Association of textbook outcomes with improved survival in pancreatic ductal adenocarcinoma following pancreaticoduodenectomy: a retrospective study.

Background: Assessing the perioperative outcomes of pancreaticoduodenectomy (PD) based solely on individual complications is not comprehensive, and the association between perioperative outcomes and the long-term prognosis of individuals diagnosed with pancreatic ductal adenocarcinoma (PDAC) remains uncertain. Our study is designed to evaluate the impact of a novel composite indicator, textbook outcomes (TO), on the long-term prognosis of patients undergoing PD for PDAC. Methods: This study conducted a retrospective analysis of 139 patients who underwent PD for pathologically confirmed PDAC at our hospital between January 2018 and December 2021. After applying exclusion criteria, a total of 111 patients were included in the subsequent analysis. These patients were categorized into two groups: the non-TO group (n=42) and the TO group (n=69). The Kaplan-Meier survival curve was employed to describe the relationship between TO and disease-free survival (DFS) and overall survival (OS). Cox regression was employed to assess the impact of achieving TO on long-term survival. Logistic regression was employed to investigate the risk factors affecting the achievement of TO. Results: Out of the 111 PDAC patients, 69 (62.2%) achieved TO following PD. The achievement of TO significantly improved the OS of PDAC patients [P=0.03; hazard ratio (HR) =0.60; 95% confidence interval (CI): 0.37-0.83]. Cox regression analysis indicated that achieving TO was a protective factor for OS (P=0.04; HR =4.08; 95% CI: 1.07-15.61). Logistic regression analysis indicated that high amylase in drainage fluid on the third day after surgery (>1,300 U/L) was detrimental to achieve TO [odds ratio (OR) =0.10; 95% CI: 0.02-0.58; P=0.01], longer surgery durations (≥6.25 hours) was detrimental to achieve TO (OR =0.19; 95% CI: 0.06-0.54; P=0.002), and soft pancreatic texture was detrimental to achieve TO (OR =0.31; 95% CI: 0.10-0.93, P=0.04). Conclusions: Achievement of TO significantly improves the OS of PDAC patients and has the potential to serve as a robust prognostic indicator. Looking ahead, it is highly necessary for TO to become a standard surgical quality control measure in hospitals.

68Ga-PSMA PET/CT and 18F-FDG PET/CT in the diagnosis of prostatic ductal cancer.

PURPOSES: To explore the characteristics of PSMA PET/CT and FDG PET/CT images in prostatic ductal adenocarcinoma (DA) patients. METHODS: We retrospectively enrolled prostatic DA patients with PET/CT scans at Tongji Hospital from 2018 to 2022. Patients with prostatic acinar adenocarcinoma (AA) and benign pathology (BP) were enrolled by 1:1 matching. Differences in the uptake of primary and metastatic foci on PET among the groups were analyzed. RESULTS: A total of 42 patients were enrolled: 14 in each group. In primary foci, the mean PSMA uptake in the DA group was lower than that in the AA group (14.2 ± 9.6 vs. 27.1 ± 14.3, P = 0.009) and greater than that in the BP group (14.2 ± 9.6 vs. 4.7 ± 1.3, P = 0.003). The AUCs of the DA-AA ROC curve and DA-BP ROC curve were 0.781 and 0.872, respectively. The median PSMA uptake of metastatic lymph nodes in the DA group was lower than that in the AA group (5.6 vs. 14.2, P = 0.033), with no significant difference in metastatic bone lesions (9.5 vs 19.1, P = 0.485). No significant difference was found in the FDG uptake of primary and metastatic foci between the DA and AA groups (P > 0.05). CONCLUSION: Prostatic DA has greater PSMA uptake than BP diseases, but lower uptake in both primary foci and metastatic lymph nodes than AA on PSMA PET/CT, aiding in the differential diagnosis of DA, AA and BP diseases. Clinicians should combine traditional imaging with PSMA PET/CT to avoid underestimating the clinical stage of DA patients.

Critical Role of Preoperative Hyperglycemia in Association with GFAT-1 Expression in Resected Pancreatic Cancer.

BACKGROUND: Hyperglycemia is involved in malignant transformation of pancreatic cancer via the hexosamine biosynthetic pathway (HBP). However, few studies have verified this mechanism based on clinical data. This study investigated the complementary effects of hyperglycemia and HBP on pancreatic cancer prognosis using detailed clinical data. METHODS: The study analyzed data of 477 patients with pancreatic cancer who underwent pancreatectomy between 2006 and 2020. The patients were divided into normoglycemia and hyperglycemia groups based on their HbA1c levels. Immunostaining for glutamine fructose-6-phosphate transaminase-1 (GFAT-1), the rate-limiting enzyme in HBP, CD4, CD8, and Foxp3, was performed to evaluate the association between survival outcomes, HBP, and local tumor immunity. RESULTS: Overall survival (OS) was significantly poorer in the hyperglycemia group than in the normoglycemia group (mean survival time [MST]: 35.0 vs. 47.9 months; p = 0.007). The patients in the hyperglycemia group with high GFAT-1 expression had significantly poorer OS than those with low GFAT-1 expression (MST, 49.0 vs. 27.6 months; p < 0.001). However, the prognosis did not differ significantly between the patients with high and low GFAT-1 expression in the normoglycemia group. In addition, the patients with hyperglycemia and high GFAT-1 expression had fewer CD4+ (p = 0.015) and CD8+ (p = 0.017) T cells and a lower CD8+/Foxp3+ ratio (p = 0.032) than those with hyperglycemia and low GFAT-1 expression. CONCLUSIONS: The patients with hyperglycemia and high GFAT-1 expression levels had an extremely poor prognosis. Furthermore, the tumors in these patients were characterized as immunologically cold tumors.

Recurrence pattern and its risk factors in patients with resected pancreatic ductal adenocarcinoma - A retrospective analysis of 272 patients.

BACKGROUND: The aim of this study was to investigate the patterns of recurrence and their associated risk factors in patients who underwent resection for pancreatic carcinoma. METHODS: This retrospective study included 272 patients, who underwent Ro/R1-resection of PDAC from 2005 to 2020 at the University Hospital Erlangen. Risk factors for different recurrence patterns and the prognostic value of recurrence pattern on the overall survival after recurrence were evaluated. RESULTS: 61 % of the patients experienced recurrence, mostly within the first 12 postoperative months (62 %) and in the form of metastases (87 %). The median overall survival from recurrence was 9.2 months. The preoperative absence of diabetes and the presence of lymph node metastasis were independent risk factors for recurrence and a preoperative CA19-9 exceeding 97 U/ml for early recurrence. Additionally, lymph node metastases were associated with a higher risk of metastatic recurrence. Early recurrence, but not the site of recurrence, was identified as an independent prognostic factor for worse overall survival from recurrence. CONCLUSION: The occurrence of recurrence and especially of early and metastatic recurrence are associated with a worse overall survival. Patients lacking preoperative diabetes, having high preoperative CA19-9 values and lymph node metastases are particularly at risk for (early) recurrence.

FRA1 controls acinar cell plasticity during murine KrasG12D-induced pancreatic acinar to ductal metaplasia.

Acinar cells have been proposed as a cell-of-origin for pancreatic ductal adenocarcinoma (PDAC) after undergoing acinar-to-ductal metaplasia (ADM). ADM can be triggered by pancreatitis, causing acinar cells to de-differentiate to a ductal-like state. We identify FRA1 (gene name Fosl1) as the most active transcription factor during KrasG12D acute pancreatitis-mediated injury, and we have elucidated a functional role of FRA1 by generating an acinar-specific Fosl1 knockout mouse expressing KrasG12D. Using a gene regulatory network and pseudotime trajectory inferred from single-nuclei ATAC-seq and bulk RNA sequencing (RNA-seq), we hypothesized a regulatory model of the acinar-ADM-pancreatic intraepithelial neoplasia (PanIN) continuum and experimentally validated that Fosl1 knockout mice are delayed in the onset of ADM and neoplastic transformation. Our study also identifies that pro-inflammatory cytokines, such as granulocyte colony stimulating factor (G-CSF), can regulate FRA1 activity to modulate ADM. Our findings identify that FRA1 is a mediator of acinar cell plasticity and is critical for acinar cell de-differentiation and transformation.

Predictors of occult metastases in potentially Resectable pancreatic ductal adenocarcinoma.

Background: Patients with resectable (R) or borderline resectable (BR) pancreatic ductal adenocarcinoma (PDAC) sometimes show unexpected liver, peritoneal, and para-aortic lymph node metastases intraoperatively. Despite radical pancreatectomy, a nonnegligible number of patients relapse within 6 months after surgery. The aim of this study was to identify the preoperative predictors of occult metastases (OM), defined as intraoperative distant metastases or within 6 months after pancreatectomy. Materials and methods: This study included patients with R and BR PDAC who underwent curative-intent pancreatectomy or staging laparoscopy between 2006 and 2021. Multivariate logistic regression and Cox hazard analyses were performed to identify the preoperative predictors of OM and to assess the impact of these factors on prognosis after pancreatectomy. Results: Of the 279 patients, OM was observed intraoperatively in 47 and postoperatively in 34. In the OM group, there were no differences in prognosis between patients who had intraoperative metastases and recurrence within 6 months (median survival time [MST], 18.1 vs. 12.9 months), and between patients who underwent pancreatectomy and those who did not (MST, 13.9 vs. 18.1 months). Preoperative tumor size ≥22 mm (odds ratio [OR], 2.03; 95 % confidence interval [CI], 1.16-3.53; p = 0.013) and preoperative CA19-9 level ≥ 118.8 U/mL (OR, 2.64; 95 % CI, 1.22-5.73; p = 0.014) were significant predictors of OM. Additionally, positive OM predictors were strong independent prognostic factors for overall survival after pancreatectomy (hazard ratio, 2.47; 95 % CI, 1.54-3.98; p < 0.001). Conclusion: Multidisciplinary treatment strategies should be considered for patients with predictors of OM to avoid inappropriate surgical interventions.

Urinary biomarkers analysis as a diagnostic tool for early detection of pancreatic adenocarcinoma: Molecular quantification approach.

BACKGROUND AND AIMS: Pancreatic ductal adenocarcinoma (PDAC) is infrequent. Currently, non-invasive biomarkers for early detection of PDAC are not accessible. Here, we intended to identify a set of urine markers able to discriminate patients with early-stage PDAC from healthy individuals. PATIENTS AND METHODS: Seventy-five urine samples from PDAC patients and 50 healthy controls were assayed using quantitative real-time PCR (qPCR). The chosen biomarkers were lymphatic vessel endothelial HA receptor (LYVE-1), regenerating islet-derived 1 alpha (REG1A), and trefoil factor family (TFF1). RESULTS: LYVE-1, REG1A, and TFF1 expression in PDAC proved to be significantly elevated compared to healthy individuals (p < 0.05). Determination of these markers' expression might be useful for early tumor diagnosis with a sensitivity of 96 %, 100 %, and 73.33 % respectively, and a specificity of 100 %, 82 %, and 100 % respectively. CONCLUSION: We have recognized three diagnostic biomarkers REG1A, TFF1, and LYVE1 that can detect patients with early-stage pancreatic cancer in non-invasive urine specimens with improved sensitivity and specificity. To the best of our knowledge, there have been no prior investigations examining the mRNA expression levels of them in urine within the Egyptian population.

Relationships between postoperative recurrences and standardized uptake value on 18F-fluorodeoxyglucose-positron emission tomography in patients with resectable and borderline resectable pancreatic ductal adenocarcinoma who underwent curative pancreatic resection after neoadjuvant chemoradiotherapy.

BACKGROUND: This study aimed to examine postoperative recurrence after curative pancreatic resection following neoadjuvant chemoradiotherapy (NACRT) in patients with resectable (R-) and borderline resectable (BR-) pancreatic ductal adenocarcinoma (PDAC), focusing on its relationship with the standardized uptake value (SUV) on 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET). METHOD: The postoperative initial recurrence patterns were examined in patients with R- and BR-PDAC who underwent NACRT followed by curative pancreatic resection. Data collected from three prospective clinical trials were retrospectively analysed. RESULTS: After a median follow-up of 29 months, 91 (60 %) of 151 patients experienced postoperative recurrence. The median recurrence-free survival (RFS) for all patients was 18 months. The sites of first recurrence were lung-only in 24 (26 %) patients, liver-only in 23 (25 %), local-only in 11 (12 %), peritoneum-only in 10 (11 %), other single site in 5 (5 %), and multiple sites in 19 (21 %) patients. Multivariate analysis identified the maximum standardized uptake value (SUVmax) on FDG-PET at diagnoses ≥5.40 (hazard ratio [HR], 1.62; 95 % confidence interval [CI], 1.01-2.61; p = 0.045) and node-positive pathology (HR, 2.01; 95 % CI, 1.32-3.08; p = 0.001) as significant predictors of RFS. Furthermore, the SUVmax at initial diagnosis and after NACRT correlated with liver metastasis. CONCLUSION: R- and BR-PDACs with high SUV on FDG-PET at diagnosis are risk factors for postoperative recurrence. Among patients who undergo surgery after NACRT, those with a high SUVmax at diagnosis or post-NACRT require careful attention for postoperative liver recurrence.

Performance of different CT enhancement quantification methods as predictors of pancreatic cancer recurrence after upfront surgery.

The prognosis of pancreatic cancer (PDAC) after tumor resection remains poor, mostly due to a high but variable risk of recurrence. A promising tool for improved prognostication is the quantification of CT tumor enhancement. For this, various enhancement formulas have been used in previous studies. However, a systematic comparison of these formulas is lacking. In the present study, we applied twenty-three previously published CT enhancement formulas to our cohort of 92 PDAC patients who underwent upfront surgery. We identified seven formulas that could reliably predict tumor recurrence. Using these formulas, weak tumor enhancement was associated with tumor recurrence at one and two years after surgery (p ≤ 0.030). Enhancement was inversely associated with adverse clinicopathological features. Low enhancement values were predictive of a high recurrence risk (Hazard Ratio ≥ 1.659, p ≤ 0.028, Cox regression) and a short time to recurrence (TTR) (p ≤ 0.027, log-rank test). Some formulas were independent predictors of TTR in multivariate models. Strikingly, almost all of the best-performing formulas measure solely tumor tissue, suggesting that normalization to non-tumor structures might be unnecessary. Among the top performers were also the absolute arterial/portal venous tumor attenuation values. These can be easily implemented in clinical practice for better recurrence prediction, thus potentially improving patient management.

Impact of endoscopic ultrasound-guided fine needle aspiration on positive peritoneal lavage cytology in patients with resectable pancreatic body and tail cancer.

BACKGROUND/PURPOSE: A recent study has demonstrated that the timing of endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) significantly influences the peritoneal lavage cytology (CY) outcomes in pancreatic body-tail cancer. The aim of this study was to clarify the impact of EUS-FNA on CY positivity in patients with resectable pancreatic body-tail cancer. METHODS: Patients with anatomically resectable pancreatic body-tail cancer surgically resected at Hiroshima University Hospital were enrolled, and elated clinicopathological factors, including EUS-FNA variables and CY positivity rate, were analyzed. RESULTS: Of the 129 eligible patients, 16 (12%) had positive CY. The EUS-FNA rates of the CY-positive and CY-negative groups were not significantly different (63% vs. 52%, p = .440). Multivariate analysis revealed that lymph node metastasis was the only independent risk factor for CY positivity (odds ratio: 5.734, p = .031). A total of 10 (14%) of the 69 patients who underwent EUS-FNA had positive CY; however, needle specifications and the interval between EUS-FNA and CY examination did not differ between the CY-positive and CY-negative groups. CY positivity rates were comparable for intervals ≤14 days and ≥15 days (17% vs. 14%, p = 1.000). CONCLUSIONS: EUS-FNA may not affect CY positivity in patients with resectable pancreatic body-tail cancer, regardless of the timing.

The Usefulness of Low-Kiloelectron Volt Virtual Monochromatic Contrast-Enhanced Computed Tomography with Deep Learning Image Reconstruction Technique in Improving the Delineation of Pancreatic Ductal Adenocarcinoma.

To evaluate the usefulness of low-keV multiphasic computed tomography (CT) with deep learning image reconstruction (DLIR) in improving the delineation of pancreatic ductal adenocarcinoma (PDAC) compared to conventional hybrid iterative reconstruction (HIR). Thirty-five patients with PDAC who underwent multiphasic CT were retrospectively evaluated. Raw data were reconstructed with two energy levels (40 keV and 70 keV) of virtual monochromatic imaging (VMI) using HIR (ASiR-V50%) and DLIR (TrueFidelity-H). Contrast-to-noise ratio (CNRtumor) was calculated from the CT values within regions of interest in tumor and normal pancreas in the pancreatic parenchymal phase images. Lesion conspicuity of PDAC in pancreatic parenchymal phase on 40-keV HIR, 40-keV DLIR, and 70-keV DLIR images was qualitatively rated on a 5-point scale, using 70-keV HIR images as reference (score 1 = poor; score 3 = equivalent to reference; score 5 = excellent) by two radiologists. CNRtumor of 40-keV DLIR images (median 10.4, interquartile range (IQR) 7.8-14.9) was significantly higher than that of the other VMIs (40 keV HIR, median 6.2, IQR 4.4-8.5, P < 0.0001; 70-keV DLIR, median 6.3, IQR 5.1-9.9, P = 0.0002; 70-keV HIR, median 4.2, IQR 3.1-6.1, P < 0.0001). CNRtumor of 40-keV DLIR images were significantly better than those of the 40-keV HIR and 70-keV HIR images by 72 ± 22% and 211 ± 340%, respectively. Lesion conspicuity scores on 40-keV DLIR images (observer 1, 4.5 ± 0.7; observer 2, 3.4 ± 0.5) were significantly higher than on 40-keV HIR (observer 1, 3.3 ± 0.9, P < 0.0001; observer 2, 3.1 ± 0.4, P = 0.013). DLIR is a promising reconstruction method to improve PDAC delineation in 40-keV VMI at the pancreatic parenchymal phase compared to conventional HIR.

Lymph node metrics following neoadjuvant therapy to refine patient selection for adjuvant chemotherapy in resected pancreatic cancer: A multi-institutional analysis.

BACKGROUND: In patients with localized pancreatic ductal adenocarcinoma (PDAC) undergoing neoadjuvant therapy (NAT) and resection, selection of adjuvant chemotherapy (AC) is typically guided by high-risk features on histopathologic examination. We evaluated the interaction between post-NAT lymph node metrics and AC receipt on survival. METHODS: Patients who received NAT followed by pancreatectomy (2010-2020) at seven centers were reviewed. Overall survival (OS) in patients receiving AC or not was stratified by lymph node positivity (LNP) or lymph node ratio (LNR) dichotomized at 0.1. Cox models evaluated the independent association between these nodal metrics, AC receipt, and OS. RESULTS: Of 464 patients undergoing NAT and resection, 264 (57%) received AC. Patients selected for AC were younger (median 63 vs. 67 years; p < 0.001), received shorter duration of NAT (2.8 vs. 3.2 months; p = 0.01), had fewer postoperative complications (Clavien-Dindo grade > 3: 1.2% vs. 11.7%; p < 0.001), and lower rates of pathologic complete response (4% vs. 11%; p = 0.01). The median number of nodes evaluated was similar between cohorts (n = 20 in both; p = 0.9). Post-NAT LNP rates were not different, and median LNR was 0.1, in AC and non-AC cohorts. Both LNP (hazard ratio [HR]: 2.1, p < 0.001) and LNR (0 < LNR ≤ 0.1: HR: 1.98, p = 0.002; LNR > 0.1: HR 2.46, p < 0.001) were independently associated with OS on Cox modeling, although receipt of AC was not associated with improved OS (median 30.6 vs. 29.4 months; p = 0.2). In patients with LNR > 0.1, receipt of AC was associated with significantly longer OS compared to non-AC (24 vs. 20 months, respectively; p = 0.04). CONCLUSIONS: LNR following NAT, not simply nodal positivity, may be useful to refine selection of AC in resected PDAC.

Prostate ductal adenocarcinoma exhibiting a late recurrence in the anterior urethra 13 years post-total prostatectomy: a case report.

BACKGROUND: Prostate ductal adenocarcinoma, a rare histology observed in 0.4-0.8% of all prostate cancers, is treated similarly to acinar adenocarcinoma but tends to have a higher likelihood of metastasis, recurrence, and poorer prognosis. CASE PRESENTATION: A 73-year-old Asian-Japanese male presented with gross hematuria, with investigations revealing a prostate ductal adenocarcinoma. Subsequent radical prostatectomy indicated a Gleason score of 8 with no lymph node metastasis. Despite initial prostate-specific antigen level reductions post-prostatectomy and salvage radiation therapy due to recurring elevated prostate-specific antigen levels, no recurrence was evident until 13 years later. A tumor in the anterior urethra was identified as metastasis of his prostate ductal adenocarcinoma. CONCLUSION: This report presents an uncommon case of prostate ductal adenocarcinoma exhibiting a late recurrence in the anterior urethra 13 years post-radical prostatectomy.

A CLIC1 network coordinates matrix stiffness and the Warburg effect to promote tumor growth in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) features substantial matrix stiffening and reprogrammed glucose metabolism, particularly the Warburg effect. However, the complex interplay between these traits and their impact on tumor advancement remains inadequately explored. Here, we integrated clinical, cellular, and bioinformatics approaches to explore the connection between matrix stiffness and the Warburg effect in PDAC, identifying CLIC1 as a key mediator. Elevated CLIC1 expression, induced by matrix stiffness through Wnt/ß-catenin/TCF4 signaling, signifies poorer prognostic outcomes in PDAC. Functionally, CLIC1 serves as a catalyst for glycolytic metabolism, propelling tumor proliferation. Mechanistically, CLIC1 fortifies HIF1α stability by curbing hydroxylation via reactive oxygen species (ROS). Collectively, PDAC cells elevate CLIC1 levels in a matrix-stiffness-responsive manner, bolstering the Warburg effect to drive tumor growth via ROS/HIF1α signaling. Our insights highlight opportunities for targeted therapies that concurrently address matrix properties and metabolic rewiring, with CLIC1 emerging as a promising intervention point.

ADRA2A promotes the classical/progenitor subtype and reduces disease aggressiveness of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Our comprehensive analysis revealed that adrenoceptor alpha 2A (ADRA2A) was downregulated in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.

DNA hypo-methylation and expression of GBP4 induces T cell exhaustion in pancreatic cancer.

Immunotherapy for pancreatic ductal carcinoma (PDAC) remains disappointing due to the repressive tumor microenvironment and T cell exhaustion, in which the roles of interferon-stimulated genes were largely unknown. Here, we focused on a typical interferon-stimulated gene, GBP4, and investigated its potential diagnostic and therapeutic value in pancreatic cancer. Expression analysis on both local samples and public databases indicated that GBP4 was one of the most dominant GBP family members present in the PDAC microenvironment, and the expression level of GBP4 was negatively associated with patient survival. We then identified DNA hypo-methylation in regulatory regions of GBP4 in PDAC, and validated its regulatory role on GBP4 expression via performing targeted methylation using dCas9-SunTag-DNMAT3A-sgRNA-targeted methylation system on selected DNA locus. After that, we investigated the downstream functions of GBP4, and chemotaxis assays indicated that GBP4 overexpression significantly improved the infiltration of CD8+T cells, but also induced upregulation of immune checkpoint genes and T cell exhaustion. Lastly, in vitro T cell killing assays using primary organoids suggested that the PDAC samples with high level of GBP4 expression displayed significantly higher sensitivity to anti-PD-1 treatment. Taken together, our studies revealed the expression patterns and epigenetic regulatory mechanisms of GBP4 in pancreatic cancer and clarified the effects of GBP4 on T cell exhaustion and antitumor immunology.

Overcome the challenge for intratumoral injection of STING agonist for pancreatic cancer by systemic administration.

Due to the challenge for intratumoral administration, innate agonists have not made it beyond preclinical studies for efficacy testing in most tumor types. Pancreatic ductal adenocarcinoma (PDAC) has a hostile tumor microenvironment that renders T cells dysfunctional. Innate agonist treatments may serve as a T cell priming mechanism to sensitize PDACs to anti-PD-1 antibody (a-PD-1) treatment. Using a transplant mouse model with spontaneously formed liver metastasis, a genetically engineered KPC mouse model that spontaneously develops PDAC, and a human patient-derived xenograft model, we compared the antitumor efficacy between intrahepatic/intratumoral and intramuscular systemic administration of BMS-986301, a next-generation STING agonist. Flow cytometry, Nanostring, and cytokine assays were used to evaluate local and systemic immune responses. This study demonstrated that administration of STING agonist systemically via intramuscular injection is equivalent to its intratumoral injection in inducing both effector T cell response and antitumor efficacy. Compared to intratumoral administration, T cell exhaustion and immunosuppressive signals induced by systemic administration were attenuated. Nonetheless, either intratumoral or systemic treatment of STING agonist was associated with increased expression of CTLA-4 on tumor-infiltrating T cells. However, the combination of a-PD-1 and anti-CTLA-4 antibody with systemic STING agonist demonstrated the antitumor efficacy in the KPC mouse spontaneous PDAC model. The mouse pancreatic and liver orthotopic model of human patient-derived xenograft reconstituted with PBMC also showed that antitumor and abscopal effects of both intratumoral and intramuscular STING agonist are equivalent. Taken together, this study supports the clinical development of innate agonists via systemic administration for treating PDAC.

Establishment of a nomogram model for predicting distant metastasis in pancreatic ductal adenocarcinoma: a comparative analysis of different lymph node staging systems based on the SEER database.

The purpose of this study was to compare the predictive value of different lymph node staging systems and to develop an optimal prognostic nomogram for predicting distant metastasis in pancreatic ductal adenocarcinoma (PDAC). Our study involved 6364 patients selected from the Surveillance, Epidemiology, and End Results (SEER) database and 126 patients from China. Independent risk factors for distant metastasis were screened by univariate and multivariate logistic regression analyses, and a model-based comparison of different lymph node staging systems was conducted. Furthermore, we developed a nomogram for predicting distant metastasis using the optimal performance lymph node staging system. The lymph node ratio (LNR), log odds of positive lymph nodes (LODDS), age, primary site, grade, tumor size, American Joint Committee on Cancer (AJCC) 7th Edition T stage, and radiotherapy recipient status were significant predictors of distant metastasis in PDAC patients. The model with the LODDS was a better fit than the model with the LNR. We developed a nomogram model based on LODDS and six clinical parameters. The area under the curve (AUC) and concordance index (C-index) of 0.753 indicated that this model satisfied the discrimination criteria. Kaplan-Meier curves indicate a significant difference in OS among patients with different metastasis risks. LODDS seems to have a superior ability to predict distant metastasis in PDAC patients compared with the AJCC 8th Edition N stage, PLN and LNR staging systems. Moreover, we developed a nomogram model for predicting distant metastasis. Clinicians can use the model to detect patients at high risk of distant metastasis and to make further clinical decisions.

Anakinra-Loaded Sphingomyelin Nanosystems Modulate In Vitro IL-1-Dependent Pro-Tumor Inflammation in Pancreatic Cancer.

Pancreatic cancer is a very aggressive disease with a dismal prognosis. The tumor microenvironment exerts immunosuppressive activities through the secretion of several cytokines, including interleukin (IL)-1. The IL-1/IL-1 receptor (IL-1R) axis is a key regulator in tumor-promoting T helper (Th)2- and Th17-type inflammation. Th2 cells are differentiated by dendritic cells endowed with Th2-polarizing capability by the thymic stromal lymphopoietin (TSLP) that is secreted by IL-1-activated cancer-associated fibroblasts (CAFs). Th17 cells are differentiated in the presence of IL-1 and other IL-1-regulated cytokines. In pancreatic cancer, the use of a recombinant IL-1R antagonist (IL1RA, anakinra, ANK) in in vitro and in vivo models has shown efficacy in targeting the IL-1/IL-1R pathway. In this study, we have developed sphingomyelin nanosystems (SNs) loaded with ANK (ANK-SNs) to compare their ability to inhibit Th2- and Th17-type inflammation with that of the free drug in vitro. We found that ANK-SNs inhibited TSLP and other pro-tumor cytokines released by CAFs at levels similar to ANK. Importantly, inhibition of IL-17 secretion by Th17 cells, but not of interferon-γ, was significantly higher, and at lower concentrations, with ANK-SNs compared to ANK. Collectively, the use of ANK-SNs might be beneficial in reducing the effective dose of the drug and its toxic effects.