRI for Pleural Invasion in Solid and Subsolid Lung Adenocarcinomas Smaller Than 3 cm.

BACKGROUND: Positron emission tomography (PET)/MRI combines the characteristics of metabolism imaging and high soft tissue resolution, and could provide high diagnostic efficacy for assessment of pleural invasion (PI) of lung cancer. PURPOSE: To investigate the application of 18 F-fluorodeoxyglucose (FDG) PET/MRI for predicting PI of lung cancer with the maximum diameter ≤3 cm. STUDY TYPE: Prospective. POPULATION: A total of 44 patients with non-small cell lung cancer (NSCLC), age from 39 to 79 years old, including 19 (56.82%) females. FIELD STRENGTH/SEQUENCE: A 3-T, hybrid PET/MRI including axial fast spin echo respiratory-triggered T2 fat-suppressed imaging (T2FS) and echo planar imaging diffusion-weighted imaging (DWI). ASSESSMENT: The maximum standardized uptake value (SUVmax) of all lesions was measured on PET images. Localized effusion outside the contact between the nodules and the pleura on T2FS and signal at the contact between the nodules and the pleura on DWI were evaluated by experienced physicians through visual assessment of the MRI sequences. STATISTICAL TESTS: Three models (models 1-3) were developed, incorporating CT, CT and PET, PET and MRI features, and Lasso regression was used in feature selection. The receiver operating characteristic (ROC) curve for PI diagnosis was visualized for each model, and the area under the curve (AUC) was calculated. The DeLong test was used to compare the different AUCs. A P value < 0.05 was considered statistically significant. RESULTS: The AUC of models 1-3 was 0.762, 0.829, and 0.915, respectively. The DeLong test showed a statistically significant difference between the AUCs of model 1 vs. model 3, while the differences between the AUCs of model 1 vs. model 2 (P = 0.253) and model 2 vs. model 3 (P = 0.075) were not statistically significant. DATA CONCLUSION: 18 F-FDG PET/MRI might show high predictive value for lung adenocarcinoma smaller than 3 cm with PI. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Estimating tree-based dynamic treatment regimes using observational data with restricted treatment sequences.

A dynamic treatment regime (DTR) is a sequence of decision rules that provide guidance on how to treat individuals based on their static and time-varying status. Existing observational data are often used to generate hypotheses about effective DTRs. A common challenge with observational data, however, is the need for analysts to consider "restrictions" on the treatment sequences. Such restrictions may be necessary for settings where (1) one or more treatment sequences that were offered to individuals when the data were collected are no longer considered viable in practice, (2) specific treatment sequences are no longer available, or (3) the scientific focus of the analysis concerns a specific type of treatment sequences (eg, "stepped-up" treatments). To address this challenge, we propose a restricted tree-based reinforcement learning (RT-RL) method that searches for an interpretable DTR with the maximum expected outcome, given a (set of) user-specified restriction(s), which specifies treatment options (at each stage) that ought not to be considered as part of the estimated tree-based DTR. In simulations, we evaluate the performance of RT-RL versus the standard approach of ignoring the partial data for individuals not following the (set of) restriction(s). The method is illustrated using an observational data set to estimate a two-stage stepped-up DTR for guiding the level of care placement for adolescents with substance use disorder.

High in-vivo stability in preclinical and first-in-human experiments with [18F]AlF-RESCA-MIRC213: a 18F-labeled nanobody as PET radiotracer for diagnosis of HER2-positive cancers.

PURPOSE: [18F]AlF-RESCA was introduced as a core particularly useful for 18F-labeling of heat-sensitive biomolecules. However, no translational studies have been reported up to now. Herein, we reported the first-in-human evaluation of an 18F-labeled anti-HER2 nanobody MIRC213 as a PET radiotracer for imaging HER2-positive cancers. METHODS: MIRC213 was produced by E. coli and conjugated with ( ±)-H3RESCA-Mal. [18F]AlF-RESCA-MIRC213 was prepared at room temperature. Its radiochemical purity and stability of were determined by radio-HPLC with the size-exclusion chromatographic column. Cell uptake was performed in NCI-N87 (HER2 +) and MCF-7 (HER2-) cells and the cell-binding affinity was verified in SK-OV-3 (HER2 +) cells. Small-animal PET/CT was performed using SK-OV-3, NCI-N87, and MCF-7 tumor-bearing mice at 30 min, 1 h, and 2 h post-injection. For blocking experiment, excess MIRC213 was co-injected with radiotracer. Biodistribution were performed on SKOV-3 and MCF-7 tumor-bearing mice at 2 h post-injection. For clinical study, PET/CT images were acquired at 2 h and 4 h after injection of [18F]AlF-RESCA-MIRC213 (1.85-3.7 MBq/kg) in six breast cancer patients (3 HER2-positive and 3 HER2-negative). All patients underwent [18F]-FDG PET/CT within a week for tissue selection purpose. Distribution and dosimetry were calculated. Standardized uptake values (SUV) were measured in tumors and normal organs. RESULTS: MIRC213 was produced with > 95% purity and modified with RESCA to obtain RESCA-MIRC213. [18F]AlF-RESCA-MIRC213 was prepared within 20 min at room temperature with the radiochemical yield of 50.48 ± 7.6% and radiochemical purity of > 98% (n > 10), and remained stable in both PBS (88%) and 5% HSA (92%) after 6 h. The 2 h cellular uptake of [18F]AlF-RESCA-MIRC213 in NCI-N87 cells was 11.22 ± 0.60 AD%/105 cells. Its binding affinity Kd value was determined to be 1.23 ± 0.58 nM. Small-animal PET/CT with [18F]AlF-RESCA-MIRC213 can clearly differentiate SK-OV-3 and NCI-N87 tumors from MCF-7 tumors and background with a high uptake of 4.73 ± 1.18 ID%/g and substantially reduced to 1.70 ± 0.13 ID%/g for the blocking group (p < 0.05) in SK-OV-3 tumors at 2 h post-injection. No significant bone radioactivity was seen in the tumor-bearing animals. In all six breast cancer patients, there was no adverse reaction during study. The uptake of [18F]AlF-RESCA-MIRC213 was mainly in lacrimal gland, parotid gland, submandibular gland, thyroid gland, gallbladder, kidneys, liver, and intestines. There was no significant bone radioactivity accumulation in cancer patients. [18F]AlF-RESCA-MIRC213 had significantly higher tumor uptake in lesions from HER2-positive patients than that lesions from HER2-negative patients (SUVmax of 3.62 ± 1.56 vs. 1.41 ± 0.41, p = 0.0012) at 2 h post-injection. The kidneys received the highest radiation dose of 2.42 × 10-1 mGy/MBq, and the effective dose was 1.56 × 10-2 mSv/MBq. CONCLUSIONS: [18F]AlF-RESCA-MIRC213 could be prepared with high radiolabeling yield under mild conditions. [18F]AlF-RESCA-MIRC213 has relatively high stability both in vitro and in vivo. The results from clinical transformation suggest that [18F]AlF-RESCA-MIRC213 PET/CT is a safe procedure with favorable pharmacokinetics and dosimetry profile, and it is a promising new PET radiotracer for noninvasive diagnosis of HER2-positive cancers.

The BRD4 Inhibitor dBET57 Exerts Anticancer Effects by Targeting Superenhancer-Related Genes in Neuroblastoma.

Neuroblastoma (NB) is the most common solid tumor of the neural crest cell origin in children and has a poor prognosis in high-risk patients. The oncogene MYCN was found to be amplified at extremely high levels in approximately 20% of neuroblastoma cases. In recent years, research on the targeted hydrolysis of BRD4 to indirectly inhibit the transcription of the MYCN created by proteolysis targeting chimaera (PROTAC) technology has become very popular. dBET57 (S0137, Selleck, TX, USA) is a novel and potent heterobifunctional small molecule degrader based on PROTAC technology. The purpose of this study was to investigate the therapeutic effect of dBET57 in NB and its potential mechanism. In this study, we found that dBET57 can target BRD4 ubiquitination and disrupt the proliferation ability of NB cells. At the same time, dBET57 can also induce apoptosis, cell cycle arrest, and decrease migration. Furthermore, dBET57 also has a strong antiproliferation function in xenograft tumor models in vivo. In terms of mechanism, dBET57 targets the BET protein family and the MYCN protein family by associating with CRBN and destroys the SE landscape of NB cells. Combined with RNA-seq and ChIP-seq public database analysis, we identified the superenhancer-related genes TBX3 and ZMYND8 in NB as potential downstream targets of dBET57 and experimentally verified that they play an important role in the occurrence and development of NB. In conclusion, these results suggest that dBET57 may be an effective new therapeutic drug for the treatment of NB.

DataSifterText: Partially Synthetic Text Generation for Sensitive Clinical Notes.

Petabytes of health data are collected annually across the globe in electronic health records (EHR), including significant information stored as unstructured free text. However, the lack of effective mechanisms to securely share clinical text has inhibited its full utilization. We propose a new method, DataSifterText, to generate partially synthetic clinical free-text that can be safely shared between stakeholders (e.g., clinicians, STEM researchers, engineers, analysts, and healthcare providers), limiting the re-identification risk while providing significantly better utility preservation than suppressing or generalizing sensitive tokens. The method creates partially synthetic free-text data, which inherits the joint population distribution of the original data, and disguises the location of true and obfuscated words. Under certain obfuscation levels, the resulting synthetic text was sufficiently altered with different choices, orders, and frequencies of words compared to the original records. The differences were comparable to machine-generated (fully synthetic) text reported in previous studies. We applied DataSifterText to two medical case studies. In the CDC work injury application, using privacy protection, 60.9-86.5% of the synthetic descriptions belong to the same cluster as the original descriptions, demonstrating better utility preservation than the naïve content suppressing method (45.8-85.7%). In the MIMIC III application, the generated synthetic data maintained over 80% of the original information regarding patients' overall health conditions. The reported DataSifterText statistical obfuscation results indicate that the technique provides sufficient privacy protection (low identification risk) while preserving population-level information (high utility).

Evaluation of 68Ga- and 177Lu-Labeled HZ20 Angiotensin-Converting Enzyme 2-Targeting Peptides for Tumor-Specific Imaging.

Angiotensin-converting enzyme 2 (ACE2) is closely related to tumor formation. We developed the radiolabeled peptide pair 68Ga/177Lu-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-conjugated DX600 (68Ga/177Lu-HZ20), for the targeting and mapping of ACE2-overexpressing tumors. 68Ga/177Lu-HZ20 was prepared with a routine labeling method. HepG2ACE2+/HepG2WT cell lines were used to evaluate the specificity of 68Ga/177Lu-HZ20. Pharmacokinetics, biodistribution, and micro-PET/CT and -SPECT/CT imaging were performed, and radiation dosimetry was estimated. Immunohistochemistry (IHC) staining was performed to assess the expression of ACE2 in tumors. The radiolabeling yields of 68Ga/177Lu-HZ20 were 88.49 ± 8.57% (n > 10) and 84.71 ± 9.75% (n > 10), with specific activities of (18.74 ± 3.72) × 106 and (17.85 ± 1.62) × 106 GBq/mol, respectively. 68Ga/177Lu-HZ20 showed significant differences in the cellular uptake of HepG2ACE2+/HepG2WT cells and fast clearance in KM mice. Moreover, HepG2ACE2+ tumors were clearly visualized in 68Ga/177Lu-HZ20 micro-PET/SPECT images. Based on micro-PET/CT, the standard uptake value (SUVmax) of HepG2ACE2+ tumors was 0.66 ± 0.02 at 30 min postinjection, IHC confirmed the high expression of ACE2 in HepG2ACE2+ tumors. In PET/CT images, the SUVmean of volunteer 1 was higher than the 18F-FDG value in the same lesion. 68Ga/177Lu-HZ20 was successfully obtained and showed high and specific uptake in tumors overexpressing ACE2. They may serve as paired probes for ACE2-targeting theranostics.

DataSifter II: Partially synthetic data sharing of sensitive information containing time-varying correlated observations.

There is a significant public demand for rapid data-driven scientific investigations using aggregated sensitive information. However, many technical challenges and regulatory policies hinder efficient data sharing. In this study, we describe a partially synthetic data generation technique for creating anonymized data archives whose joint distributions closely resemble those of the original (sensitive) data. Specifically, we introduce the DataSifter technique for time-varying correlated data (DataSifter II), which relies on an iterative model-based imputation using generalized linear mixed model and random effects-expectation maximization tree. DataSifter II can be used to generate synthetic repeated measures data for testing and validating new analytical techniques. Compared to the multiple imputation method, DataSifter II application on simulated and real clinical data demonstrates that the new method provides extensive reduction of re-identification risk (data privacy) while preserving the analytical value (data utility) in the obfuscated data. The performance of the DataSifter II on a simulation involving 20% artificially missingness in the data, shows at least 80% reduction of the disclosure risk, compared to the multiple imputation method, without a substantial impact on the data analytical value. In a separate clinical data (Medical Information Mart for Intensive Care III) validation, a model-based statistical inference drawn from the original data agrees with an analogous analytical inference obtained using the DataSifter II obfuscated (sifted) data. For large time-varying datasets containing sensitive information, the proposed technique provides an automated tool for alleviating the barriers of data sharing and facilitating effective, advanced, and collaborative analytics.

18F-FDG distribution pattern improves the diagnostic accuracy of single pulmonary solid nodule.

Background: The main purpose is to explore the use of visual assessment of the heterogeneous distribution of 18F-FDG in single pulmonary solid lesions to differentiate the benign from the malignant. Methods: The 200 cases of pulmonary nodules or masses examined by 18F-FDG PET/CT were retrospectively analyzed. The heterogeneity of 18F-FDG distribution of the lesion was visually and quantitatively evaluated and the higher part of metabolism was observed and measured at the proximal or distal part to determine the lesion nature. The sensitivity, specificity, PPV, NPV, and accuracy of this method were calculated. Results: Total 171 pulmonary lesions showed heterogeneity of 18F-FDG uptake, including the 111 malignant and 60 benign. 54/60 (90.00%) benign lesions showed higher 18F-FDG uptake visually at distal part, while 104/111 (93.69%) malignant lesions showed higher 18F-FDG uptake visually at the proximal part. This visual method has good repeatability with a high kappa value (0.821, p<0.001). 52/60 (86.67%) benign lesions showed higher 18F-FDG uptake quantitatively at distal part, while 107/111 (96.40%) malignant lesions showed higher 18F-FDG uptake quantitatively at the proximal part. The sensitivity, specificity, PPV, NPV and accuracy of visual and quantitative methods were 93.69%; 96.40%, 90.0%; 86.67%, 94.55%; 93.04%, 88.52%; 92.86%, 92.40%; 92.98%, respectively (p<0.001). When combining the metabolic value and morphological characteristics of PET/CT with visual 18F-FDG heterogeneous features, the accuracy reached to 98.25%. The other 29 lesions (14.5%) with no heterogeneity were smaller (2.17 ± 1.06 vs 3.58 ± 1.48, P<0.001). Conclusions: Benign and malignant lung lesions showed different heterogeneity of 18F-FDG uptake. Lung cancer can be effectively distinguished from infectious or inflammatory lesions by this simple and convenient method.

Giant tumor resection under ultrasound-guided nerve block in a patient with severe asthma: A case report.

BACKGROUND: General anesthesia in critically ill patients is associated with increased risk of complications. Nerve block anesthesia is an alternative, but could be challenging in cases with surgical field that involves multiple dermatomes. CASE SUMMARY: We report resection of a giant lipoma in the left shoulder and upper back under supraclavicular brachial plexus block plus T3-4 paravertebral block in an older patient with severe asthma. A 70-year-old patient presented with a slow-growing giant mass (25, 15 and 5 cm in length, width and depth, respectively) that extended from the lateral side of the left scapula to the axillary midline, and from the T5 thoracic vertebra intercostal to the mid-medial section of the left upper arm. He had sharp intermittent pain over the mass for the past 7 d. The patient also had severe bronchial asthma for the past 8 years. A pulmonary function test revealed only 20% of the predicted forced expiratory volume in 1 second (FEV1, 0.49 L). After controlling asthma with glucocorticoid, the tumor was resected under ultrasound-guided supraclavicular brachial plexus block and T3-4 paravertebral block. The surgery was completed without incident. CONCLUSION: Ultrasound-guided regional nerve block is a viable alternative for patients with poor cardiopulmonary function undergoing shoulder, back and axillary surgery.

Optimal dynamic treatment regime estimation using information extraction from unstructured clinical text.

The wide-scale adoption of electronic health records (EHRs) provides extensive information to support precision medicine and personalized health care. In addition to structured EHRs, we leverage free-text clinical information extraction (IE) techniques to estimate optimal dynamic treatment regimes (DTRs), a sequence of decision rules that dictate how to individualize treatments to patients based on treatment and covariate history. The proposed IE of patient characteristics closely resembles "The clinical Text Analysis and Knowledge Extraction System" and employs named entity recognition, boundary detection, and negation annotation. It also utilizes regular expressions to extract numerical information. Combining the proposed IE with optimal DTR estimation, we extract derived patient characteristics and use tree-based reinforcement learning (T-RL) to estimate multistage optimal DTRs. IE significantly improved the estimation in counterfactual outcome models compared to using structured EHR data alone, which often include incomplete data, data entry errors, and other potentially unobserved risk factors. Moreover, including IE in optimal DTR estimation provides larger study cohorts and a broader pool of candidate tailoring variables. We demonstrate the performance of our proposed method via simulations and an application using clinical records to guide blood pressure control treatments among critically ill patients with severe acute hypertension. This joint estimation approach improves the accuracy of identifying the optimal treatment sequence by 14-24% compared to traditional inference without using IE, based on our simulations over various scenarios. In the blood pressure control application, we successfully extracted significant blood pressure predictors that are unobserved or partially missing from structured EHR.

Parent report of sleep health and attention regulation in a cross-sectional study of infants and preschool-aged children with atopic dermatitis.

BACKGROUND/OBJECTIVES: Older children with atopic dermatitis (AD) suffer from poor sleep and attention problems. However, until recently, the dearth of developmentally sensitive assessment tools impeded characterization in younger children. We aimed to characterize sleep and attention problems in young children with AD and identify modifiable factors. METHODS: A cross-sectional study of children with AD aged 1-4 years was stratified by disease severity (Patient-Oriented Eczema Measure), age, and racial/ethnic groups. Developmentally sensitive surveys assessed attention (Multidimensional Assessment Profile of Attention Regulation), sleep, and itch (Patient-Reported Outcomes Measurement Information System). Linear regression models identified predictors of sleep health and attention dysregulation. RESULTS: Parents (n = 60) of children aged 2.78 ± 0.98 years with severe (n = 25), moderate (n = 25), or mild (n = 10) AD were recruited across the United States. Significantly reduced sleep health (T-score ≥ 60) was reported in 86% of children with moderate/severe disease (n = 43), and 50% had ≥5 nights of disturbed sleep per week. A suboptimal sleep environment was identified with 32% of children with too much light, noise, or electronic device usage. With regard to attention regulation, in children with severe AD, 80% had trouble sitting still and 72% of children had trouble paying attention no matter their surroundings. In fully adjusted models, AD severity was a significant predictor of poor sleep health (B = 0.79 [0.31-1.28], p < .01) and attention dysregulation (B = 1.22 [0.51-1.93], p < .01). CONCLUSIONS: More severe AD correlates with poor sleep health and attention dysregulation. In addition to aggressive treatment of AD, clinicians should advise on modifiable sleep hygiene practices and consider screening for attention dysregulation in young children.

The Value of 18F-FDG PET/CT and Abdominal PET/MRI as a One-Stop Protocol in Patients With Potentially Resectable Colorectal Liver Metastases.

PURPOSE: The aim of this study was to evaluate the clinical value of simultaneous positron emission tomography/computed tomography (PET/CT) and abdominal positron emission tomography/magnet resonance imaging (PET/MRI) in the detection of liver metastases and extrahepatic disease (EHD) in patients with potentially resectable colorectal liver metastases (CLM). METHODS: Fifty-six patients with CLM underwent conventional imaging (chest and abdomen CT, liver contrast-enhanced CT or MRI) and PET imaging [fluorine-18 fluorodeoxyglucose (18F-FDG) PET/CT and subsequent liver PET/MRI] for staging or restaging. Diagnostic ability of PET imaging was compared with conventional imaging. Abnormal findings were correlated with follow-up imaging and/or histology. The influence of the PET imaging findings was categorized for each patient in relation to operability and other significant findings. The clinical management included three modalities (surgery for resectable CLM, unresectable CLM with conversion treatment, and systemic therapy). The clinical impact of the imaging modality was analyzed. The operative histopathological analysis and/or imaging follow-up were performed as the standard of reference. RESULTS: This study enrolled a total of 56 patients (median age 60 years, 62.5% were male, 36 with colon cancer and 20 with rectal cancer). For EHD detection, PET/CT detected more EHD than conventional imaging (60.7% vs. 46.4%). PET/CT had different findings in 19 (33.9%) patients, including downstaging in 4 (7.1%) patients and upstaging in 15 (26.8%) patients. For liver lesion detection, PET/MRI showed comparable detection ability with CE-MRI and CE-CT (99.5%, 99.4%, and 86.5%, respectively) based on lesion analysis, much higher than PET/CT (47.5%). PET imaging had a major impact in 10/56 (17.9%) patients (4 from unresectable to resectable, 6 from resectable to unresectable) and a minor impact in 4/56 (7.1%) patients for changing the surgery extent. The therapeutic strategies had been altered in a total of 14/56 patients (25%) after PET/CT and PET/MRI scans. CONCLUSION: The results of this study indicate that simultaneous 18F-FDG PET/CT and abdominal PET/MRI scans can provide accurate information regarding CLM status and EHD, and can affect the management of 25% of the patients by changing the therapeutic strategies determined by conventional imaging. This new modality may serve as a new one-stop method in patients with potentially resectable CLM.

Application Analysis of 124I-PPMN for Enhanced Retention in Tumors of Prostate Cancer Xenograft Mice.

BACKGROUND: In recent years, nuclear medicine imaging and therapy for prostate cancer have radically changed through the introduction of radiolabeled prostate-specific membrane antigen (PSMA)-binding peptides. However, these small molecular probes have some inherent limitations, including high nephrotoxicity and short circulation time, which limits their utility in biological systems. METHODS AND RESULTS: In this study, organic melanin nanoparticles were used to directly label the long half-life radionuclide 124I (t1/2=100.8 h), and PSMA small molecular groups were efficiently bonded on the surface of nanoparticles to construct the PSMA-targeted long-retention nanoprobe 124I-PPMN, which has the potential to increase tumor uptake and prolong residence time. The results showed that the nanoprobe could substantially aggregate in the tumors of prostate cancer xenograft mice and was visible for more than 72 h. Positron Emission Computed Tomography (PET) imaging showed that the nanoprobe could be used for precise imaging of prostate cancer with high expression of PSMA. In addition, organic melanin nanoparticles labeled with an elemental radionuclide achieved a stable, metal-free structure. Cell experiments and mouse toxicity experiments indicated that the nanoprobe has high safety. CONCLUSION: The new nanoprobe constructed in this study has high specificity and biocompatibility. In the future, combined with the multifunctional potential of melanin nanoparticles, this nanoprobe is expected to be used in the integrated theranostics of prostate cancer.