Citations

(1) Background: To determine the optimal cut-off values of two risk stratification systems to discriminate malignant thyroid nodules and to compare the diagnostic performance; (2) Methods: True and false positive and negative data were collected, and methodological quality was assessed for forty-six studies involving 39,085 patients; (3) Results: The highest area under the receiver operating characteristic (ROC) curve (AUC) of ACR and Kwak TI-RADS were 0.875 and 0.884. Based on the optimal sensitivity and specificity, the highest accuracy values of ROC curves or diagnostic odds ratios (DOR) were taken as the cut-off values for TR4 (moderate suspicious) and 4B. The sensitivity, specificity, DOR, and AUC by ACR (TR4) and Kwak TI-RADS (4B) for malignancy risk stratification of thyroid nodules were 94.3% and 96.4%; 52.2% and 53.7%; 17.5185 and 31.8051; 0.786 and 0.884, respectively. There were no significant differences in diagnostic accuracy in any of the direction comparisons of the two systems; (4) Conclusions: ACR and Kwak TI-RADS had good diagnostic performances (AUCs > 85%). Although we determined the best cut-off values in individual risk stratification systems based on statistical assessment, clinicians can adjust the optimal cut-off value according to the clinical purpose of the ultrasonography because raising or lowering cut-points leads to reciprocal changes in sensitivity and specificity.

Abstract The external globus pallidus (GPe) coordinates action-selection through GABAergic projections throughout the basal ganglia. GPe arkypallidal (arky) neurons project exclusively to the dorsal striatum, which regulates goal-directed and habitual reward-seeking. However, the role of GPe arky neurons in reward-seeking remains unknown. Here, we identified that a majority of arky neurons target the dorsolateral striatum (DLS). Using fiber photometry, we found that arky activities were higher during random interval (RI; habit) compared to random ratio (RR; goal) operant reward-seeking. Support vector machine analysis demonstrated that arky neuron activities have sufficient information to distinguish between RR and RI behavior. Genetic ablation of this arkyGPe◊DLS circuit facilitated a shift from goal-directed to habitual behavior. Conversely, chemogenetic activation reduced habitual seeking-behaviors, which was blocked by systemic D1R agonism. Our findings reveal a novel role of this arkyGPe◊DLS circuit in constraining habitual reward-seeking, which is relevant to addictive behaviors and other compulsive disorders.

Abstract Background: PDAC is a highly morbid disease with no validated biomarkers for first-line (1L) treatment selection. The PurIST single-sample molecular subtyping gene signature, initially described by Rashid et al. (Clin. Cancer Res., 2020), classifies PDAC tumors as basal or classical. Prior work showed that these subtypes are associated with prognosis and that basal subtype patients have significantly lower objective response rate to FOLFIRINOX (FFX) compared to classical subtype patients. This suggests potential implications for treatment with FFX versus gemcitabine and nab-paclitaxel (GnP). Here, we retrospectively demonstrate the clinical validity of PurIST implemented as a laboratory developed test (LDT) on the Tempus Labs sequencing platform using a real-world dataset of advanced PDAC patients. Methods: De-identified PDAC patients were selected from the Tempus Oncology Data Ecosystem under an IRB-approved protocol according to the following inclusion criteria: no systemic treatment, surgically unresectable/metastatic, available RNA-sequencing data from primary or metastatic tissue, and FFX or GnP as 1L systemic therapy with available outcomes. Sequencing was performed by the CAP/CLIA validated Tempus xT assay. The PurIST model was applied to normalized RNA-sequence abundance files to compute a basal or classical subtype label. Predefined statistical analysis parameters included 12-month survival rate and median overall survival (OS) in FFX treated patients. OS was compared using Kaplan-Meier estimates, hazard ratios, and log-rank statistical tests. Results: 258 PDAC patients (64.9 +/- 9.9 yrs, 42% female), were identified for analysis with median OS of 11.7 months (95% CI: 10.6-13.7) and 12-month censorship rate of 12.8%. 151 patients were treated with FFX and 107 with GnP. 42 patients (28%) receiving FFX and 31 patients (29%) receiving GnP were classified as basal. Among FFX treated patients, median OS was 14.4 months (95% CI: 12.5-16.9) in classical patients vs. 9.4 months (95% CI: 8.3-14.5) in basal patients (HR = 1.72, 95% CI = 1.2-2.6, p=0.006). The 12-month survival rate was significantly lower in basal patients receiving FFX vs. classical patients (33.3% vs. 59.4%, p=0.011). In basal patients, no difference in OS was observed between FFX and GnP groups (p=0.6). Classical patients receiving FFX had a 14.4 months median OS vs. 10.8 months for patients receiving GnP (p=0.046). Conclusions: In this real-world cohort, we validate the association between PurIST subtypes and PDAC patient survival when administered FFX or GnP. Among FFX-treated patients, classical patients had significantly better outcomes compared to basal patients. Moreover, classical patients appeared to have improved outcomes with FFX vs. GnP. These findings represent underlying biological PDAC differences and demonstrate the clinical validity of PurIST as a prognostic marker in PDAC patients when performed as an LDT on the Tempus xT platform. Ongoing evaluation of PurIST performance will be continuously monitored through the Tempus Oncology Data ecosystem. Citation Format: Stephane Wenric, James M. Davison, Yun E. Wang, Gregory M. Mayhew, Kirk Beebe, Hyunseok P. Kang, Michael V. Milburn, Vincent Chung, Tanios Bekaii-Saab, Charles M. Perou. Purity Independent Subtyping of Tumor (PurIST): Real-world data validation of a pancreatic ductal adenocarcinoma (PDAC) gene expression classifier and its prognostic implications [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A002.

AbstractHow to deliver best care in various clinical settings remains a vexing problem. All pertinent healthcare-related questions have not, cannot, and will not be addressable with costly time- and resource-consuming controlled clinical trials. At present, evidence-based guidelines can address only a small fraction of the types of care that clinicians deliver. Furthermore, underserved areas rarely can access state-of-the-art evidence-based guidelines in real-time, and often lack the wherewithal to implement advanced guidelines. Care providers in such settings frequently do not have sufficient training to undertake advanced guideline implementation. Nevertheless, in advanced modern healthcare delivery environments, use of eActions (validated clinical decision support systems) could help overcome the cognitive limitations of overburdened clinicians. Widespread use of eActions will require surmounting current healthcare technical and cultural barriers and installing clinical evidence/data curation systems. The authors expect that increased numbers of evidence-based guidelines will result from future comparative effectiveness clinical research carried out during routine healthcare delivery within learning healthcare systems.

Arginine-rich dipeptide repeat proteins (R-DPRs), abnormal translational products of a GGGGCC hexanucleotide repeat expansion in C9ORF72 , play a critical role in C9ORF72 -related amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), the most common genetic form of the disorders (c9ALS/FTD). R-DPRs form liquid condensates in vitro, induce stress granule formation in cultured cells, aggregate, and sometimes coaggregate with TDP-43 in postmortem tissue from patients with c9ALS/FTD. However, how these processes are regulated is unclear. Here, we show that loss of poly(ADP-ribose) (PAR) suppresses neurodegeneration in c9ALS/FTD fly models and neurons differentiated from patient-derived induced pluripotent stem cells. Mechanistically, PAR induces R-DPR condensation and promotes R-DPR–induced stress granule formation and TDP-43 aggregation. Moreover, PAR associates with insoluble R-DPR and TDP-43 in postmortem tissue from patients. These findings identified PAR as a promoter of R-DPR toxicity and thus a potential target for treating c9ALS/FTD.

Alzheimer’s disease (AD) is a form of dementia associated with abnormal glucose metabolism resulting from amyloid-beta (Aβ) plaques and intracellular neurofibrillary tau protein tangles. In a previous study, we confirmed that carboxy-dehydroevodiamine∙HCl (cx-DHED), a derivative of DHED, was effective at improving cognitive impairment and reducing phosphorylated tau levels and synaptic loss in an AD mouse model. However, the specific mechanism of action of cx-DHED is unclear. In this study, we investigated how the cx-DHED attenuates AD pathologies in the 5xFAD mouse model, focusing particularly on abnormal glucose metabolism. We analyzed behavioral changes and AD pathologies in mice after intraperitoneal injection of cx-DHED for 2 months. As expected, cx-DHED reversed memory impairment and reduced Aβ plaques and astrocyte overexpression in the brains of 5xFAD mice. Interestingly, cx-DHED reversed the abnormal expression of glucose transporters in the brains of 5xFAD mice. In addition, otherwise low O-GlcNac levels increased, and the overactivity of phosphorylated GSK-3β decreased in the brains of cx-DHED-treated 5xFAD mice. Finally, the reduction in synaptic proteins was found to also improve by treatment with cx-DHED. Therefore, we specifically demonstrated the protective effects of cx-DHED against AD pathologies and suggest that cx-DHED may be a potential therapeutic drug for AD.

Objective This study investigates a locally low-rank (LLR) denoising algorithm applied to source images from a clinical task-based functional MRI (fMRI) exam before post-processing for improving statistical confidence of task-based activation maps. Methods Task-based motor and language fMRI was obtained in eleven healthy volunteers under an IRB approved protocol. LLR denoising was then applied to raw complex-valued image data before fMRI processing. Activation maps generated from conventional non-denoised (control) data were compared with maps derived from LLR-denoised image data. Four board-certified neuroradiologists completed consensus assessment of activation maps; region-specific and aggregate motor and language consensus thresholds were then compared with nonparametric statistical tests. Additional evaluation included retrospective truncation of exam data without and with LLR denoising; a ROI-based analysis tracked t-statistics and temporal SNR (tSNR) as scan durations decreased. A test-retest assessment was performed; retest data were matched with initial test data and compared for one subject. Results fMRI activation maps generated from LLR-denoised data predominantly exhibited statistically significant ( p = 4.88×10 –4 to p = 0.042; one p = 0.062) increases in consensus t-statistic thresholds for motor and language activation maps. Following data truncation, LLR data showed task-specific increases in t-statistics and tSNR respectively exceeding 20 and 50% compared to control. LLR denoising enabled truncation of exam durations while preserving cluster volumes at fixed thresholds. Test-retest showed variable activation with LLR data thresholded higher in matching initial test data. Conclusion LLR denoising affords robust increases in t-statistics on fMRI activation maps compared to routine processing, and offers potential for reduced scan duration while preserving map quality.

Background: To assess the safety and effectiveness of transoral robotic thyroidectomy (TORT) in thyroid tumor. Methods: PubMed, Embase, Web of Science, SCOPUS, Cochrane database, and Google Scholar up to June 2022. Studies comparing outcomes and complications between TORT and control groups (robotic bilateral axillo-breast, trans-axillary, postauricular approach, conventional open thyroidectomy (OT), and transoral endoscopic approach) were analyzed. Results: Ten studies of 1420 individuals. The operative time (SMD 1.15, 95%CI [0.48; 1.89]) was significantly longer and the number of retrieved lymph nodes (LNs) (SMD −0.27, 95%CI [−0.39; −0.16]) was fewer in TORT than in the control group. The postoperative cosmetic satisfaction score (SMD 0.60, 95%CI [0.28; 0.92]) was statistically higher in TORT than in the control group. In subgroup analysis, there was no significant difference between robotic surgeries. However, TORT had significantly longer operative times (SMD 2.08, 95%CI [0.95; 3.20]) and fewer retrieved LNs (SMD −0.32, 95%CI [−0.46; −0.17]) than OT. TORT satisfied significantly more patients in cosmetic view. However, it increased hospitalization days and postoperative pain on the operation day and first day compared to OT. Conclusions: TORT is not inferior to other robotic-assisted approaches. Its operation time and hospitalization days are longer and postoperative pain is greater than OT, although its cosmetic satisfaction is high.

ImportanceApproval by the US Food and Drug Administration of immune checkpoint inhibition (ICI) for advanced gastroesophageal cancer (aGEC) irrespective of PD-L1 status has generated controversy. Exploratory analyses from individual trials indicate a lack of meaningful benefit from ICI in patients with absent or low PD-L1 expression; however, analysis of a single variable while ignoring others may not consider the instability inherent in exploratory analyses.ObjectiveTo systematically examine the predictive value of tissue-based PD-L1 status compared with that of other variables for ICI benefit in aGEC to assess its stability.Data SourcesMEDLINE, Embase, Scopus, Web of Science, Cochrane Central Register (2000-2022).Study Selection, Data Extraction, and SynthesisRandomized clinical trials (RCTs) were included of adults with aGEC (adenocarcinoma [AC] or squamous cell carcinoma [SCC]) randomized to anti−PD-1 or PD-L1−containing treatment vs standard of care (SOC). Study screening, data abstraction, and bias assessment were completed independently by 2 reviewers. Of 5752 records screened, 26 were assessed for eligibility; 17 trials were included in the analysis.Main Outcomes and MeasuresThe prespecified primary end point was overall survival. The mean hazard ratio (HR) for ICI vs SOC was calculated (random-effects model). Predictive values were quantified by calculating the ratio of mean HRs between 2 levels of each variable.ResultsIn all, 17 RCTs (9 first line, 8 after first line) at low risk of bias and 14 predictive variables were included, totaling 11 166 participants (5067 with SCC, 6099 with ACC; 77.6% were male and 22.4% were female; 59.5% of patients were younger than 65 years, 40.5% were 65 years or older). Among patients with SCCs, PD-L1 tumor proportion score (TPS) was the strongest predictor of ICI benefit (HR, 0.60 [95% CI, 0.53-0.68] for high TPS; and HR, 0.84 [95% CI, 0.75-0.95] for low TPS), yielding a predictive value of 41.0% favoring high TPS (vs ≤16.0% for other variables). Among patients with AC, PD-L1 combined positive score (CPS) was the strongest predictor (after microsatellite instability high status) of ICI benefit (HR, 0.73 [95% CI, 0.66-0.81] for high CPS; and HR, 0.95 [95% CI, 0.84-1.07] for low CPS), yielding a predictive value of 29.4% favoring CPS-high (vs ≤12.9% for other variables). Head-to-head analyses of trials containing both levels of a variable and/or having similar design generally yielded consistent results.Conclusions and RelevanceTissue-based PD-L1 expression, more than any variable other than microsatellite instability-high, identified varying degrees of benefit from ICI-containing therapy vs SOC among patients with aGEC in 17 RCTs.