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Radiologists play a key role in establishing an early and accurate diagnosis, especially for rare diseases. Mahvash disease (OMIM 619290) is an autosomal recessive hereditary disease caused by inactivating mutations of the glucagon receptor and its main clinical consequences are pancreatic neuroendocrine tumors and in some cases, porto-sinusoidal vascular disease and portal hypertension. Untreated Mahvash disease can be lethal. The diagnosis of Mahvash disease has almost always been delayed in the past due to radiologists unawareness of or unfamiliarity with the unique imaging features of Mahvash disease which are moderately to enormously enlarge pancreas with preserved pancreas contour and parenchyma without vascular involvement or lymphadenopathy. These features help differentiate Mahvash disease from other etiologies of diffusely enlarged pancreas such as diffuse pancreatic ductal carcinoma, diffuse pancreatic lymphoma, and autoimmune pancreatitis. Invoking Mahvash disease in the differential diagnosis of an enlarged pancreas has recently been shown to facilitate early diagnosis. To prevent missing the diagnosis of this significant disease, I sincerely ask radiologists to consider Mahvash disease in their differential diagnoses of diffusely enlarged pancreas.

Objectives: To investigate the imaging features of pancreatic ductal adenocarcinoma (PDAC) with histological large duct pattern. Methods: Our study included 37 patients (mean age, 66.5 years; 22 women) with surgically proven PDAC with histological large duct pattern, whose imaging features were classified into four types: Type I, solid mass; Type II, predominantly cystic mass with intracystic solid components; Type III, predominantly solid mass with intratumoral cysts; and Type IV, solid mass with peritumoral retention cysts or pseudocysts. Two radiologists independently analyzed both CT and MRI images for the morphological type, presence of abrupt main pancreatic duct (MPD) cutoff, adjacent vascular invasion, diffusion restriction, and reached consensus. Results: On CT, 26 patients (70.3%) had Type I tumors, five (13.5%) had Type II, three (8.1%) had Type III, and three (8.1%) had Type IV. Among the 26 patients with Type I tumors on CT, 16 had tumors with multiple intratumoral cysts within the solid mass on MRI and were subsequently classified as Type III. Accordingly, 10 patients (27.0%) were classified as Type I, five (13.5%) as Type II, 19 (51.7%) as Type III, and three (8.1%) as Type IV on MRI. Of the 37 patients, 27 (73.0%) had an abrupt MPD cutoff, 15 (40.5%) had adjacent vascular invasion, and 25 (67.6%) had diffusion restriction on MRI. Conclusions: Predominantly solid pancreatic masses with small intratumoral cysts visualized on MRI may be a characteristic imaging finding of PDAC with histological large duct pattern, and differentiate it from conventional PDAC or other cystic pancreatic tumors. Clinical relevance statement: Radiologists should be familiar with the various imaging features of PDAC with histological large duct pattern and should be aware that it may mimic other solid or cystic tumors of the pancreas. Key Points: Imaging features of pancreatic ductal adenocarcinoma with histological large duct pattern can be classified into four types. This pathology more frequently appears as a predominantly solid mass with intratumoral cysts on MRI than on CT. Adding MRI to CT may help identify pancreatic ductal adenocarcinoma with histological large duct pattern. [ABSTRACT FROM AUTHOR]

Background: Sarcopenia and sarcopenic obesity, perceived as a reflection of cancer-induced cachexia, are often diagnosed in patients with periampullary malignancies. The pathophysiology of those conditions is multifactorial regarding the tumor microenvironment, immunological response, and the relationship to surrounding tissues. Methods: The PubMed and SCOPUS databases were systematically searched between November 2023 and December 2023. A total of 254 studies were primarily identified. Regarding the inclusion and exclusion criteria, 26 studies were finally included in the review. Results: Evaluated papers disclosed that sarcopenia was significantly associated with a higher incidence of postoperative complications, including pancreatic fistula (POPF) type B and C, with the odds ratio (OR) ranging from 2.65 (95%CI 1.43–4.93, p = 0.002) to 4.30 (95%CI 1.15–16.01, p < 0.03). Sarcopenic patients also suffered more often from delayed gastric emptying (DGE) with an OR of 6.04 (95%CI 1.13–32.32, p = 0.036). Infectious complications, postoperative hemorrhage, and intra-abdominal abscesses occurred more often in sarcopenic patients. Surgical complications were also noted more frequently when sarcopenic obesity was present. Preoperative nutritional prehabilitation seems to reduce the risk of postoperative complications. However, more prospective studies are needed. Conclusions: Sarcopenia and sarcopenic obesity were associated with a higher incidence of multiple postoperative complications, including POPF (type B and C), DGE, hemorrhage, and infectious complications. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to compare the different versions of the National Comprehensive Cancer Network (NCCN) guidelines for defining resectability of pancreatic ductal adenocarcinoma (PDAC) in predicting margin-negative (R0) resection, and to assess inter-reader agreement. Methods: This retrospective study included 283 patients (mean age, 65.1 years ± 9.4 [SD]; 155 men) who underwent upfront pancreatectomy for PDAC between 2017 and 2019. Two radiologists independently determined the resectability on preoperative CT according to the 2017, 2019, and 2020 NCCN guidelines. The sensitivity and specificity for R0 resection were analyzed using a multivariable logistic regression analysis with generalized estimating equations. Inter-reader agreement was assessed using kappa statistics. Results: R0 resection was accomplished in 239 patients (84.5%). The sensitivity and specificity averaged across two readers were, respectively, 76.6% and 29.5% for the 2020 guidelines, 74.1% and 32.9% for the 2019 guidelines, and 72.6% and 34.1% for the 2017 guidelines. Compared with the 2020 guidelines, both 2019 and 2017 guidelines showed significantly lower sensitivity for R0 resection (p ≤.009). Specificity was significantly higher with the 2017 guidelines (p =.043) than with the 2020 guidelines. Inter-reader agreements for determining the resectability of PDCA were strong (k ≥ 0.83) with all guidelines, being highest with the 2020 guidelines (k = 0.91). Conclusion: The 2020 NCCN guidelines showed significantly higher sensitivity for prediction of R0 resection than the 2017 and 2019 guidelines. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) with a diameter ≤10 mm and high-grade pancreatic intraepithelial neoplasia (HG-PanIN) require pre-operative diagnosis. Most cases present only indirect imaging findings without visible tumors on endoscopic ultrasound (EUS). Therefore, EUS-guided fine-needle aspiration/biopsy is not applicable. An alternative diagnostic method is pancreatic juice cytology (PJC) via endoscopic naso-pancreatic drainage (ENPD-PJC), which is not the standard practice. This study aimed to investigate ENPD-PJC for diagnosing suspected PDAC/HG-PanIN cases without visible tumors on EUS. Data of patients with suspected PDAC/HG-PanIN without visible tumors who underwent PJC were retrospectively evaluated. One PJC sample was collected during endoscopic retrograde pancreatography (ERP-PJC), and 12 samples were collected during ENPD-PJC, 3-hourly for cytological analysis. ERP-PJC, ERP/ENPD-PJC, and ENPD-PJC positivity indicated cytologically positive samples. Patients with positive/negative PJC with follow-up for <4-years were excluded as undiagnosed cases. A non-malignant diagnosis was based on histopathological absence/stable imaging findings for ≥4-years. The primary endpoint was to demonstrate that ERP/ENPD-PJC has a higher diagnostic ability than ERP-PJC. Twenty-two patients with histopathologically diagnosed PDAC/HG-PanIN and 31 with a non-malignant diagnosis were enrolled. ERP-PJC, ERP/ENPD-PJC, and ENPD-PJC showed sensitivities of 36.4 %, 86.4 %, and 77.3 %, specificities of 93.5 %, 87.1 %, and 93.5 %, and accuracies of 69.8 %, 86.7 %, and 86.7 %, respectively. ERP/ENPD-PJC and ENPD-PJC demonstrated superior sensitivity and accuracy compared to ERP-PJC. A greater occurrence of positive outcomes markedly distinguished true positives from false positives. ERP/ENPD-PJC and ENPD-PJC had higher diagnostic accuracies for PDAC/HG-PanIN without visible tumors on EUS. ENPD-PJC is recommended for the diagnosis of these lesions. [ABSTRACT FROM AUTHOR]

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive tumor with a poor prognosis that poses challenges for diagnosis using traditional tissuebased techniques. DNA methylation alterations have emerged as potential and promising biomarkers for PDAC. In this study, we aimed to assess the diagnostic potential of a novel DNA methylation assay based on epigenetic-specific peptide nucleic acid (Epi-sPNA) in both tissue and plasma samples for detecting PDAC. Materials and methods: The study involved 46 patients with PDAC who underwent surgical resection. Epi-TOP pancreatic assay was used to detect PDAC-specific epigenetic biomarkers. The Epi-sPNA allowed accurate and rapid methylation analysis without bisulfite sample processing. Genomic DNA extracted from paired normal pancreatic and PDAC tissues was used to assess the diagnostic efficacy of epigenetic biomarkers for PDAC. Subsequent validation was conducted on cell-free DNA (cfDNA) extracted from plasma samples, with 10 individuals represented in each group: PDAC, benign pancreatic cystic neoplasm, and healthy control. Results: The combination of seven epigenetic biomarkers (HOXA9, TWIST, WT1, RPRM, BMP3, NPTX2, and BNC1) achieved 93.5% sensitivity and 96.7% specificity in discerning normal pancreatic from PDAC tissues. Plasma cfDNA, analyzed using these markers and KRAS mutations, exhibited a substantial 90.0% sensitivity, 95.0% specificity, and an overall 93.3% accuracy for discriminating PDAC. Notably, cancer antigen 19-9 and carcinoembryonic antigen both had an accuracy of 90.0%. Conclusion: Our study suggests that analyzing seven differentially methylated genes with KRAS mutations in cfDNA using the novel Epi-TOP pancreatic assay is a potential blood-based biomarker for the diagnosis of PDAC. [ABSTRACT FROM AUTHOR]

Simple Summary: This manuscript systematically reviewed the literature on the use of vascular shunts during advanced pancreatic surgery, analyzing intraoperative and postoperative outcomes, and enlightening excellent long-term patency, negligible additional operative time, and acceptable postoperative morbidity. The importance of the study was to underline feasibility of this technical artifice, which may help expert surgeons to achieve clear margins in borderline or locally advanced PDAC. Background: The rising diffusion of vascular resections during complex pancreatectomy for malignancy, for both oncological and technical matters, brought with it the use of vascular shunts, either temporary or definitive, to prevent bowel congestion and liver ischemia. This study aimed to systematically review the literature on the technical feasibility of vascular shunts during advanced pancreatic surgery, analyzing intraoperative and postoperative outcomes. Methods: A systematic literature search was performed on PubMed, Scopus, Web of Science, and the Cochrane Library Central, according to PRISMA guidelines. Studies published before 2006 were excluded, considering the lack of a standardized definition of locally advanced pancreatic cancer. The main outcomes evaluated were the overall complication rate and shunt patency. Results: Among 789 papers retrieved from the database search, only five fulfilled the inclusion criteria and were included in the review, amounting to a total of 145 patients undergoing a shunt creation at the time of pancreatectomy. Pancreatic adenocarcinoma (PDAC) was found to be the most common diagnosis and pancreaticoduodenectomy was the main surgical procedure, accounting for 88% and 83% of the overall cohort, respectively. The distal splenorenal shunt was the most performed. Overall, 44 out of 145 patients (30%) experienced postoperative complications; the long-term patency of definitive shunts was 83% (110 out of 120 patients). Conclusions: An increasing number of patients with borderline resectable or locally advanced PDAC are becoming amenable to resection and shunt creation may facilitate vascular resection with clear margins, becoming a valid tool of modern pancreatic surgery. [ABSTRACT FROM AUTHOR]

Background: Improved systemic therapy has made long term (≥ 5 years) overall survival (LTS) after resection of pancreatic ductal adenocarcinoma (PDAC) increasingly common. However, a systematic review on predictors of LTS following resection of PDAC is lacking. Methods: The PubMed, Embase, Scopus, and Cochrane CENTRAL databases were systematically searched from inception until March 2023. Studies reporting actual survival data (based on follow-up and not survival analysis estimates) on factors associated with LTS were included. Meta-analyses were conducted by using a random effects model, and study quality was gauged by using the Newcastle-Ottawa Scale (NOS). Results: Twenty-five studies with 27,091 patients (LTS: 2,132, non-LTS: 24,959) who underwent surgical resection for PDAC were meta-analyzed. The median proportion of LTS patients was 18.32% (IQR 12.97–21.18%) based on 20 studies. Predictors for LTS included sex, body mass index (BMI), preoperative levels of CA19-9, CEA, and albumin, neutrophil-lymphocyte ratio, tumor grade, AJCC stage, lymphovascular and perineural invasion, pathologic T-stage, nodal disease, metastatic disease, margin status, adjuvant therapy, vascular resection, operative time, operative blood loss, and perioperative blood transfusion. Most articles received a "good" NOS assessment, indicating an acceptable risk of bias. Conclusions: Our meta-analysis pools all true follow up data in the literature to quantify associations between prognostic factors and LTS after resection of PDAC. While there appears to be evidence of a complex interplay between risk, tumor biology, patient characteristics, and management related factors, no single parameter can predict LTS after the resection of PDAC. [ABSTRACT FROM AUTHOR]

Background: The relative success of cisplatin-based chemotherapy regimens for PDAC in clinical trials warrants a review of the literature to assess the cumulative results. This study aims to assess the efficacy of cisplatin-containing regimens for PDAC in terms of survival and response outcomes using a systematic review and proportional meta-analysis. Methods: In this study, an electronic search was conducted on PubMed, Cochrane Library, Scopus, and Google Scholar to find relevant literature. The random effects model was used to assess pooled overall response rate, stable disease rate, progressive disease rate, 1-year overall survival rate, and their 95% CIs. Publication bias was assessed using funnel plot symmetry and the one-tailed Eggers' test. In all cases, p-value < 0.05 was indicative of significant results. The review is registered with PROSPERO: CRD42023459243. Results: A total of 34 studies consisting of 1599 patients were included in this review. All the included studies were of good quality. In total, 906 patients were male, and the median age of the patients was 58–69 years. Overall, 599 patients had cancer of the pancreatic head, 139 had cancer of the pancreatic body, and 102 patients had cancer of the pancreatic tail. The pooled risk ratios (RRs) revealed an overall response rate of 19.2% (95% CI, 14.6–24.2%), a stable disease rate of 42.3% (95% CI, 36.6–48.8), a 1-year overall survival rate of 40% (95% CI, 34.3–45.8), and progressive disease rate of 24.7% (95% CI, 18.8–31.2). Commonly reported adverse events were anemia, thrombocytopenia, abdominal adverse events, neutropenia, fatigue, leukopenia, alopecia, anorexia, mucositis, stomatitis, and hepatobiliary adverse events. Conclusion: Cisplatin-containing regimens have shown moderate efficacy with significant improvement in overall survival at 1 year, stable disease rate, and progressive disease rate; however, only a small percentage of patients achieved an overall response rate. [ABSTRACT FROM AUTHOR]

This investigation examined the potential pharmacotherapeutic efficacy of emetine, a natural alkaloid, against pancreatic ductal carcinoma, utilizing the PaCa3 cell line as a model. Employing a multifaceted approach, the study explored emetine's impact on cell viability, clonogenic potential, and apoptotic pathways, unravelling its molecular mechanisms. Additionally, an in vivo assessment was conducted to evaluate emetine's antitumor efficacy against PaCa3 xenografts. Under standard conditions, PaCa3 cells were treated with varying emetine concentrations and subjected to MTT, clonogenic, DAPI, AO/EB, Annexin V-FITC/PI, and Western blot assays. In vivo experiments involved the administration of emetine to female nude mice with PaCa3 xenografts, with subsequent measurement of tumor weight and volume. Statistical analyses included Tukey-test and ANOVA. Emetine demonstrated a significant and doseand time-dependent cytotoxic effect on PaCa3 cells, reducing viability from 98% to 8% (***p < 0.001). Clonogenic assay indicated a substantial inhibition of colony formation. DAPI staining revealed nuclear chromatin condensation, while AO/EB staining indicated heightened apoptosis. Annexin V-FITC/PI assay exhibited a dose-dependent decrease in normal cell viability and an increase in apoptotic events. Western blot analysis showed a concentration-dependent downregulation of anti-apoptotic Bcl-2 and the upregulation of pro-apoptotic markers. In vivo experiments illustrated a dose-dependent reduction in tumor weight (5 g to 1.6 g) and volume (2400 mm³ to 844 mm³) with emetine treatment. In conclusion, emetine emerges as a potent anticancer agent against pancreatic ductal carcinoma, exhibiting cytotoxicity, clonogenic inhibition, and apoptotic induction in PaCa3 cells. The in vivo study further highlights its promising therapeutic potential, laying the groundwork for future clinical studies in pancreatic cancer treatment. [ABSTRACT FROM AUTHOR]

Background: Pancreatic ductal adenocarcinoma (PDAC) stromal viscoelasticity can be measured using MR elastography (MRE). Bowel preparation regimens could affect MRE quality and knowledge on repeatability is crucial for clinical implementation. Purpose: To assess effects of four bowel preparation regimens on MRE quality and to evaluate repeatability and differentiate patients from healthy controls. Study Type: Prospective. Population: 15 controls (41 ± 16 years; 47% female), 16 PDAC patients (one excluded, 66 ± 12 years; 40% female) with 15 age‐/sex‐matched controls (65 ± 11 years; 40% female). Final sample size was 25 controls and 15 PDAC. Field Strength/Sequence: 3‐T, spin‐echo echo‐planar‐imaging, turbo spin‐echo, and fast field echo gradient‐echo. Assessment: Four different regimens were used: fasting; scopolaminebutyl; drinking 0.5 L water; combination of 0.5 L water and scopolaminebutyl. MRE signal‐to‐noise ratio (SNR) was compared between all regimens. MRE repeatability (test–retest) and differences in shear wave speed (SWS) and phase angle (ϕ) were assessed in PDAC and controls. Regions‐of‐interest were defined for tumor, nontumorous (n = 8) tissue in PDAC, and whole pancreas in controls. Two radiologists delineated tumors twice for evaluation of intraobserver and interobserver variability. Statistical Tests: Repeated measures analysis of variance, coefficients of variation (CoVs), Bland–Altman analysis, (un)paired t‐test, Mann–Whitney U‐test, and Wilcoxon signed‐rank test. P‐value<0.05 was considered statistically significant. Results: Preparation regimens did not significantly influence MRE‐SNR. Therefore, the least burdensome preparation (fasting only) was continued. CoVs for tumor SWS were: intrasession (12.8%) and intersession (21.7%), and intraobserver (7.9%) and interobserver (10.3%) comparisons. For controls, CoVs were intrasession (4.6%) and intersession (6.4%). Average SWS for tumor, nontumor, and healthy tissue were: 1.74 ± 0.58, 1.38 ± 0.27, and 1.18 ± 0.16 m/sec (ϕ: 1.02 ± 0.17, 0.91 ± 0.07, and 0.85 ± 0.08 rad), respectively. Significant differences were found between all groups, except for ϕ between healthy–nontumor (P = 0.094). Data Conclusion: The proposed bowel preparation regimens may not influence MRE quality. MRE may be able to differentiate between healthy tissue–tumor and tumor–nontumor. Level of Evidence: 2 Technical Efficacy Stage: 2 [ABSTRACT FROM AUTHOR]

To elucidate the currently unknown molecular mechanisms responsible for the similarity and difference during the acquirement of resistance against gemcitabine (GEM) and paclitaxel (PTX) in patients with pancreatic carcinoma, we examined two-dimensional (2D) and three-dimensional (3D) cultures of parent MIA PaCa-2 cells (MIA PaCa-2-PA) and their GEM resistance cell line (MIA PaCa-2-GR) and PTX resistance (MIA PaCa-2-PR). Using these cells, we examined 3D spheroid configurations and cellular metabolism, including mitochondrial and glycolytic functions, with a Seahorse bio-analyzer and RNA sequencing analysis. Compared to the MIA PaCa-2-PA, (1) the formation of the 3D spheroids of MIA PaCa-2-GR or -PR was much slower, and (2) their mitochondrial and glycolytic functions were greatly modulated in MIA PaCa-2-GR or -PR, and such metabolic changes were also different between their 2D and 3D culture conditions. RNA sequencing and bioinformatic analyses of the differentially expressed genes (DEGs) using an ingenuity pathway analysis (IPA) suggested that various modulatory factors related to epithelial –mesenchymal transition (EMT) including STAT3, GLI1, ZNF367, NKX3-2, ZIC2, IFIT2, HEY1 and FBLX, may be the possible upstream regulators and/or causal network master regulators responsible for the acquirement of drug resistance in MIA PaCa-2-GR and -PR. In addition, among the prominently altered DEGs (Log2 fold changes more than 6 or less than −6), FABP5, IQSEC3, and GASK1B were identified as unique genes associated with their antisense RNA or pseudogenes, and among these, FABP5 and GASK1B are known to function as modulators of cancerous EMT. Therefore, the observations reported herein suggest that modulations of cancerous EMT may be key molecular mechanisms that are responsible for inducing chemoresistance against GEM or PTX in MIA PaCa-2 cells. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to identify the most useful contrast-enhanced computed tomography (CECT) features for differentiating pancreatic ductal adenocarcinoma (PDAC) from mass-forming chronic pancreatitis (MFCP) in chronic calcific pancreatitis (CCP).

Purpose: To evaluate robustness of a radiomics-based support vector machine (SVM) model for detection of visually occult PDA on pre-diagnostic CTs by simulating common variations in image acquisition and radiomics workflow using image perturbation methods. Methods: Eighteen algorithmically generated-perturbations, which simulated variations in image noise levels (σ, 2σ, 3σ, 5σ), image rotation [both CT image and the corresponding pancreas segmentation mask by 45° and 90° in axial plane], voxel resampling (isotropic and anisotropic), gray-level discretization [bin width (BW) 32 and 64)], and pancreas segmentation (sequential erosions by 3, 4, 6, and 8 pixels and dilations by 3, 4, and 6 pixels from the boundary), were introduced to the original (unperturbed) test subset (n = 128; 45 pre-diagnostic CTs, 83 control CTs with normal pancreas). Radiomic features were extracted from pancreas masks of these additional test subsets, and the model's performance was compared vis-a-vis the unperturbed test subset. Results: The model correctly classified 43 out of 45 pre-diagnostic CTs and 75 out of 83 control CTs in the unperturbed test subset, achieving 92.2% accuracy and 0.98 AUC. Model's performance was unaffected by a three-fold increase in noise level except for sensitivity declining to 80% at 3σ (p = 0.02). Performance remained comparable vis-a-vis the unperturbed test subset despite variations in image rotation (p = 0.99), voxel resampling (p = 0.25–0.31), change in gray-level BW to 32 (p = 0.31–0.99), and erosions/dilations up to 4 pixels from the pancreas boundary (p = 0.12–0.34). Conclusion: The model's high performance for detection of visually occult PDA was robust within a broad range of clinically relevant variations in image acquisition and radiomics workflow. [ABSTRACT FROM AUTHOR]

Introduction: Radical resection is the only potentially curative treatment for pancreatic adenocarcinoma; however, only a minor fraction of patients are eligible for resection. Induction therapy may be offered to patients, but the response rate in cases with significant vascular involvement is limited. This study aimed to evaluate the efficacy and safety of modified of FOLFIRINOX chemotherapy (mFFX) + stereotactic body radiotherapy (SBRT) in combination as induction therapy for locally advanced pancreatic carcinoma. The primary endpoints were the resection rate and one-year overall survival (OS). The secondary endpoints were progression-free survival (PFS), toxicity, and quality of live (QoL). Material and methods: Thirty patients with locally advanced pancreatic adenocarcinoma were treated with 6 cycles of mFFX, followed by SBRT and additional 3 cycles of mFFX. The response was measured prior to SBRT and after regimen completion. In the absence of disease progression, the patients were referred for surgery. The patients were requested to complete quality of life questionnaires (QLQ)-C30 and QLQ-PAN26 questionnaires biweekly. Results: On the first evaluation, disease control was noted in 26 (86.7%) patients. Stereotactic body radiotherapy was performed in 20 patients. Twelve patients underwent laparotomy, with radical resection possible in 3 cases. The one-year OS rate was 63.3%. Overall, 11 grade ≥ 3 adverse events were noted. No deterioration in the overall QoL was observed. The median PFS was 7.53 months. Conclusions: The expected resection rate of ≥ 30% was not achieved. However, the combination was associated with good local control, low adverse event rate, and good QoL, which advocate its further investigation in this clinical situation. [ABSTRACT FROM AUTHOR]

Purpose Clinical prognostic criteria using preoperative factors were not developed for post-neoadjuvant therapy (NAT) surgery of pancreatic ductal adenocarcinoma (PDAC). We aimed to identify preoperative factors associated with overall survival (OS) in PDAC patients who underwent post-NAT curative-intent surgery and develop risk stratification criteria. Materials and Methods Consecutive PDAC patients who underwent post-NAT curative-intent surgeries between 2007 and 2020 were retrospectively analyzed. Demographic, laboratory, surgical, and histopathologic variables were collected. Baseline, preoperative, and interval changes of computed tomography (CT) findings proposed by the Society of Abdominal Radiology and the American Pancreatic Association were analyzed. Cox proportional hazard analysis was used to select preoperative variables associated with OS. We developed risk stratification criteria composed of the significant preoperative variables, i.e., post-NAT response criteria. We compared the discrimination performance of post-NAT response criteria with that of post-NAT pathological (yp) American Joint Cancer Committee TNM staging system. Results One hundred forty-five PDAC patients were included. Stable or increased tumor size on CT (hazard ratio [HR], 2.58; 95% confidence interval [CI], 1.58 to 4.21; p < 0.001) and elevated preoperative carbohydrate antigen 19-9 (CA19-9) level (HR, 1.98; 95% CI, 1.11 to 3.55; p=0.021) were independent factors of OS. The OS of the patient groups stratified by post-NAT response criteria which combined changes in tumor size and CA19-9 showed significant difference (p < 0.001). Such stratification was comparable to ypTNM staging in discrimination performance (difference of C-index, 0.068; 95% CI, -0.012 to 0.142). Conclusion "Any degree of decrease in tumor size on CT" and CA19-9 normalization or staying normal were independent favorable factors of OS. The combination of the two factors discriminated OS comparably to ypTNM staging. [ABSTRACT FROM AUTHOR]

Objective The aim of this study was to identify the most useful contrast-enhanced computed tomography (CECT) features for differentiating pancreatic ductal adenocarcinoma (PDAC) from mass-forming chronic pancreatitis (MFCP) in chronic calcific pancreatitis (CCP). Methods In total, 101 patients with CCP and focal pancreatic mass formed the study group. Sixteen qualitative and four quantitative parameters were analyzed. Qualitative parameters included size, site, margin, intralesional hypodensity, collateral duct sign, abrupt pancreatic duct (PD) cutoff, upstream PD dilatation, distal pancreatic atrophy, double duct sign, enhancement pattern, contrast attenuation, peripancreatic inflammation, vascular involvement, regional nodes, and metastasis. Quantitative parameters included duct-to-body ratio, common bile duct (CBD) diameter, main pancreatic duct (MPD) diameter, and carcinoembryonic antigen 19-9 (CA19-9). Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for prediction of PDAC. A receiver operating characteristic (ROC) curve analysis was performed and the area under ROC curve (AUROC) was calculated to determine diagnostic accuracy to assess the optimal cutoff. Results PDAC was confirmed in 48 patients and MFCP in 53 patients. A duct-to-body ratio greater than 0.48 had 95.5% sensitivity, 83.3% specificity, 80.8% PPV, 96.2% NPV, and 88.5% accuracy for predicting PDAC. A CBD diameter cutoff ≥9.5 mm had an accuracy of 75% (p < 0.019) and an MPD cutoff ≥6.25 mm had an accuracy of 67.8% (p = 0.008) for predicting PDAC. On binary logistic regression, the duct-to-body ratio was found to be the significant independent factor associated with malignancy. Conclusion A duct-to-body ratio greater than 0.48, intralesional hypodensity, and abrupt duct cutoff are the most helpful computed tomography (CT) features for distinguishing PDAC from MFCP in CCP. On binary logistic regression, the duct-to-body ratio was found to be a significant independent factor. Interspersed normal parenchyma was observed as a very specific sign of MFCP. Intraparenchymal hypodensity has high specificity, but further validation is needed. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the utility of dual-energy CT (DECT) in differentiating non-hypervascular pancreatic neuroendocrine neoplasms (PNENs) from pancreatic ductal adenocarcinomas (PDACs) with negative carbohydrate antigen 19–9 (CA 19-9). Methods: This retrospective study included 26 and 39 patients with pathologically confirmed non-hypervascular PNENs and CA 19-9-negative PDACs, respectively, who underwent contrast-enhanced DECT before treatment between June 2019 and December 2021. The clinical, conventional CT qualitative, conventional CT quantitative, and DECT quantitative parameters of the two groups were compared using univariate analysis and selected by least absolute shrinkage and selection operator regression (LASSO) analysis. Multivariate logistic regression analyses were performed to build qualitative, conventional CT quantitative, DECT quantitative, and comprehensive models. The areas under the receiver operating characteristic curve (AUCs) of the models were compared using DeLong's test. Results: The AUCs of the DECT quantitative (based on normalized iodine concentrations [nICs] in the arterial and portal venous phases: 0.918; 95% confidence interval [CI] 0.852–0.985) and comprehensive (based on tumour location and nICs in the arterial and portal venous phases: 0.966; 95% CI 0.889–0.995) models were higher than those of the qualitative (based on tumour location: 0.782; 95% CI 0.665–0.899) and conventional CT quantitative (based on normalized conventional CT attenuation in the arterial phase: 0.665; 95% CI 0.533–0.797; all P < 0.05) models. The DECT quantitative and comprehensive models had comparable performances (P = 0.076). Conclusions: Higher nICs in the arterial and portal venous phases were associated with higher blood supply improving the identification of non-hypervascular PNENs. [ABSTRACT FROM AUTHOR]

Abstract Background and Aims Endoscopic ultrasonography‐guided fine‐needle aspiration/biopsy (EUS‐FNA/B) is considered to be a first‐line procedure for the pathological diagnosis of pancreatic cancer owing to its high accuracy and low complication rate. The number of new cases of pancreatic ductal adenocarcinoma (PDAC) is increasing, and its accurate pathological diagnosis poses a challenge for cytopathologists. Our aim was to develop a hyperspectral imaging (HSI)‐based convolution neural network (CNN) algorithm to aid in the diagnosis of pancreatic EUS‐FNA cytology specimens. Methods HSI images were captured of pancreatic EUS‐FNA cytological specimens from benign pancreatic tissues (n = 33) and PDAC (n = 39) prepared using a liquid‐based cytology method. A CNN was established to test the diagnostic performance, and Attribution Guided Factorization Visualization (AGF‐Visualization) was used to visualize the regions of important classification features identified by the model. Results A total of 1913 HSI images were obtained. Our ResNet18‐SimSiam model achieved an accuracy of 0.9204, sensitivity of 0.9310 and specificity of 0.9123 (area under the curve of 0.9625) when trained on HSI images for the differentiation of PDAC cytological specimens from benign pancreatic cells. AGF‐Visualization confirmed that the diagnoses were based on the features of tumor cell nuclei. Conclusions An HSI‐based model was developed to diagnose cytological PDAC specimens obtained using EUS‐guided sampling. Under the supervision of experienced cytopathologists, we performed multi‐staged consecutive in‐depth learning of the model. Its superior diagnostic performance could be of value for cytologists when diagnosing PDAC.

Pancreatic cancer is the seventh leading cause of cancer deaths worldwide, accounting for 4.7% of all cancer deaths, and is expected to climb significantly over the next decade. The purpose of this systematic review and guidance document was to synthesize the evidence surrounding the role of adjuvant treatment (chemotherapy and chemoradiation therapy [CRT], and stereotactic body radiation therapy [SBRT]) in resected pancreatic ductal adenocarcinoma (PDAC). Systematic literature searches of MEDLINE, EMBASE, and 11 guideline databases were conducted. Both direct and indirect comparisons indicate adjuvant chemotherapy offers a survival advantage over surgery alone. The optimal regimens recommended are mFOLFIRINOX with alternative options of gemcitabine plus capecitabine, gemcitabine alone, or S-1 (which is not available in North America). Trials comparing a CRT strategy to modern chemotherapy regimens are lacking. However, current evidence demonstrates that the addition of CRT to chemotherapy does not result in a survival advantage over chemotherapy alone and is therefore not recommended. Trials evaluating SBRT in PDAC are also lacking. SBRT should only be used within a clinical trial or multi-institutional registry.

Purpose: Systemic chemotherapy is generally used for metastatic pancreatic cancer; however, pulmonary resection may be a treatment option for lung oligometastases from pancreatic cancer. The current study aimed to clarify the oncological outcomes and clinical benefits of pulmonary resection for lung metastases. Methods: Of 510 patients who underwent pancreatic resection for pancreatic cancer, 44 patients with recurrence of isolated lung metastases and one patient with simultaneous lung metastases were evaluated. Results: Of the 45 patients, 20 patients were selected as candidates for pulmonary resection based on clinical factors such as recurrence-free interval (RFI) from pancreatectomy to lung metastases, number of lung metastases, and serum CA19-9 level. The post-recurrent survival of patients with pulmonary resection was significantly better than that of patients without pulmonary resection. Fourteen of the 20 patients with pulmonary resection developed tumor recurrence with a median disease-free survival (DFS) of 15 months. Univariate analyses revealed that an RFI from pancreatectomy to lung metastases of ≥28 months was associated with better DFS after pulmonary resection. Of the 14 patients with an RFI of ≥28 months, pulmonary resection resulted in prolonged chemotherapy-free interval in 12 patients. Furthermore, repeat pulmonary resection for recurrent tumors after pulmonary resection led to further cancer-free interval in some cases. Conclusions: Although many patients had tumor recurrence after pulmonary resection, pulmonary resection for lung metastases from pancreatic cancer may provide prolonged cancer-free interval without the need for chemotherapy. Pulmonary resection should be performed for the patients with a long RFI from pancreatectomy to lung metastases. [ABSTRACT FROM AUTHOR]

To pathologically clarify the macroscopic features of endoscopic ultrasound-guided fine needle aspiration/biopsy (EUS-FNA/B) specimens in representative pancreatic diseases and establish tissue-handling standards based on the macroscopic findings. We gathered EUS-FNA/B specimens of cases at our institution with the final diagnoses of pancreatic ductal adenocarcinoma (PDAC, n = 172), neuroendocrine tumor (NET, n = 19), and chronic inflammatory lesion (CIL, n = 24) including autoimmune pancreatitis. We classified the specimens' macroscopic features in five categories (red strings, mixed-red-and-white strings, white cores, gray tissues, gelatinous tissues) and compared the specimens' features on cytological and histological slides. All five macroscopic categories were observed in variable combinations in the PDACs; red strings and white cores predominated in the NETs and CILs. White cores represented neoplastic (PDAC, NET) or lesion (CIL) tissues. Mixed-red-and-white strings were unique to PDACs and contained cancerous cells. Neoplastic cells were numerous in red strings in NETs but not the other groups. Gray and gelatinous tissues represented necrosis and mucin, respectively, and the former were almost exclusively observed in PDACs. Red strings, mixed-red-and-white strings, and white cores were suitable for histological examination, whereas gray and gelatinous tissues were suitable for cytological examination. The white cores, mixed-red-and-white strings, and gelatinous tissues may be composed of non-neoplastic tissues such as contaminated gastrointestinal epithelium. In seven PDACs, although white cores were obtained, a histological diagnosis was not established. Macroscopic evaluations of EUS-FNA/B can enable the identification of specimen components and a possible diagnosis. They also contribute to the selection of the optimal tissue-handling methods. [ABSTRACT FROM AUTHOR]

Objectives: To determine the sensitivity of contrast-enhanced computed tomography (CECT) in detecting pancreatic ductal adenocarcinoma (PDAC) and identify factors associated with false negatives (FNs). Methods: Patients diagnosed with PDAC in 2014–2015 were retrospectively identified by a cancer registry. CECTs performed during the diagnostic interval were retrospectively classified as true positive (TP), indeterminate, or FN. Sensitivity TP/(TP+FN) was calculated for all CECTs and the following subgroups: protocol (uniphasic vs. biphasic); tumor size (≤ 2 cm vs. > 2 cm); and resectability (potentially resectable vs. unresectable). Multivariate logistic regression was performed to assess which of the following factors were associated with FN: clinical suspicion of PDAC; size >2 cm; presence of metastases; protocol; isoattenuating tumor; and potentially resectable disease on imaging. Results: In total, 176 CECTs (127 uniphasic; 49 biphasic) in 154 patients (90 men, mean age 72 ± 11 years) were included. Sensitivity was 125/149 (83.9%) overall and 87/106 (82.1%) and 38/43 (88.4%) for uniphasic and biphasic protocols, respectively. Sensitivity was decreased for tumors ≤ 2 cm (45.4% vs. 90.6%), no liver metastases (78.0% vs. 95.9%), and potentially resectable disease (65.3% vs. 93.0%). Factors significantly associated with FN were clinical suspicion (OR, 0.24, 95% CI: 0.07–0.75), size>2 cm (OR, 0.10, 95% CI: 0.02–0.44), absence of liver metastases (OR, 4.94, 95% CI: 1.29–22.99), and potentially resectable disease (OR, 4.13, 95% CI: 1.07–16.65). Conclusions: In our population, the overall sensitivity of CECT to detect PDAC is 83.9%; however, this is substantially lower in several scenarios, including patients with potentially resectable disease. This finding has important implications for patient outcomes and efforts to maximize CECT sensitivity should be sought. Clinical relevance statement: The sensitivity of CECT to detect PDAC is significantly decreased in the setting of sub-2 cm tumors and potentially resectable disease. A dedicated biphasic pancreatic CECT protocol has higher sensitivity and should be applied in patients with suspected pancreatic disease. Key Points: • The sensitivities of contrast-enhanced CT for the detection of PDAC were 87/106 (82.1%) and 38/43 (88.4%) for uniphasic and biphasic protocols, respectively. • The sensitivity of contrast-enhanced CT was decreased for small tumors ≤ 2 cm (45.4% vs. 90.6%), if there were no liver metastases (78.0% vs. 95.9%), and with potentially resectable disease (65.3% vs. 93.0%). • Absence of liver metastases (OR, 4.94, 95% CI: 1.29–22.99) and potentially resectable disease (OR, 4.13, 95% CI: 1.07–16.65) were associated with a false--negative (FN) CT result; suspicion of malignancy on the imaging requisition (OR, 0.24, 95% CI: 0.07–0.75) and size > 2 cm (OR, 0.10, 95% CI: 0.02–0.44) were negatively associated with FN. [ABSTRACT FROM AUTHOR]

PDAC (pancreatic ductal adenocarcinoma) is a highly aggressive malignant tumor. We have previously developed induced tumor-suppressing cells (iTSCs) that secrete a group of tumor-suppressing proteins. Here, we examined a unique procedure to identify anticancer peptides (ACPs), using trypsin-digested iTSCs-derived protein fragments. Among the 10 ACP candidates, P04 (IGEHTPSALAIMENANVLAR) presented the most efficient anti-PDAC activities. P04 was derived from aldolase A (ALDOA), a glycolytic enzyme. Extracellular ALDOA, as well as P04, was predicted to interact with epidermal growth factor receptor (EGFR), and P04 downregulated oncoproteins such as Snail and Src. Importantly, P04 has no inhibitory effect on mesenchymal stem cells (MSCs). We also generated iTSCs by overexpressing ALDOA in MSCs and peripheral blood mononuclear cells (PBMCs). iTSC-derived conditioned medium (CM) inhibited the progression of PDAC cells as well as PDAC tissue fragments. The inhibitory effect of P04 was additive to that of CM and chemotherapeutic drugs such as 5-Flu and gemcitabine. Notably, applying mechanical vibration to PBMCs elevated ALDOA and converted PBMCs into iTSCs. Collectively, this study presented a unique procedure for selecting anticancer P04 from ALDOA in an iTSCs-derived proteome for the treatment of PDAC. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a devastating tumor type where a very high proportion of people diagnosed end up dying from cancer. Surgical resection is an option for only about 20% of patients, where the 5-year survival increase ranges from 10 to 25%. In addition to surgical resection, there are adjuvant chemotherapy schemes, such as FOLFIRINOX (a mix of Irinotecan, oxaliplatin, 5-Fluorouraci and leucovorin) or gemcitabine-based treatment. These last two drugs have been compared in the NAPOLI-3 clinical trial, and the NALIRIFOX arm was found to have a higher overall survival (OS) (11.1 months vs. 9.2 months). Despite these exciting improvements, PDAC still has no effective treatment. An interesting approach would be to drive ferroptosis in PDAC cells. A non-apoptotic reactive oxygen species (ROS)-dependent cell death, ferroptosis was first described by Dixon et al. in 2012. ROS are constantly produced in the tumor cell due to high cell metabolism, which is even higher when exposed to chemotherapy. Tumor cells have detoxifying mechanisms, such as Mn-SOD or the GSH-GPX system. However, when a threshold of ROS is exceeded in the tumor cell, the cell's antioxidant systems are overwhelmed, resulting in lipid peroxidation and, ultimately, ferroptosis. In this review, we point out ferroptosis as an approach to consider in PDAC and propose that altering the cellular ROS balance by combining oxidizing agents or with inhibitors of the main cellular detoxifiers triggers ferroptosis in PDAC. [ABSTRACT FROM AUTHOR]

To elucidate the currently unknown molecular mechanisms responsible for the similarity and difference during the acquirement of resistance against gemcitabine (GEM) and paclitaxel (PTX) in patients with pancreatic carcinoma, we examined two-dimensional (2D) and three-dimensional (3D) cultures of parent MIA PaCa-2 cells (MIA PaCa-2-PA) and their GEM resistance cell line (MIA PaCa-2-GR) and PTX resistance (MIA PaCa-2-PR). Using these cells, we examined 3D spheroid configurations and cellular metabolism, including mitochondrial and glycolytic functions, with a Seahorse bio-analyzer and RNA sequencing analysis. Compared to the MIA PaCa-2-PA, (1) the formation of the 3D spheroids of MIA PaCa-2-GR or -PR was much slower, and (2) their mitochondrial and glycolytic functions were greatly modulated in MIA PaCa-2-GR or -PR, and such metabolic changes were also different between their 2D and 3D culture conditions. RNA sequencing and bioinformatic analyses of the differentially expressed genes (DEGs) using an ingenuity pathway analysis (IPA) suggested that various modulatory factors related to epithelial –mesenchymal transition (EMT) including STAT3, GLI1, ZNF367, NKX3-2, ZIC2, IFIT2, HEY1 and FBLX, may be the possible upstream regulators and/or causal network master regulators responsible for the acquirement of drug resistance in MIA PaCa-2-GR and -PR. In addition, among the prominently altered DEGs (Log2 fold changes more than 6 or less than −6), FABP5, IQSEC3, and GASK1B were identified as unique genes associated with their antisense RNA or pseudogenes, and among these, FABP5 and GASK1B are known to function as modulators of cancerous EMT. Therefore, the observations reported herein suggest that modulations of cancerous EMT may be key molecular mechanisms that are responsible for inducing chemoresistance against GEM or PTX in MIA PaCa-2 cells.

Background and Aims: Endoscopic ultrasonography‐guided fine‐needle aspiration/biopsy (EUS‐FNA/B) is considered to be a first‐line procedure for the pathological diagnosis of pancreatic cancer owing to its high accuracy and low complication rate. The number of new cases of pancreatic ductal adenocarcinoma (PDAC) is increasing, and its accurate pathological diagnosis poses a challenge for cytopathologists. Our aim was to develop a hyperspectral imaging (HSI)‐based convolution neural network (CNN) algorithm to aid in the diagnosis of pancreatic EUS‐FNA cytology specimens. Methods: HSI images were captured of pancreatic EUS‐FNA cytological specimens from benign pancreatic tissues (n = 33) and PDAC (n = 39) prepared using a liquid‐based cytology method. A CNN was established to test the diagnostic performance, and Attribution Guided Factorization Visualization (AGF‐Visualization) was used to visualize the regions of important classification features identified by the model. Results: A total of 1913 HSI images were obtained. Our ResNet18‐SimSiam model achieved an accuracy of 0.9204, sensitivity of 0.9310 and specificity of 0.9123 (area under the curve of 0.9625) when trained on HSI images for the differentiation of PDAC cytological specimens from benign pancreatic cells. AGF‐Visualization confirmed that the diagnoses were based on the features of tumor cell nuclei. Conclusions: An HSI‐based model was developed to diagnose cytological PDAC specimens obtained using EUS‐guided sampling. Under the supervision of experienced cytopathologists, we performed multi‐staged consecutive in‐depth learning of the model. Its superior diagnostic performance could be of value for cytologists when diagnosing PDAC. [ABSTRACT FROM AUTHOR]

Purpose: To assess interobserver variability and accuracy of preoperative computed tomography (CT) and magnetic resonance imaging (MRI) in pancreatic ductal adenocarcinoma (PDAC) size estimation using surgical specimens as standard of reference. Methods: Patients with PDAC who underwent preoperative CT and MRI examinations before surgery were included. PDAC largest axial dimension was measured by 2 readers on 8 MRI sequence and 2 CT imaging phases (pancreatic parenchymal and portal venous). Measurements were compared to actual tumour size at pathologic examination. Interobserver variability was assessed using intraclass correlation coefficients (ICC) and Bland-Altman plots. Differences in tumour size (Δdiameter) between imaging and actual tumour size were searched using Wilcoxon rank sum test. Results: Twenty-nine patients (16 men; median age, 70 years) with surgically resected PDAC were included. Interobserver reproducibility was good to excellent for all MRI sequences and the 2 CT imaging phases with ICCs between.862 (95%CI:.692-.942) for fat-saturated in-phase T1-weighted sequence and.955 (95%CI:.898-.980) for portal venous phase CT images. Best accuracy in PDAC size measurement was obtained with pancreatic parenchymal phase CT images with median Δdiameters of −2 mm for both readers, mean relative differences of −9% and −6% and no significant differences with dimensions at histopathological analysis (P =.051). All MRI sequences led to significant underestimation of PDAC size (median Δdiameters, −6 to −1 mm; mean relative differences, −21% to −11%). Conclusions: Most accurate measurement of PDAC size is obtained with CT images obtained during the pancreatic parenchymal phase. MRI results in significant underestimation of PDAC size. Graphical Abstract [ABSTRACT FROM AUTHOR]

To develop a bounding-box-based 3D convolutional neural network (CNN) for user-guided volumetric pancreas ductal adenocarcinoma (PDA) segmentation. Reference segmentations were obtained on CTs (2006–2020) of treatment-naïve PDA. Images were algorithmically cropped using a tumor-centered bounding box for training a 3D nnUNet-based-CNN. Three radiologists independently segmented tumors on test subset, which were combined with reference segmentations using STAPLE to derive composite segmentations. Generalizability was evaluated on Cancer Imaging Archive (TCIA) (n = 41) and Medical Segmentation Decathlon (MSD) (n = 152) datasets. Total 1151 patients [667 males; age:65.3 ± 10.2 years; T1:34, T2:477, T3:237, T4:403; mean (range) tumor diameter:4.34 (1.1–12.6)-cm] were randomly divided between training/validation (n = 921) and test subsets (n = 230; 75% from other institutions). Model had a high DSC (mean ± SD) against reference segmentations (0.84 ± 0.06), which was comparable to its DSC against composite segmentations (0.84 ± 0.11, p = 0.52). Model-predicted versus reference tumor volumes were comparable (mean ± SD) (29.1 ± 42.2-cc versus 27.1 ± 32.9-cc, p = 0.69, CCC = 0.93). Inter-reader variability was high (mean DSC 0.69 ± 0.16), especially for smaller and isodense tumors. Conversely, model's high performance was comparable between tumor stages, volumes and densities (p > 0.05). Model was resilient to different tumor locations, status of pancreatic/biliary ducts, pancreatic atrophy, CT vendors and slice thicknesses, as well as to the epicenter and dimensions of the bounding-box (p > 0.05). Performance was generalizable on MSD (DSC:0.82 ± 0.06) and TCIA datasets (DSC:0.84 ± 0.08). A computationally efficient bounding box-based AI model developed on a large and diverse dataset shows high accuracy, generalizability, and robustness to clinically encountered variations for user-guided volumetric PDA segmentation including for small and isodense tumors. AI-driven bounding box-based user-guided PDA segmentation offers a discovery tool for image-based multi-omics models for applications such as risk-stratification, treatment response assessment, and prognostication, which are urgently needed to customize treatment strategies to the unique biological profile of each patient's tumor. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is the seventh leading cause of cancer deaths worldwide, accounting for 4.7% of all cancer deaths, and is expected to climb significantly over the next decade. The purpose of this systematic review and guidance document was to synthesize the evidence surrounding the role of adjuvant treatment (chemotherapy and chemoradiation therapy [CRT], and stereotactic body radiation therapy [SBRT]) in resected pancreatic ductal adenocarcinoma (PDAC). Systematic literature searches of MEDLINE, EMBASE, and 11 guideline databases were conducted. Both direct and indirect comparisons indicate adjuvant chemotherapy offers a survival advantage over surgery alone. The optimal regimens recommended are mFOLFIRINOX with alternative options of gemcitabine plus capecitabine, gemcitabine alone, or S-1 (which is not available in North America). Trials comparing a CRT strategy to modern chemotherapy regimens are lacking. However, current evidence demonstrates that the addition of CRT to chemotherapy does not result in a survival advantage over chemotherapy alone and is therefore not recommended. Trials evaluating SBRT in PDAC are also lacking. SBRT should only be used within a clinical trial or multi-institutional registry. [ABSTRACT FROM AUTHOR]

Abstract Aim This study was performed to evaluate the efficacy of a multidisciplinary approach incorporating neoadjuvant chemoradiotherapy with S1 (S1‐NACRT) for resectable pancreatic ductal adenocarcinoma. Methods The medical records of 132 patients who received S1‐NACRT for resectable pancreatic ductal adenocarcinoma from 2010 to 2019 were reviewed. The S1‐NACRT regimen consisted of S1 at a dose of 80‐120 mg/body/day together with 1.8 Gy of radiation in 28 fractions. The patients were re‐evaluated 4 weeks after S1‐NACRT completion, and a pancreatectomy was then considered. Results Adverse events of S1‐NACRT ≥grade 3 occurred in 22.7% of the patients, and 1.5% discontinued therapy. Of the 112 patients who underwent a pancreatectomy, 109 underwent R0 resection. Adjuvant chemotherapy with relative dose intensity ≥50% was administered to 74.1% of the patients who underwent resection. The median overall survival of all patients was 47 months, and the median overall survival and recurrence‐free survival of patients who underwent resection was 71 and 32 months, respectively. According to the multivariate analyses of prognostic factors for overall survival in patients who underwent resection, negative margin status (hazard ratio: 0.182; P = 0.006) and relative dose intensity of adjuvant chemotherapy ≥50% (hazard ratio 0.294; P

Purpose: To develop and validate an automated magnetic resonance imaging (MRI)-based model to preoperatively differentiate pancreatic adenosquamous carcinoma (PASC) from pancreatic ductal adenocarcinoma (PDAC). Methods: This retrospective study included patients with surgically resected, histopathologically confirmed PASC or PDAC who underwent MRI between January 2011 and December 2020. According to time of treatment, they were divided into training and validation sets. Automated deep-learning-based artificial intelligence was used for pancreatic tumor segmentation. Linear discriminant analysis was performed with conventional MRI and radiomic features to develop clinical, radiomics, and mixed models in the training set. The models' performances were determined from their discrimination and clinical utility. Kaplan–Meier and log-rank tests were used for survival analysis. Results: Overall, 389 and 123 patients with PDAC (age, 61.37 ± 9.47 years; 251 men) and PASC (age, 61.99 ± 9.82 years; 78 men) were included, respectively; they were split into the training (n = 358) and validation (n = 154) sets. The mixed model showed good performance in the training and validation sets (area under the curve: 0.94 and 0.96, respectively). The sensitivity, specificity, and accuracy were 76.74%, 93.38%, and 89.39% for the training set, respectively, and 67.57%, 97.44%, and 90.26% for the validation set, respectively. The mixed model outperformed the clinical (p = 0.001) and radiomics (p = 0.04) models in the validation set. Log-rank test revealed significantly longer survival in the predicted PDAC group than in the predicted PASC group (p = 0.003), according to the mixed model. Conclusion: Our mixed model, which combined MRI and radiomic features, can be used to differentiate PASC from PDAC. [ABSTRACT FROM AUTHOR]

Abstract Background Recent imaging modalities have helped inthe early detection of pancreatic ductal adenocarcinoma (PDAC), resulting inimproved survival rates for patients with early‐stage PDAC. However, preoperative pathological diagnosis of early‐stage PDAC remains a challenge, particularly for small PDAC that is difficult to diagnose through standardendoscopic ultrasound‐guided fine‐needle biopsy. In this context, pancreaticjuice cytology has been re‐evaluated as an important tool for the preoperativediagnosis of early‐stage PDAC. Main Pancreatic juice (PJ) comes in directcontact with PDAC lesions in the pancreatic duct and thus may contain a fewHG‐PanIN/PDAC cells and specific molecules. Additionally, the PJ may containconcentrated small extracellular vesicles (sEVs) that are released from cancerlesions. sEVs are double‐layered lipid‐bound particles that contain cargoassociated with the cell‐of‐origin, including proteins, microRNA, and RNA. sEVsreleased from cancer lesions found in body fluids, such as blood, urine, andsaliva, have already been studied as potential sources of diagnostic biomarkersfor cancer. PJ‐derived sEVs could serve as a “liquid biopsy” for theearly diagnosis of PDAC. However, little is known about the existence,physiological status, and function of PJ‐derived sEVs and their potentialutility as biomarkers for diagnostic, surveillance, and monitoring purposes oras therapeutic targets. Conclusion PJ‐derived sEVs represent a promisingavenue for the early diagnosis of PDAC. The utility of these particles as biomarkersfor diagnostic, surveillance, and monitoring purposes, or as therapeutictargets, warrants further research. Understanding the existence, physiologicalstatus, and function of PJ‐derived sEVs is crucial to unlocking their potentialas a valuable tool for overcoming PDAC.

Introduction. Difficulties in advanced pancreatic ductal adenocarcinoma (PDAC) treatment require a constant search for novel prognostic factors. The aim of this study is to determine the role of various morphological parameters in predicting the prognosis of advanced PDAC during systemic therapy with a FOLFIRINOX regimen. Material and methods. The data of 52 patients, treated with FOLFIRINOX chemotherapy due to metastatic PDAC were analyzed retrospectively in this study. Results. The median time of overall survival (OS) in the group of patients with neutrophil-to-lymphocyte ratio (NLR) ≥3 was 5.8 months, compared to 14.5 months in patients with NLR < 3. Median progression-free survival (PFS) in patients with NLR ≥ 3 was 4.1 months, compared to 8.5 months in patients with NLR < 3. There were no statistically significant differences among patients concerning the lymphocyte-to-monocyte ratio (LMR) and platelets-to-lymphocyte ratio (PLR). Conclusions. Higher NLR is a negative prognostic factor in metastatic PDAC. [ABSTRACT FROM AUTHOR]

Aim: This study was performed to evaluate the efficacy of a multidisciplinary approach incorporating neoadjuvant chemoradiotherapy with S1 (S1‐NACRT) for resectable pancreatic ductal adenocarcinoma. Methods: The medical records of 132 patients who received S1‐NACRT for resectable pancreatic ductal adenocarcinoma from 2010 to 2019 were reviewed. The S1‐NACRT regimen consisted of S1 at a dose of 80‐120 mg/body/day together with 1.8 Gy of radiation in 28 fractions. The patients were re‐evaluated 4 weeks after S1‐NACRT completion, and a pancreatectomy was then considered. Results: Adverse events of S1‐NACRT ≥grade 3 occurred in 22.7% of the patients, and 1.5% discontinued therapy. Of the 112 patients who underwent a pancreatectomy, 109 underwent R0 resection. Adjuvant chemotherapy with relative dose intensity ≥50% was administered to 74.1% of the patients who underwent resection. The median overall survival of all patients was 47 months, and the median overall survival and recurrence‐free survival of patients who underwent resection was 71 and 32 months, respectively. According to the multivariate analyses of prognostic factors for overall survival in patients who underwent resection, negative margin status (hazard ratio: 0.182; P = 0.006) and relative dose intensity of adjuvant chemotherapy ≥50% (hazard ratio 0.294; P < 0.001) were independent prognostic factors of overall survival. Conclusions: A multidisciplinary approach incorporating S1‐NACRT for resectable pancreatic ductal adenocarcinoma demonstrated acceptable tolerability and good local control and resulted in comparable survival benefits. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma is one of the most lethal malignancies, and there are vast unmet medical needs. In this study, we hypothesized that chimeric antigen receptor engineered T cell (CAR-T) targeting carcinoembryonic antigen (CEA) would be effective in the treatment of pancreatic ductal adenocarcinoma. In vivo experiments in a more clinically similar environment were considered necessary; we examined the antitumor effects of adoptive anti-CEA-CAR-T, using orthotopic xenograft mouse models of pancreatic ductal adenocarcinoma. As result, the therapeutic effect of anti-CEA-CAR-T therapy was related to the CEA expression level. Furthermore, the retrospective analysis of pathological findings from pancreatic ductal adenocarcinoma patients showed a correlation between the intensity of CEA immunostaining and tumor heterogeneity. These findings show that anti-CEA-CAR-T therapy can be useful for pancreatic ductal adenocarcinoma; furthermore, the pathological findings of CEA can be clinically used as biomarkers to select cases for anti-CEA-CAR-T therapy. Chimeric antigen receptor engineered T cell (CAR-T) therapy has high therapeutic efficacy against blood cancers, but it has not shown satisfactory results in solid tumors. Therefore, we examined the therapeutic effect of CAR-T therapy targeting carcinoembryonic antigen (CEA) in pancreatic adenocarcinoma (PDAC). CEA expression levels on the cell membranes of various PDAC cell lines were evaluated using flow cytometry and the cells were divided into high, medium, and low expression groups. The relationship between CEA expression level and the antitumor effect of anti-CEA-CAR-T was evaluated using a functional assay for various PDAC cell lines; a significant correlation was observed between CEA expression level and the antitumor effect. We created orthotopic PDAC xenograft mouse models and injected with anti-CEA-CAR-T; only the cell line with high CEA expression exhibited a significant therapeutic effect. Thus, the therapeutic effect of CAR-T therapy was related to the target antigen expression level, and the further retrospective analysis of pathological findings from PDAC patients showed a correlation between the intensity of CEA immunostaining and tumor heterogeneity. Therefore, CEA expression levels in biopsies or surgical specimens can be clinically used as biomarkers to select PDAC patients for anti-CAR-T therapy. [ABSTRACT FROM AUTHOR]

Endoscopic ultrasound (EUS)-guided hepaticogastrostomy (HGS) is widely performed not only as an alternative to transpapillary biliary drainage, but also as primary drainage for malignant biliary obstruction. For anatomical reasons, this technique carries an unavoidable risk of mispuncturing intrahepatic vessels. We report a technique for troubleshooting EUS-guided portal vein coiling to prevent bleeding from the intrahepatic portal vein after mispuncture during interventional EUS. EUS-HGS was planned for a 59-year-old male patient with unresectable pancreatic cancer. The dilated bile duct (lumen diameter, 2.8 mm) was punctured with a 19-gauge needle, and a guidewire was inserted. After bougie dilation, the guidewire was found to be inside the intrahepatic portal vein. Embolizing coils were placed to prevent bleeding. Embolization coils were successfully inserted under stabilization of the catheter using a double-lumen cannula with a guidewire. Following these procedures, the patient was asymptomatic. Computed tomography performed the next day revealed no complications.

PDAC (pancreatic ductal adenocarcinoma) is a highly aggressive malignant tumor. We have previously developed induced tumor-suppressing cells (iTSCs) that secrete a group of tumor-suppressing proteins. Here, we examined a unique procedure to identify anticancer peptides (ACPs), using trypsin-digested iTSCs-derived protein fragments. Among the 10 ACP candidates, P04 (IGEHTPSALAIMENANVLAR) presented the most efficient anti-PDAC activities. P04 was derived from aldolase A (ALDOA), a glycolytic enzyme. Extracellular ALDOA, as well as P04, was predicted to interact with epidermal growth factor receptor (EGFR), and P04 downregulated oncoproteins such as Snail and Src. Importantly, P04 has no inhibitory effect on mesenchymal stem cells (MSCs). We also generated iTSCs by overexpressing ALDOA in MSCs and peripheral blood mononuclear cells (PBMCs). iTSC-derived conditioned medium (CM) inhibited the progression of PDAC cells as well as PDAC tissue fragments. The inhibitory effect of P04 was additive to that of CM and chemotherapeutic drugs such as 5-Flu and gemcitabine. Notably, applying mechanical vibration to PBMCs elevated ALDOA and converted PBMCs into iTSCs. Collectively, this study presented a unique procedure for selecting anticancer P04 from ALDOA in an iTSCs-derived proteome for the treatment of PDAC.

Abstract The prognosis of pancreatic ductal carcinoma (PDAC) with peritoneal metastasis remains dismal. Systemic chemotherapy alone may not be effective, and the combination of intraperitoneal chemotherapy with systemic chemotherapy is expected to prolong the overall survival in patients with peritoneal metastasis. We have designed a randomized phase III trial to confirm the superiority of intravenous (i.v.) and intraperitoneal (i.p.) paclitaxel (PTX) with S-1 relative to gemcitabine plus nab-PTX (GnP), which is the current standard therapy for patients with metastatic PDAC. A total of 180 patients will be accrued from 30 institutions within 3 years. Patients will be randomly assigned in a 1:1 ratio to receive either i.v. and i.p. PTX with S-1 or GnP (target of 90 patients per group). The primary endpoint is overall survival; secondary endpoints are progression-free survival, response rate, proportion with negative peritoneal washing cytology during chemotherapy, proportion requiring conversion surgery, and adverse event profiles. Japan Registry of Clinical Trials jRCTs051180199 ( https://jrct.niph.go.jp/ ).

Background: Endoscopic ultrasound-guided puncture aspiration biopsy (EUS-FNA) of pancreatic ductal adenocarcinoma (PDAC) is highly diagnostic, but it is difficult to distinguish from benign disease. Our objective was to determine the usefulness of maspin staining, in addition to conventional p53 staining, in the diagnosis of PDAC by EUS-FNA. Methods: Of the patients who underwent EUS-FNA and were diagnosed with PDAC, we retrospectively identified 90 cases in which both maspin and p53 staining were performed. In addition, we identified 28 cases of benign pancreatic disease diagnosed using EUS-FNA and these were selected as a control group. For analysis of EUS-FNA specimens, Cohen's Kappa (κ) coefficient and the prevalence and bias adjusted Kappa statistic (PABAK) were applied to assess the significance of sensitivity and specificity, comparing p53, maspin, p53+maspin. Results: The sensitivity and specificity of p53 staining were 48.9% and 100%. The κ coefficient was 0.31 (95%CI 0.18–0.44) (p < 0.01) and the PABAK coefficient was 0.22 (95%CI 0.03–0.40). The results for maspin staining were 88.9% and 92.9%. The κ coefficient was 0.72 (95%CI 0.54–0.90) (p < 0.01) and the PABAK coefficient was 0.78 (95%CI 0.64–0.88). The results for the combination of maspin and p53 staining were 94.4% and 92.2%. The κ coefficient was 0.82 (95%CI 0.64–1.00) (p < 0.01) and the PABAK coefficient was 0.86 (95%CI 0.74–0.94). Conclusion: Adding maspin staining to p53 staining showed high sensitivity and specificity. Our results demonstrated the usefulness of their combined use that might contribute to the improvement of tissue diagnostic performance of PDAC by EUS-FNA. [ABSTRACT FROM AUTHOR]

Objectives: Necroptosis, a programmed inflammatory cell death, is implicated in the pathogenesis of pancreatitis and its potential progression to pancreatic ductal adenocarcinoma (PDAC), but its role remains unclear. We compared plasma levels of necroptosis-related markers - mixed lineage kinase domain-like protein (MLKL), interleukin (IL)-33, and its soluble receptor (sST2)- in patients with chronic pancreatitis (CP), PDAC, and healthy controls (HC), to explore their diagnostic and prognostic significance., Methods: Plasma was collected from patients pre-procedurally (PDAC, n = 82; CP, n = 25) and from HC (n = 39), and studied by ELISA. Clinical and routine laboratory data were collected, and pancreas was defined as soft or non-soft based on intraoperative or imaging findings. Mann-Whitney U test, Spearman correlation coefficients, ROC analysis were used for statistical analysis., Results: Plasma MLKL was lower in patients with CP than in other groups (p < 0.001) and PDAC patients treated with upfront surgery (PDACUS, n = 65) had lower MLKL than HC (p = 0.035). MLKL differentiated CP from PDACUS (AUC 0.83, p < 0.001). sST2 levels were significantly lower in HC than in other groups (p < 0.001) and in PDAC patients with a soft pancreas compared with non-soft (p < 0.005). In Lewis antigen positive PDACUS (n = 59), sST2 had positive correlations with CA19-9 measured concurrently and after 1 month, and with CEA measured after 1 or 6 months., Conclusions: Circulating levels of MLKL are lower in patients with CP than PDAC. Elevated sST2 levels are associated with pancreatic diseases. Further studies are required to show whether MLKL and sST2 could be useful biomarkers in evaluating pancreatic diseases., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Carcinosarcoma of the pancreas is a rare entity with poor prognosis. Here, we report a case of pancreatic carcinosarcoma in a 68-year-old male patient who underwent a pancreatoduodenectomy for a unilocular cystic mass in the head of the pancreas. Histologically, the lesion showed a biphasic tumor with a carcinoma component and a spindle cell sarcomatous component, which were intimately intermingled. Most of the carcinoma components are well-differentiated ductal adenocarcinoma with small areas of moderately to poorly differentiated ductal adenocarcinoma. The sarcomatous component is a high-grade highly cellular spindle cell tumor with frequent mitosis and apoptosis. Immunohistochemical studies demonstrated that the carcinomatous component was positive for epithelial markers and cyclin D1, and the sarcomatous component was negative for these markers while positive for vimentin, p16, and DOG1 with patchy positivity for S100. Other markers, including SOX10, CD117, Melan A, HMB45, actin, desmin, myogenin, beta-catenin, TLE1, and p53, were negative in both components. Molecular studies demonstrated that the tumor was microsatellite stable. Whole exome next generation sequencing analysis was performed and no pathogenic alterations in the genes were identified.

Purpose: The optimal range of lymph-node dissection for pancreatic tail cancer remains unclear. We investigated the location and frequency of lymph-node metastases to identify the correct range of lymph-node dissection for pancreatic tail cancer. Methods: We analyzed clinical data retrospectively, on patients who underwent distal pancreatectomy for resectable left-sided pancreatic cancer, between February, 2006 and March, 2021. Eligible patients were divided into two groups according to the tumor location: those with pancreatic tail cancer (Pt group) and those with pancreatic body or body and tail cancer (non-Pt group). Results: Of the 96 patients analyzed, 61 (64%) were assigned to the Pt group and 35 (36%) were assigned to the non-Pt group. Metastases to stations 7, 8, 9, 10, 11, 14, and 18 were found in 0 (0%), 0 (0%), 0 (0%), 4 (7%), 18 (30%), 2 (4%), and 10 (17%) patients in the Pt group, and in 1 (3%), 4 (12%), 2 (6%), 1 (3%), 18 (51%), 3 (9%), and 6 (17%) patients in the non-Pt group, respectively. Conclusion: Lymph-node dissection at stations 7, 8, and 9 might not be necessary in patients with resectable pancreatic cancer confined to the pancreatic tail. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the potential role of MR findings and DWI parameters in predicting small regional lymph nodes metastases (with short-axis diameter < 10 mm) in pancreatic ductal adenocarcinomas (PDACs). Methods: A total of 127 patients, 82 in training group and 45 in testing group, with histopathologically diagnosed PDACs who underwent pancreatectomy were retrospectively analyzed. PDACs were divided into two groups of positive and negative lymph node metastases (LNM) based on the pathological results. Pancreatic cancer characteristics, short axis of largest lymph node, and DWI parameters of PDACs were evaluated. Results: Univariate and multivariate analyses showed that extrapancreatic distance of tumor invasion, short-axis diameter of the largest lymph node, and mean diffusivity of tumor were independently associated with small LNM in patients with PDACs. The combining MRI diagnostic model yielded AUCs of 0.836 and 0.873, and accuracies of 81.7% and 80% in the training and testing groups. The AUC of the MRI model for predicting LNM was higher than that of subjective MRI diagnosis in the training group (rater 1, P = 0.01; rater 2, 0.008) and in a testing group (rater 1, P = 0.036; rater 2, 0.024). Comparing the subjective diagnosis, the error rate of the MRI model was decreased. The defined LNM-positive group by the MRI model showed significantly inferior overall survival compared to the negative group (P = 0.006). Conclusions: The MRI model showed excellent performance for individualized and noninvasive prediction of small regional LNM in PDACs. It may be used to identify PDACs with small LNM and contribute to determining an appropriate treatment strategy for PDACs. [ABSTRACT FROM AUTHOR]

Purpose: To compare the characteristics detected by 7Tesla (7 T) MR and the histological composition of ex-vivo specimens from lesions diagnosed at preoperative CT scan as Pancreatic Ductal Adenocarcinoma (PDAC). Materials and methods: Ten pancreatic specimens were examined. The 7 T imaging protocol included both morphologic and quantitative sequences; the latter was acquired by conventional methods and a novel multiparametric method, the magnetic resonance fingerprinting (MRF) sequence. Two radiologists reviewed the images to: (1) evaluate the quality of the morphological and quantitative sequences by assigning an "image consistency score" on a 4-point scale; (2) identify the lesion, recording its characteristics; (3) perform the quantitative analysis on "target lesion" and "non target tissue". Finally, the specimen was analysed by two pathologists. Results: Seven out of 10 lesions were PDAC, 2/10 were biliary carcinomas, whereas one lesion was an ampullary adenocarcinoma. The quality of the morphological sequences was judged "excellent". The "image consistency score" for the conventional quantitative sequences and MRF were 2.8 ± 0.42 and 2.9 ± 0.57; the "overall MR examination score" was 3.5 ± 0.53. A statistical correlation was found between the relaxation time values of conventional and MRF T1-weighted sequences (p < 0.0001), as well as between conventional and MRF fat- and water-fraction maps (p < 0.05). The "target lesion" and "non target tissue" relaxation time values were statistically different according to conventional T1-, T2-weighted, and MRF T1-weighted sequences. Conclusions: Conventional T1-, T2-weighted sequences and MRF derived relaxometries may be useful in differentiating between tumour and non-target pancreatic tissue. Moreover, the MRF sequence can be used to obtain reliable relaxation time data. [ABSTRACT FROM AUTHOR]

Objective: Most patients with pancreatic ductal adenocarcinoma receive chemo‐radiotherapy as first approach, some of them with the future hope to undergo surgery. Methodology: The aim of the study was to estimate the probabilities to receive surgery, to experience tumour progression or post‐operative recurrence. We performed a competing‐risk approach to estimate competing events of disease progression and surgery, as well as post‐operative recurrence and death without recurrence. Results: Of 96 enrolled patients, 49 received chemotherapy because they were judged borderline resectable, 21 were locally advanced and 7 had liver‐only limited metastatic disease. Competing‐risk analyses showed that resectability status at diagnosis not only determines future probabilities of surgery, but also tumour progression and post‐operative recurrence (p <.05 in all cases). CA19‐9 decrease ≥50% predicted surgery (p =.032), whereas CA19‐9 ≥ 300 U/mL predicted post‐operative recurrence (p =.001). Younger age also predicted surgery (p =.001) and margin status predicted recurrence (p =.047). The combination of the competing events suggested that the best outcomes since diagnosis depended not only on resectability and final surgical margin, but also on the combination of relative decrease of CA19‐9 and its absolute value after therapy. Conclusions: The combination of CA19‐9 decrease, added to resectability criteria, can be used to optimise the selection of surgical candidates. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis because it is often detected at an advanced stage, and drug resistance interferes with treatment. However, the mechanism underlying drug resistance in PDAC remains unclear. Here, we investigated metabolic changes between a parental PDAC cell line and a gemcitabine (GEM)-resistant PDAC cell line. We established a GEM-resistant cell line, MIA-G, from MIA-PaCa-2 parental (MIA-P) cells using continuous therapeutic-dose GEM treatment. MIA-G cells were also more resistant to 5-fluorouracil in comparison to MIA-P cells. Metabolic flux analysis showed a higher oxygen consumption rate (OCR) in MIA-G cells than in MIA-P cells. Notably, OCR was suppressed by GEM treatment only in MIA-G cells. GEM treatment increased mitochondrial membrane potential and mitochondrial reactive oxygen species (ROS) in MIA-P cells, but not in MIA-G cells. Glutamine uptake and peroxidase levels were elevated in MIA-G cells. The antioxidants N-acetyl-L-cysteine and vitamin C increased the sensitivity to GEM in both cell lines. In MIA-G cells, the expression of the mitochondrial transcription factor A also decreased. Furthermore, rotenone reduced the sensitivity of MIA-P cells to GEM. These findings suggest that the suppression of oxidative phosphorylation contributes to GEM resistance by reducing ROS production. Our study provides a new approach for reducing GEM resistance in PDAC. [ABSTRACT FROM AUTHOR]