OBJECTIVE: Patients with localized pancreatic adenocarcinoma who do not respond to neoadjuvant therapy present a challenge. We sought to define the characteristics and outcomes of those patients to guide clinical practice.
METHODS: Patients included were those without evidence of biochemical or radiographic response and no evidence of distant progression at the first reassessment after initiation of therapy.
RESULTS: Of the 45 patients in the cohort, 23 (51.1%) proceeded to surgical exploration with all but one of those undergoing resection. The median overall survival of the study cohort was 28.6 and 48.6 months in those who underwent resection. A total of 13 patients (28.9%) underwent chemotherapy switch (CS) during their course of neoadjuvant therapy. The CS cohort demonstrated higher rates of radiologic progression (25% vs. 10%, p = 0.329), new or worse vascular involvement (58.3% vs. 30%, p = 0.082), and CA 19-9 increase (30.8% vs. 12.9%, p = 0.209) at initial re-staging. Despite this, overall survival was similar between the two groups (20.7 vs. 28.7 months, p = 0.674).
CONCLUSIONS: Non-responders to first-line neoadjuvant therapy have poor rates of curative-intent resection. However, resection should be undertaken when feasible. CS may be considered in patients who do not respond to first-line chemotherapy.

BACKGROUND: Pancreatic adenocarcinoma of distal pancreas is hard to treat due to late presentation. While open distal pancreatectomy with splenectomy has had favourable outcomes, it has also had many complications which were low among Minimally invasive procedures. This retrospective cohort analysis compares minimally invasive and open distal pancreatectomy (MIDP) outcomes using a national inpatient database.
METHODS: The study used 2016-2020 NIS data. The study included 1577 distal pancreatic malignant tumor surgery patients. There were 530 Minimally Invasive and 1047 Open groups. Propensity matched analysis was performed on surgical groups to reduce confounding variables.
RESULTS: In comparison to open procedures, minimally invasive techniques reduced hospital stays by 10 ​% (OR ​= ​0.90, 95 ​% CI 0.86-0.93). While not statistically significant, the unmatched analysis linked MIDP to lower in-hospital mortality. African Americans were 37 ​% less likely to undergo MIDP than Caucasians (OR ​= ​0.63, 95 ​% CI ​= ​0.40-0.96).
CONCLUSIONS: Nationwide analysis suggests MIDP may be a safe and effective surgical treatment for distal pancreatic adenocarcinoma. It may reduce hospital stays and mortality over open surgery. The study also suggests race may affect minimally invasive procedure rates.

BACKGROUND: Pancreatic adenocarcinomas (PAADs) often exhibit a \"cold\" or immunosuppressive tumor milieu, which is associated with resistance to immune checkpoint blockade therapy; however, the underlying mechanisms are incompletely understood. Here, we aimed to improve our understanding of the molecular mechanisms occurring in the tumor microenvironment and to identify biomarkers, therapeutic targets, and potential drugs to improve PAAD treatment.
METHODS: Patients were categorized according to immunologically hot or cold PAAD subtypes with distinct disease outcomes. Cox regression and weighted correlation network analysis were performed to construct a novel gene signature, referred to as \'Downregulated in hot tumors, Prognostic, and Immune-Related Genes\' (DPIRGs), which was used to develop prognostic models for PAAD via machine learning (ML). The role of DPIRGs in PAAD was comprehensively analyzed, and biomarker genes able to distinguish PAAD immune subtypes and predict prognosis were identified by ML. The expression of biomarkers was verified using public single-cell transcriptomic and proteomic resources. Drug candidates for turning cold tumors hot and corresponding target proteins were identified via molecular docking studies.
RESULTS: Using the DPIRG signature as input data, a combination of survival random forest and partial least squares regression Cox was selected from 137 ML combinations to construct an optimized PAAD prognostic model. The effects and molecular mechanisms of DPIRGs were investigated by analysis of genetic/epigenetic alterations, immune infiltration, pathway enrichment, and miRNA regulation. Biomarkers and potential therapeutic targets, including PLEC, TRPV1, and ITGB4, among others, were identified, and the cell type-specific expression of the biomarkers was validated. Drug candidates, including thalidomide, SB-431542, and bleomycin A2, were identified based on their ability to modulate DPIRG expression favorably.
CONCLUSIONS: By combining multiple ML algorithms, we developed a novel prognostic model with excellent performance in PAAD cohorts. ML also proved to be powerful for identifying biomarkers and potential targets for improved PAAD patient stratification and immunotherapy.

Pancreatic adenocarcinoma (PDAC) is a major health burden and may become the second cause of death by cancer in developed countries. The incidence of early-onset pancreatic cancer (EOPC, defined by an age at diagnosis <50 years old) is increasing. Here, we conducted a study of all PDAC patients followed at our institution. Patients were classified as EOPC or non-early onset (nEOPC, >50). Eight hundred and seventy eight patients were included, of which 113 EOPC, exhibiting a comparable performance status. EOPC were more often diagnosed at the metastatic stage (70.0% vs 58.3%) and liver metastases were more prevalent at diagnosis (60.2% vs. 43.9%). The median overall survival (OS) from diagnosis was 18.1 months, similar between EOPC and nEOPC. Among patients who underwent surgery, recurrence-free survival was similar between age groups. Among metastatic patients, first line progression free survival was similar but EOPC received more treatment lines (72.3% vs. 58.1% received ≥2 lines). Regarding molecular alterations, the mean tumor mutational burden (TMB) was lower in EOPC (1.42 vs. 2.95 mut/Mb). The prevalence of KRAS and BRCA1/2 mutations was similar, but EOPC displayed fewer alterations in CNKN2A/B. Fifty eight patients (18.6%) had actionable alterations (ESCAT I-III) and 31 of them received molecularly matched treatments. On the transcriptomic level, despite its clinical aggressiveness, EOPC was less likely to display a basal-like phenotype. To conclude, EOPC were diagnosed more frequently at the metastatic stage. OS and 1st line PFS were similar to nEOPC. EOPC displayed specific molecular features, such as a lower TMB and fewer alterations in CDKN2A/B.

UNASSIGNED: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive human tumor that is typically diagnosed at a later stage when surgery is not possible.
UNASSIGNED: We report the case of a 62-year-old woman who presented to the emergency department with abdominal pain. Computed tomography (CT) revealed a solitary hepatic lesion and a pancreatic body lesion. The pancreatic body lesion was biopsied endoscopically, and a tissue diagnosis was obtained to confirm the diagnosis of PDAC. She was then treated with 12 cycles of FOLFIRINOX with stable disease on CT. Due to the history of a hepatic lesion, she received 11 cycles of gemcitabine/Abraxane and a combination of a MEK inhibitor, Mekinist, and a BRAF inhibitor, BRAFTOVI. Subsequently, the patient underwent a liver biopsy. The biopsy result was negative, and the tumor was deemed resectable. The patient underwent a distal pancreatectomy. Surgical pathology demonstrated a 1.1-cm low-grade papillary mucinous neoplasm with negative margins and lymph nodes, staged T0N0. Adjuvant chemotherapy was not administered.
UNASSIGNED: To our knowledge, this is the first report of a patient with metastatic pancreatic adenocarcinoma who received prolonged IV and oral chemotherapy. At the time of the operation, the pathological stage was T0N0. The patient has recently been seen 9 months after surgery with no evidence cancer recurrence. Additionally, ctDNA remains negative.

BACKGROUND: Difficulties in distinguishing fibrosis from tumor in borderline and locally advanced pancreatic adenocarcinoma (PDAC) justify surgical exploration to assess resectability. This issue is especially relevant after neoadjuvant treatments (NAT) prior to pancreaticoduodenectomy (PD) although outcomes of aborted PD are unknown.
OBJECTIVE: This study aimed to evaluate early outcomes after aborted PD in patients with PDAC.
METHODS: Data were collected over a ten-year period, in three University Hospitals in France. Perioperative patient management was similar. The causes of intraoperative PD abortions were recorded, and outcomes of patients who underwent early (metastases, carcinomatosis) and late (following extensive vascular dissection) PD abortion were compared.
RESULTS: Of 774 PD for PDAC, 131 (17%) were aborted. 97 (74%) patients underwent early PD abortion due to carcinomatosis (n = 14; 14%), liver metastases (n = 32; 33%), aortocaval lymph node invasion (n = 28; 29%) and massive vascular extension (n = 23; 24%). Late PD abortion occurred after extensive vascular dissection in 34 (26%) patients due to invasion of the common hepatic (n = 16; 47%), superior mesenteric (n = 5; 15%) and right hepatic (n = 1; 3%) arteries and nonreconstructable venous invasion (n = 12; 35%). Patients who underwent late PD abortion had higher rates of overall morbidity (n = 22; 65% vs n = 27; 28%, p = 0.0001), severe complications (n = 14; 41% vs n = 11; 11%, p = 0.0005), mortality (n = 4; 12% vs n = 0; 0%, p = 0.003). They also had higher rates of delayed gastric emptying (n = 11; 32% vs n = 6; 6%, p = 0.0003), deep space infections (n = 10; 29% vs n = 7; 7%, p = 0.002), wound infections (n = 5; 15% vs n = 4; 4%, p = 0.05), and bleeding (n = 8; 24% vs n = 0; 0%, p < 0.0001).
CONCLUSIONS: Aborted PD after extensive vascular dissection has high morbidity and mortality rates. Appropriate information and counseling should be delivered to patients with borderline/locally advanced PDAC considered for PD.

This study aimed to introduce specific image feature analysis, focusing on pancreatic margins, and to provide a quantitative measure of edge irregularity, evidencing correlations with the presence/absence of pancreatic adenocarcinoma. We selected 50 patients (36 men, 14 women; mean age 63.7 years) who underwent Multi-detector computed tomography (MDCT) for the staging of pancreatic adenocarcinoma of the tail of the pancreas. Computer-assisted quantitative edge analysis was performed on the border fragments in MDCT images of neoplastic and healthy glandular parenchyma, from which we obtained the root mean square deviation SD of the actual border from the average boundary line. The SD values relative to healthy and neoplastic borders were compared using a paired t-test. A significant SD difference was observed between healthy and neoplastic borders. A threshold SD value was also found, enabling the differentiation of adenocarcinoma with 96% specificity and sensitivity. We introduced a quantitative measure of boundary irregularity, which correlates with the presence/absence of pancreatic adenocarcinoma. Quantitative edge analysis can be promptly performed on select border fragments in MDCT images, providing a useful supporting tool for diagnostics and a possible starting point for machine learning recognition based on lower-dimensional feature space.

Early detection of PDAC remains challenging due to the lack of early symptoms and the absence of reliable biomarkers. The aim of the present project was to identify miRNA and proteomics signatures discriminating PDAC patients with DM from nondiabetic PDAC patients. Proteomics analysis and miRNA array were used for protein and miRNA screening. We used Western blotting and Real-Time Quantitative Reverse Transcription polymerase chain reaction (qRT-PCR) for protein and miRNA validation. Comparisons between experimental groups with normal distributions were performed using one-way ANOVA followed by Tukey\'s post hoc test, and pairwise tests were performed using t-tests. p ≤ 0.05 was considered statistically significant. Protein clusters of differentiation 166 (CD166), glycoprotein CD63 (CD63), S100 calcium-binding protein A13 (S100A13), and tumor necrosis factor-β (TNF-β) were detected in the proteomics screening. The miRNA assay revealed a differential miRNA 1285 regulation. Previously described target proteins of miR-1285 cadherin-1 (CDH-1), cellular Jun (c-Jun), p53, mothers against decapentaplegic homolog 4 (Smad4), human transglutaminase 2 (TGM2) and yes-associated protein (YAP), were validated via Western blotting. miR-1285-3p was successfully validated as differentially regulated in PDAC + DM via qRT-PCR. Overall, our data suggest miRNA1285-3p, TGM2, CDH-1, CD166, and S100A13 as potential meaningful biomarker candidates to characterize patients with PDAC + DM. Data are available via ProteomeXchange with the identifier PXD053169.

OBJECTIVE: The main focus of this study is to explore the molecular mechanism of IRF7 regulation on RPS18 transcription in M1-type macrophages in pancreatic adenocarcinoma (PAAD) tissue, as well as the transfer of RPS18 by IRF7 via exosomes to PAAD cells and the regulation of ILF3 expression.
METHODS: By utilising single-cell RNA sequencing (scRNA-seq) data and spatial transcriptomics (ST) data from the Gene Expression Omnibus database, we identified distinct cell types with significant expression differences in PAAD tissue. Among these cell types, we identified those closely associated with lipid metabolism. The differentially expressed genes within these cell types were analysed, and target genes relevant to prognosis were identified. Flow cytometry was employed to assess the expression levels of target genes in M1 and M2 macrophages. Cell lines with target gene knockout were constructed using CRISPR/Cas9 editing technology, and cell lines with target gene knockdown and overexpression were established using lentiviral vectors. Additionally, a co-culture model of exosomes derived from M1 macrophages with PAAD cells was developed. The impact of M1 macrophage-derived exosomes on the lipid metabolism of PAAD cells in the model was evaluated through metabolomics analysis. The effects of M1 macrophage-derived exosomes on the viability, proliferation, division, migration and apoptosis of PAAD cells were assessed using MTT assay, flow cytometry, EdU assay, wound healing assay, Transwell assay and TUNEL staining. Furthermore, a mouse PAAD orthotopic implantation model was established, and bioluminescence imaging was utilised to assess the influence of M1 macrophage-derived exosomes on the intratumoural formation capacity of PAAD cells, as well as measuring tumour weight and volume. The expression of proliferation-associated proteins in tumour tissues was examined using immunohistochemistry.
RESULTS: Through combined analysis of scRNA-seq and ST technologies, we discovered a close association between M1 macrophages in PAAD samples and lipid metabolism signals, as well as a negative correlation between M1 macrophages and cancer cells. The construction of a prognostic risk score model identified RPS18 and IRF7 as two prognostically relevant genes in M1 macrophages, exhibiting negative and positive correlations, respectively. Mechanistically, it was found that IRF7 in M1 macrophages can inhibit the transcription of RPS18, reducing the transfer of RPS18 to PAAD cells via exosomes, consequently affecting the expression of ILF3 in PAAD cells. IRF7/RPS18 in M1 macrophages can also suppress lipid metabolism, cell viability, proliferation, migration, invasion and intratumoural formation capacity of PAAD cells, while promoting cell apoptosis.
CONCLUSIONS: Overexpression of IRF7 in M1 macrophages may inhibit RPS18 transcription, reduce the transfer of RPS18 from M1 macrophage-derived exosomes to PAAD cells, thereby suppressing ILF3 expression in PAAD cells, inhibiting the lipid metabolism pathway, and curtailing the viability, proliferation, migration, invasion of PAAD cells, as well as enhancing cell apoptosis, ultimately inhibiting tumour formation in PAAD cells in vivo. Targeting IRF7/RPS18 in M1 macrophages could represent a promising immunotherapeutic approach for PAAD in the future.

BACKGROUND: Knowledge about environmental pancreatic adenocarcinoma (PA) risk factors, including pesticide exposure, remains limited. Organochlorine (OC) accumulates in adipose tissue and can help reflect long-term exposure.
METHODS: Age and body mass index (BMI) of patients with PA were matched with those undergoing a surgery for a benign disease on age and BMI (1:1). Targeted analyses screened 345 pesticides and metabolites, including 29 OC, in adipose tissue and urine samples. The primary aim was to investigate the association between organochlorine concentrations in visceral fat or urine, and PA. Adjusted conditional logistic regressions were carried out accounting for multiple testing.
RESULTS: Trans-nonachlor (odds ratio [OR] = 1.325, 95% confidence interval [CI] [1.108-1.586]), cis-nonachlor (OR = 15.433, 95% CI [2.733-87.136]), Mirex (OR = 2.853, 95% CI [1.213-6.713]) and 4,4 DDE (OR = 1.019, 95% CI [1.005-1.034]) in fat and a greater number of positive samples (OR = 1.758 95% CI [1.11-2.997]) were significantly associated with higher odds of PA. In contrast, as awaited, urine samples did not yield any statistically significant associations for all tested pesticides.
CONCLUSIONS: Some OCs were associated with higher odds of PA. The underlying mechanisms of pancreatic aggression need to be investigated to refine these findings.
BACKGROUND: Clinicaltrials.gov NCT04429490.