Dynamic field mapping and distortion correction using single-shot blip-rewound EPI and joint multi-echo reconstruction.

PURPOSE: To develop a method for dynamic ∆ B 0 $$ \Delta {B}_0 $$ mapping and distortion correction. METHODS: A blip-rewound EPI trajectory was developed to acquire multiple 2D EPI images in a single readout with an interleaved order, which allows a short TE difference. A joint multi-echo reconstruction was utilized to exploit the shared information between EPI images. The reconstructed images from each readout are combined to produce a final magnitude image. A ∆ B 0 $$ \Delta {B}_0 $$ map is calculated from the phase of these images for distortion correction. The efficacy of the proposed method is assessed with phantom and in vivo experiments. The performance of the proposed method in the presence of subject motion is also investigated. RESULTS: Compared to conventional multi-echo EPI, the proposed method allows dynamic ∆ B 0 $$ \Delta {B}_0 $$ mapping at matched resolution with a much shorter TR. Phantom and in vivo results show that the proposed method can provide a comparable magnitude image as conventional single-shot EPI. The ∆ B 0 $$ \Delta {B}_0 $$ maps calculated from the proposed method are consistent with conventional multi-echo EPI in the phantom experiment. For in vivo experiments, the proposed method provides a more accurate estimation of ∆ B 0 $$ \Delta {B}_0 $$ than conventional multi-echo EPI, which is prone to phase wrapping problems due to the long TE difference. In-vivo scan with subject motion shows the proposed dynamic field mapping method can improve the temporal stability of EPI time series compared to gradient echo (GRE) based static field mapping. CONCLUSION: The proposed method allows accurate dynamic ∆ B 0 $$ \Delta {B}_0 $$ mapping for robust distortion correction without compromising spatial or temporal resolution.

Motion compensated structured low-rank reconstruction for 3D multi-shot EPI.

PURPOSE: The 3D multi-shot EPI imaging offers several benefits including higher SNR and high isotropic resolution compared to 2D single shot EPI. However, it suffers from shot-to-shot inconsistencies arising from physiologically induced phase variations and bulk motion. This work proposed a motion compensated structured low-rank (mcSLR) reconstruction method to address both issues for 3D multi-shot EPI. METHODS: Structured low-rank reconstruction has been successfully used in previous work to deal with inter-shot phase variations for 3D multi-shot EPI imaging. It circumvents the estimation of phase variations by reconstructing an individual image for each phase state which are then sum-of-squares combined, exploiting their linear interdependency encoded in structured low-rank constraints. However, structured low-rank constraints become less effective in the presence of inter-shot motion, which corrupts image magnitude consistency and invalidates the linear relationship between shots. Thus, this work jointly models inter-shot phase variations and motion corruptions by incorporating rigid motion compensation for structured low-rank reconstruction, where motion estimates are obtained in a fully data-driven way without relying on external hardware or imaging navigators. RESULTS: Simulation and in vivo experiments at 7T have demonstrated that the mcSLR method can effectively reduce image artifacts and improve the robustness of 3D multi-shot EPI, outperforming existing methods which only address inter-shot phase variations or motion, but not both. CONCLUSION: The proposed mcSLR reconstruction compensates for rigid motion, and thus improves the validity of structured low-rank constraints, resulting in improved robustness of 3D multi-shot EPI to both inter-shot motion and phase variations.

Efficient 3D cone trajectory design for improved combined angiographic and perfusion imaging using arterial spin labeling.

PURPOSE: To improve the spatial resolution and repeatability of a non-contrast MRI technique for simultaneous time resolved 3D angiography and perfusion imaging by developing an efficient 3D cone trajectory design. METHODS: A novel parameterized 3D cone trajectory design incorporating the 3D golden angle was integrated into 4D combined angiography and perfusion using radial imaging and arterial spin labeling (CAPRIA) to achieve higher spatial resolution and sampling efficiency for both dynamic angiography and perfusion imaging with flexible spatiotemporal resolution. Numerical simulations and physical phantom scanning were used to optimize the cone design. Eight healthy volunteers were scanned to compare the original radial trajectory in 4D CAPRIA with our newly designed cone trajectory. A locally low rank reconstruction method was used to leverage the complementary k-space sampling across time. RESULTS: The improved sampling in the periphery of k-space obtained with the optimized 3D cone trajectory resulted in improved spatial resolution compared with the radial trajectory in phantom scans. Improved vessel sharpness and perfusion visualization were also achieved in vivo. Less dephasing was observed in the angiograms because of the short TE of our cone trajectory and the improved k-space sampling efficiency also resulted in higher repeatability compared to the original radial approach. CONCLUSION: The proposed 3D cone trajectory combined with 3D golden angle ordering resulted in improved spatial resolution and image quality for both angiography and perfusion imaging and could potentially benefit other applications that require an efficient sampling scheme with flexible spatial and temporal resolution.

Improving robustness of 3D multi-shot EPI by structured low-rank reconstruction of segmented CAIPI sampling for fMRI at 7T.

Three-dimensional (3D) encoding methods are increasingly being explored as alternatives to two-dimensional (2D) multi-slice acquisitions in fMRI, particularly in cases where high isotropic resolution is needed. 3D multi-shot EPI acquisition, as the workhorse of 3D fMRI imaging, is susceptible to physiological fluctuations which can induce inter-shot phase variations, and thus reducing the achievable tSNR, negating some of the benefit of 3D encoding. This issue can be particularly problematic at ultra-high fields like 7T, which have more severe off-resonance effects. In this work, we aim to improve the temporal stability of 3D multi-shot EPI at 7T by improving its robustness to inter-shot phase variations. We presented a 3D segmented CAIPI sampling trajectory ("seg-CAIPI") and an improved reconstruction method based on Hankel structured low-rank matrix recovery. Simulation and in-vivo results demonstrate that the combination of the seg-CAIPI sampling scheme and the proposed structured low-rank reconstruction is a promising way to effectively reduce the unwanted temporal variance induced by inter-shot physiological fluctuations, and thus improve the robustness of 3D multi-shot EPI for fMRI.

The evolution and heterogeneity of neutrophils in cancers: origins, subsets, functions, orchestrations and clinical applications.

Neutrophils, the most prevalent innate immune cells in humans, have garnered significant attention in recent years due to their involvement in cancer progression. This comprehensive review aimed to elucidate the important roles and underlying mechanisms of neutrophils in cancer from the perspective of their whole life cycle, tracking them from development in the bone marrow to circulation and finally to the tumor microenvironment (TME). Based on an understanding of their heterogeneity, we described the relationship between abnormal neutrophils and clinical manifestations in cancer. Specifically, we explored the function, origin, and polarization of neutrophils within the TME. Furthermore, we also undertook an extensive analysis of the intricate relationship between neutrophils and clinical management, including neutrophil-based clinical treatment strategies. In conclusion, we firmly assert that directing future research endeavors towards comprehending the remarkable heterogeneity exhibited by neutrophils is of paramount importance.

Highly accelerated intracranial time-of-flight magnetic resonance angiography using wave-encoding.

PURPOSE: To develop an accelerated 3D intracranial time-of-flight (TOF) magnetic resonance angiography (MRA) sequence with wave-encoding (referred to as 3D wave-TOF) and to evaluate two variants: wave-controlled aliasing in parallel imaging (CAIPI) and compressed-sensing wave (CS-wave). METHODS: A wave-TOF sequence was implemented on a 3 T clinical scanner. Wave-encoded and Cartesian k-space datasets from six healthy volunteers were retrospectively and prospectively undersampled with 2D-CAIPI sampling and variable-density Poisson disk sampling. 2D-CAIPI, wave-CAIPI, standard CS, and CS-wave schemes were compared at various acceleration factors. Flow-related artifacts in wave-TOF were investigated, and a set of practicable wave parameters was developed. Quantitative analysis of wave-TOF and traditional Cartesian TOF MRA was performed by comparing the contrast-to-background ratio between the vessel and background tissue in source images, and the structural similarity index measure (SSIM) between the maximum intensity projection images from accelerated acquisitions and their respective fully sampled references. RESULTS: Flow-related artifacts caused by the wave-encoding gradients in wave-TOF were eliminated by properly chosen parameters. Images from wave-CAIPI and CS-wave acquisitions had a higher SNR and better-preserved contrast than traditional parallel imaging (PI) and CS methods. Maximum intensity projection images from wave-CAIPI and CS-wave acquisitions had a cleaner background, with vessels that were better depicted. Quantitative analyses indicated that wave-CAIPI had the highest contrast-to-background ratio, SSIM, and vessel-masked SSIM among the sampling schemes studied, followed by the CS-wave acquisition. CONCLUSION: 3D wave-TOF improves the capability of accelerated MRA and provides better image quality at higher acceleration factors compared to traditional PI- or CS-accelerated TOF, suggesting the potential use of wave-TOF in cerebrovascular disease.

A temperature-controlled cooling system for accurate quantitative post-mortem MRI.

PURPOSE: To develop a temperature-controlled cooling system to facilitate accurate quantitative post-mortem MRI and enable scanning of unfixed tissue. METHODS: A water cooling system was built and integrated with a 7T scanner to minimize temperature drift during MRI scans. The system was optimized for operational convenience and rapid deployment to ensure efficient workflow, which is critical for scanning unfixed post-mortem samples. The performance of the system was evaluated using a 7-h diffusion MRI protocol at 7T with a porcine tissue sample. Quantitative T1 , T2 , and ADC maps were interspersed with the diffusion scans at seven different time points to investigate the temperature dependence of MRI tissue parameters. The impact of temperature changes on biophysical model fitting of diffusion MRI data was investigated using simulation. RESULTS: Tissue T1 , T2 , and ADC values remained stable throughout the diffusion MRI scan using the developed cooling system, but varied substantially using a conventional scan setup without temperature control. The cooling system enabled accurate estimation of biophysical model parameters by stabilizing the tissue temperature throughout the diffusion scan, while the conventional setup showed evidence of significantly biased estimation. CONCLUSION: A temperature-controlled cooling system was developed to tackle the challenge of heating in post-mortem imaging, which shows potential to improve the accuracy and reliability of quantitative post-mortem imaging and enables long scans of unfixed tissue.

Sampling strategies and integrated reconstruction for reducing distortion and boundary slice aliasing in high-resolution 3D diffusion MRI.

PURPOSE: To develop a new method for high-fidelity, high-resolution 3D multi-slab diffusion MRI with minimal distortion and boundary slice aliasing. METHODS: Our method modifies 3D multi-slab imaging to integrate blip-reversed acquisitions for distortion correction and oversampling in the slice direction (kz ) for reducing boundary slice aliasing. Our aim is to achieve robust acceleration to keep the scan time the same as conventional 3D multi-slab acquisitions, in which data are acquired with a single direction of blip traversal and without kz -oversampling. We employ a two-stage reconstruction. In the first stage, the blip-up/down images are respectively reconstructed and analyzed to produce a field map for each diffusion direction. In the second stage, the blip-reversed data and the field map are incorporated into a joint reconstruction to produce images that are corrected for distortion and boundary slice aliasing. RESULTS: We conducted experiments at 7T in six healthy subjects. Stage 1 reconstruction produces images from highly under-sampled data (R = 7.2) with sufficient quality to provide accurate field map estimation. Stage 2 joint reconstruction substantially reduces distortion artifacts with comparable quality to fully-sampled blip-reversed results (2.4× scan time). Whole-brain in-vivo results acquired at 1.22 mm and 1.05 mm isotropic resolutions demonstrate improved anatomical fidelity compared to conventional 3D multi-slab imaging. Data demonstrate good reliability and reproducibility of the proposed method over multiple subjects. CONCLUSION: The proposed acquisition and reconstruction framework provide major reductions in distortion and boundary slice aliasing for 3D multi-slab diffusion MRI without increasing the scan time, which can potentially produce high-quality, high-resolution diffusion MRI.

Baseline characteristics and treatment response predictive of nAMD outcomes with ranibizumab therapy in treatment-naive patients: the RACER subgroup analysis.

BACKGROUND: The Ranibizumab AMD Clinical Efficacy Study (RACER) conducted in treatment-naive adult Taiwanese patients with neovascular age-related macular degeneration (nAMD) suggested the importance of early and intensive dosing of ranibizumab for optimal treatment outcomes. This subgroup analysis aims to provide clinical information on treatment response that can potentially guide on maintaining the treatment or switching anti-VEGF agents in the real-world setting. METHODS: Visual acuity (VA) and central retinal thickness (CRT) were assessed in the RACER subgroup population. Subgroup analysis sets were categorised based on: (1) baseline best-corrected VA (BCVA; ≤ 48 and > 48 letters); (2) baseline CRT (≤ 325 or > 325 µm); and (3) treatment response after three monthly initial injections: < or ≥ 5-letter gain in BCVA and reduction of < or ≥ 50 µm in CRT. RESULTS: Patient age, sex, nAMD duration and number of ranibizumab injections did not differ significantly between the treatment subgroups. Poor baseline BCVA (≤ 48 letters) and baseline CRT severity (> 325 µm) were predictors of maximum BCVA gains (9.6 ± 12.9 letters [95%CI: 6.3 to 12.9] and 5.1 ± 18.3 letters [95%CI: - 0.5 to 10.8] at Months 3 and 12, respectively) and better CRT reductions (- 127.6 ± 104.2 µm and - 104.2 ± 107.4 µm at Months 3 and 12, respectively; both P < 0.001). For the subgroup showing favourable treatment improvement with BCVA gains ≥ 5 letters after three monthly initial injections, 75.6% of patients maintained follow-up at Month 12 with a mean of 6.5 ± 14.3 letter gains (95% CI: 1.2 to 11.7). The BCVA gains < 5-letter subgroup nevertheless had stable BCVA (0.4 ± 12.1 letter gains) and CRT (- 41.9 ± 61.2 µm) at Month 12, respectively. In the subgroup with ≥ 50 µm CRT reduction after three monthly initial injections, there are significantly higher BCVA improvements vs. the < 50 µm CRT reduction subgroup at Month 3 (5.0 ± 8.6 letter gains vs. 1.5 ± 11.6 letter gains, respectively; intergroup P = 0.005). CONCLUSION: Lower baseline BCVA and higher baseline CRT were associated with BCVA gains and CRT reductions throughout the 12-month study period. Early CRT improvements after three monthly initial injections were associated with BCVA gains as early as Month 3.

Optimal approaches and criteria to treat-and-extend regimen implementation for Neovascular age-related macular degeneration: experts consensus in Taiwan.

The management of neovascular age-related macular degeneration (nAMD) has taken a major stride forward with the advent of anti-VEGF agents. The treat-and-extend (T&E) approach is a refined management strategy, tailoring to the individual patient's disease course and treatment outcome. To provide guidance to implementing anti-VEGF T&E regimens for nAMD in resource-limited health care systems, an advisory board was held to discuss and generate expert consensus, based on local and international guidelines, current evidence, as well as local experience and reimbursement policies. In the experts' opinion, treatment of nAMD should aim to maximize and maintain visual acuity benefits while minimizing treatment burden. Based on current evidence, treatment could be initiated with 3 consecutive monthly injections. After the initial period, treatment interval may be extended by 2 or 4 weeks each time for the qualified patients (i.e. no BCVA loss ≥5 ETDRS letters and dry retina), and a maximum interval of 16 weeks is permitted. For patients meeting the shortening criteria (i.e. any increased fluid with BCVA loss ≥5 ETDRS letters, or presence of new macular hemorrhage or new neovascularization), the treatment interval should be reduced by 2 or 4 weeks each time, with a minimal interval of 4 weeks. Discontinuation of anti-VEGF may be considered for those who have received 2-3 consecutive injections spaced 16 weeks apart and present with stable disease. For these individuals, regular monitoring (e.g. 3-4 months) is recommended and monthly injections should be reinstated upon signs of disease recurrence.

A Confidential QR Code Approach with Higher Information Privacy.

In present times, barcode decoders on mobile phones can extract the data content of QR codes. However, this convenience raises concerns about security issues when using QR codes to transmit confidential information, such as e-tickets, coupons, and other private data. Moreover, current secret hiding techniques are unsuitable for QR code applications since QR codes are module-oriented, which is different from the pixel-oriented hiding manner. In this article, we propose an algorithm to conceal confidential information by changing the modules of the QR Code. This new scheme designs the triple module groups based on the concept of the error correction capability. Additionally, this manner can conceal two secret bits by changing only one module, and the amount of hidden confidential information can be twice the original amount. As a result, the ordinary data content (such as URL) can be extracted correctly from the generated QR code by any barcode decoders, which does not affect the readability of scanning. Furthermore, only authorized users with the secret key can further extract the concealed confidential information. This designed scheme can provide secure and reliable applications for the QR system.

Comparison of Choroidal Thickness, Foveal Avascular Zone, and Macular Capillary Density in Macular Edema Secondary to Branch Retinal Vein Occlusion Treated with Ranibizumab or Aflibercept-A Prospective Study.

This prospective comparative case series aims to compare best-corrected visual acuity (BCVA), retinal microvasculature, and retinal structural changes in patients treated with either ranibizumab or aflibercept for macular edema (ME) secondary to treatment-naïve branch retinal vein occlusion (BRVO) by optical coherence tomography angiography (OCTA). Ten patients were enrolled with macular capillary density of the superficial capillary plexus (SCP) and deep capillary plexus (DCP) and foveal avascular zone (FAZ) measured in both eyes before and after treatment. Final central retinal thickness and BCVA improved significantly (p < 0.05), and densities of SCP and DCP of BRVO sectors were significantly lower at baseline than fellow eye counterparts and remained persistently lower during treatment, particularly in the aflibercept group (p < 0.05). SCP density, DCP density of both BRVO sectors (p = 0.0001, p < 0.0001), and non-BRVO sectors (p < 0.0001, p < 0.0001) were significantly correlated with final BCVA for diseased eyes. Using multivariate general linear model analysis, and including OCTA parameters only, but not all of the available clinical data, DCP density of BRVO sectors in both eyes was the most predictive factor for final visual outcome (probability p < 0.0001). OCTA offered further qualitative and quantitative evaluation of treatment-naïve BRVO. Judging by OCTA parameters, not only in the diseased eye but also in the fellow eye, DCP density of BRVO sectors was the most predictive factor of final visual outcome.

Chemokine C-C motif ligand 21 synergized with programmed death-ligand 1 blockade restrains tumor growth.

Programmed death-ligand 1 (PD-L1) blockade has revolutionized the prognosis of several cancers, but shows a weak effect on pancreatic cancer (PC) due to poor effective immune infiltration. Chemokine C-C motif ligand 21 (CCL21), a chemokine promoting T cell immunity by recruiting and colocalizing dendritic cells (DCs) and T cells, serves as a potential antitumor agent in many cancers. However, its antitumor response and mechanism combined with PD-L1 blockade in PC remain unclear. In our study, we found CCL21 played an important role in leukocyte chemotaxis, inflammatory response, and positive regulation of PI3K-AKT signaling in PC using Metascape and gene set enrichment analysis. The CCL21 level was verified to be positively correlated with infiltration of CD8+ T cells by the CIBERSORT algorithm, but no significant difference in survival was observed in either The Cancer Genome Atlas or the International Cancer Genome Consortium cohort when stratified by CCL21 expression. Additionally, we found the growth rate of allograft tumors was reduced and T cell infiltration was increased, but tumor PD-L1 abundance elevated simultaneously in the CCL21-overexpressed tumors. Then, CCL21 was further verified to increase tumor PD-L1 level through the AKT-glycogen synthase kinase-3ß axis in human PC cells, which partly impaired the antitumor T cell immunity. Finally, the combination of CCL21 and PD-L1 blockade showed superior synergistic tumor suppression in vitro and in vivo. Together, our findings suggested that CCL21 in combination with PD-L1 blockade might be an efficient and promising option for the treatment of PC.

Quantifying myelin in crossing fibers using diffusion-prepared phase imaging: Theory and simulations.

PURPOSE: Myelin has long been the target of neuroimaging research. However, most available techniques can only provide a voxel-averaged estimate of myelin content. In the human brain, white matter fiber pathways connecting different brain areas and carrying different functions often cross each other in the same voxel. A measure that can differentiate the degree of myelination of crossing fibers would provide a more specific marker of myelination. THEORY AND METHODS: One MRI signal property that is sensitive to myelin is the phase accumulation. This sensitivity is used by measuring the phase accumulation of the signal remaining after diffusion-weighting, which is called diffusion-prepared phase imaging (DIPPI). Including diffusion-weighting before estimating the phase accumulation has two distinct advantages for estimating the degree of myelination: (1) It increases the relative contribution of intra-axonal water, whose phase is related linearly to the thickness of the surrounding myelin (in particular the log g-ratio); and (2) it gives directional information, which can be used to distinguish between crossing fibers. Here the DIPPI sequence is described, an approach is proposed to estimate the log g-ratio, and simulations are used and DIPPI data acquired in an isotropic phantom to quantify other sources of phase accumulation. RESULTS: The expected bias is estimated in the log g-ratio for reasonable in vivo acquisition parameters caused by eddy currents (~4%-10%), remaining extra-axonal signal (~15%), and gradients in the bulk off-resonance field (<10% for most of the brain). CONCLUSION: This new sequence may provide a g-ratio estimate per fiber population crossing within a voxel.

Grading Solid Pseudopapillary Tumors of the Pancreas: the Fudan Prognostic Index.

BACKGROUND: Ki-67 has been shown to predict outcome of patients with solid pseudopapillary tumor of the pancreas (SPTP) but has not been incorporated into a formal classification system to predict recurrence-free survival (RFS). METHODS: This is a retrospective cohort study of patients with histologically confirmed diagnosis of SPTP who had at least 1 year of follow-up at two tertiary academic centers. Survival data were assessed by Kaplan-Meier method and multivariable Cox regression model. Prognostic performance was compared among various systems. RESULTS: A total of 193 consecutive patients were included, ranging in age from 12 to 70 years (median 33 years). Seven patients (3.6%) developed tumor recurrence. The 3-, 5-, and 10-year RFS rates were estimated at 96.9%, 96.1%, and 94.8%, respectively. For the AJCC staging system, patients with stage I had similar prognosis to those with stage II. For the ENETS staging system, patients with stage I to III had similar prognosis. Grade based on Ki-67 was superior to both the AJCC and ENETS systems for predicting survival. Multivariate analysis revealed that large tumor size [> 10 cm; hazard ratio (HR), 6.177 95% confidence interval (CI), 1.289-29.603; P = 0.023] and Ki-67 (HR, 17.199 95% CI, 4.001-73.930; P < 0.001) were independent predictors for RFS. The Fudan Prognostic Index based on the combination of Ki-67 and tumor size showed excellent discrimination for RFS and was more accurate and informative than other grading/staging systems. CONCLUSION: The Fudan Prognostic Index better predicts RFS compared with either Ki-67 alone or the current AJCC and ENETS TNM-based staging systems.

Prognostic value of preoperative glucose to lymphocyte ratio in patients with resected pancreatic cancer.

BACKGROUND: Inflammatory factors and fasting blood glucose were verified to be associated with the prognosis of pancreatic ductal adenocarcinoma. The goal of this study is to confirm the prognostic role of preoperative blood glucose to lymphocyte ratio for patients with resected pancreatic ductal adenocarcinoma. METHODS: A total of 259 pancreatic ductal adenocarcinoma patients were enrolled and randomly divided into training cohort and validation cohort. The training cohort was used to generate an optimal cutoff value and the validation cohort was used to further validate the model. RESULTS: A total of 259 patients were incorporated in this study and randomly divided into the training cohort (n = 130, 1/2 of 259) and the validation cohort (129, 1/2 of 259). The optimal cutoff value of glucose to lymphocyte ratio was calculated to be 3.47 for overall survival. Cox regression analysis found that preoperative blood glucose to lymphocyte ratio was independent risk factor (p = 0.040) for overall survival. Prognostic values of glucose to lymphocyte ratio on overall survival were observed in younger male patients with pancreatic body and tail cancer, American Joint Committee on Cancer 8th N1 stage, without microvascular and peripancreatic fat invasion, and Carbohydrate antigen 19-9 higher than 200 U/ml. A prognostic prediction model of overall survival was designed and presented in nomogram. CONCLUSION: Preoperative blood glucose to lymphocyte ratio is an independent biomarker to predict the overall survival for pancreatic ductal adenocarcinoma patients who underwent curative resection.

CD73 acts as a prognostic biomarker and promotes progression and immune escape in pancreatic cancer.

CD73 is a glycosylphosphatidylinositol (GPI)-anchored protein that attenuates tumour immunity via cooperating with CD39 to generate immunosuppressive adenosine. Therefore, CD73 blockade has been incorporated into clinical trials for cancers based on preclinical efficacy. However, the biological role and underlying mechanism of CD73 in pancreatic cancer (PC) microenvironment and its prognostic impact have not been comprehensively studied. In this article, we found that the expression of CD73 was up-regulated in PC tissues and patients with higher CD73 expression had poorer overall survival (OS) and disease-free survival (DFS) in multiple publicly available databases. Higher CD73 expression was significantly associated with its reduced methylation, and only the hypomethylation of CpG site at cg23172664 was obviously correlated with poorer OS. Then, Metascape analysis and GSEA showed that CD73 may play an important role in PC progression and immune regulations. Notably, CD73 was verified to be negatively correlated with infiltrating levels of CD8+ T cells and γδ+ T cells in both TCGA and GEO cohorts via the CIBERSORT algorithm. In addition, patients with higher CD73 expression also tended to have higher PD-L1 expression and tumour mutation load. It seemed that CD73 might be a promising biomarker for the response to the anti-PD-1/PD-L1 treatment in PC. In conclusion, these results reveal that CD73 may function as a promotor in cancer progression and a regulator in immune patterns via CD73-related pathways. Blockade of CD73 might be a promising therapeutic strategy for PC.

Preoperative radiotherapy improves overall survival of pT4 pancreatic ductal adenocarcinoma patients after surgical resection.

OBJECTIVE: The aim of delivering radiotherapy for pancreatic ductal adenocarcinoma patients was to sterilize vessel margin, increase R0 resection rate and delay local progression. Whether preoperative radiotherapy could prolong overall survival of surgical candidates remained unknown. METHODS: Pancreatic ductal adenocarcinoma patients receiving radical resection from surveillance, epidemiology and end result database were enrolled. Propensity score matching was conducted to balance difference in baseline characteristics, and survival analyses were performed to compare overall survival between preoperative radiotherapy and upfront resection groups. Cox proportional hazard regression model and subgroup analyses were utilized to identify prognostic factors. RESULTS: A total of 11 665 and 597 pancreatic ductal adenocarcinoma patients receiving upfront resection and preoperative radiotherapy followed by resection from 2004 to 2016 were identified, respectively, while baseline characteristics were distinct between groups. After propensity score matching, preoperative radiotherapy was not associated with better overall survival (upfront resection vs preoperative radiotherapy, 26 vs 27 months). Subgroup analyses showed that preoperative radiotherapy was a protective factor in pT4 (hazard ratio = 0.64, 95% confidence interval: 0.47-0.88) but a negative predictor in pT1 (hazard ratio = 1.79, 95% confidence interval: 1.08-2.97) patient populations. Survival analyses showed that preoperative radiotherapy improved overall survival of patients with pT4 stage (upfront resection vs preoperative radiotherapy, 19 vs 25 months) and involvement of celiac axis, superior mesenteric artery and aorta (upfront resection vs preoperative radiotherapy, 20 vs 27 months), while preoperative radiotherapy was associated with worse overall survival in patients with pT1 tumor (upfront resection vs preoperative radiotherapy, 39 vs 24 months). CONCLUSION: Preoperative radiotherapy could improve survival of resected pancreatic ductal adenocarcinoma patients with pT4 stage or with celiac axis, superior mesenteric artery and aorta invasion.

Exosomal miRNA-106b from cancer-associated fibroblast promotes gemcitabine resistance in pancreatic cancer.

Gemcitabine (GEM)-based chemotherapy is commonly used to treat pancreatic cancer. However, acquired resistance to GEM remains a challenge in pancreatic cancer patients. Here we tested whether cancer-associated fibroblasts (CAFs) play vital roles in regulating drug resistance by transferring exosomal miRNA to cancer cells. CAFs were isolated from primary fibroblast of pancreatic cancer patients, and exosomes were collected and identified through transmission electron microscopy and western blotting analysis. The functions of CAFs-derived exosomal miRNA in regulating drug resistance were further investigated. We found that CAFs were innately resistant to GEM. The conditioned medium (CM) and the exosomes derived from CAFs contributed to GEM resistance, and GEM treatment further enhanced the effect of CAFs or CAFs-exosomes on pancreatic cancer cells proliferation. MiR-106b level was upregulated in CAFs and CAFs-exosomes following GEM treatment. MiR-106b was directly transferred from CAFs to pancreatic cancer cells through exosomes. Pretreatment of CAFs with miR-106b inhibitor suppressed miR-106b expression in CAFs-exosomes and resulted in a decreased resistance of cancer cells to GEM. MiR-106b promoted GEM resistance of cancer cells by directly targeting TP53INP1. Summarily, our data demonstrated that CAFs-derived exosomal miR-106b plays a vital role in causing GEM resistance of pancreatic cancer, thus offering a new target for sensitizing pancreatic cancer cells to GEM.

MANAGEMENT OF REFRACTORY LARGE MACULAR HOLE WITH AUTOLOGOUS NEUROSENSORY RETINAL FREE FLAP TRANSPLANTATION.

PURPOSE: To investigate the morphological and functional outcome of refractory large macular hole (MH) with autologous neurosensory retinal free flap transplantation. METHODS: This case series enrolled 10 patients suffering from refractory large MH at Kaohsiung Medical University Hospital, Kaohsiung, Taiwan. All eyes underwent pars plana vitrectomy, a neurosensory retinal free flap with a 1.5 to 2-MH diameter was harvested. We used an adhesive agent such as whole blood or Viscoat to assist the stabilization of the retinal free flap and then use tamponade silicone oil to tamponade the vitreous cavity. Silicone oil was removed 6 months postoperatively. Main outcome measures including closure of MH and change in best-corrected visual acuity change were recorded. RESULTS: The mean age was 64.9 ± 11.5 years. Before presentation, all cases had received at least two vitreoretinal procedures including vitrectomy, internal limiting membrane peeling, and fluid-gas exchange. At last visit, closure of the MH was achieved in 9 of 10 (90%) cases. The mean preoperative best-corrected visual acuity and that after 12 months of surgery improved from 1.65 ± 0.43 logarithm of minimum angle of resolution to 0.88 ± 0.49 logarithm of minimum angle of resolution (P < 0.001). CONCLUSION: For eyes with refractory or large MH, autologous neurosensory retinal free flap under silicone oil tamponade may provide a new option to improve the anatomical and function outcome, especially in cases where insufficient internal limiting membrane is left.