Renal pelvic plasmacytoid subtype urothelial carcinoma accompanied with solitary mammary metastasis.

A 72-year-old female was referred to our institution for further evaluation of right renal tumor detected during work-up for macroscopic hematuria in other hospital. CT urography performed at our institution suggested renal pelvic tumor. Voiding cytology was atypical. CT also revealed a small mass in the right mammary gland. Percutaneous needle biopsies were performed on the right mammary gland and renal mass, leading to a pathological diagnosis of UC with plasmacytoid subtype, suggesting metastasis from the renal pelvic UC to the mammary gland. She had a favorable response to four cycles of dose-dense MVAC therapy; therefore, we performed nephroureterectomy. One month after nephroureterectomy, new intraperitoneal metastatic lesions were observed and pembrolizumab therapy was started. After seven doses of pembrolizumab, CT revealed a marked size reduction of intraperitoneal metastases and the mammary metastasis remained small.

Exploratory mass cytometry analysis reveals immunophenotypes of cancer treatment-related pneumonitis.

Anticancer treatments can result in various adverse effects, including infections due to immune suppression/dysregulation and drug-induced toxicity in the lung. One of the major opportunistic infections is Pneumocystis jirovecii pneumonia (PCP), which can cause severe respiratory complications and high mortality rates. Cytotoxic drugs and immune-checkpoint inhibitors (ICIs) can induce interstitial lung diseases (ILDs). Nonetheless, the differentiation of these diseases can be difficult, and the pathogenic mechanisms of such diseases are not yet fully understood. To better comprehend the immunophenotypes, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid from patients with PCP, cytotoxic drug-induced ILD (DI-ILD), and ICI-associated ILD (ICI-ILD) using two panels containing 64 markers. In PCP, we observed an expansion of the CD16+ T cell population, with the highest CD16+ T proportion in a fatal case. In ICI-ILD, we found an increase in CD57+ CD8+ T cells expressing immune checkpoints (TIGIT+ LAG3+ TIM-3+ PD-1+), FCRL5+ B cells, and CCR2+ CCR5+ CD14+ monocytes. These findings uncover the diverse immunophenotypes and possible pathomechanisms of cancer treatment-related pneumonitis.

Visualization of small brain nuclei with a high-spatial resolution, clinically available whole-body PET scanner.

OBJECTIVE: To verify the visibility of physiological 18F-fluorodeoxyglucose (18F-FDG) uptake in nuclei in and around the brainstem by a whole-body (WB) silicon photomultiplier positron emission tomography (SiPM-PET) scanner with point-spread function (PSF) reconstruction using various iteration numbers. METHODS: Ten healthy subjects (5 men, 5 women; mean age, 56.0 ± 5.0 years) who underwent 18F-FDG PET/CT using a WB SiPM-PET scanner and magnetic resonance imaging (MRI) of the brain including a spin-echo three-dimensional sampling perfection with application-optimized contrasts using different flip angle evolutions fluid-attenuated inversion recovery (3D-FLAIR) and a 3D-T1 magnetization-prepared rapid gradient-echo (T1-MPRAGE) images were enrolled. Each acquired PET image was reconstructed using ordered-subset expectation maximization (OSEM) with iteration numbers of 4, 16, 64, and 256 (subset 5 fixed) + time-of-flight (TOF) + PSF. The reconstructed PET images and 3D-FLAIR images for each subject were registered to individual T1-MPRAGE volumes using normalized mutual information criteria. For each MR-coregistered individual PET image, the pattern of FDG uptake in the inferior olivary nuclei (ION), dentate nuclei (DN), midbrain raphe nuclei (MRN), inferior colliculi (IC), mammillary bodies (MB), red nuclei (RN), subthalamic nuclei (STN), lateral geniculate nuclei (LGN), medial geniculate nuclei (MGN), and superior colliculi (SC) was visually classified into the following three categories: good, clearly distinguishable FDG accumulation; fair, obscure contour of FDG accumulation; poor, FDG accumulation indistinguishable from surrounding uptake. RESULTS: Among individual 18F-FDG PET images with OSEM iterations of 4, 16, 64, and 256 + TOF + PSF, the iteration numbers that showed the best visibility in each structure were as follows: ION, MRN, LGN, MGN, and SC, iteration 64; DN, iteration 16; IC, iterations 16, 64, and 256; MB, iterations 64 and 256; and RN and STN, iterations 16 and 64, respectively. Of the four iterations, the 18F-FDG PET image of iteration 64 visualized FDG accumulation in small structures in and around the brainstem most clearly (good, 98 structures; fair, 2 structures). CONCLUSIONS: A clinically available WB SiPM-PET scanner is useful for visualizing physiological FDG uptake in small brain nuclei, using a sufficiently high number of iterations for OSEM with TOF and PSF reconstructions.

Altered macrophage phenotypes in a case of autoimmune pulmonary alveolar proteinosis.

Mass cytometry of BALF cells from a pulmonary alveolar proteinosis patient, positive for anti-GM-CSF antibodies, suggests potential impairment in human alveolar macrophage differentiation https://bit.ly/45JHUrz.

Expansion of ST2-expressing macrophages in a patient with bronchiolitis obliterans syndrome.

This case study of a patient with BOS after HSCT found increased ST2+CD64+ macrophages in BALF, a potential therapeutic target for treatment-refractory BOS, and reduced CCR2+CD14+ monocytes compared to other lung disorders https://bit.ly/406Uyy9.

Cholesterol sulfate limits neutrophil recruitment and gut inflammation during mucosal injury.

During mucosal injury, intestinal immune cells play a crucial role in eliminating invading bacteria. However, as the excessive accumulation of immune cells promotes inflammation and delays tissue repair, it is essential to identify the mechanism that limits the infiltration of immune cells to the mucosal-luminal interface. Cholesterol sulfate (CS) is the lipid product of the sulfotransferase SULT2B1 and suppresses immune reactions by inhibiting DOCK2-mediated Rac activation. In this study, we aimed to elucidate the physiological role of CS in the intestinal tract. We found that, in the small intestine and colon, CS is predominantly produced in the epithelial cells close to the lumen. While dextran sodium sulfate (DSS)-induced colitis was exacerbated in Sult2b1-deficient mice with increased prevalence of neutrophils, the elimination of either neutrophils or intestinal bacteria in Sult2b1-deficient mice attenuated disease development. Similar results were obtained when the Dock2 was genetically deleted in Sult2b1-deficient mice. In addition, we also show that indomethacin-induced ulcer formation in the small intestine was exacerbated in Sult2b1-deficient mice and was ameliorated by CS administration. Thus, our results uncover that CS acts on inflammatory neutrophils, and prevents excessive gut inflammation by inhibiting the Rac activator DOCK2. The administration of CS may be a novel therapeutic strategy for inflammatory bowel disease and non-steroidal anti-inflammatory drug-induced ulcers.

Mass cytometry identifies characteristic immune cell subsets in bronchoalveolar lavage fluid from interstitial lung diseases.

Immune cells have been implicated in interstitial lung diseases (ILDs), although their phenotypes and effector mechanisms remain poorly understood. To better understand these cells, we conducted an exploratory mass cytometry analysis of immune cell subsets in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF), connective-tissue disease (CTD)-related ILD, and sarcoidosis, using two panels including 64 markers. Among myeloid cells, we observed the expansion of CD14+ CD36hi CD84hiCCR2- monocyte populations in IPF. These CD14+ CD36hi CD84hi CCR2- subsets were also increased in ILDs with a progressive phenotype, particularly in a case of acute exacerbation (AEx) of IPF. Analysis of B cells revealed the presence of cells at various stages of differentiation in BALF, with a higher percentage of IgG memory B cells in CTD-ILDs and a trend toward more FCRL5+ B cells. These FCRL5+ B cells were also present in the patient with AEx-IPF and sarcoidosis with advanced lung lesions. Among T cells, we found increased levels of IL-2R+ TIGIT+ LAG3+ CD4+ T cells in IPF, increased levels of CXCR3+ CD226+ CD4+ T cells in sarcoidosis, and increased levels of PD1+ TIGIT+ CD57+ CD8+ T cells in CTD-ILDs. Together, these findings underscore the diverse immunopathogenesis of ILDs.

Association between forefoot pain and sesamoid rotation angle determined using a weight-bearing plantar ultrasound imaging device.

Forefoot pain is a common symptom for several foot problems. This study aimed to determine whether parameters of forefoot structure (hallux valgus angle (HVA), transverse arch height (TAH) and sesamoid rotation angle (SRA)) are associated with forefoot pain. 547 feet of adult women were divided into two groups: without pain (n = 472) and with pain (n = 75). HVA was measured with a goniometer, TAH and SRA were measured using a weight bearing plantar ultrasound imaging device.Associations between forefoot pain and parameters of forefoot structure were analyzed using the Mann-Whitney U test and univariate and multivariate logistic regression analyses. The intra-rater and inter-rater reliability of the ultrasound images were also tested. SRA was significantly greater in the group with pain compared to the group without pain (p = 0.031) but not HVA (p = 0.057) nor TAH (p = 0.117). The association between forefoot pain and SRA was significant (univariate: p = 0.015 and multivariate p = 0.015), but not between HVA nor TAH. The intra-rater and inter-rater reliability were almost perfect (SRA: ICC1,1 = 0.94, ICC2,1 = 0.91 and TAH: ICC1,1 = 0.88, ICC2,1 = 0.81). We conclude that a higher SRA is related to forefoot pain and should be taken into consideration for assessment of patients with forefoot pain.

DOCK2 regulates MRGPRX2/B2-mediated mast cell degranulation and drug-induced anaphylaxis.

BACKGROUND: Drug-induced anaphylaxis is triggered by the direct stimulation of mast cells (MCs) via Mas-related G protein-coupled receptor X2 (MRGPRX2; mouse ortholog MRGPRB2). However, the precise mechanism that links MRGPRX2/B2 to MC degranulation is poorly understood. Dedicator of cytokinesis 2 (DOCK2) is a Rac activator predominantly expressed in hematopoietic cells. Although DOCK2 regulates migration and activation of leukocytes, its role in MCs remains unknown. OBJECTIVE: We aimed to elucidate whether-and if so, how-DOCK2 is involved in MRGPRX2/B2-mediated MC degranulation and anaphylaxis. METHODS: Induction of drug-induced systemic and cutaneous anaphylaxis was compared between wild-type and DOCK2-deficient mice. In addition, genetic or pharmacologic inactivation of DOCK2 in human and murine MCs was used to reveal its role in MRGPRX2/B2-mediated signal transduction and degranulation. RESULTS: Induction of MC degranulation and anaphylaxis by compound 48/80 and ciprofloxacin was severely attenuated in the absence of DOCK2. Although calcium influx and phosphorylation of several signaling molecules were unaffected, MRGPRB2-mediated Rac activation and phosphorylation of p21-activated kinase 1 (PAK1) were impaired in DOCK2-deficient MCs. Similar results were obtained when mice or MCs were treated with small-molecule inhibitors that bind to the catalytic domain of DOCK2 and inhibit Rac activation. CONCLUSION: DOCK2 regulates MRGPRX2/B2-mediated MC degranulation through Rac activation and PAK1 phosphorylation, thereby indicating that the DOCK2-Rac-PAK1 axis could be a target for preventing drug-induced anaphylaxis.

Massively parallel single-cell genomics of microbiomes in rice paddies.

Plant growth-promoting microbes (PGPMs) have attracted increasing attention because they may be useful in increasing crop yield in a low-input and sustainable manner to ensure food security. Previous studies have attempted to understand the principles underlying the rhizosphere ecology and interactions between plants and PGPMs using ribosomal RNA sequencing, metagenomic sequencing, and genome-resolved metagenomics; however, these approaches do not provide comprehensive genomic information for individual species and do not facilitate detailed analyses of plant-microbe interactions. In the present study, we developed a pipeline to analyze the genomic diversity of the rice rhizosphere microbiome at single-cell resolution. We isolated microbial cells from paddy soil and determined their genomic sequences by using massively parallel whole-genome amplification in microfluidic-generated gel capsules. We successfully obtained 3,237 single-amplified genomes in a single experiment, and these genomic sequences provided insights into microbial functions in the paddy ecosystem. Our approach offers a promising platform for gaining novel insights into the roles of microbes in the rice rhizomicrobiome and to develop microbial technologies for improved and sustainable rice production.

DeepPVC: prediction of a partial volume-corrected map for brain positron emission tomography studies via a deep convolutional neural network.

BACKGROUND: Partial volume correction with anatomical magnetic resonance (MR) images (MR-PVC) is useful for accurately quantifying tracer uptake on brain positron emission tomography (PET) images. However, MR segmentation processes for MR-PVC are time-consuming and prevent the widespread clinical use of MR-PVC. Here, we aimed to develop a deep learning model to directly predict PV-corrected maps from PET and MR images, ultimately improving the MR-PVC throughput. METHODS: We used MR T1-weighted and [11C]PiB PET images as input data from 192 participants from the Alzheimer's Disease Neuroimaging Initiative database. We calculated PV-corrected maps as the training target using the region-based voxel-wise PVC method. Two-dimensional U-Net model was trained and validated by sixfold cross-validation with the dataset from the 156 participants, and then tested using MR T1-weighted and [11C]PiB PET images from 36 participants acquired at sites other than the training dataset. We calculated the structural similarity index (SSIM) of the PV-corrected maps and intraclass correlation (ICC) of the PV-corrected standardized uptake value between the region-based voxel-wise (RBV) PVC and deepPVC as indicators for validation and testing. RESULTS: A high SSIM (0.884 ± 0.021) and ICC (0.921 ± 0.042) were observed in the validation and test data (SSIM, 0.876 ± 0.028; ICC, 0.894 ± 0.051). The computation time required to predict a PV-corrected map for a participant (48 s without a graphics processing unit) was much shorter than that for the RBV PVC and MR segmentation processes. CONCLUSION: These results suggest that the deepPVC model directly predicts PV-corrected maps from MR and PET images and improves the throughput of MR-PVC by skipping the MR segmentation processes.

Phase I study of alvocidib plus cytarabine/mitoxantrone or cytarabine/daunorubicin for acute myeloid leukemia in Japan.

Therapeutic improvements are needed for patients with acute myeloid leukemia (AML), particularly those who have relapsed or who have treatment-refractory (R/R) AML or newly diagnosed patients with poor prognostic factors. Alvocidib (DSP-2033), a potent cyclin-dependent kinase 9 inhibitor, has previously demonstrated promising clinical activity for the treatment of AML. In this multicenter, open-label, uncontrolled, 3 + 3 phase I study, we investigated the safety and tolerability of alvocidib administered in combination with either cytarabine and mitoxantrone (ACM) for R/R AML or cytarabine/daunorubicin (A + 7 + 3) for newly diagnosed AML. Alvocidib was administered to all patients as a 30-min intravenous (i.v.) bolus (30 mg/m2 /d), followed by a continuous i.v. infusion over 4 h on days 1-3 (60 mg/m2 /d). A total of 10 patients were enrolled: six received ACM (at two dose levels of cytarabine and mitoxantrone) and four received A + 7 + 3. Alvocidib was tolerated and no dose-limiting toxicities were observed. All patients experienced adverse events, of which diarrhea was the most frequent (100%); hematologic events were also common. Alvocidib concentration peaked at the end of dosing (4.5 h after start of administration), plasma accumulation after repeated dosing was minimal and urinary excretion was negligible. The rate of complete remission/complete remission with incomplete hematologic recovery was 66.7% with the ACM regimen in R/R AML, including four complete remission (median duration 13.6 months), and 75% (three complete remission) with the A + 7 + 3 regimen. Further development of alvocidib in hematologic malignancies is warranted. The trial is registered with Clinicaltrials.gov, NCT03563560.

Brain partial volume correction with point spreading function reconstruction in high-resolution digital PET: comparison with an MR-based method in FDG imaging.

OBJECTIVE: In quantitative positron emission tomography (PET) of the brain, partial volume effect due mainly to the finite spatial resolution of the PET scanner (> 3 mm full width at half maximum [FWHM]) is a primary source of error in the measurement of tracer uptake, especially in small structures such as the cerebral cortex (typically < 3 mm thickness). The aim of this study was to evaluate the partial volume correction (PVC) performance of point spread function-incorporated reconstruction (PSF reconstruction) in combination with the latest digital PET scanner. This evaluation was performed through direct comparisons with magnetic resonance imaging (MR)-based PVC (used as a reference method) in a human brain study. METHODS: Ten healthy subjects underwent brain 18F-FDG PET (30-min acquisition) on a digital PET/CT system (Siemens Biograph Vision, 3.5-mm FWHM scanner resolution at the center of the field of view) and anatomical T1-weighted MR imaging for MR-based PVC. PSF reconstruction was applied with a wide range of iterations (4 to 256; 5 subsets). FDG uptake in the cerebral cortex was evaluated using the standardized uptake value ratio (SUVR) and compared between PSF reconstruction and MR-based PVC. RESULTS: Cortical structures were visualized by PSF reconstruction with several tens of iterations and were anatomically well matched with the MR-derived cortical segments. Higher numbers of iterations resulted in higher cortical SUVRs, which approached those of MR-based PVC (1.76), although even with the maximum number of iterations they were still smaller by 16% (1.47), corresponding to approximately 1.5-mm FWHM of the effective spatial resolution. CONCLUSION: With the latest digital PET scanner, PSF reconstruction can be used as a PVC technique in brain PET, albeit with suboptimal resolution recovery. A relative advantage of PSF reconstruction is that it can be applied not only to cerebral cortical regions, but also to various small structures such as small brain nuclei that are hardly visualized on anatomical T1-weighted imaging, and thus hardly recovered by MR-based PVC.

A review on AI in PET imaging.

Artificial intelligence (AI) has been applied to various medical imaging tasks, such as computer-aided diagnosis. Specifically, deep learning techniques such as convolutional neural network (CNN) and generative adversarial network (GAN) have been extensively used for medical image generation. Image generation with deep learning has been investigated in studies using positron emission tomography (PET). This article reviews studies that applied deep learning techniques for image generation on PET. We categorized the studies for PET image generation with deep learning into three themes as follows: (1) recovering full PET data from noisy data by denoising with deep learning, (2) PET image reconstruction and attenuation correction with deep learning and (3) PET image translation and synthesis with deep learning. We introduce recent studies based on these three categories. Finally, we mention the limitations of applying deep learning techniques to PET image generation and future prospects for PET image generation.

Effect of hematocrit on cerebral blood flow measured by pseudo-continuous arterial spin labeling MRI: A comparative study with 15O-water positron emission tomography.

INTRODUCTION: In cerebral blood flow (CBF) quantification with pseudo-continuous arterial spin labeling (pCASL) MRI, arterial blood T1 (T1a) is usually fixed to a typical value (e.g., 1650 ms). However, individual T1a depends strongly on hematocrit (Hct) level. To investigate the utility of Hct-based T1a as an alternative to the fixed T1a method, we performed a comparative study with 15O-water positron emission tomography (PET). METHODS: For patients with unilateral occlusion or stenosis of major arteries, hemispheric CBF on the healthy side was measured using pCASL and 15O-water PET. The pCASL CBFs were calculated with both (a) fixed T1a (1650 ms) and (b) individual T1a estimated from blood-sampled Hct (Hct-based T1a). Correlation coefficients of Hct-CBF were calculated and compared between pCASL and PET. RESULTS: In pCASL, CBF with fixed T1a showed a strong negative correlation with Hct (r = -0.568), which was reduced with individual Hct-based T1a (r = -0.341 to -0.190), consistent with the Hct-CBF relation measured with PET (r = -0.349). DISCUSSION AND CONCLUSION: We demonstrated that Hct-based T1a resulted in smaller inter-individual variations in pCASL CBF and an inverse Hct-CBF relationship more similar to that of PET. Care must be taken in the interpretation of pCASL CBF imaging in relation to Hct level even in subjects without anemia. Further comparative studies are needed to investigate whether advanced techniques improve pCASL CBF quantification at the individual level.

DOCK8 deficiency causes a skewing to type 2 immunity in the gut with expansion of group 2 innate lymphoid cells.

Dedicator of cytokinesis 8 (DOCK8) is a guanine nucleotide exchange factor (GEF) for Cdc42. In humans, homozygous or compound heterozygous deletions in DOCK8 cause a combined immunodeficiency characterized by various allergic diseases including food allergies. Although group 2 innate lymphoid cells (ILC2s) contribute to the development of allergic inflammation by producing interleukin (IL)-5 and IL-13, the role of ILC2s in DOCK8 deficiency has not been fully explored. With the use of cytometry by time-of-flight (CyTOF), we performed high-dimensional phenotyping of intestinal immune cells and found that DOCK8-deficient (Dock8-/-) mice exhibited expansion of ILC2s and other leukocytes associated with type 2 immunity in the small intestine. Moreover, IL-5- and IL-13-producing cells markedly increased in Dock8-/- mice, and the majority of them were lineage-negative cells, most likely ILC2s. Intestinal ILC2s expanded when DOCK8 expression was selectively deleted in hematopoietic cells. Importantly, intestinal ILC2 expansion was also observed in Dock8VAGR mice having mutations in the catalytic center of DOCK8, thereby failing to activate Cdc42. Our findings indicate that DOCK8 is a negative regulator of intestinal ILC2s to inhibit their expansion via Cdc42 activation, and that deletion of DOCK8 causes a skewing to type 2 immunity in the gut.

Prediction of an oxygen extraction fraction map by convolutional neural network: validation of input data among MR and PET images.

PURPOSE: Oxygen extraction fraction (OEF) is a biomarker for the viability of brain tissue in ischemic stroke. However, acquisition of the OEF map using positron emission tomography (PET) with oxygen-15 gas is uncomfortable for patients because of the long fixation time, invasive arterial sampling, and radiation exposure. We aimed to predict the OEF map from magnetic resonance (MR) and PET images using a deep convolutional neural network (CNN) and to demonstrate which PET and MR images are optimal as inputs for the prediction of OEF maps. METHODS: Cerebral blood flow at rest (CBF) and during stress (sCBF), cerebral blood volume (CBV) maps acquired from oxygen-15 PET, and routine MR images (T1-, T2-, and T2*-weighted images) for 113 patients with steno-occlusive disease were learned with U-Net. MR and PET images acquired from the other 25 patients were used as test data. We compared the predicted OEF maps and intraclass correlation (ICC) with the real OEF values among combinations of MRI, CBF, CBV, and sCBF. RESULTS: Among the combinations of input images, OEF maps predicted by the model learned with MRI, CBF, CBV, and sCBF maps were the most similar to the real OEF maps (ICC: 0.597 ± 0.082). However, the contrast of predicted OEF maps was lower than that of real OEF maps. CONCLUSION: These results suggest that the deep CNN learned useful features from CBF, sCBF, CBV, and MR images and predict qualitatively realistic OEF maps. These findings suggest that the deep CNN model can shorten the fixation time for 15O PET by skipping 15O2 scans. Further training with a larger data set is required to predict accurate OEF maps quantitatively.

Iterative framework for image registration and partial volume correction in brain positron emission tomography.

Imprecise registration between positron emission tomography (PET) and anatomical magnetic resonance (MR) images is a critical source of error in MR imaging-guided partial volume correction (MR-PVC). Here, we propose a novel framework for image registration and partial volume correction, which we term PVC-optimized registration (PoR), to address imprecise registration. The PoR framework iterates PVC and registration between uncorrected PET and smoothed PV-corrected images to obtain precise registration. We applied PoR to the [11C]PiB PET data of 92 participants obtained from the Alzheimer's Disease Neuroimaging Initiative database and compared the registration results, PV-corrected standardized uptake value (SUV) and its ratio to the cerebellum (SUVR), and intra-region coefficient of variation (CoV) between PoR and conventional registration. Significant differences in registration of as much as 2.74 mm and 3.02° were observed between the two methods (effect size < - 0.8 or > 0.8), which resulted in considerable SUVR differences throughout the brain, reaching a maximal difference of 62.3% in the sensory motor cortex. Intra-region CoV was significantly reduced using the PoR throughout the brain. These results suggest that PoR reduces error as a result of imprecise registration in PVC and is a useful method for accurately quantifying the amyloid burden in PET.