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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with a 5-year survival rate of 7.2% in China. However, effective approaches for diagnosis of PDAC are limited. Tumor-originating genomic and epigenomic aberration in circulating free DNA (cfDNA) have potential as liquid biopsy biomarkers for cancer diagnosis. Our study aims to assess the feasibility of cfDNA-based liquid biopsy assay for PDAC diagnosis. In this study, we performed parallel genomic and epigenomic profiling of plasma cfDNA from Chinese PDAC patients and healthy individuals. Diagnostic models were built to distinguish PDAC patients from healthy individuals. Cancer-specific changes in cfDNA methylation landscape were identified, and a diagnostic model based on six methylation markers achieved high sensitivity (88.7% for overall cases and 78.0% for stage I patients) and specificity (96.8%), outperforming the mutation-based model significantly. Moreover, the combination of the methylation-based model with carbohydrate antigen 19-9 (CA19-9) levels further improved the performance (sensitivity: 95.7% for overall cases and 95.5% for stage I patients; specificity: 93.3%). In conclusion, our findings suggest that both methylation-based and integrated liquid biopsy assays hold promise as non-invasive tools for detection of PDAC., (© 2024 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

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., (© 2024 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

3D multi-slab acquisitions are an appealing approach for diffusion MRI because they are compatible with the imaging regime delivering optimal SNR efficiency. In conventional 3D multi-slab imaging, shot-to-shot phase variations caused by motion pose challenges due to the use of multi-shot k-space acquisition. Navigator acquisition after each imaging echo is typically employed to correct phase variations, which prolongs scan time and increases the specific absorption rate (SAR). The aim of this study is to develop a highly efficient, self-navigated method to correct for phase variations in 3D multi-slab diffusion MRI without explicitly acquiring navigators. The sampling of each shot is carefully designed to intersect with the central kz=0 plane of each slab, and the multi-shot sampling is optimized for self-navigation performance while retaining decent reconstruction quality. The kz=0 intersections from all shots are jointly used to reconstruct a 2D phase map for each shot using a structured low-rank constrained reconstruction that leverages the redundancy in shot and coil dimensions. The phase maps are used to eliminate the shot-to-shot phase inconsistency in the final 3D multi-shot reconstruction. We demonstrate the method's efficacy using retrospective simulations and prospectively acquired in-vivo experiments at 1.22 mm and 1.09 mm isotropic resolutions. Compared to conventional navigated 3D multi-slab imaging, the proposed self-navigated method achieves comparable image quality while shortening the scan time by 31.7% and improving the SNR efficiency by 15.5%. The proposed method produces comparable quality of DTI and white matter tractography to conventional navigated 3D multi-slab acquisition with a much shorter scan time.

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., (© 2024 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: The role of CD161 expression on CD8 + T cells in tumor immunology has been explored in a few studies, and the clinical significance of CD161 + CD8 + T cells in pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study seeks to clarify the prognostic value and molecular characteristics linked to CD161 + CD8 + T cell infiltration in PDAC., Methods: This study included 186 patients with confirmed PDAC histology after radical resection. CD161 + CD8 + T cell infiltration was assessed using immunofluorescence staining on tumor microarrays. Flow cytometry and single-cell RNA sequencing were used to evaluate their functional status., Results: We observed significant associations between tumor-infiltrating CD161 + CD8 + T cells and clinicopathological factors, such as tumor differentiation, perineural invasion, and serum CA19-9 levels. Patients with higher tumor-infiltrating CD161 + CD8 + T cell levels had longer overall survival (OS) and recurrence-free survival (RFS) than those with lower levels. Multivariable analysis confirmed tumor-infiltrating CD161 + CD8 + T cell as an independent prognostic indicator for both OS and RFS. Notably, a combination of tumor-infiltrating CD161 + CD8 + T cell and CA19-9 levels showed a superior power for survival prediction, and patients with low tumor-infiltrating CD161 + CD8 + T cell and high CA19-9 levels had the worst survival. Furthermore, lower tumor-infiltrating CD161 + CD8 + T cells were associated with a better response to adjuvant chemotherapy. Finally, we identified tumor-infiltrating CD161 + CD8 + T cells as a unique subtype of responsive CD8 + T cells characterized by increased levels of cytotoxic cytokines and immune checkpoint molecules., Conclusion: CD161 + CD8 + T cells exhibit elevated levels of both cytotoxic and immune-checkpoint molecules, indicating as a potential and attractive target for immunotherapy. The tumor-infiltrating CD161 + CD8 + T cell is a valuable and promising predictor for survival and therapeutic response to adjuvant chemotherapy in PDAC. Further research is warranted to validate its role in the risk stratification and optimization of therapeutic strategies., Competing Interests: Competing interests: No, there are no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Patients with advanced pancreatic cancer (PC) need a cost-effective treatment regimen. The present study was designed to compare the efficacy and safety of nab-paclitaxel plus S-1 (AS) and gemcitabine plus S-1 (GS) regimens in patients with chemotherapy-naïve advanced PC. In this open-label, multicenter, randomized study named AvGmPC, eligible patients with chemotherapy-naïve advanced PC were randomly assigned (1:1) to receive AS (125 mg/m 2 nab-paclitaxel, days 1 and 8; 80-120 mg S-1, days 1-14) or GS (1,000 mg/m 2 gemcitabine, days 1 and 8; 80-120 mg S-1, days 1-14). The treatment was administered every 3 weeks until intolerable toxicity or disease progression occurred. The primary endpoint was progression-free survival (PFS). Between December 2018 and March 2022, 101 of 106 randomized patients were treated and evaluated for analysis (AS, n=49; GS, n=52). As of the data cutoff, the median follow-up time was 11.37 months [95% confidence interval (CI), 9.31-13.24]. The median PFS was 7.16 months (95% CI, 5.19-12.32) for patients treated with AS and 6.41 months (95% CI, 3.72-8.84) for patients treated with GS (HR=0.78; 95% CI, 0.51-1.21; P=0.264). The AS regimen showed a slightly improved overall survival (OS; 13.27 vs. 10.64 months) and a significantly improved ORR (44.90 vs. 15.38%; P=0.001) compared with the GS regimen. In the subgroup analyses, PFS and OS benefits were observed in patients treated with the AS regimen who had KRAS gene mutations and high C-reactive protein (CRP) levels (≥5 mg/l). The most common grade ≥3 adverse events were neutropenia, anemia and alopecia in the two groups. Thrombocytopenia occurred more frequently in the GS group than in the AS group. While the study did not meet the primary endpoint, the response benefit observed for AS may be suggestive of meaningful clinical activity in this population. In particular, promising survival benefits were observed in the subsets of patients with KRAS gene mutations and high CRP levels, which is encouraging and warrants further investigation. This trial was retrospectively registered as ChiCTR1900024588 on July 18, 2019., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2024 Guo et al.)

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 T 1 , T 2 , 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 T 1 , T 2 , 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., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: To investigate whether interleukin (IL)-6 could predict the post-operative complications of elective pancreatectomy early. Patients and Methods: Overall, 122 patients who underwent elective pancreatectomy from June 2020 to May 2021 in our hospital were enrolled. Interleukin-6 was measured on the day before and at six hours after surgery, and on post-operative day one, three, and five. The associations between IL-6 level and post-operative complications were analyzed, and the predictive value of IL-6 for complications was assessed. Results: Sixty-three patients developed post-operative complications. Higher IL-6 was observed in patients with post-operative complications on post-operative day one, post-operative day three, and post-operative day five, with odd ratios of 1.43, 1.68, and 2.54 (p = 0.01, p = 0.01, and p = 0.01), respectively. These trends were also observed in patients with infectious complications preoperatively, on post-operative day one, post-operative day three, and post-operative day five, with ORs of 2.46, 1.95, 2.01, and 2.49 (p = 0.00, 0.00, 0.01, 0.00) respectively. Multivariate regression revealed that IL-6 is the only predictor for infectious complications on post-operative day one (p = 0.016). Based on the optimal cutoffs, pre-operative IL-6, IL-6 on post-operative day one and post-operative day three for predicting infectious complications yielded area under the curve (AUC) of 0.73, 0.70, and 0.70, with high negative predictive value of 82.7%, 92.2%, and of 91.3%, respectively. Conclusions: This study validated the early predictive value of IL-6 on infectious complications after pancreatectomy. Because of the performance of serum IL-6 in predicting infectious complications and high NPV, we endorse that IL-6 could be a potential biomarker for early prediction and antibiotic optimization after pancreatectomy.

CD73 plays a critical role in the pathogenesis and immune escape in pancreatic ductal adenocarcinoma (PDAC). AB680, an exceptionally potent and selective inhibitor of CD73, is administered in an early clinical trial, in conjunction with gemcitabine and anti-PD-1 therapy, for the treatment of PDAC. Nevertheless, the specific therapeutic efficacy and immunoregulation within the microenvironment of AB680 monotherapy in PDAC have yet to be fully elucidated. In this study, AB680 exhibits a significant effect in augmenting the infiltration of responsive CD8 + T cells and prolongs the survival in both subcutaneous and orthotopic murine PDAC models. In parallel, it also facilitates chemotaxis of myeloid-derived suppressor cells (MDSCs) by tumor-derived CXCL5 in an AMP-dependent manner, which may potentially contribute to enhanced immunosuppression. The concurrent administration of AB680 and PD-1 blockade, rather than gemcitabine, synergistically restrain tumor growth. Notably, gemcitabine weakened the efficacy of AB680, which is dependent on CD8 + T cells. Finally, the supplementation of a CXCR2 inhibitor is validated to further enhance the therapeutic efficacy when combined with AB680 plus PD-1 inhibitor. These findings systematically demonstrate the efficacy and immunoregulatory mechanism of AB680, providing a novel, efficient, and promising immunotherapeutic combination strategy for PDAC., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Background: Patients with pancreatic ductal adenocarcinoma (PDAC) are increasingly receiving systemic neoadjuvant chemotherapy (NAC), particularly those with borderline resectable and locally advanced disease. However, the specific role of additional adjuvant chemotherapy (AC) in these patients is unknown. The objective of this study is to further assess the clinical benefit and impact of systemic AC in patients with resected PDAC after NAC., Methods: Data on PDAC patients with or without AC following systemic NAC and surgical resection were retrospectively retrieved from the Surveillance, Epidemiology, and End Results (SEER) database between 2006 and 2019. A matched cohort was created using propensity score matching (PSM), and baseline characteristics were balanced to reduce bias. Overall survival (OS) and cancer-specific survival (CSS) were calculated using matching cohorts., Results: The study enrolled a total of 1589 patients, with 623 (39.2%) in the AC group and 966 (51.8%) in the non-AC group [mean age, 64.0 (9.9) years; 766 (48.2%) were females and 823 (51.8%) were males]. All patients received NAC, and among the crude population, 582 (36.6%) received neoadjuvant radiotherapy, while 168 (10.6%) received adjuvant radiotherapy. Following the 1:1 PSM, 597 patients from each group were evaluated further. The AC and non-AC groups had significantly different median OS (30.0 vs. 25.0 months, P =0.002) and CSS (33.0 vs. 27.0 months, P =0.004). After multivariate Cox regression analysis, systemic AC was independently associated with improved survival ( P =0.003, HR=0.782; 95% CI, 0.667-0.917 for OS; P =0.004, HR=0.784; 95% CI, 0.663-0.926 for CSS), and age, tumor grade, and AJCC N staging were also independent predictors of survival. Only patients younger than 65 years old and those with a pathological N1 category showed a significant association between systemic AC and improved survival in the subgroup analysis adjusted for these covariates., Conclusion: Systemic AC provides a significant survival benefit in patients with resected PDAC following NAC compared to non-AC patients. Our study discovered that younger patients, patients with aggressive tumors and potentially well response to NAC might benefit from AC to achieve prolonged survival after curative tumor resection., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

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 (k z ) 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 k z -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., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

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., (© 2023. BioMed Central Ltd., part of Springer Nature.)

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., (© 2023 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: While adjuvant chemotherapy has been established as standard practice following radical resection of pancreatic ductal adenocarcinoma (PDAC), the role of adjuvant radiation therapy (RT) and which patients may benefit remains unclear., Methods: This retrospective study included PDAC patients who received pancreatic surgery from April 2012 to December 2019 in Zhongshan Hospital Fudan University. Patients with carcinoma in situ , distant metastasis, and without adjuvant chemotherapy were excluded. Cox proportional hazards modeling of survival were constructed to find potential prognostic factors. Propensity score matching (PSM) and exploratory subgroup analyses were used to create a balanced covariate distribution between groups and to investigate therapeutic effect of radiotherapy in certain subgroups., Results: A total of 399 patients were finally included, 93 of them receiving adjuvant chemoradiotherapy (C+R+) and 306 of them receiving chemotherapy only. Patients in C+R+ group were more likely to be male patients with T3-4 disease. Lymph node metastases was the only negative prognostic factor associated with overall survival (OS). Additional adjuvant RT was not associated with an OS benefit both before and after PSM. Surprisingly, a trend towards improved OS with RT among patients with either T4, N2 disease or R1 resection becomes significant in patients alive more than 1 year after surgery., Conclusion: Adjuvant RT was not associated with an OS benefit across all patients, though did show a possible OS benefit for the subgroup with T4N2 disease or R1 resection at 1 year after surgery., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Xu, Zhou, Zeng, Fan, Wang, Wu, Guo, Lv, Ouyang, Du and Lou.)

Diffusion MRI is a useful neuroimaging tool for non-invasive mapping of human brain microstructure and structural connections. The analysis of diffusion MRI data often requires brain segmentation, including volumetric segmentation and cerebral cortical surfaces, from additional high-resolution T 1 -weighted (T1w) anatomical MRI data, which may be unacquired, corrupted by subject motion or hardware failure, or cannot be accurately co-registered to the diffusion data that are not corrected for susceptibility-induced geometric distortion. To address these challenges, this study proposes to synthesize high-quality T1w anatomical images directly from diffusion data using convolutional neural networks (CNNs) (entitled "DeepAnat"), including a U-Net and a hybrid generative adversarial network (GAN), and perform brain segmentation on synthesized T1w images or assist the co-registration using synthesized T1w images. The quantitative and systematic evaluations using data of 60 young subjects provided by the Human Connectome Project (HCP) show that the synthesized T1w images and results for brain segmentation and comprehensive diffusion analysis tasks are highly similar to those from native T1w data. The brain segmentation accuracy is slightly higher for the U-Net than the GAN. The efficacy of DeepAnat is further validated on a larger dataset of 300 more elderly subjects provided by the UK Biobank. Moreover, the U-Nets trained and validated on the HCP and UK Biobank data are shown to be highly generalizable to the diffusion data from Massachusetts General Hospital Connectome Diffusion Microstructure Dataset (MGH CDMD) acquired with different hardware systems and imaging protocols and therefore can be used directly without retraining or with fine-tuning for further improved performance. Finally, it is quantitatively demonstrated that the alignment between native T1w images and diffusion images uncorrected for geometric distortion assisted by synthesized T1w images substantially improves upon that by directly co-registering the diffusion and T1w images using the data of 20 subjects from MGH CDMD. In summary, our study demonstrates the benefits and practical feasibility of DeepAnat for assisting various diffusion MRI data analyses and supports its use in neuroscientific applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

Background: Intraductal papillary mucinous neoplasms (IPMNs) are the precursor lesions of pancreatic cancers, requiring active surgical intervention during cancer development. However, the current criteria for predicting malignant IPMNs remain challenging and limited. Hence, this study aimed to assess the discriminatory performance of circulating cytokines, including TNF-α, IL-2R, IL-6, and IL-8, then build a novel predictive model to improve the diagnostic accuracy., Method: A total of 131 retrospective (from March 2016 to December 2019) and 53 prospective (from March 2020 to January 2021) patients who were histologically confirmed as IPMNs were consecutively collected and analyzed., Result: The circulating levels of TNF-α, IL-2R, IL-6, and IL-8 were significantly elevated in malignant IPMNs, and were verified as independent factors for malignant IPMNs (p < 0.05). Then, a novel score, the circulating cytokine score (CCS), was calculated and demonstrated as an independent predictive indicator with a higher area under the curve (AUC) than each cytokine alone (p < 0.001). Besides the CCS, two high-risk stigmata features, the presence of solid component (PSC), and main pancreatic duct (MPD) dilation ≥10 mm were also demonstrated as independent indicators for predicting malignant IPMNs. Finally, a novel nomogram incorporating the CCS and these two high-risk stigmata features presented a remarkable diagnostic performance, both in the training and validation cohorts with AUCs of 0.928 and 0.873, respectively., Conclusion: The CCS can be considered a novel independent predictive indicator for malignant IPMNs. Additionally, the formulated nomogram model integrating the CCS, PSC, and MPD ≥10 mm can be a valuable and promising tool for predicting the malignant transformation of IPMNs during long-term follow-ups to assist in timely and accurate surgical decisions., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: As an integral part of the tumor microenvironment (TME), tumor-associated neutrophils play a crucial role in tumor development. The objective of this study was to investigate the plasticity of tumor-associated N1 and N2 neutrophils in the TME of pancreatic ductal adenocarcinoma (PDAC), along with its impact on survival and association with immune infiltrations., Methods: The primary and validation cohorts including 90 radical resection patients from September 2012 to May 2016 and 29 radical resection patients from September 2018 to October 2019, respectively, with complete survival data, were enrolled. Immunofluorescence staining was used to identify tumor-associated N1 and N2 neutrophils, and the N1/N2 ratio was used to evaluate N1 and N2 plasticity. Thereafter, the association between tumor-associated N1/N2 neutrophil plasticity, clinical features, and immune infiltrations was investigated., Results: There was a significant increase in tumor-associated N2 neutrophils compared with tumor-associated N1 neutrophils. Low N1/N2 ratios were associated with the poorer differentiation of tumors, easier lymph node metastases, and a higher TNM stage. The median overall survival (OS) and recurrence-free survival (RFS) of the high tumor-associated N1 neutrophil group were significantly longer than those of the low group, while the tumor-associated N2 neutrophils played an opposite role. The multivariable analysis revealed that a high N1/N2 ratio was a significant prognostic indicator for OS and RFS. In addition, tumor-associated N1/N2 neutrophils showed an opposite correlation with tumor-infiltrating CD8 + T cells and Tregs., Conclusion: The plasticity of tumor-associated N1/N2 neutrophils was identified as a crucial prognostic indicator that might reflect the TME and immune escape in patients with PDAC. On further investigation and validation, our findings may be used to further stratify patients with varying prognoses to optimize treatment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: The authors declare no conflict of interest.

Pancreatic cancer is one of the most aggressive diseases in the world due to a lack of early detection, leading to an overall 5-year survival of only 10%. In recent years, clinical trials targeted pancreatic cancer in efforts to improve survival. These studies introduce new technologies, concepts, and evidence which have instilled new optimism for improving prognosis. This review summarizes the current status of the recent (5-year) clinical trials and describes contemporary research on pancreatic cancer, including surgical technology, diagnostic skills, traditional chemoradiotherapy, neoadjuvant chemotherapy, immunotherapy, targeted therapy, and precision medicine. Then, the future trend and direction of clinical trials on pancreatic cancer are discussed., (© 2021 Japanese Society of Hepato-Biliary-Pancreatic Surgery.)

Background: Cancer stem cells (CSCs) play pivotal roles in the growth, invasion, metastasis, and chemoresistance of pancreatic cancer (PC). The current characterization of CSCs in PC is not complete. Glutamine-fructose-6-phosphate transaminase 1 (GFAT1) is a key enzyme that regulates the hexosamine pathway (HP), in which it not only controls glucose influx but also catalyzes the reaction to form glucosamine 6-phosphate. Recently, it was reported that GFAT1 is highly expressed in PC. However, the relevance of this high expression of GFAT1, especially its association with cancer stemness, has not been well defined and is thus addressed in the current study., Methods: GFAT1 levels were determined in PC from a public database and assessed by bioinformatics tools. GFAT1 expression in CD133 + and CD44 + CSCs in PC was analyzed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and immunostaining on cytospun cells after flow cytometry-based cell sorting. GFAT1 + cells were separated from GFAT1 - cells by transfection of PC cell lines with a designed plasmid that expressed red fluorescent protein (RFP) under a GFAT1 promoter. Tumor sphere formation, tumor growth, tumor cell invasion, cell migration, and the resistance to gemcitabine-induced apoptosis were determined in GFAT1 + vs. GFAT1 - PC cells., Results: GFAT1 levels were significantly upregulated in PC compared to the adjacent non-PC tissue. There were significantly more GFAT1 + cells in the CD133 + population than in the CD133 - population, and similarly, there were significantly more GFAT1 + cells in the CD44 + population than in the CD44 - population. Compared to GFAT1 - PC cells, GFAT1 + PC cells generated significantly more tumor spheres in culture, appeared to be more invasive and migratory, and were significantly more resistant to gemcitabine-induced cell apoptosis., Conclusions: GFAT1 is highly expressed in CSCs among PC cells and may be crucial for PC growth, metastasis, and chemoresistance., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-1946/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Background: Adjuvant chemotherapy (ACT) is widely accepted in patients with pancreatic ductal adenocarcinoma (PDAC) after surgery; however, effective models for predicting ACT response are scarce. Thus, the objective of this study was to develop a novel signature for predicting its response and overall survival (OS) in resected PDAC patients., Methods: A total of 50 PDAC patients with the transcriptome expression profiles, information about chemotherapy, and relevant clinical data were retrieved from the Cancer Genome Atlas (TCGA), and twenty-nine patients with tissue specimens and clinical data from our hospital were included as a validation. A novel gene signature was developed using bioinformatic differentially expressed genes (DEGs) analysis, Lasso-penalized Cox regression, and multivariate Cox regression studies., Results: Between chemotherapy-resistant and chemotherapy-sensitive cohorts, 569 DEGs were identified, with 490 upregulated and 79 downregulated genes mainly specialized in the regulation of peptide/protein/hormone secretion, calcium ion homeostasis, and T cell activation regulation in biological processes. After Lasso-penalized Cox and multivariate Cox regression analysis, BAT (BCHE, ADH1A, and TNS4) signature was established to predict ACT response and OS. Moreover, BAT signature was verified as an independent risk factor for ACT response (p = 0.042) and OS (median OS: 17.5 months vs. 34.8 months, p = 0.040) and significantly associated with immune infiltrations (p < 0.05). Then, this signature was further validated as the independent risk factor for recurrence-free survival (RFS) in PDAC patients receiving postoperative ACT (median RFS: 9.0 months vs. not reached, p = 0.014), and tumor-infiltrating CD4 + and CD8 + T cells were further validated to be significantly decreased in tissues with higher BAT signature scores (p = 0.015 and 0.021, respectively)., Conclusion: The BAT signature is a novel formulated and independent risk factor for predicting ACT response and long-term survival in patients with resected PDAC. This signature could comprehensively reflect local immune-related response, tumor purity, potential biological behavior, and chemo drug susceptibility., (© 2021. The Society for Surgery of the Alimentary Tract.)

Background: While the elderly population account for an indispensable proportion in pancreatic ductal adenocarcinoma (PDAC), these patients are underrepresented in clinical trials. Whether surgery offered the same benefit for elderly patients as that for younger cohort and which factors affected long-term outcome of elderly population remained unclear., Aims: This study aims to evaluate long-term prognosis of elderly PDAC patients (≥70 years old) after surgery and to investigate potential prognostic factors., Methods: This retrospective study included PDAC patients receiving radical resection from January 2012 to July 2019 in Zhongshan Hospital Fudan University. Patients were divided into young (<70) and old groups (≥70). Propensity score matching (PSM) was conducted to eliminate the confounding factors. We investigated potential prognostic factors via Cox proportional hazards model and Kaplan-Meier estimator. Nomogram model and forest plot were constructed to illustrate the prognostic value of age., Results: A total of 552 PDAC patients who received radical resection were included in this research. Elderly patients showed poorer nutritional status and were less likely to received adjuvant treatment. After matching, although age [hazard ratio (HR)=1.025, 95%CI 0.997-1.054; p=0.083] was not statistically significant in the multivariate cox regression analysis, further survival analysis showed that patients in the old group had poorer overall survival (OS) when compared with young group (p=0.039). Furthermore, reception of adjuvant chemotherapy (HR=0.411, 95%CI 0.201-0.837; p=0.014) was the only independent prognostic factor among elderly patients and could significantly improve OS. Subgroup analysis indicated that age had better prognostic value in PDAC patients with good preoperative nutritional status and relative low tumor burden. Finally, a prognostic prediction model contained age, reception of adjuvant chemotherapy, American Joint Committee on Cancer (AJCC) 8th T and N stage was constructed and presented in nomogram, whose Harrell's concordance index was 0.7478 (95%CI, 0.6960-0.7996). The calibration curves at 1 and 3 years indicated an optimal conformity between actual and nomogram-predicted survival probability in the PDAC patient who received surgery., Conclusion: The elderly PDAC patients were associated with worse OS survival after radical resection, and the noticeable negative effect of age was observed among PDAC patients with better preoperative nutritional status and less aggressive tumor biology. Adjuvant chemotherapy was essential to improve survival outcome of elderly PDAC patients following radical resection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xu, Zhang, Han, Jin, Xu, Kuang, Wu, Wang and Lou.)

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignant tumor with an extremely poor prognosis in digestive tumors. Pyrroline-5-carboxylate reductase 1 (PYCR1) plays an important role in tumor development. Therefore, we aimed to explore the effect of PYCR1 on the growth of PDAC cells. Methods: Tumor tissues and adjacent normal pancreatic tissues were collected from 89 patients with PDAC. And immunohistochemistry (IHC) was used to analyze the expression level of PYCR1 in both. RNA interference was used to inhibit the expression of PYCR1 in PANC- 1 and AsPC-1 cells. After infection, the expression of PYCR1 protein was detected by Western blot. The proliferation and growth of PDAC cells were detected by Celigo analysis, MTT, and clone formation assay. Cell apoptosis was analyzed by flow cytometry. Furthermore, the effect of PYCR1 interference on tumor growth was evaluated in vivo through injecting tumor cells subcutaneously into nude mice. Results: The expression of PYCR1 in pancreatic cancer tissues was significantly higher than in paired adjacent normal pancreatic tissues (P <0.01). In vitro , the downregulation of PYCR1 expression significantly inhibited the cell proliferation and colony formation, and increased apoptosis in PANC-1 cells and AsPC-1 cells compared with the shCtrl group (P <0.01). And in vivo , PYCR1 interference also significantly inhibited tumor growth both in the tumor volume and weight. Conclusion: PYCR1 interference was able to inhibit cell proliferation and promote cell apoptosis of pancreatic cancer. The PYCR1 may serve as a potential therapeutic and prognostic biomarker for the treatment of pancreatic cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Although several altered metabolic genes have been identified to be involved in the tumorigenesis and advance of pancreatic cancer (PC), their prognostic values remained unclear. The purpose of this study was to explore new targets and establish a metabolic signature to predict prognosis and chemotherapy response for optimal individualized treatment. The expression data of PC patients from two independent cohorts and metabolism-related genes from KEGG were utilized and analyzed for the establishment of the signature via lasso regression. Then, the differentially expressed candidate genes were further confirmed via online data mining platform and qRT-PCR of clinical specimens. Then, the analyses of gene set enrichment, mutation, and chemotherapeutic response were performed via R package. As results showed, 109 differentially expressed metabolic genes were screened out in PC. Then a metabolism-related five-gene signature comprising B3GNT3, BCAT1, KYNU, LDHA, and TYMS was constructed and showed excellent ability for predicting survival. A novel nomogram coordinating the metabolic signature and other independent prognostic parameters was developed and showed better predictive power in predicting survival. In addition, this metabolic signature was significantly involved in the activation of multiple oncological pathways and regulation of the tumor immune microenvironment. The patients with high risk scores had higher tumor mutation burdens and were prone to be more sensitive to chemotherapy. In summary, our work identified a new metabolic signature and established a superior prognostic nomogram which may supply more indications to explore novel strategies for diagnosis and treatment.

Basophils, which are considered as redundant relatives of mast cells and the rarest granulocytes in peripheral circulation, have been neglected by researchers in the past decades. Previous studies have revealed their vital roles in allergic diseases and parasitic infections. Intriguingly, recent studies even reported that basophils might be associated with cancer development, as activated basophils synthesize and release a variety of cytokines and chemokines in response to cancers. However, it is still subject to debate whether basophils function as tumor-protecting or tumor-promoting components; the answer may depend on the tumor biology and the microenvironment. Herein, we reviewed the role of basophils in cancers, and highlighted some potential and promising therapeutic strategies.

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., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

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-3β 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., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Large-scale comparative neuroscience requires data from many species and, ideally, at multiple levels of description. Here, we contribute to this endeavor by presenting diffusion and structural MRI data from eight primate species that have not or rarely been described in the literature. The selected samples from the Primate Brain Bank cover a prosimian, New and Old World monkeys, and a great ape. We present preliminary labelling of the cortical sulci and tractography of the optic radiation, dorsal part of the cingulum bundle, and dorsal parietal-frontal and ventral temporal-frontal longitudinal white matter tracts. Both dorsal and ventral association fiber systems could be observed in all samples, with the dorsal tracts occupying much less relative volume in the prosimian than in other species. We discuss the results in the context of known primate specializations and present hypotheses for further research. All data and results presented here are available online as a resource for the scientific community., (© 2021. The Author(s).)

Lipopolysaccharide (LPS) as an important inflammatory mediator activates the innate/adaptive immune system. The existence of LPS in pancreatic ductal adenocarcinoma (PDAC) has been reported, however, its biological function in PDAC remains unclear. Here, we demonstrated that circulating and tumoral LPS was significantly increased by intestinal leakage in the orthotopic murine PDAC model, and LPS administration promoted T cell infiltration but exhaustion paradoxically in the subcutaneous murine PDAC model. By bioinformatic analysis, Toll-like receptor 4 (TLR4), LPS receptor, was further found to enrich in immune tolerance signaling in PDAC tissues. Then, a significant positive correlation was found between TLR4 and programmed death ligand-1 (PD-L1) in clinical PDAC tissues, as well as serum LPS and tumoral PD-L1. Meanwhile, LPS stimulation in vitro and in vivo obviously upregulated tumor PD-L1 expression, and effectively promoted cancer cells resistance to T cell cytotoxicity. Mechanistically, the activation of TLR4/MyD88/AKT/NF-κB cascade was found to participate in LPS mediated PD-L1 transcription via binding to its promoter regions, which was enhanced by crosstalk between NF-κB and AKT pathways. Finally, PD-L1 blockade could significantly reverse LPS-induced immune escape, and synergized with LPS treatment. Taken together, LPS can remodel tumor microenvironment, and synergize with PD-L1 blockade to suppress tumor growth, which may be a promising comprehensive strategy for PDAC., (© 2021. The Author(s).)

RAS is the most common mutated gene in colorectal cancer (CRC), and its occurrence is associated with primary and acquired resistance to anti-epidermal growth factor receptor (EGFR) blockade. Cancer community ecology, such as the competitive exclusion principle, is a valuable focus and would contribute to the understanding of drug resistance. We have presented several articles on RAS mutant clonal evolution monitoring during anti-EGFR treatment in CRC. In these articles, the availability of serially collected samples provided a unique opportunity to model the tumor evolutionary process from the perspective of cancer community ecology in those patients upon treatment. In this perspective article, we presented a theoretical basis and evidence from several experimental or phase II clinical trials for the contemporary application of ecological mechanisms in CRC treatment. In general, a reduction in targetable RAS wild-type cells to a maximum tolerated extent, such as continuous treatment, might lead to the competitive release of inextirpable RAS mutant cells and cancer progression. A full understanding of subclonal competition might be beneficial in managing CRC. Several ecological strategies, including anti-EGFR treatment reintroduced at an appropriate point of time for RAS mutant patients, intermittent treatment instead of continuous treatment, the appropriate sequence of nonselective targeted therapy, and combination therapy, were proposed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Wang, Wu, Zheng and Chi.)

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies. Larger tumor size is widely acknowledged to be associated with increased lymph node (LN) metastatic potential. However, the quantitative relationships between tumor size and LN metastasis or survival remain unclear. This study aims to quantify the objective relationship between tumor size and the prevalence of LN metastases across a spectrum primary tumor size., Methods: The Surveillance, Epidemiology, and End Results (SEER) database was used to identify 9958 patients with resected PDAC without distant metastasis. The prevalence of LN metastases, LN ratio (LNR), and N2/N1 ratio were assessed amongst different tumor sizes, and the relationships were displayed by matched curves., Results: In the enrolled cohort, age, tumor site, grade, American Joint Committee on Cancer (AJCC) 8th node staging, tumor size, chemotherapy, and radiotherapy were identified as significant independent predictors for overall survival (OS) and cancer-specific survival (CSS). For tumors within 1-40 mm in size, the prevalence of node-positive disease is closely modelled using a logarithmic formula [0.249 × ln (size) + 0.452] × 100%. The prevalence plateaued between 70% and 80% beyond 40 mm. The mean LNR increased in a stepwise manner as tumor size increased from 1-5 mm (LNR = 0.024) to 41-45 mm (LNR = 0.177); then, beyond 45 mm, it plateaued near 0.170. N2/N1 ratio gradually increased along with tumor size from 1-5 mm (N2/N1 = 0.286) to 41-45 mm (N2/N1 = 1.016), and when tumor size reached to 41-45 mm or more, the ratio stabilized around 1.000. In addition, significant survival prediction by AJCC N staging was observed when tumors ranging between 16 and 45 mm in size., Conclusion: Regional LN involvement demonstrated a logarithmic growth with increasing tumor sizes in patients with resected PDAC . The probability of metastasis in each regional LN for resected PDAC with tumors greater than 40 mm in size was near 17.0% and their overall prevalence of LN metastasis was 70-80%. Among which, 50% of patients had an N2 stage. Such prediction may be a potential and promising tool for guiding lymphadenectomy in PDAC surgery., (© 2021. The Author(s), under exclusive licence to Springer Healthcare Ltd., part of Springer Nature.)

Background: Clinically relevant postoperative pancreatic fistula (CR-POPF) remains a severe and challenging complication of pancreaticoduodenectomy (PD). This study aimed to establish a novel postoperative nomogram-based diagnostic model for the early detection of CR-POPF in patients subjected to PD., Methods: Consecutive patients who underwent PD in Zhongshan Hospital, Fudan University from December 2018 to October 2020 were retrospectively enrolled. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for CR-POPF. Then, a novel predictive nomogram was established accordingly., Results: Among the consecutive 176 patients who underwent PD, 37 (21.1%) patients developed CR-POPF. Through univariate and multivariate analyses, the drain amylase (P = 0.002), serum creatinine (P = 0.009), and serum C reactive protein (P = 0.045) at postoperative day 1 (POD1) as well as the neutrophil count (P = 0.025) and temperature (P = 0.025) at POD3 were identified as independent risk factors for CR-POPF. Based on this, a novel predictive nomogram containing these factors was constructed to predict the probability of CR-POPF after PD. The formulated nomogram showed better performance to detect CR-POPF after PD with a sensitivity of 0.784, specificity of 0.770, positive predictive value of 0.475, and negative predictive value of 0.930 when compared to other predictors. In addition, the predictive value of the nomogram was assessed by a concordance index of 0.814 (95% CI, 0.736-0.892), which was significantly higher than indicators alone. This was further validated and depicted by decision curve analysis and clinical impact curve., Conclusion: This study established a diagnostic nomogram of postoperative objective parameters that can predict the development of CR-POPF after PD with a good discriminative ability and predictive accuracy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Pu, Chen, Mei, Wang, Jin, Wu, Zhang and Lou.)

Background: The incidence of indolent gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) has increased dramatically. GEP-NENs often present late with concomitant liver metastasis, which is associated with poorer outcomes., Methods: This is a retrospective cohort study of 3,188 patients with liver metastatic GEP-NENs from the national scale Surveillance, Epidemiology, and End Results (SEER) database in the USA between 2010 and 2016. The population-based sample of GEP-NENs with liver metastasis was stratified by primary site (intestinal, pancreatic or gastric), surgical intervention and functional status., Results: Of the 3,188 patients with liver metastatic GEP-NENs in this study, intestinal NENs (iNENs) were the most common and displayed the best 5-year survival of 42.6% compared to 25.8% in pancreatic NENs (pNENs) and 12.0% in gastric NENs (gNENs). Surgical intervention [hazard ratio (HR): 0.46, 95% CI: (0.40-0.53), P<0.001] and carcinoid subtype showed robust survival advantages across all groups. pNENs with liver metastasis were associated with the greatest benefit of surgery [HR: 0.55, 95% CI: (0.41-0.75), P<0.001] while iNENs were the most commonly treated by surgery. After risk adjustment, primary site was not associated with outcome in the non-surgical group., Conclusions: Taken collectively, when diagnosed with liver metastasis, iNENs conferred a better overall prognosis than both pNENs and gNENs. Primary surgical resection, especially of carcinoid type tumors, emerged as a robust prognostic indicator of better outcomes irrespective of primary site. This finding was most pronounced in liver metastatic pNENs. When possible, we recommend surgical intervention in GEP-NENs with liver metastasis., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-20-5348). The authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

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.

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.

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., (© 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

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., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Competing Interests: Declaration of competing interest We declared no conflict of interest.

Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm.2020.04.30). The authors have no conflicts of interest to declare.

Background: It is unclear if the modified extended pancreaticoduodenectomy (PD) has better outcome superior the conventional PD for patients with pancreatic head carcinoma (PHC). The objective of this study is to compare the survival outcomes of the classic PD procedure and the modified extended PD procedure for PHC., Methods: A total of 7,084 resected PHC patients with PD and extended PD procedure from the SEER database from 2004 to 2014 were stratified. With the utilization of propensity score matching (PSM), patient baseline characteristics were balanced to decrease the bias. Overall survival (OS) and cancer-specific survival (CSS) were analyzed in both groups., Results: Of the 7,084 patients, 6,541 (92.3%) and 543 (7.7%) patients received PD and extended PD surgical procedures, respectively. After 2:1 ratio of PSM, 543 patients with extended PD procedure and 1,084 patients with PD procedure were completely matched. The median CSS and OS for PD and extended PD group were 20.0 and 19.0 months, and 19.0 and 18.0 months, respectively. The 5-year CSS and OS rates for PD and extended PD group were 17.5% and 16.1%, and 13.9% and 13.1%, respectively., Conclusions: There is no distinct difference in survival outcomes between PD and extended PD procedure in patients with PHC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2020.01.38). NP serves as an unpaid section editor of Translational Cancer Research from Jan 2020 to Dec 2021. The other authors have no conflicts of interest to declare., (2020 Translational Cancer Research. All rights reserved.)

Background: Serous cystic neoplasms (SCN) rarely have malignant potential, so accurate diagnosis of SCN is crucial for proper clinical management, especially to avoid unnecessary surgeries. However, the misdiagnosis of other pancreatic cystic neoplasm instead of SCN may highly increase the risk of malignancy in patients who receive no surgery., Methods: Data from a total of 678 patients with pathologically confirmed to have SCN at sixteen institutions in China from January 1 st , 2006 to December 31 st , 2016 were retrieved to evaluate the malignancy risk of SCN., Results: Among the 678 patients confirmed to have SCN with postoperative pathologic analysis, 649 patients (95.7%) had only one lesion and the average maximum diameter was 3.8±2.47 cm. Four patients were pathologically verified as having serous cystadenocarcinoma, so the SCN actual malignancy rate was 0.6%, while the mortality due to pancreatic surgery in these high-volume centers was nearly 0.2-2%. However, among the 99 SCN patients based on preoperative radiology, three were confirmed to have intraductal papillary mucinous neoplasms (IPMN), nine as mucinous cystic neoplasms (MCN), and four as solid pseudopapillary tumors (SPT) after postoperative pathological analysis. Thus, the total theoretical malignancy rate resulting from preoperative misdiagnosis was elevated to approximately 2.9%, higher than the risk of perioperative mortality., Conclusions: When SCN can't be accurately distinguished from cystic tumors of pancreas, the malignant risk of cystic tumors may be higher than perioperative risk. However, if it can be diagnosed as SCN accurately, surgery can be avoided as well., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)

Background: The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains dismally poor and is widely considered as an intricate genetic disorder. The mutational landscape of PDAC may directly reflect cancer immunogenicity and dictate the extent and phenotype of immune cell infiltration. In adverse, the microenvironment may also effect the gene expression of cancer cells, which is associated with clinical prognosis. Thus, it is crucial to identify genomic alterations in PDAC microenvironment and its impacts on clinical prognosis., Methods: The gene expression profiles, mutation data and clinical information of 179 pancreatic cancer patients with an initial pathologic diagnosis ranging from 2001 to 2013 were retrieved from The Cancer Genome Atlas (TCGA) database. The MAlignant Tumor tissues using Expression data (ESTIMATE) algorithm for calculating immune scores and stromal scores and Tumor IMmune Estimation Resource (TIMER) resource for cell infiltrations were applied in this study., Results: The average immune score or stromal score of PDAC subtype was significantly higher than that of other specific subtypes. KRAS mutant cases had significantly lower immune scores (P=0.001) and stromal scores (P=0.007), in concert with lower immune scores in TP53 mutant cases (P=0.030). However, no significant difference was found in SMAD4 and CDKN2A mutations. In the cohort OS/RFS, the infiltration levels of CD8+ T cells, B cells, Macrophages, Neutrophils and DCs in high stromal score group were higher than those in the low score group (all P<0.001), as well as in immune score groups except for Macrophages in the cohort RFS. In the cohort OS/RFS, 317/379 upregulated genes and 9/6 downregulated genes were observed in the high immune score group, while 227/205 upregulated genes and 17/6 downregulated genes in the high stromal score group. With the analysis for prognostic value of DEGs, 82 and 58 DEGs respectively in the high immune and stromal score group were verified to be significantly associated with better OS (P<0.05), while 53 and 17 DEGs respectively with longer RFS (P<0.05). Functional enrichment analysis showed genes of prognostic values were significantly related to immune response., Conclusions: A list of genes with prognostic value in PDAC microenvironment were obtained from functional enrichment analysis based on immune and stromal scores, which indicates a series of potential auxiliary prognostic biomarkers for PDAC are available. Further research on these genes may be valuable and helpful to understand the crosstalk between tumor and microenvironment, new immune evasion mechanisms and underlying novel therapeutic targets in an integrated manner., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)

Background: A growing body of evidence supports the use of laparoscopic pancreaticoduodenectomy (LPD) as an efficient and feasible surgical technique. However, few studies have investigated its applicability in pancreatic ductal adenocarcinoma (PDAC), and the long-term efficacy of LPD on PDAC remains unclear. This study aimed to compare the short- and long-term outcomes between LPD and open pancreaticoduodenectomy (OPD) for PDAC., Methods: The data of patients who had OPD or LPD for PDAC between January 2013 and September 2017 were retrieved. Their postoperative outcomes and survival were compared after propensity score matching., Results: A total of 309 patients were included. After a 2:1 matching, 93 cases in the OPD group and 55 in the LPD group were identified. Delayed gastric emptying (DGE), particularly grade B/C DGE, occurred less frequently in the LPD group than in the OPD group (1.8% vs. 36.6%, P < 0.001; 1.8% vs. 22.6%, P = 0.001). The overall complication rates were significantly lower in the LPD group than in the OPD group (49.1% vs. 71.0%, P = 0.008), whereas the rates of major complications were similar (10.9% vs. 14.0%, P = 0.590). In addition, the median overall survival was comparable between the two groups (20.0 vs. 18.7 months, P = 0.293)., Conclusion: LPD was found to be technically feasible with efficacy similar to OPD for patients with PDAC.

Background: The prognosis of pancreatic ductal adenocarcinoma (PDAC) remains poor. Open distal pancreatosplenectomy (ODPS) is prevalent in the patients of early PDAC located in pancreatic body or tail. However, the models for relapse or survival prediction in those patients are still limited. Postoperative neutrophil-to-lymphocyte rate (poNLR), a novel inflammation-based score, has been formulated to analyze the prognostic significance in PDAC patients with ODPS. Therefore, this study aims to generate a valuable prognostic nomogram for PDAC following ODPS. Methods: We retrospectively enrolled 97 patients of PDAC undergoing ODPS in this study. The Cox proportional hazards regression methodology was used in univariate and multivariate survival analyses to identify significant independent prognostic factors. The prognostic nomograms integrating poNLR into the American Joint Commission on Cancer (AJCC) staging system (8th edition) for predicting overall survival (OS) and relapse free survival (RFS) were established to achieve superior discriminatory abilities. Further, these prognostic nomograms were verified according to concordance index (C-index), calibrations and decision curve analyses (DCA). Results: The optimal cut-off value of poNLR for assessing OS determined by X-tile program was 14.1. Higher poNLR was associated with higher postoperative neutrophil (poNeutrophil), lower postoperative lymphocyte (poLymphocyte), lower preoperative lymphocyte-to-monocyte rate (preLMR) and higher △NLR (postoperative-preoperative NLR). In the univariate and multivariate analysis, poNLR was identified as an independent prognostic indicator for OS and RFS (P=0.044 and 0.028, respectively) and patients with higher poNLR level were probable to have shorter OS and RFS. Compared with the TNM staging system of the AJCC 8th edition, the nomogram comprising of poNLR and AJCC 8th edition exhibited superior predictive accuracy for OS and RFS. Conclusions: poNLR can be a proven, inexpensive and novel survival predictor of PDAC patients with ODPS. One more advanced and accurate predictive model will be achieved to assist in risk stratification via the incorporation of poNLR into nomograms., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The prognosis of pancreatic adenosquamous carcinoma (PASC) after surgery is poor. The purpose of this study was to clarify the prognostic factors of PASC and evaluate the efficacy of combination chemoradiotherapy., Methods: The patients' data retrieved from the Surveillance, Epidemiology, and End Results database (SEER) between 2004 and 2015 were stratified and analyzed in this study. The univariate and multivariate analysis were used for overall survival (OS) and cancer-specific survival (CSS)., Results: T staging, M staging, chemotherapy and radiotherapy is the independent prognostic indicator after PASC resection for both OS and CSS. In the total cohort, 44 patients had both chemo and radiotherapy, with median OS 23 months and CSS 29 months, which was significantly better than neither chemo nor radiotherapy group (68 patients, median OS 8 months and CSS 11 months), and either chemotherapy or radiotherapy group (91 patients, median OS 13 months and CSS 15 months). The survival benefit of chemoradiotherapy was validated in the specific group (n=159) who had only primary PASC. PASC patients receiving chemoradiotherapy had longer OS and CSS than those with neither chemo nor radiotherapy in TNM stage I, II and IV subgroups., Conclusions: The chemoradiotherapy revealed its prognostic superiority in PASC treatment., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare., (2019 Annals of Translational Medicine. All rights reserved.)