Ductal Adenocarcinoma Of Pancreas Research Articles

The function of p97/valosin-containing protein (VCP) and small VCP-interacting protein (SVIP) in invasion and migration of pancreatic cancer cells.

Misfolded proteins are eliminated by a process known as endoplasmic reticulum-associated protein degradation (ERAD). ERAD has an impact on a variety of illnesses, such as diabetes, cystic fibrosis, cancer, and neurological conditions. As one of the many proteins involved in ERAD, this study is focused on p97/valosin-containing protein (VCP) and small VCP-interacting protein (SVIP). The existence and function of SVIP and p97/VCP in various types of pancreatic cancer have not yet been investigated. The study's objectives are to examine the expressions of SVIP and p97/VCP in two pancreatic cancer types and to show whether these proteins aid in the invasion and migration of pancreatic cancer cells. In this work, MIA PaCa-2 and PANC-1 human cell lines were examined. Immunocytochemistry and immunofluorescence were performed to detect the cellular localization and presence of p97/VCP and SVIP in pancreatic cancer cells. Following p97/VCP siRNA and SVIP siRNA transfection of the cells, protein expressions were assessed using Western blot analysis. The effects of this suppression on cell invasion and migration were determined using the xCELLigence real-time analysis system (RTAC). In the nucleus and cytoplasm of MIA PaCa-2 and PANC-1 cells, p97/VCP and SVIP immunoexpressions were seen. The decrease in protein expressions of p97/VCPsi and SVIPsi was significant in pancreatic cells compared to the controlsi. The p97/VCP siRNA transfection reduced the invasion and migration of MIA PaCa-2 and PANC-1 cells. In addition, the SVIP siRNA suppression resulted in increasing the invasion and migration ability of both cells. This study also demonstrated, for the first time, SVIP expression in MIA PaCa-2 and PANC-1 cells. Overall, the findings show the differential expression and function of p97/VCP and SVIP in pancreas ductal adenocarcinoma cells. The potential of the pancreatic cancer cells to migrate and invade altered when the two cell lines were transfected with p97/VCPsi and SVIPsi.

Optimizing pseudo-spiral sampling for abdominal DCE MRI using a digital anthropomorphic phantom.

For reliable DCE MRI parameter estimation, k-space undersampling is essential to meet resolution, coverage, and signal-to-noise requirements. Pseudo-spiral (PS) sampling achieves this by sampling k-space on a Cartesian grid following a spiral trajectory. The goal was to optimize PS k-space sampling patterns for abdomin al DCE MRI. The optimal PS k-space sampling pattern was determined using an anthropomorphic digital phantom. Contrast agent inflow was simulated in the liver, spleen, pancreas, and pancreatic ductal adenocarcinoma (PDAC). A total of 704 variable sampling and reconstruction approaches were created using three algorithms using different parametrizations to control sampling density, halfscan and compressed sensing regularization. The sampling patterns were evaluated based on image quality scores and the accuracy and precision of the DCE pharmacokinetic parameters. The best and worst strategies were assessed in vivo in five healthy volunteers without contrast agent administration. The best strategy was tested in a DCE scan of a PDAC patient. The best PS reconstruction was found to be PS-diffuse based, with quadratic distribution of readouts on a spiral, without random shuffling, halfscan factor of 0.8, and total variation regularization of 0.05 in the spatial and temporal domains. The best scoring strategy showed sharper images with less prominent artifacts in healthy volunteers compared to the worst strategy. Our suggested DCE sampling strategy also showed high quality DCE images in the PDAC patient. Using an anthropomorphic digital phantom, we identified an optimal PS sampling strategy for abdominal DCE MRI, and demonstrated feasibility in a PDAC patient.

Comparison between solid pseudopapillary neoplasms of the pancreas and pancreatic ductal adenocarcinoma with cystic changes using computed tomography

BACKGROUND Solid pseudopapillary neoplasms of the pancreas (SPN) share similar imaging findings with pancreatic ductal adenocarcinoma with cystic changes (PDAC with cystic changes), which may result in unnecessary surgery. AIM To investigate the value of computed tomography (CT) in differentiation of SPN from PDAC with cystic changes. METHODS This study retrospectively analyzed the clinical and imaging findings of 32 patients diagnosed with SPN and 14 patients diagnosed with PDAC exhibiting cystic changes, confirmed through pathological diagnosis. Quantitative and qualitative analysis was performed, including assessment of age, sex, tumor size, shape, margin, density, enhancement pattern, CT values of tumors, CT contrast enhancement ratios, “floating cloud sign,” calcification, main pancreatic duct dilatation, pancreatic atrophy, and peripancreatic invasion or distal metastasis. Multivariate logistic regression analysis was used to identify relevant features to differentiate between SPN and PDAC with cystic changes, and receiver operating characteristic curves were obtained to evaluate the diagnostic performance of each variable and their combination. RESULTS When compared to PDAC with cystic changes, SPN had a lower age (32 years vs 64 years, P < 0.05) and a slightly larger size (5.41 cm vs 3.90 cm, P < 0.05). SPN had a higher frequency of “floating cloud sign” and peripancreatic invasion or distal metastasis than PDAC with cystic changes (both P < 0.05). No significant difference was found with respect to sex, tumor location, shape, margin, density, main pancreatic duct dilatation, calcification, pancreatic atrophy, enhancement pattern, CT values of tumors, or CT contrast enhancement ratios between the two groups (all P > 0.05). The area under the receiver operating characteristic curve of the combination was 0.833 (95% confidence interval: 0.708-0.957) with 78.6% sensitivity, 81.3% specificity, and 80.4% accuracy in differentiation of SPN from PDAC with cystic changes. CONCLUSION A larger tumor size, “floating cloud sign,” and peripancreatic invasion or distal metastasis are useful CT imaging features that are more common in SPN and may help discriminate SPN from PDAC with cystic changes.

Sphingosine is involved in PAPTP-induced death of pancreas cancer cells by interfering with mitochondrial functions

Pancreas ductal adenocarcinoma belongs to the most common cancers, but also to the tumors with the poorest prognosis. Here, we pharmacologically targeted a mitochondrial potassium channel, namely mitochondrial Kv1.3, and investigated the role of sphingolipids and mutated Kirsten Rat Sarcoma Virus (KRAS) in Kv1.3-mediated cell death. We demonstrate that inhibition of Kv1.3 using the Kv1.3-inhibitor PAPTP results in an increase of sphingosine and superoxide in membranes and/or membranes associated with mitochondria, which is enhanced by KRAS mutation. The effect of PAPTP on sphingosine and mitochondrial superoxide formation as well as cell death is prevented by sh-RNA-mediated downregulation of Kv1.3. Induction of sphingosine in human pancreas cancer cells by PAPTP is mediated by activation of sphingosine-1-phosphate phosphatase and prevented by an inhibitor of sphingosine-1-phosphate phosphatase. A rapid depolarization of isolated mitochondria is triggered by binding of sphingosine to cardiolipin, which is neutralized by addition of exogenous cardiolipin. The significance of these findings is indicated by treatment of mutated KRAS-harboring metastasized pancreas cancer with PAPTP in combination with ABC294640, a blocker of sphingosine kinases. This treatment results in increased formation of sphingosine and death of pancreas cancer cells in vitro and, most importantly, prolongs in vivo survival of mice challenged with metastatic pancreas cancer.Key messagesPancreatic ductal adenocarcinoma (PDAC) is a common tumor with poor prognosis.The mitochondrial Kv1.3 ion channel blocker induced mitochondrial sphingosine.Sphingosine binds to cardiolipin thereby mediating mitochondrial depolarization.Sphingosine is formed by a PAPTP-mediated activation of S1P-Phosphatase.Inhibition of sphingosine-consumption amplifies PAPTP effects on PDAC in vivo.

Multimodal Approaches to Patient Selection for Pancreas Cancer Surgery.

With an overall 5-year survival rate of 12%, pancreas ductal adenocarcinoma (PDAC) is an aggressive cancer that claims more than 50,000 patient lives each year in the United States alone. Even those few patients who undergo curative-intent resection with favorable pathology reports are likely to experience recurrence within the first two years after surgery and ultimately die from their cancer. We hypothesize that risk factors for these early recurrences can be identified with thorough preoperative staging, thus enabling proper patient selection for surgical resection and avoiding unnecessary harm. Herein, we review evidence supporting multidisciplinary and multimodality staging, comprehensive neoadjuvant treatment strategies, and optimal patient selection for curative-intent surgical resections. We further review data generated from our standardized approach at the Mayo Clinic and extrapolate to inform potential future investigations.

LINC00909 up-regulates pluripotency factors and promotes cancer stemness and metastasis in pancreatic ductal adenocarcinoma by targeting SMAD4

BackgroundPancreatic cancer stem cells are crucial for tumorigenesis and cancer metastasis. Presently, long non-coding RNAs were found to be associated with Pancreatic Ductal Adenocarcinoma stemness characteristics but the underlying mechanism is largely known. Here, we aim to explore the function of LINC00909 in regulating pancreatic cancer stemness and cancer metastasis.MethodsThe expression level and clinical characteristics of LINC00909 were verified in 80-paired normal pancreas and Pancreatic Ductal Adenocarcinoma tissues from Guangdong Provincial People’s Hospital cohort by in situ hybridization. RNA sequencing of PANC-1 cells with empty vector or vector encoding LINC00909 was experimented for subsequent bioinformatics analysis. The effect of LINC00909 in cancer stemness and metastasis was examined by in vitro and in vivo experiments. The interaction between LINC00909 with SMAD4 and the pluripotency factors were studied.ResultsLINC00909 was generally upregulated in pancreatic cancer tissues and was associated with inferior clinicopathologic features and outcome. Over-expression of LINC00909 enhanced the expression of pluripotency factors and cancer stem cells phenotype, while knock-down of LINC00909 decreased the expression of pluripotency factors and cancer stem cells phenotype. Moreover, LINC00909 inversely regulated SMAD4 expression, knock-down of SMAD4 rescued the effect of LINC00909-deletion inhibition on pluripotency factors and cancer stem cells phenotype. These indicated the effect of LINC00909 on pluripotency factors and CSC phenotype was dependent on SMAD4 and MAPK/JNK signaling pathway, another downstream pathway of SMAD4 was also activated by LINC00909. Specifically, LINC00909 was localized in the cytoplasm in pancreatic cancer cells and decreased the stability the SMAD4 mRNA. Finally, we found over-expression of LINC00909 not only accelerated tumor growth in subcutaneous mice models, but also facilitated tumorigenicity and spleen metastasis in orthotopic mice models.ConclusionWe demonstrate LINC00909 inhibits SMAD4 expression at the post-transcriptional level, which up-regulates the expression of pluripotency factors and activates the MAPK/JNK signaling pathway, leading to enrichment of cancer stem cells and cancer metastasis in pancreatic cancer.

A commentary on 'Survival benefit and impact of adjuvant chemotherapy following systemic neoadjuvant chemotherapy in patients with resected pancreas ductal adenocarcinoma: a retrospective cohort study'.

A commentary on 'Survival benefit and impact of adjuvant chemotherapy following systemic neoadjuvant chemotherapy in patients with resected pancreas ductal adenocarcinoma: a retrospective cohort study'.

Exosomes define a local and systemic communication network in healthy pancreas and pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC), a lethal disease, requires a grasp of its biology for effective therapies. Exosomes, implicated in cancer, are poorly understood in living systems. Here we use the genetically engineered mouse model (ExoBow) to map the spatiotemporal distribution of exosomes from healthy and PDAC pancreas in vivo to determine their biological significance. We show that, within the PDAC microenvironment, cancer cells establish preferential communication routes through exosomes with cancer associated fibroblasts and endothelial cells. The latter being a conserved event in the healthy pancreas. Inhibiting exosomes secretion in both scenarios enhances angiogenesis, underscoring their contribution to vascularization and to cancer. Inter-organ communication is significantly increased in PDAC with specific organs as most frequent targets of exosomes communication occurring in health with the thymus, bone-marrow, brain, and intestines, and in PDAC with the kidneys, lungs and thymus. In sum, we find that exosomes mediate an organized intra- and inter- pancreas communication network with modulatory effects in vivo.

Abstract C104: Dual primary pancreas cancers – Related or independent lesions?

Abstract Background: Not infrequently, an apparent second pancreas ductal adenocarcinoma (PDAC) is identified either synchronously or metachronously. To date, it remains unclear whether these individual PDACs represent intrapancreatic metastases or a new primary PDAC. Here, we sought to understand the clinicogenomic features of this patient population to provide insights on the underlying biology and management implications. Methods: Memorial Sloan Kettering Cancer Center (MSK) institutional databases were searched for patients with two PDAC diagnoses and at least one pancreatic resection or patients who had undergone completion/total pancreatectomy and then manually curated. Detailed demographic and clinical information were abstracted from the medical record. Metachronous patients excluded if previous surgical margin positive for invasive or pre-invasive carcinoma. All patients were either consented to MSK IMPACT for somatic and germline sequencing (N=16), were approved for de-identified genomic analyses by IRB (N=3), or were excluded from genomic analysis (N=2). KRAS wild-type (WT) tumors were interrogated for targetable fusions with Archer FusionPlex solid tumor panel. Results: N=21 patients (pts) identified, N=6 synchronous, N=15 metachronous. Mean age at diagnosis of first PDAC (PDAC1): 67.1y (51.2–79.1y). PDAC risk factors: 52% (10/19) smoking history, 15% (2/13) with first degree relative with PDAC, 85% (11/13) with first degree relative with any malignancy, and 40% (8/20) with history of premalignant pancreas lesion. N=2 pts with pathogenic germline mutation in ATM. By morphology, 80% (4/5) of synchronous and 65% (11/17) of asynchronous lesions indistinguishable. Two lesions, both metachronous, demonstrated divergent histology while remaining cases demonstrated focal differences. Genomically, 40% (10/25) samples with mKRAS G12V, G12R (16%), G12D (12%), Q61H (8%), G12C (4%); 20% KRAS WT. Of available paired tumor samples, 71% (5/7) with identical KRAS alleles and additional driver mutations. N= 1 pt with different KRAS alleles also had divergent TP53 alleles and CDKN2A/B loss occur in metachronous lesions 14 m apart. N=1 pt with KRAS WT tumor had an actionable fusion involving FGFR2. For metachronous lesions, median interval PDAC1 to PDAC2: 5.1 y (1.1 – 15.2 y). At median follow-up of 7.2 y (0.2 – 15.4 y) from PDAC1, 90% (19/21) have undergone completion/total pancreatectomy and N=16 (76%) alive with 5-year survival rate of 93% (14/15). Conclusions: The clinical, pathologic, and genomic data strongly suggest that two PDAC, independent of disease interval, most often represent the same phylogenetic entity. KRAS allele variant adjudication was the single most important discriminator and was in concordance with other driver oncogenes. Pathogenic germline variants were rare and limited to gATM; notably no gBRCA/PALB2. Acknowledging the highly selected nature of this cohort, solitary intrapancreatic metastases demonstrate a more favorable biology and these patients may benefit from personalized management approaches beyond traditional paradigms. Citation Format: Joshua D. Schoenfeld, Hulya Sahan-Ozkan, Nadeem Bilani, Michael I. D'Angelica, William R. Jarnagin, Jeffrey Drebin, Diane Reidy-Lagunes, Alice C. Wei, Sree B. Chalasani, Anna M. Varghese, Fiyinfolu Balogun, Wungki Park, Kenneth H. Yu, Olca Basturk, Eileen M. O'Reilly. Dual primary pancreas cancers – Related or independent lesions? [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C104.

Abstract B009: Identifying of a novel diagnostic markers for pancreatic neuroendocrine tumors by proteomics with patient blood

Abstract Neuroendocrine tumors are tumors originating from endocrine cells in various organs, and present very heterogeneous characteristics, and the incidence rate is gradually increasing. Among them, neuroendocrine tumors originating from pancreas are divided into functional tumors and non-functional tumors according to the presence hormone secretion function. Since non-functional tumors are often asymptomatic, early diagnosis is not easy, and differential diagnosis from pancreas ductal adenocarcinoma (PDAC) is difficult, making it difficult to determine the direction of treatment. Therefore, we aimed to find protein biomarkers for the diagnosis and differential diagnosis of pancreatic neuroendocrine tumors (PNET) through proteomic analysis of human blood. First, a total of 60 human plasma samples were obtained from 17 PNETs, 23 PDACs, and 20 Healthy donors (HD), and liquid chromatography-mass spectrometry (LC-MS) proteomics analysis was performed. For 60 cases of raw data obtained through LC-MS analysis, identification and label-free quantification were performed through the Human swissprot protein sequence database. Through pre-processing and normalization, an average of 549 protein lists for each sample were obtained. And through quantitative evaluation, the proteomes that were increased or decreased for each disease were analyzed and classified, and ACTR3, CD163, and LECT2, which were increased in PNET, were selected as diagnostic biomarker candidates. The diagnostic AUC for distinguishing PNET from HD was 0.706 for ACTR3, 0.971 for CD163, and 0.541 for LECT2. The diagnostic AUC to distinguish PNET from PDAC was 0.821 for ACTR3, 0.870 for CD163, and 0.783 for LECT2. We selected three candidates, ACTR3, CD163, and LECT2, as blood biomarkers for the accurate diagnosis of PNET. And through the combination of markers, it is expected that the sensitivity and accuracy of the diagnosis can be further increased. In the future, we will study the function as a marker that can simultaneously predict diagnosis and treatment response by identifying the molecular biological mechanism for the generation and progression of PNET through these three markers. Citation Format: Eun-Young Koh, Ji Hye Jeong, Hee-Sung Ahn, Kyunggon Kim, Eunsung Jun. Identifying of a novel diagnostic markers for pancreatic neuroendocrine tumors by proteomics with patient blood [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr B009.

Hydrogen Peroxide Mediates Pharmacological Ascorbate Induced Radio-Sensitization of Pancreatic Cancer Cells by Enhancing G2-accumulation and Reducing Cyclin B1 Protein Levels.

Pharmacological ascorbate (P-AscH-, high dose, intravenous vitamin C) preferentially sensitizes human pancreas ductal adenocarcinoma (PDAC) cells to radiation-induced toxicity compared to non-tumorigenic epithelial cells. Radiation-induced G2-checkpoint activation contributes to the resistance of cancer cells to DNA damage induced toxicity. We hypothesized that P-AscH- induced radio-sensitization of PDAC cells is mediated by perturbations in the radiation induced activation of the G2-checkpoint pathway. Both non-tumorigenic pancreatic ductal epithelial and PDAC cells display decreased clonogenic survival and increased doubling times after radiation treatment. In contrast, the addition of P-AscH- to radiation increases clonogenic survival and decreases the doubling time of non-tumorigenic epithelial cells but decreasing clonogenic survival and increasing the doubling time of PDAC cells. Results from the mitotic index and propidium iodide assays showed that while the P-AscH- treatments did not affect radiation-induced G2-checkpoint activation, it enhanced G2-accumulation. The addition of catalase reverses the increases in G2-accumulation, indicating a peroxide-mediated mechanism. In addition, P-AscH- treatment of PDAC cells suppresses radiation-induced accumulation of cyclin B1 protein levels. Both translational and post-translational pathways appear to regulate cyclin B1 protein levels after the combination treatment of PDAC cells with P-AscH- and radiation. The protein changes seen are reversed by the addition of catalase suggesting that hydrogen peroxide mediates P-AscH- induced radiation sensitization of PDAC cells by enhancing G2-accumulation and reducing cyclin B1 protein levels.

Survival benefit and impact of adjuvant chemotherapy following systemic neoadjuvant chemotherapy in patients with resected pancreas ductal adenocarcinoma: a retrospective cohort study.

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

Bounding box-based 3D AI model for user-guided volumetric segmentation of pancreatic ductal adenocarcinoma on standard-of-care CTs

ObjectivesTo develop a bounding-box-based 3D convolutional neural network (CNN) for user-guided volumetric pancreas ductal adenocarcinoma (PDA) segmentation. MethodsReference 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. ResultsTotal 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). ConclusionA 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. Clinical relevanceAI-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.

Changing patterns of care for pancreas cancer in Victoria: the 2022 Pancreas Tumour Summit.

The Victorian Government convened the second Pancreas Cancer Summit in 2021 to identify unwarranted variation in care 2016-2019, and to assess trends compared with the first Summit 2017 (reporting 2011-2015). State-wide administrative data were assessed at population level in alignment with optimal care pathways across all stages of the cancer care continuum. Data linkage performed by Centre for Victorian Data Linkage combined data from Victorian Cancer Registry with other administrative data sets including Victorian Admitted Episodes Dataset, Victorian Radiotherapy Minimum Data Set, Victorian Emergency Minimum Dataset and Victorian Death Index. A Cancer Service Performance Indicator audit was carried out providing an in-depth analysis of identified areas of interest. Of 3138 Victorians diagnosed with pancreas ductal adenocarcinoma 2016-2019, 63% were metastatic at diagnosis. One-year survival increased between time periods, from 29.7% overall 2011-2015 (59.1% for non-metastatic, and 15.1% metastatic) to 32.5% overall 2016-2019 (P < 0.001), 61.2% non-metastatic (P = 0.008), 15.7% metastatic (P = NS). A higher proportion of non-metastatic patients progressed to surgery (35% vs. 31%, P = 0.020), and more received neoadjuvant therapy (16% vs. 4%, P < 0.001). Postoperative mortality following pancreatectomy at 30 and 90 days remained low at 2%. Utilization of 5FU-based chemotherapy regimens increased between 2016 and 2020. Multidisciplinary Meeting (MDM) presentation was still below the 85% target (74%) as was supportive care screening (39%, target 80%). Surgical outcomes remain world-class and there has been an appropriate shift in chemotherapy administration towards neoadjuvant timing with increasing use of 5FU-based regimens. MDM presentation rates, supportive care and overall care coordination remain areas of deficiency.

Simultaneous targeting of mitochondrial Kv1.3 and lysosomal acid sphingomyelinase amplifies killing of pancreatic ductal adenocarcinoma cells in vitro and in vivo

Pancreas ductal adenocarcinoma (PDAC) remains a malignant tumor with very poor prognosis and low 5-year overall survival. Here, we aimed to simultaneously target mitochondria and lysosomes as a new treatment paradigm of malignant pancreas cancer in vitro and in vivo. We demonstrate that the clinically used sphingosine analog FTY-720 together with PAPTP, an inhibitor of mitochondrial Kv1.3, induce death of pancreas cancer cells in vitro and in vivo. The combination of both drugs results in a marked inhibition of the acid sphingomyelinase and accumulation of cellular sphingomyelin in vitro and in vivo in orthotopic and flank pancreas cancers. Mechanistically, PAPTP and FTY-720 cause a disruption of both mitochondria and lysosomes, an alteration of mitochondrial bioenergetics and accumulation of cytoplasmic Ca2+, events that collectively mediate cell death. Our findings point to an unexpected cross-talk between lysosomes and mitochondria mediated by sphingolipid metabolism. We show that the combination of PAPTP and FTY-720 induces massive death of pancreas cancer cells, thereby leading to a substantially delayed and reduced PDAC growth in vivo.Key messagesFTY-720 inhibits acid sphingomyelinase in pancreas cancer cells (PDAC).FTY-720 induces sphingomyelin accumulation and lysosomal dysfunction.The mitochondrial Kv1.3 inhibitor PAPTP disrupts mitochondrial functions.PAPTP and FTY-720 synergistically kill PDAC in vitro.The combination of FTY-720 and PAPTP greatly delays PDAC growth in vivo.

Effect of resection margin status on recurrence pattern and survival in distal pancreatectomy for left-sided pancreatic ductal adenocarcinoma.

675 Background: The association of resection margin status with recurrence and survival after pancreatectomy for pancreas ductal adenocarcinoma (PDAC) remains controversial. The aim of this study was to identify the effect of R1 resection on recurrence pattern and survival after distal pancreatectomy for left-sided PDAC. Methods: Patients who underwent distal pancreatectomy for PDAC at two high-volume institutions between January 2010 and December 2017 were retrospectively reviewed. Perioperative characteristics, pathological outcomes, recurrence pattern and survival data were collected to compare R0 resection and R1 resection. Results: Among 558 patients who underwent distal pancreatectomy for PDAC, 158 patients (28.3%) showed R1 resection margin. R1 patients were associated with large tumor size (3.3 cm vs. 3.7 cm, p= 0.006) and lower number of positive lymph nodes (1.3 vs. 2.0, p= 0.001). Median overall survival (37.3 months vs. 20.1 months, p&lt; 0.001) and recurrence-free survival (14.6 months vs. 6.9 months, p&lt; 0.001) significantly differed between the R0 and R1 groups. Disease recurrence patterns were not statistically different between the two groups ( p = 0.182). Among the recurrence patterns, peritoneal carcinomatosis had the shortest recurrence-free survival (5.6 months, p &lt; 0.05) and overall survival (13.6 months, p &lt; 0.05) compared with all other recurrence patterns. Conclusions: R1 resection margin after distal pancreatectomy was associated with poor survival and early recurrence. There is no significant difference in recurrence pattern between R0 and R1. Among the recurrence patterns, peritoneal carcinomatosis showed the worst prognosis.

Prognostic significance of ımmunhistochemical axl expression in pancreas ductal adenocarcinomas.

Pancreas Ductal Adenocarcinomas (PDACs) are among the leading causes of cancer-related death. Tyrosine kinase receptors (TKRs) are responsible for cell plasticity, chemoresistance, immunosuppression and metastasis potential. Axl is a receptor of the TKR family, and it has come to the fore in cancer treatment in the last decade. This study aimed to investigate the relationship of immunohistochemical Axl expression with histological features and its prognostic importance in PDACs. Fifty-three patients who were operated on for PDAC between 2006-2017 were evaluated retrospectively. Features of tumors; size, lymphovascular invasion (LVI), perineural invasion (PNI), resection margin (RM), lymph node metastasis (LNM), differentiation, tumor-infiltrating lymphocyte, stage and overall survival were recorded. Immunohistochemically, membranous and or cytoplasmic staining was considered positive for Axl. Statistically, Pearson Chi-Square, Cox regression and Kaplan Mayer tests were used in the SPSS 21.0 program. Axl was positive in 28 patients (52.8%). Axl positivity was found to be associated with the presence of LVI (P = 0.009) and LNM (P = 0.002) and was an independent prognostic factor in short survival (P = 0.006). It was found that increased expression of Axl, which is known to increase EMT-mediated metastasis in carcinogenesis, may be an indicator of local spread and poor prognosis in PDAC patients. In this respect, it can be promising as a targeted molecule in PDAC patient's individualized treatments.

Protection of gemcitabine-loaded polylactic-co-glycolic acid microspheres combined with CAR-T treatment against pancreatic ductal adenocarcinoma

Pancreas ductal adenocarcinoma has a highly aggressive phenotype and is one of the most lethal malignancies in the world. Although the use of FOLFIRINOX and abraxane plus gemcitabine chemotherapy regimens have improved patient care, their recurrence rates and long-term survival are still not promising. In this study, PLGA/gemcitabine microspheres were prepared by emulsification–solvent volatilization using gemcitabine as the drug model, and scanning electron microsopy showed that the microspheres had a smooth surface, small size, and large specific surface area. The PLGA microspheres have a high loading capacity and are capable of long-term release. The combination of PLGA/gemcitabine microspheres with chimeric antigen receptor T-cell treatment can regulate MUC1 expression in epithelial cells and reduce the aggressiveness of tumors; thus, it is expected to be applied in the treatment of pancreatic ductal adenocarcinoma.

Prognostic value of tumor-associated N1/N2 neutrophil plasticity in patients following radical resection of pancreas ductal adenocarcinoma

BackgroundAs an integral part of the tumor microenvironment (TME), tumor-associated neutrophils play a crucial role in tumor development. The objective of this study was to investigate the plasticity of tumor-associated...

Effect of resection margin status on recurrence pattern and survival in distal pancreatectomy for left-sided pancreatic ductal adenocarcinoma.

The association of resection margin status with recurrence and survival after pancreatectomy for pancreas ductal adenocarcinoma (PDAC) remains controversial. The aim of this study was to identify the effect of R1 resection on recurrence pattern and survival after distal pancreatectomy for left-sided PDAC. Patients who underwent distal pancreatectomy for PDAC at two high-volume institutions between January 2010 and December 2017 were retrospectively reviewed. Perioperative characteristics, pathological outcomes, recurrence pattern, and survival data were collected to compare R0 resection and R1 resection. Among 558 patients who underwent distal pancreatectomy for PDAC, 158 patients (28.3%) showed R1 resection margin. R1 patients were associated with large tumor size (3.3cm vs. 3.7 cm, p=.006) and lower number of positive lymph nodes (1.3 vs. 2.0, p=.001). Median overall survival (37.3months vs. 20.1 months, p < .001) and recurrence-free survival (14.6months vs. 6.9 months, p < .001) significantly differed between the R0 and R1 groups. Disease recurrence patterns were not statistically different between the two groups (p=.182). Among the recurrence patterns, peritoneal carcinomatosis had the shortest recurrence-free survival (5.6months, p < .05) and overall survival (13.6months, p < .05) compared with all other recurrence patterns. R1 resection margin after distal pancreatectomy was associated with poor survival and early recurrence. There is no significant difference in recurrence pattern between R0 and R1. Among the recurrence patterns, peritoneal carcinomatosis showed the worst prognosis.