Novel insights into paclitaxel's role on tumor-associated macrophages in enhancing PD-1 blockade in breast cancer treatment.

BACKGROUND: Triple-negative breast cancer (TNBC) poses unique challenges due to its complex nature and the need for more effective treatments. Recent studies showed encouraging outcomes from combining paclitaxel (PTX) with programmed cell death protein-1 (PD-1) blockade in treating TNBC, although the exact mechanisms behind the improved results are unclear. METHODS: We employed an integrated approach, analyzing spatial transcriptomics and single-cell RNA sequencing data from TNBC patients to understand why the combination of PTX and PD-1 blockade showed better response in TNBC patients. We focused on toll-like receptor 4 (TLR4), a receptor of PTX, and its role in modulating the cross-presentation signaling pathways in tumor-associated macrophages (TAMs) within the tumor microenvironment. Leveraging insights obtained from patient-derived data, we conducted in vitro experiments using immunosuppressive bone marrow-derived macrophages (iBMDMs) to validate if PTX could augment the cross-presentation and phagocytosis activities. Subsequently, we extended our study to an in vivo murine model of TNBC to ascertain the effects of PTX on the cross-presentation capabilities of TAMs and its downstream impact on CD8+ T cell-mediated immune responses. RESULTS: Data analysis from TNBC patients revealed that the activation of TLR4 and cross-presentation signaling pathways are crucial for the antitumor efficacy of PTX. In vitro studies showed that PTX treatment enhances the cross-presentation ability of iBMDMs. In vivo experiments demonstrated that PTX activates TLR4-dependent cross-presentation in TAMs, improving CD8+ T cell-mediated antitumor responses. The efficacy of PTX in promoting antitumor immunity was elicited when combined with PD-1 blockade, suggesting a complementary interaction. CONCLUSIONS: This study reveals how PTX boosts the effectiveness of PD-1 inhibitors in treating TNBC. We found that PTX activates TLR4 signaling in TAMs. This activation enhances their ability to present antigens, thereby boosting CD8+ T cell antitumor responses. These findings not only shed light on PTX's immunomodulatory role in TNBC but also underscore the potential of targeting TAMs' antigen presentation capabilities in immunotherapy approaches.

Clinical Factors Affecting Discrepancy Between Predicted and Long-term Actual Lung Function Following Surgery.

PURPOSE: Lung cancer surgery outcomes depend heavily on preoperative pulmonary reserve, with forced expiratory volume in 1 second (FEV1) being a critical preoperative evaluation factor. Our study investigates the discrepancies between predicted and long-term actual postoperative lung function, focusing on clinical factors affecting these outcomes. METHODS: This retrospective observational study encompassed lung cancer patients who underwent preoperative lung perfusion SPECT/CT between 2015 and 2021. We evaluated preoperative and postoperative pulmonary function tests, considering factors such as surgery type, resected volume, and patient history including tuberculosis. Predicted postoperative lung function was calculated using SPECT/CT imaging. RESULTS: From 216 patients (men:women, 150:66; age, 67.9 ± 8.7 years), predicted postoperative FEV1% (ppoFEV1%) showed significant correlation with actual postoperative FEV1% (r = 0.667; P < 0.001). Paired t test revealed that ppoFEV1% was significantly lower compared with actual postoperative FEV1% (P < 0.001). The study identified video-assisted thoracic surgery (VATS) (odds ratio [OR], 3.90; 95% confidence interval [CI], 1.98-7.69; P < 0.001) and higher percentage of resected volume (OR per 1% increase, 1.05; 95% CI, 1.01-1.09; P = 0.014) as significant predictors of postsurgical lung function improvement. Conversely, for the decline in lung function postsurgery, significant predictors included lower percentage of resected lung volume (OR per 1% increase, 0.92; 95% CI, 0.86-0.98; P = 0.011), higher preoperative FEV1% (OR, 1.03; 95% CI, 1.01-1.07; P = 0.009), and the presence of tuberculosis (OR, 5.19; 95% CI, 1.48-18.15; P = 0.010). Additionally, in a subgroup of patients with borderline lung function, VATS was related with improvement. CONCLUSIONS: Our findings demonstrate that in more than half of the patients, actual postsurgical lung function exceeded predicted values, particularly following VATS and with higher volume of lung resection. It also identifies lower resected lung volume, higher preoperative FEV1%, and tuberculosis as factors associated with a postsurgical decline in lung function. The study underscores the need for precise preoperative lung function assessment and tailored postoperative management, with particular attention to patients with relevant clinical factors. Future research should focus on validation of clinical factors and exploring tailored approaches to lung cancer surgery and recovery.

Clinical Performance Evaluation of an Artificial Intelligence-Powered Amyloid Brain PET Quantification Method.

Purpose: This study assesses the clinical performance of BTXBrain-Amyloid, an artificial intelligence-powered software for quantifying amyloid uptake in brain PET images. Methods: 150 amyloid brain PET images were visually assessed by experts and categorized as negative and positive. Standardized uptake value ratio (SUVR) was calculated with cerebellum grey matter as the reference region, and receiver operating characteristic (ROC) and precision-recall (PR) analysis for BTXBrain-Amyloid were conducted. For comparison, same image processing and analysis was performed using Statistical Parametric Mapping (SPM) program. In addition, to evaluate the spatial normalization (SN) performance, mutual information (MI) between MRI template and spatially normalized PET images was calculated and SPM group analysis was conducted. Results: Both BTXBrain and SPM methods discriminated between negative and positive groups. However, BTXBrain exhibited lower SUVR standard deviation (0.06 and 0.21 for negative and positive, respectively) than SPM method (0.11 and 0.25). In ROC analysis, BTXBrain had an AUC of 0.979, compared to 0.959 for SPM, while PR curves showed an AUC of 0.983 for BTXBrain and 0.949 for SPM. At the optimal cut-off, the sensitivity and specificity were 0.983 and 0.921 for BTXBrain and 0.917 and 0.921 for SPM12, respectively. MI evaluation also favored BTXBrain (0.848 vs. 0.823), indicating improved SN. In SPM group analysis, BTXBrain exhibited higher sensitivity in detecting basal ganglia differences between negative and positive groups. Conclusion: BTXBrain-Amyloid outperformed SPM in clinical performance evaluation, also demonstrating superior SN and improved detection of deep brain differences. These results suggest the potential of BTXBrain-Amyloid as a valuable tool for clinical amyloid PET image evaluation.

Spatial transcriptomic brain imaging reveals the effects of immunomodulation therapy on specific regional brain cells in a mouse dementia model.

Increasing evidence of brain-immune crosstalk raises expectations for the efficacy of novel immunotherapies in Alzheimer's disease (AD), but the lack of methods to examine brain tissues makes it difficult to evaluate therapeutics. Here, we investigated the changes in spatial transcriptomic signatures and brain cell types using the 10x Genomics Visium platform in immune-modulated AD models after various treatments. To proceed with an analysis suitable for barcode-based spatial transcriptomics, we first organized a workflow for segmentation of neuroanatomical regions, establishment of appropriate gene combinations, and comprehensive review of altered brain cell signatures. Ultimately, we investigated spatial transcriptomic changes following administration of immunomodulators, NK cell supplements and an anti-CD4 antibody, which ameliorated behavior impairment, and designated brain cells and regions showing probable associations with behavior changes. We provided the customized analytic pipeline into an application named STquantool. Thus, we anticipate that our approach can help researchers interpret the real action of drug candidates by simultaneously investigating the dynamics of all transcripts for the development of novel AD therapeutics.

Symmetric and Profound Monoaminergic Degeneration in Parkinson's Disease with Premotor REM Sleep Behavior Disorder.

Background: Rapid eye movement sleep behavior disorder (RBD) may precede or follow motor symptoms in Parkinson's disease (PD). While over 70% of idiopathic RBD cases phenoconvert within a decade, a small subset develops PD after a more extended period or remains nonconverted. These heterogeneous manifestations of RBD in PD prompt subtype investigations. Premotor RBD may signify "body-first" PD with bottom-up, symmetric synucleinopathy propagation. Objective: Explore brainstem and nigrostriatal monoaminergic degeneration pattern differences based on premotor RBD presence and duration in de novo PD patients. Methods: In a cross-sectional analysis of de novo PD patients (n = 150) undergoing FP-CIT PET and RBD Single-Question Screen, the cohort was categorized into groups with and without premotor RBD (PDRBD +/-), with further classification of PDRBD + based on a 10-year duration of premotor RBD. Analysis of FP-CIT binding in the striatum and pons, striatal asymmetry, and striatum-to-pons ratios compared patterns of nigrostriatal and brainstem monoaminergic degeneration. Results: PDRBD + exhibited more severe and symmetrical striatal dopaminergic denervation compared to PDRBD-, with the difference in severity accentuated in the least-affected hemisphere. The PDRBD +<10Y subgroup displayed the most prominent striatal symmetry, supporting a more homogeneous "body-first" subtype. Pontine uptakes remained lower in PDRBD + even after adjusting for striatal uptake, suggesting early degeneration of pontine monoaminergic nuclei. Conclusions: Premotor RBD in PD is associated with severe, symmetrical nigrostriatal and brainstem monoaminergic degeneration, especially in cases with PD onset within 10 years of RBD. This supports the concept of a "widespread, bottom-up" pathophysiological mechanism associated with premotor RBD in PD.

SpatialSPM: statistical parametric mapping for the comparison of gene expression pattern images in multiple spatial transcriptomic datasets.

Spatial transcriptomic (ST) techniques help us understand the gene expression levels in specific parts of tissues and organs, providing insights into their biological functions. Even though ST dataset provides information on the gene expression and its location for each sample, it is challenging to compare spatial gene expression patterns across tissue samples with different shapes and coordinates. Here, we propose a method, SpatialSPM, that reconstructs ST data into multi-dimensional image matrices to ensure comparability across different samples through spatial registration process. We demonstrated the applicability of this method by kidney and mouse olfactory bulb datasets as well as mouse brain ST datasets to investigate and directly compare gene expression in a specific anatomical region of interest, pixel by pixel, across various biological statuses. Beyond traditional analyses, SpatialSPM is capable of generating statistical parametric maps, including T-scores and Pearson correlation coefficients. This feature enables the identification of specific regions exhibiting differentially expressed genes across tissue samples, enhancing the depth and specificity of ST studies. Our approach provides an efficient way to analyze ST datasets and may offer detailed insights into various biological conditions.

[18F]FDOPA PET/CT in Solid Pseudopapillary Tumor of the Pancreas: a Recurred Tumor Mimicking Splenosis.

Solid pseudopapillary tumor (SPT) of the pancreas is a neoplasm with low malignant potential. It is often challenging to diagnose SPT due to its nonspecific clinical and radiological features, and [18F]FDOPA is effective in diagnosing SPT, particularly in differentiating SPT from benign conditions such as splenosis. A 55-year-old woman underwent distal pancreatectomy and splenectomy for histologically confirmed SPT. She was also initially diagnosed with splenosis. During follow-up, sizes of multiple nodular lesions were increased, raising the possibility of peritoneal seeding of SPT. For diagnosis, a spleen scan and SPECT/CT were performed using 99mTc-labeled damaged red blood cells, which showed no uptake in the peritoneal nodules. Subsequent [18F]FDOPA PET/CT revealed [18F]FDOPA-avidity of the nodules. The patient underwent tumor resection surgery, and the nodules were pathologically confirmed as SPT.

Preoperative evaluation of mediastinal lymph nodes in non-small cell lung cancer using [68Ga]FAPI-46 PET/CT: a prospective pilot study.

PURPOSE: Mediastinal nodal staging is crucial for surgical candidate selection in non-small cell lung cancer (NSCLC), but conventional imaging has limitations often necessitating invasive staging. We investigated the additive clinical value of fibroblast activation protein inhibitor (FAPI) PET/CT, an imaging technique targeting fibroblast activation protein, for mediastinal nodal staging of NSCLC. METHODS: In this prospective pilot study, we enrolled patients scheduled for surgical resection of NSCLC based on specific criteria designed to align with indications for invasive staging procedures. Patients were included when meeting at least one of the following: (1) presence of FDG-positive N2 lymph nodes, (2) clinical N1 stage, (3) central tumor location or tumor diameter of ≥ 3 cm, and (4) adenocarcinoma exhibiting high FDG uptake. [68Ga]FAPI-46 PET/CT was performed before surgery after a staging workup including [18F]FDG PET/CT. The diagnostic accuracy of [68Ga]FAPI-46 PET/CT for "N2" nodes was assessed through per-patient visual assessment and per-station quantitative analysis using histopathologic results as reference standards. RESULTS: Twenty-three patients with 75 nodal stations were analyzed. Histopathologic examination confirmed that nine patients (39.1%) were N2-positive. In per-patient assessment, [68Ga]FAPI-46 PET/CT successfully identified metastasis in eight patients (sensitivity 0.89 (0.52-1.00)), upstaging three patients compared to [18F]FDG PET/CT. [18F]FDG PET/CT detected FDG-avid nodes in six (42.8%) of 14 N2-negative patients. Among them, five were considered non-metastatic based on calcification and distribution pattern, and one was considered metastatic. In contrast, [68Ga]FAPI-46 PET/CT correctly identified all non-metastatic patients solely based on tracer avidity. In per-station analysis, [68Ga]FAPI-46 PET/CT discriminated metastasis more effectively compared to [18F]FDG PET/CT-based (AUC of ROC curve 0.96 (0.88-0.99) vs. 0.68 (0.56-0.78), P < 0.001). CONCLUSION: [68Ga]FAPI-46 PET/CT holds promise as an imaging tool for preoperative mediastinal nodal staging in NSCLC, with improved sensitivity and the potential to reduce false-positive results, optimizing the need for invasive staging procedures.

The Usefulness of 18F-FDG PET to Differentiate Subtypes of Dementia: The Systematic Review and Meta-Analysis.

Background and Purpose: Dementia subtypes, including Alzheimer's dementia (AD), dementia with Lewy bodies (DLB), and frontotemporal dementia (FTD), pose diagnostic challenges. This review examines the effectiveness of 18F-Fluorodeoxyglucose Positron Emission Tomography (18F-FDG PET) in differentiating these subtypes for precise treatment and management. Methods: A systematic review following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines was conducted using databases like PubMed and Embase to identify studies on the diagnostic utility of 18F-FDG PET in dementia. The search included studies up to November 16, 2022, focusing on peer-reviewed journals and applying the gold-standard clinical diagnosis for dementia subtypes. Results: From 12,815 articles, 14 were selected for final analysis. For AD versus FTD, the sensitivity was 0.96 (95% confidence interval [CI], 0.88-0.98) and specificity was 0.84 (95% CI, 0.70-0.92). In the case of AD versus DLB, 18F-FDG PET showed a sensitivity of 0.93 (95% CI 0.88-0.98) and specificity of 0.92 (95% CI, 0.70-0.92). Lastly, when differentiating AD from non-AD dementias, the sensitivity was 0.86 (95% CI, 0.80-0.91) and the specificity was 0.88 (95% CI, 0.80-0.91). The studies mostly used case-control designs with visual and quantitative assessments. Conclusions: 18F-FDG PET exhibits high sensitivity and specificity in differentiating dementia subtypes, particularly AD, FTD, and DLB. This method, while not a standalone diagnostic tool, significantly enhances diagnostic accuracy in uncertain cases, complementing clinical assessments and structural imaging.

Comprehensive characterization of early-programmed tumor microenvironment by tumor-associated macrophages reveals galectin-1 as an immune modulatory target in breast cancer.

Background: In recent years, there has been considerable interest in the therapeutic targeting of tumor-associated macrophages (TAMs) to modulate the tumor microenvironment (TME), resulting in antitumoral phenotypes. However, key mediators suitable for TAM-mediated remodeling of the TME remain poorly understood. Methods: In this study, we used single-cell RNA sequencing analyses to analyze the landscape of the TME modulated by TAMs in terms of a protumor microenvironment during early tumor development. Results: Our data revealed that the depletion of TAMs leads to a decreased epithelial-to-mesenchymal transition (EMT) signature in cancer cells and a distinct transcriptional state characterized by CD8+ T cell activation. Moreover, notable alterations in gene expression were observed upon the depletion of TAMs, identifying Galectin-1 (Gal-1) as a crucial molecular factor responsible for the observed effect. Gal-1 inhibition reversed immune suppression via the reinvigoration of CD8+ T cells, impairing tumor growth and potentiating immune checkpoint inhibitors in breast tumor models. Conclusion: These results provide comprehensive insights into TAM-mediated early tumor microenvironments and reveal immune evasion mechanisms that can be targeted by Gal-1 to induce antitumor immune responses.

Distinct subtypes of spatial brain metabolism patterns in Alzheimer's disease identified by deep learning-based FDG PET clusters.

PURPOSE: Alzheimer's disease (AD) is a heterogeneous disease that presents a broad spectrum of clinicopathologic profiles. To date, objective subtyping of AD independent of disease progression using brain imaging has been required. Our study aimed to extract representations of unique brain metabolism patterns different from disease progression to identify objective subtypes of AD. METHODS: A total of 3620 FDG brain PET images with AD, mild cognitive impairment (MCI), and cognitively normal (CN) were obtained from the ADNI database from 1607 participants at enrollment and follow-up visits. A conditional variational autoencoder model was trained on FDG brain PET images of AD patients with the corresponding condition of AD severity score. The k-means algorithm was applied to generate clusters from the encoded representations. The trained deep learning-based cluster model was also transferred to FDG PET of MCI patients and predicted the prognosis of subtypes for conversion from MCI to AD. Spatial metabolism patterns, clinical and biological characteristics, and conversion rate from MCI to AD were compared across the subtypes. RESULTS: Four distinct subtypes of spatial metabolism patterns in AD with different brain pathologies and clinical profiles were identified: (i) angular, (ii) occipital, (iii) orbitofrontal, and (iv) minimal hypometabolic patterns. The deep learning model was also successfully transferred for subtyping MCI, and significant differences in frequency (P < 0.001) and risk of conversion (log-rank P < 0.0001) from MCI to AD were observed across the subtypes, highest in S2 (35.7%) followed by S1 (23.4%). CONCLUSION: We identified distinct subtypes of AD with different clinicopathologic features. The deep learning-based approach to distinguish AD subtypes on FDG PET could have implications for predicting individual outcomes and provide a clue to understanding the heterogeneous pathophysiology of AD.

Spatiotemporal characterization of glial cell activation in an Alzheimer's disease model by spatially resolved transcriptomics.

The molecular changes that occur with the progression of Alzheimer's disease (AD) are well known, but an understanding of the spatiotemporal heterogeneity of changes in the brain is lacking. Here, we investigated the spatially resolved transcriptome in a 5XFAD AD model at different ages to understand regional changes at the molecular level. Spatially resolved transcriptomic data were obtained from 5XFAD AD models and age-matched control mice. Differentially expressed genes were identified using spots clustered by anatomical structures. Gene signatures of activation of microglia and astrocytes were calculated and mapped on the spatially resolved transcriptomic data. We identified early alterations in the white matter (WM) of the AD model before the definite accumulation of amyloid plaques in the gray matter (GM). Changes in the early stage of the disease involved primarily glial cell activation in the WM, whereas the changes in the later stage of pathology were prominent in the GM. We confirmed that disease-associated microglia (DAM) and astrocyte (DAA) signatures also showed initial changes in WM and that activation spreads to GM. Trajectory inference using microglial gene sets revealed the subdivision of DAMs with different spatial patterns. Taken together, these results help to understand the spatiotemporal changes associated with reactive glial cells as a major pathophysiological characteristic of AD. The heterogeneous spatial molecular changes apply to identifying diagnostic and therapeutic targets caused by amyloid accumulation in AD.

Deep Learning-Based Feature Extraction from Whole-Body PET/CT Employing Maximum Intensity Projection Images: Preliminary Results of Lung Cancer Data.

Purpose: Deep learning (DL) has been widely used in various medical imaging analyses. Because of the difficulty in processing volume data, it is difficult to train a DL model as an end-to-end approach using PET volume as an input for various purposes including diagnostic classification. We suggest an approach employing two maximum intensity projection (MIP) images generated by whole-body FDG PET volume to employ pre-trained models based on 2-D images. Methods: As a retrospective, proof-of-concept study, 562 [18F]FDG PET/CT images and clinicopathological factors of lung cancer patients were collected. MIP images of anterior and lateral views were used as inputs, and image features were extracted by a pre-trained convolutional neural network (CNN) model, ResNet-50. The relationship between the images was depicted on a parametric 2-D axes map using t-distributed stochastic neighborhood embedding (t-SNE), with clinicopathological factors. Results: A DL-based feature map extracted by two MIP images was embedded by t-SNE. According to the visualization of the t-SNE map, PET images were clustered by clinicopathological features. The representative difference between the clusters of PET patterns according to the posture of a patient was visually identified. This map showed a pattern of clustering according to various clinicopathological factors including sex as well as tumor staging. Conclusion: A 2-D image-based pre-trained model could extract image patterns of whole-body FDG PET volume by using anterior and lateral views of MIP images bypassing the direct use of 3-D PET volume that requires large datasets and resources. We suggest that this approach could be implemented as a backbone model for various applications for whole-body PET image analyses.

FDG uptake reflects an immune-enriched subtype of thyroid cancer: Clinical implications of imaging-based molecular characterization.

INTRODUCTION: Iodine and FDG uptakes have been established as methods to define the biological properties of thyroid cancer. As various cells in the tumor microenvironment (TME) affect tumor metabolism, we investigated the association between glucose metabolism in thyroid cancer and the TME using transcriptomic analyses. METHODS: We used F-18 FDG PET and RNA sequencing data of thyroid cancer to find associations between TME cell types and glucose metabolism. In addition, publicly available single-cell RNA sequencing data of papillary thyroid cancer was used to investigate glucose metabolism in cell types of the TME. The correlations between the FDG uptake and biological properties of the TME, including glucose metabolism and tumor differentiation score (TDS) were evaluated. Estimation of the proportions of immune and cancer cells (EPIC) was performed. The biological properties of each cell type were also assessed in the single-cell RNA sequencing data. RESULTS: FDG uptake showed a positive correlation with the enrichment score of macrophages and glycolysis activity. In single-cell RNA sequencing, immune cells had both high glucose transporters (GLUTs) and glycolysis signatures, while thyrocytes including cancer cells showed relatively low GLUTs and glycolysis signatures, suggesting that FDG uptake mainly occurred in immune cells of the TME. Moreover, the high GLUTs of myeloid cells were negatively associated with TDS. CONCLUSIONS: Our findings suggest that thyroid cancer with high FDG uptake can be mediated by enriched immune cells of the TME. We suggest that FDG uptake in thyroid cancer could be a marker for the immune-rich type and provide clinical implications for treatment stratification.

Correlation between standardized uptake value of 18F-FDG PET/CT and conductivity with pathologic prognostic factors in breast cancer.

We investigated the correlation between standardized uptake value (SUV) of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and conductivity parameters in breast cancer and explored the feasibility of conductivity as an imaging biomarker. Both SUV and conductivity have the potential to reflect the tumors' heterogeneous characteristics, but their correlations have not been investigated until now. Forty four women diagnosed with breast cancer who underwent breast MRI and 18F-FDG PET/CT at the time of diagnosis were included. Among them, 17 women received neoadjuvant chemotherapy followed by surgery and 27 women underwent upfront surgery. For conductivity parameters, maximum and mean values of the tumor region-of-interests were examined. For SUV parameters, SUVmax, SUVmean, and SUVpeak of the tumor region-of-interests were examined. Correlations between conductivity and SUV were evaluated, and among them, the highest correlation was observed between mean conductivity and SUVpeak (Spearman's correlation coefficient = 0.381). In a subgroup analysis for 27 women with upfront surgery, tumors with lymphovascular invasion (LVI) showed higher mean conductivity than those without LVI (median: 0.49 S/m vs 0.06 S/m, p < 0.001). In conclusion, our study shows a low positive correlation between SUVpeak and mean conductivity in breast cancer. Furthermore, conductivity showed a potential to noninvasively predict LVI status.

99mTc-MAA accumulation within tumor in preoperative lung perfusion SPECT/CT associated with occult lymph node metastasis in patients with clinically N0 non-small cell lung cancer.

BACKGROUND: 99mTc-MAA accumulation within the tumor representing pulmonary arterial perfusion, which is variable and may have a clinical significance. We evaluated the prognostic significance of 99mTc-MAA distribution within the tumor in non-small cell lung cancer (NSCLC) patients in terms of detecting occult nodal metastasis and lymphovascular invasion, as well as predicting the recurrence-free survival (RFS). METHODS: Two hundred thirty-nine NSCLC patients with clinical N0 status who underwent preoperative lung perfusion SPECT/CT were retrospectively evaluated and classified according to the visual grading of 99mTc-MAA accumulation in the tumor. Visual grade was compared with the quantitative parameter, standardized tumor to lung ratio (TLR). The predictive value of 99mTc-MAA accumulation with occult nodal metastasis, lymphovascular invasion, and RFS was assessed. RESULTS: Eighty-nine (37.2%) patients showed 99mTc-MAA accumulation and 150 (62.8%) patients showed the defect on 99mTc-MAA SPECT/CT. Among the accumulation group, 45 (50.5%) were classified as grade 1, 40 (44.9%) were grade 2, and 4 (4.5%) were grade 3. TLR gradually and significantly increased from grade 0 (0.009 ± 0.005) to grade 1 (0.021 ± 0.005, P < 0.05) and to grade 2-3 (0.033 ± 0.013, P < 0.05). The following factors were significant predictors for occult nodal metastasis in univariate analysis: central location, histology different from adenocarcinoma, tumor size greater than 3 cm representing clinical T2 or higher, and the absence of 99mTc-MAA accumulation within the tumor. Defect in the lung perfusion SPECT/CT remained significant at the multivariate analysis (Odd ratio 3.25, 95%CI [1.24 to 8.48], p = 0.016). With a median follow-up of 31.5 months, the RFS was significantly shorter in the defect group (p = 0.008). Univariate analysis revealed that cell type of non-adenocarcinoma, clinical stage II-III, pathologic stage II-III, age greater than 65 years, and the 99mTc-MAA defect within tumor as significant predictors for shorter RFS. However, only the pathologic stage remained statistically significant, in multivariate analysis. CONCLUSION: The absence of 99mTc-MAA accumulation within the tumor in preoperative lung perfusion SPECT/CT represents an independent risk factor for occult nodal metastasis and is relevant as a poor prognostic factor in clinically N0 NSCLC patients. 99mTc-MAA tumor distribution may serve as a new imaging biomarker reflecting tumor vasculatures and perfusion which can be associated with tumor biology and prognosis.

spSeudoMap: cell type mapping of spatial transcriptomics using unmatched single-cell RNA-seq data.

Since many single-cell RNA-seq (scRNA-seq) data are obtained after cell sorting, such as when investigating immune cells, tracking cellular landscape by integrating single-cell data with spatial transcriptomic data is limited due to cell type and cell composition mismatch between the two datasets. We developed a method, spSeudoMap, which utilizes sorted scRNA-seq data to create virtual cell mixtures that closely mimic the gene expression of spatial data and trains a domain adaptation model for predicting spatial cell compositions. The method was applied in brain and breast cancer tissues and accurately predicted the topography of cell subpopulations. spSeudoMap may help clarify the roles of a few, but crucial cell types.

Automatic Lung Cancer Segmentation in [18F]FDG PET/CT Using a Two-Stage Deep Learning Approach.

Purpose: Since accurate lung cancer segmentation is required to determine the functional volume of a tumor in [18F]FDG PET/CT, we propose a two-stage U-Net architecture to enhance the performance of lung cancer segmentation using [18F]FDG PET/CT. Methods: The whole-body [18F]FDG PET/CT scan data of 887 patients with lung cancer were retrospectively used for network training and evaluation. The ground-truth tumor volume of interest was drawn using the LifeX software. The dataset was randomly partitioned into training, validation, and test sets. Among the 887 PET/CT and VOI datasets, 730 were used to train the proposed models, 81 were used as the validation set, and the remaining 76 were used to evaluate the model. In Stage 1, the global U-net receives 3D PET/CT volume as input and extracts the preliminary tumor area, generating a 3D binary volume as output. In Stage 2, the regional U-net receives eight consecutive PET/CT slices around the slice selected by the Global U-net in Stage 1 and generates a 2D binary image as the output. Results: The proposed two-stage U-Net architecture outperformed the conventional one-stage 3D U-Net in primary lung cancer segmentation. The two-stage U-Net model successfully predicted the detailed margin of the tumors, which was determined by manually drawing spherical VOIs and applying an adaptive threshold. Quantitative analysis using the Dice similarity coefficient confirmed the advantages of the two-stage U-Net. Conclusion: The proposed method will be useful for reducing the time and effort required for accurate lung cancer segmentation in [18F]FDG PET/CT.

Mannosylated-serum albumin nanoparticle imaging to monitor tumor-associated macrophages under anti-PD1 treatment.

BACKGROUND: Immune checkpoint inhibitors such as anti-programmed cell death protein 1 (PD1) block tumor growth by reinvigorating the immune system; however, determining their efficacy only by the changes in tumor size may prove inaccurate. As the immune cells including macrophages in the tumor microenvironment (TME) are associated with the response to anti-PD1 therapy, tumor-associated macrophages (TAMs) imaging using nanoparticles can noninvasively provide the immune enrichment status of TME. Herein, the mannosylated-serum albumin (MSA) nanoparticle was labeled with radioactive isotope 68Ga to target the mannose receptors on macrophages for noninvasive monitoring of the TME according to anti-PD1 therapy. RESULTS: B16F10-Luc and MC38-Luc tumor-bearing mice were treated with anti-PD1, and the response to anti-PD1 was determined by the tumor volume. According to the flow cytometry, the responders to anti-PD1 showed an increased proportion of TAMs, as well as lymphocytes, and the most enriched immune cell population in the TME was also TAMs. For noninvasive imaging of TAMs as a surrogate of immune cell augmentation in the TME via anti-PD1, we acquired [68Ga] Ga-MSA positron emission tomography. According to the imaging study, an increased number of TAMs in responders at the early phase of anti-PD1 treatment was observed in both B16F10-Luc and MC38-Luc tumor-bearing mice models. CONCLUSION: As representative immune cells in the TME, non-invasive imaging of TAMs using MSA nanoparticles can reflect the immune cell enrichment status in the TME closely associated with the response to anti-PD1. As non-invasive imaging using MSA nanoparticles, this approach shows a potential to monitor and evaluate anti-tumor response to immune checkpoint inhibitors.