Pancreatic Carcinoma Research Articles

Gemcitabine/nab-paclitaxel in first line treatment of advanced pancreatic cancer - head-to-head comparison with the mFOLFIRINOX regimen.

Metastatic pancreatic ductal carcinoma (mPDAC) is one of the most lethal malignancies. The European Society for Medical Oncology (ESMO) guidelines recommend a gemcitabine doublet + nab-paclitaxel (Gem/Nab-P) or a modified FOLFIRINOX regimen (mFOLFIRINOX) as options for systemic chemotherapy. Gemcitabine monotherapy is an option for patients in a worse performance status (PS). Indirect comparisons of pivotal trials with Gem/Nab-P and mFOLFIRINOX vs. gemcitabine monotherapy (PRODIGE-4 and MPACT) indicated longer overall survival (OS) in patients treated with mFOLFIRINOX. However, it should be taken into account that the MPACT study with Gem/Nab-P included patients with an overall worse performance status. A direct comparison of these chemotherapy regimens was lacking. Indirect comparisons from real practice show their comparable effectiveness in terms of OS, progression-free survival and overall response rate. The safety profile is consistently different. The recently published phase II/III GENERATE trial, which directly compared Gem/Nab-P and mFOLFIRINOX in treatment-naïve mPDAC patients, demonstrated significantly longer OS in Gem/Nab-P-treated patients exceeding 17 months with a lower incidence of non-hematologic toxicity. The results sparked a lively discussion at the ESMO 2023 Congress. The comparison of Gem/Nab-P and mFOLFIRINOX was also addressed by prof. Prager in his presentation at the PragueONCO 2024 conference. Prager, who highlighted comparable efficacy of both regimens and better safety of Gem/Nab-P and demonstrated the benefit of Gem/Nab-P also in patients older than 70 years and those with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2. It should also be taken into account that the choice of first line treatment determines the therapeutic options in the 2nd line. If the Gem/Nab-P regimen is used in the first line, pegylated liposomal irinotecan (nal-IRI) in combination with 5-fluorouracil and leucovorin (5-FU/LV) can be used in the second line. This regimen demonstrated prolongation of OS compared to 5-FU/LV in phase III study NAPOLI-1. In patients pretreated with the mFOLFIRINOX regimen, gemcitabine monotherapy or Gem/Nab-P can be used in the second line. Early examination of molecular predictive parameters will enable the identification of cases for which appropriate targeted therapy or immunotherapy is available.

Cytokine-armed vaccinia virus promotes cytotoxicity toward pancreatic carcinoma cells via activation of human intermediary CD56dimCD16dim natural killer cells.

Pancreatic ductal adenocarcinoma (PDAC) remains a particularly aggressive disease with few effective treatments. The PDAC tumor immune microenvironment (TIME) is known to be immune suppressive. Oncolytic viruses can increase tumor immunogenicity via immunogenic cell death (ICD). We focused on tumor-selective (vvDD) and cytokine-armed Western-reserve vaccinia viruses (vvDD-IL2 and vvDD-IL15) and infected carcinoma cell lines as well as patient-derived primary PDAC cells. In co-culture experiments, we investigated the cytotoxic response and the activation of human natural killer (NK). Infection and virus replication were assessed by measuring virus encoded YFP. We then analyzed intracellular signaling processes and oncolysis via in-depth proteomic analysis, immunoblotting and TUNEL assay. Following the co-culture of mock or virus infected carcinoma cell lines with allogenic PBMCs or NK cell lines, CD56+ NK cells were analyzed with respect to their activation, cytotoxicity and effector function. Both, dose- and time-dependent release of danger signals following infection weremeasured. Viruses effectively entered PDAC cells, emitted YFP signals and resulted in concomitant oncolysis. The proteome showed reprogramming of normally active core signaling pathways in PDAC (e.g., MAPK-ERK signaling). Danger-associated molecular patterns were released upon infection and stimulated co-cultured NK cells for enhanced effector cytotoxicity. NK cell subtyping revealed enhanced numbers and activation of a rare CD56dimCD16dim population. Tumor cell killing was primarily triggered via Fas ligands rather than granule release, resulting in marked apoptosis. Overall, the cytokine-armed vaccinia viruses induced NK cell activation and enhanced cytotoxicity toward human PDAC cells in vitro. We could show that cytokine-armed virus targets the carcinoma cells and thus hasgreat potential to modulate the TIME in PDAC.

Molecular and Clinical Features of Pancreatic Acinar Cell Carcinoma: A Single-Institution Case Series

Objectives: Acinar cell carcinoma (ACC) accounts for about 1% of pancreatic cancers. The molecular and clinical features of ACC are less characterized than those of pancreatic ductal adenocarcinoma. Methods: We retrospectively evaluated the clinical and molecular features of ACC patients who underwent germline and/or somatic molecular testing at The University of Texas MD Anderson Cancer Center from 2008 to 2022 and two cases from 2023–2024 who underwent RNA and TME analysis by Boston Gene. Patient information was extracted from our institutional database with the approval of the Institutional Review Board. Results: We identified 16 patients with available molecular testing results. Fourteen patients had metastatic disease, one had borderline resectable disease, and one had localized resectable disease at diagnosis. Fifteen patients were wild type for KRAS (one patient had unknown KRAS status). Somatic/germline mutations of DNA damage repair genes (BRCA1/2, PALB2, and ATM) were present in 5 of 12 patients tested for these genes. One patient was found to have RET fusion and responded favorably to selpercatinib for over 42 months. The median overall survival (OS) was 24 months for patients with metastatic disease. One of the additional two cases who underwent BostonGene testing was found to have NTRK1 fusion. RNA and TME analysis by Boston Gene of the two cases reported immune desert features and relatively lower RNA levels of CEACAM5, CD47, CD74, and MMP1 and higher RNA levels of CDH6 compared with PDAC.

The Impact of Combined Chemotherapy and Intra-Tumoural Injection of Phosphorus-32 Microparticles on Vascularity in Locally Advanced Pancreatic Carcinoma.

Poor intra-tumoural vascularity contributes to a lack of response to chemotherapy in pancreatic cancers. Preliminary data suggest that the addition of endoscopic ultrasound (EUS)-guided intra-tumoural injection of phosphorus-32 (32P) microparticles to standard chemotherapy is potentially beneficial in locally advanced pancreatic cancer (LAPC). We aimed to assess changes in pancreatic tumour vascularity following 32P implantation, using contrast-enhanced EUS (CE-EUS). This was a prospective single-centre trial from January 2022 to 2024 of patients with unresectable, non-metastatic LAPC undergoing standard FOLFIRINOX chemotherapy and 32P implantation. We performed CE-EUS pre-implantation after two chemotherapy cycles and 4 and 12 weeks after implantation. Time-intensity curves were analysed for 90 s after IV contrast bolus to ascertain peak intensity and intensity gain. A total of 20 patients underwent 32P implantation, with 15 completing 12-week follow-up. The technical success of 32P implantation was 100%. The median primary tumour size reduced from 32 mm (IQR 27.5-38.75) pre-implantation to 24 mm (IQR 16-26) 12 weeks post-implantation (p < 0.001). Five patients (25%) had tumour downstaging, and four underwent resections. The baseline (pre-implantation, post-chemotherapy) median intensity gain of contrast enhancement within the tumour was 32.15 (IQR 18.08-54.35). This increased to 46.85 (IQR 35.05-76.6; p = 0.007) and 66.3 (IQR 54.7-76.3; p = 0.001) at 4 weeks and 12 weeks post-implantation, respectively. Over a median follow-up of 11.2 months (IQR 7.8-12.8), 15/20 (75%) of patients remained alive, with 3/20 (15%) demonstrating local disease progression. Overall survival was not significantly different between patients with or without an increased intensity of 10 a.u. or more at 12 weeks post-implantation. This is the first clinical study to demonstrate treatment-induced increased vascularity within pancreatic primary tumours, which followed 32P implantation and FOLFIRINOX chemotherapy. Larger comparative trials are warranted.

THE ROLE OF CA 19.9 IN PREDICTING THE OPERABILITY OF CARCINOMA PANCREAS

Objectives: Adenocarcinoma of the pancreas remains a relatively incurable disease despite advances in surgical care. Approximately 25% of patients will be found to have unresectable tumors during surgery even though computed tomography (CT) has demonstrated that they are resectable. There is a controversy regarding the use of cancer antigen 19-9 (CA 19-9) to decide the resectability of pancreatic adenocarcinoma [1]. Our aim is to study the use of CA 19-9 in determining the operability of carcinoma pancreas [2]. Methods: This was a prospective study which included 69 patients and the study period was from December 2021 to December 2022. Data were collected from all patients with carcinoma of the pancreas who underwent surgical management. CA 19-9 levels were measured and recorded [3]. During surgery, the operative findings on resectability were documented and tabulated against corresponding CA 19-9 levels and contrast-enhanced CT (CECT) findings. Results: Of the 69 patients who were operated on, 38 patients had resectable tumors and underwent the Whipples procedure and 31 of them had non-resectable tumors and had to undergo palliative bypass procedures. Among the 31 patients whose tumors were non-resectable, only four were diagnosed non-resectable preoperatively with CECT, and the other 27 were found to be non-resectable only during surgery. That shows the relevance of this study. Of the 31 non-resectable cases, 14 (45.2%) patients had elevated CA 19-9 values of more than 501, and the rest 17 (54.8%) patients had low CA 19-9 values. Among the 38 resectable cases, 12 patients (31.6%) had elevated CA 19-9 more than 501, and 26 patients (68.4%) had low values. In conclusion, among non-resectable cases, 45.2% had raised CA 19-9, and among operable cases, 31.6% showed raised CA 19-9. Hence, CA 19-9 seems to be an insignificant predictor of tumor resectability [4]. Conclusion: It was found that the need for a pre-operative predictor for resectability of carcinoma pancreas is relevant while considering mortality and morbidity in operating carcinoma pancreas cases. On evaluating CA 19-9 as a pre-operative predictor, we found that CA 19-9 has no significant role as an indicator of local advancement or metastasis. Hence, we cannot consider CA 19-9 as a predictor of resectability of carcinoma pancreas preoperatively [5].

POLQ immunostaining behaves as a prognostic factor for pancreatic carcinoma.

DNA polymerase theta (POLQ) is a translesion synthesis polymerase essential for the repair of double strand breaks by the error-prone TMEJ (Theta Mediated End Joining) pathway. Although POLQ participates in maintaining genome stability, several studies have shown that its overexpression correlates with cancer progression and poor prognosis. Due to the fact that its role as a biomarker in pancreatic cancer remains unexplored, we aimed to study the usefulness of POLQ H-score as a prognostic factor in a pancreatic cancer patient cohort. We evaluated POLQ gene expression using a web-based tool to deliver gene expression profiling and interactive analyses based on TCGA and GTEx (GEPIA) and we examined the POLQ immunostaining in 152 biliopancreatic cancer surgical specimens using tissue microarrays. Association with survival was evaluated by Kaplan Meier curves and uni-multivariate Cox regression. GEPIA analysis showed statistical differences according to POLQ mRNA levels in Disease Free Survival (DFS) (log rank 0.023, HR 2.8, p=0.029) and Overall Survival (OS) (log rank 0.011, HR 3.1, p=0.016). For immunohistochemistry (IHC) evaluation, POLQ H-score was calculated, and showed statistical differences for OS in Kaplan Meier curves (log rank 0.001) and uni-multivariate analysis (HR 2.27; 95% CI 1.24-4.15, p=0.008). Our results indicate that POLQ is an independent prognostic factor in pancreatic cancer when analyzed by immunostaining, which is in agreement with the results shown by the POLQ gene expression analysis (GEPIA).

7340 Elucidating the Role of Steroid Hormone Receptors in Anaplastic Thyroid Carcinoma and Pancreatic Ductal Carcinoma Models

Abstract Disclosure: O.M. Stockert: None. C.A. Lange: None. Steroid hormones play important roles in modulating transcription mechanisms in a variety of cancers, including breast cancer, prostate cancer, and ovarian cancer. These interactions are highly context-dependent and regulated by diverse ligands, cofactors, and dynamic post-translational modifications that occur in response to the activation of stress-sensing and oncogenic signaling pathways. Numerous other cancers are associated with elevated steroid hormones, steroid hormone receptors, or both, but have not been studied to explore the possibility of leveraging steroid or steroid receptor (SR)-modulated transcriptional regulation to combat cancerous growth. Two of these cancers are pancreatic ductal adenocarcinoma (PDAC) and anaplastic thyroid carcinoma (ATC). PDAC is an aggressive cancer with a very poor 5-year survival of 8-11%. It is also rapidly growing in incidence and has been shown to be associated with other increasing health conditions, including diabetes and obesity. PDAC is associated with metabolic reprogramming and elevated Progesterone Receptor (PR), Glucocorticoid Receptor (GR), and Mineralocorticoid Receptor (MR) expression. ATC is another aggressive cancer with less than 10% 6-month survival from diagnosis. Like PDAC, ATC has a rapidly increasing incidence and is associated with obesity and high-fat diets. ATC is also associated with elevated cholesterol biosynthesis and elevated GR expression. Herein, we probed public data sets and screened a panel of PDAC and ATC models to demonstrate the expression of mixed SRs. In this study, we take an initial exploration of the hypothesis that related SRs (such as PR, GR, and/or MR) contribute to PDAC and ATC progression and that post-translational modifications, ligand binding, and/or selected cofactors modulate SR actions in the context of activated signaling pathways associated with these aggressive cancers. This study gives us a preliminary understanding of the potential role of steroid hormones and their receptors in the aggressive biology of two deadly and increasingly prevalent endocrine cancers in aging and obese populations. Presentation: 6/3/2024

Clinical Practice Guideline: Recommendations for the Perioperative Management of Pancreatic and Colorectal Cancer Patients.

Colorectal and pancreatic carcinoma are the most common cancers of the gastrointestinal tract. Their surgical treatment carries a high morbidity: Complications arise in 25% to 30% of cases, often prolonging recovery times and delaying the initiation of adjuvant therapy, leading, in turn, to worse oncological outcomes. The goal of multimodal perioperative management (mPOM) is to lower the postoperative complication rate through a combination of perioperative measures. This guideline on the perioperative management of gastrointestinal tumors (POMGAT) meets all requirements for an S3 guideline as specified by the Association of the Scientific Medical Societies in Germany (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften, AWMF). These include a systematic literature search, quality assessment of the included publications, an evaluation of the reliability of the evidence according to the GRADE approach, and a structured consensus process. Meta-analyses have shown that mPOM lowers the complication rates of both pancreatic and colorectal resections (RD 0.96 with 95% confidence interval [0.92; 0.99] and RR 0.66 [0.54; 0.80], respectively). This shortens the hospital stay after pancreatic resections by a median of 2.33 days [-2.98; -1.69] and after colorectal resections by a median of 2.59 days [-3.22; -1.97]. Adherence to the POMGAT-S3 guideline for pancreatic and colorectal cancer surgery is associated with improved recovery, which can lead to a faster return to intended oncological treatment (RIOT) and thus to better long-term outcomes. These recommendations are not restricted to gastrointestinal cancer surgery; they can also be applied to visceral surgery for benign conditions, as well as to gynecological and urological operations.

SARIFA-anew multi-entity biomarker

A stroma a‑reactive invasion front area (SARIFA) is anew prognostic biomarker in carcinomas. Essentially, SARIFA describes the occurrence of direct contact between at least five tumor cells and adipocytes. This phenomenon is extremely easy and quick to identify, shows an extremely low interobserver variability, and does not require any additional staining as it can be identified on standard HE sections. The prognostic efficiency has now been demonstrated in gastric, colorectal, pancreatic, and prostate carcinoma.

Is pancreatic adenosquamous carcinoma (PASC) a surgical disease? A large healthcare system review

IntroductionPancreatic cancer represents an increasing cause of cancer-related deaths. Pancreatic adenosquamous carcinoma (PASC) is a rare subtype of pancreas cancer. Optimal treatment is not well-defined. This review aims to provide a detailed analysis of the natural history, management, and outcomes of the patients with PASC within a single large healthcare system. Materials and methodsA large healthcare database was used to retrospectively identify all patients with histological diagnosis of PASC from 2010 to 2020. The cohort was evaluated as a whole and according to the following management modalities: operative, non-metastatic non-operative, and patients with metastatic disease. Abstracted data included patient characteristics, oncologic characteristics at presentation, and details of surgical and non-surgical treatment. ResultsIn total, 60 patients with PASC were identified. All patients had confirmed histopathological diagnosis of PASC. Mean age at the time of diagnosis was 70.9 years, and 28 patients were male (46.7 %). Most patients presented with pancreas head tumors (60 %). Thirty-four patients presented with non-metastatic disease (56.6 %). The operative group consisted of 17 patients (28.3 %). Most patients received adjuvant systemic therapy (70.6 %). Majority of patients experienced recurrence (76.5 %), with median time to recurrence at 6.5 months. Median overall survival in the operative group was 19.1 months. Seventeen patients with non-metastatic disease (28.3 %) did not undergo resection. Median overall survival of this cohort was 3.3 months. Systemic chemotherapy was used in 8 patients. Approximately half of patients with non-metastatic disease (9/17) did not receive any treatment due to rapid physical deterioration or poor functional status at baseline. Median survival for the non-treatment group was 1.7 months. At presentation, 26 patients (43.3 %) had metastatic disease. Most common site of metastasis was the liver. Median survival for patients with metastatic disease was 3.1 months. DiscussionPASC is a distinct entity from glandular PDAC, and it appears to be a more aggressive disease process. Complete resection confers survival benefit but is not curative. Furthermore, few patients undergo surgery, even with seemingly resectable disease. Systemic therapy administration is limited in many patients due to physiologic decline. Dismal clinical course and poor survival is universal among all patients who do not undergo any treatment modality, regardless of metastatic status. Globally grim prognosis appears to be due early systemic effects, disease progression and lack of effective systemic therapy. ConclusionsPASC remains a poorly understood cancer and portends particularly poor prognosis. It is associated with a rapid clinical decline, poor response to systemic therapy, early recurrence, and poor overall survival. However, ability to treat with surgery and chemotherapy may best prolong survival. SynopsisPancreatic adenosquamous carcinoma (PASC) is a rare subtype of pancreatic cancer. In this study, we evaluated 60 patients with PASC. PASC is a systemic disease characterized by rapid clinical decline, poor response to systemic therapy, early recurrence, and poor survival. Despite resection or systemic therapy, patients succumb rapidly.

Proteomic basis for pancreatic acinar cell carcinoma and pancreatoblastoma as similar yet distinct entities

Acinar cell carcinoma (ACC) and pancreatoblastoma (PBL) are rare pancreatic malignancies with acinar differentiation. Proteogenomic profiling of ACC and PBL revealed distinct protein expression patterns compared to pancreatic ductal adenocarcinoma (PDAC) and benign pancreas. ACC and PBL exhibited similarities, with enrichment in proteins related to RNA processing, chromosome organization, and the mitoribosome, while PDACs overexpressed proteins associated with actin-based processes, extracellular matrix, and immune-active stroma. Pathway activity differences in metabolic adaptation, epithelial-to-mesenchymal transition, and DNA repair were characterized between these diseases. PBL showed upregulation of Wnt-CTNNB1 and IGF2 pathways. Seventeen ACC-specific proteins suggested connections to metabolic diseases with mitochondrial dysfunction, while 34 PBL-specific proteins marked this pediatric cancer with an embryonic stem cell phenotype and alterations in chromosomal proteins and the cell cycle. This study provides novel insights into the proteomic landscapes of ACC and PBL, offering potential targets for diagnostic and therapeutic development.

Unveiling the 4-aminoquinoline derivatives as potent agents against pancreatic ductal adenocarcinoma (PDAC) cell lines

Common antimalarials such as artemisinins, chloroquine and their derivatives also possess potent anti-inflamantory, antiviral and anticancer properties. In the search for new therapeutics to combat difficult-to-treat pancreatic carcinomas, we unveiled that 4-aminoquinoline derivatives, with significant antiplasmodial properties and a great safety profile in vivo, have remarkable anticancer activity against pancreatic ductal adenocarcinoma (PDAC) and considerable efficacy in the xenograft model in vivo. The aim of the present study was to further investigate anticancer properties of these compounds in a drug-repurposing manner. The compounds showed profound cytotoxic effects at nanomolar to low micromolar concentration in 2D cultured cells (in vitro) and in the zebrafish PDAC xenograft model (in vivo). A deeper insight into their mechanisms of cytotoxic action showed these compounds induce apoptosis while increasing reactive oxygen species levels along with autophagy inhibition. Additional investigation of the autophagy modulation proved that tested quinoline derivatives cause P62 and LC3-II accumulation in PDAC cells alongside lysosomal alkalinization. Further, in vivo toxicity studies in the zebrafish model showed low toxicity without developmental side effects of the investigated 4-aminoquinolines, while the applied compounds effectively inhibited tumor growth and prevented the metastasis of xenografted pancreatic cells. Taken together, these results highlight the 4-aminoquinolines as privileged structures that ought to be investigated further for potential application in pancreatic carcinoma treatment.

Development and validation of a prognostic nomogram for elderly-onset pancreatic neuroendocrine carcinoma: a prospective cohort study from the SEER database

Development and validation of a prognostic nomogram for elderly-onset pancreatic neuroendocrine carcinoma: a prospective cohort study from the SEER database

Keratin 17 and A2ML1 are negative prognostic biomarkers in non-small cell lung cancer

Although the overall prognosis for patients with non-small cell lung cancer (NSCLC) has improved over the past several decades, there are still survival differences that are not accurately defined by clinicopathological factors. Thus, there is an unmet clinical need to develop novel approaches to enhance prognostic accuracy for these patients. Keratin 17 (K17) is a negative prognostic biomarker in a wide range of cancer types, including pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, and pulmonary adenocarcinoma (LUAD), but has yet to be investigated as a prognostic biomarker in primary lung squamous cell carcinoma (LSCC). Based on TCGA RNA-seq data, alpha-2-macroglobulin like 1 (A2ML1), a protease inhibitor, is highly correlated with K17 in other solid tumors, including pancreatic ductal adenocarcinoma and is also a prognostic biomarker for LSCC, although the prognostic accuracy of A2ML1 for LUAD has not been tested. Thus, we hypothesized that A2ML1 expression correlates with K17 expression and that K17/A2ML1 co-testing could provide complementary prognostic data for NSCLC. The aims of this study were to explore K17 and A2ML1 as dual prognostic biomarkers, using publicly available gene expression databases [The Cancer Genome Atlas (TCGA)] LSCC (n=266), LUAD (n=271)] and multiplexed immunohistochemistry (mIHC) on representative sections of LSCC (n=104) and LUAD (n=107) from two major academic medical centers. Our results suggest that using either mRNA or mIHC-based methods, combined K17 and A2ML1 testing provides information, independent of other clinicopathologic variables, that could impact treatment decisions for patients with NSCLC.

Nano-synthesis, characterization, theoretical, biological and catalytic studies of Mn(II), Cu(II), Cd(II), and Th(IV) complexes based on antipyrine azo dye ligand

The design and detailed characterization of the azo dye ligand obtained from the reaction of 4-aminoantipyrine diazonium salt with 3-hydroxybenzaldehyde (HL) and its novel metal chelates with Mn2+, Cu2+, Cd2+ and Th4+ ions have been presented. Utilizing modern spectroscopic and analytical techniques, these complexes were found to adopt an octahedral geometry, demonstrate inner sphere d2sp3 hybridization for Th(IV) complex and outer sphere sp3d2 hybridization for other complexes. Particle sizes calculated using the Debye-Scherrer equation on XRD patterns were 32.05 nm for Mn(II), 34.07 nm for Cu(II), 30.90 nm for Cd(II), and 22.05 nm for Th(IV). These substances' anticancer activity was assessed on human lung cancer cells (A-549) and pancreatic carcinoma cell lines (PANC-1). Cd(II) complex exhibited higher cytotoxicity against the A-549 cell line than the reference drug vinblastine sulfate which revealing its potential application as a new anticancer agent. Quantum chemical computations using the DMOL3 module's density functional theory (DFT) and molecular docking studies with the Schrödinger suite demonstrated significant inhibitory effects of the free organic compound and Cu(II) chelate on the FGFR1 protein, crucial for cell development and differentiation. Additionally, the study examined the catalytic activity of HL and its metal chelates in the oxidative degradation of methyl violet 2B dye in presence of H2O2. The order was followed by the pseudo-first-order rate constants: Th(IV) chelate (0.9556 min⁻¹) > HL (0.4911 min⁻¹) > Cu(II) chelate (0.5979 min⁻¹) > Mn(II) chelate (0.2645 min⁻¹) > Cd(II) chelate (0.2280 min⁻¹).

Ductal hamartoma of the pancreas: A clinicopathologic study

BackgroundBenign ductular proliferative lesions that resemble hepatic von-Meyenburg Complexes(VMC)/bile duct hamartomas have been noted to occur in the pancreas, but their incidence, clinicopathologic features and pathogenesis remains unknown. We present herein 3 patients that presented as cysts and call them pancreatic ductal hamartomas (PDH). MethodsThree cases of PDH were identified form a multi-institutional collaborative group, and their clinicopathological were reviewed. In addition, we also examined 115 consecutive pancreatic resections at our institutions for the presence of incidental PDHs. ResultsThe lesions were detected in each case during imaging for abdominal symptoms or grossing. The clinical suspicion was intra-ductal pancreatic mucinous cystic neoplasm (IPMN) in each case that led to pancreatectomy. The cyst fluid CEA was elevated in 2 of the patients tested. The patient age and gender were 73/M (case1), 68/F (case2) and 73/M (case3). In case1 besides the larger cystic lesion, numerous tiny lesions (0.1–0.3 cm) were seen throughout the pancreas. In case2 this was the only lesion, while in case3 there was another gastric-type IPMN with high-grade dysplasia. PDH were identified in 5(4.3%) of 115 consecutive pancreatectomy specimens. The PDHs measured 0.1–2.3 cm, and the histology is characterized by proliferation of irregular ductal structures lined by bland flattened to low columnar epithelium, variable cystic change and inspissated luminal secretions. The lining epithelium varied from non-mucinous pancreatico-biliary type to mucinous gastric foveolar-type, with occasional squamous metaplasia. SummaryPDH are seen in 4.5% of all pancreatectomy specimens and detected incidentally, but occasionally may become large and/or cystic enough leading to pancreatectomy. Their relationship to pancreatic carcinoma or IPMN remains currently unknown.

Anticancer effects of emetine against cisplatin resistant pancreatic cancer cells via activation of Cyto-c/Caspase-9/Caspase-3/Bax/Bad axis

This investigation examines 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 explores emetine's impact on cell viability, clonogenic potential, and apoptotic pathways, unravelling its molecular mechanisms. Additionally, an in-vivo assessment is 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 dose- and time-dependent cytotoxic effect on PaCa3 cells, reducing viability from 98% to 8% (***p&lt;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 showcased concentration-dependent downregulation of anti-apoptotic Bcl-2 and 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.

Using Transnasal Humidified Rapid-Insufflation Ventilatory Exchange (THRIVE) on a Terminally Ill Patient with Carcinoma Pancreas for Placement of a Self-Expandable Metallic Stent in Common Bile Duct.

Using Transnasal Humidified Rapid-Insufflation Ventilatory Exchange (THRIVE) on a Terminally Ill Patient with Carcinoma Pancreas for Placement of a Self-Expandable Metallic Stent in Common Bile Duct.

Cancer-associated fibroblast-derived exosome Leptin promotes malignant biological lineage in pancreatic ductal adenocarcinoma by regulating ABL2 via miR-224-3p

BackgroundCancer-associated fibroblasts, as a major component of the tumor microenvironment, have been shown to exhibit protumorigenic effects in pancreatic ductal adenocarcinoma. Moreover, cancer-associated fibroblasts-derived exosomes have been reported to promote tumor development, but exact mechanisms have not been elucidated. The purpose of this study was to investigate the processes by which exosomes generated from cancer-associated fibroblasts promote tumor growth.Methodstwenty-one patients with pancreatic ductal adenocarcinoma who evaluated preoperatively as potentially surgically resectable without distant metastasis and pathologically examined postoperatively as pancreatic ductal cell carcinoma were included. We determined the expression of Leptin as well as downstream proteins at the clinical and cellular levels. Cancer-associated fibroblast-derived exosomes were characterised by nanoparticle transmission electron microscopy and tracking analysis. To ascertain the mechanism mediating the action of exosomal Leptin in pancreatic ductal adenocarcinoma, we performed CCK-8 assay, colony formation assays, transwell and wound healing assays in PSN1 cells to evaluate cell proliferation, migration and invasion. Western blotting was used to detect the level of Leptin, ABL2 and exosome markers. qRT-PCR was employed to evaluate miR-224-3p. Cancer-associated fibroblasts markers and exosome uptake were verified by immunofluorescence.ResultsWestern blotting assays show that Leptin is present inside tissues and cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Cancer-associated fibroblasts stimulated PSN1 cells growth, migration and invasion in vitro by secreting the exosomal Leptin. Exosomal Leptin could regulate miR-224-3p, which targets negative regulation of ABL2. Inhibiting Leptin significantly limited PSN1 cells growth, migration and invasion. In vitro analyses revealed that miR-224-3p mimics mitigate the inhibitory effect of cancer-associated fibroblasts knockdown of Leptin on PSN1 cells development, but overexpression of ABL2 partly abolished the tumor-promoting phenotype of miR-224-3p mimics.ConclusionOur results revealed that cancer-associated fibroblasts mediate pancreatic ductal adenocarcinoma development by regulating the miR-224-3p/ABL2 molecular axis through the secretion of the exosomal Leptin.

Comparative Effectiveness of ERCP and EUS-Guided Techniques for "Primary Biliary Drainage" in Malignant Distal Biliary Obstruction: A Systematic Review and Meta-Analysis.

Endoscopic ultrasound-guided biliary drainage (EUS-BD) is a viable alternative in cases with failed ERCP transpapillary drainage (ERCP-TPD). This systematic review and meta-analysis aimed to compare the efficacy and safety of EUS-BD and ERCP-TPD for primary biliary drainage in patients with distal malignant biliary obstruction (DMBO). We searched Embase, PubMed, and Medline databases for studies comparing EUS-BD and ERCP-TPD in DMBO, from inception until September 2023. The primary endpoint was clinical success and secondary endpoints included technical success, procedure duration, and adverse events. Eight studies (815 patients, 56.1% male) were included in this analysis. Indications for biliary drainage were pancreatic carcinoma (75.1%), followed by cholangiocarcinoma (10.1%). Clinical success was comparable between EUS-BD and ERCP-TPD groups (OR 1.34; 95% CI, 0.75-2.40; P=0.32). Technical success was similar between the 2 groups (OR 2.09; 95% CI, 0.83-5.25; P=0.12). There was a trend toward fewer adverse events in the EUS-BD group (OR 0.65; 95% CI, 0.40-1.07; P=0.09), with significantly lower odds of post-procedure pancreatitis (OR 0.17; 95% CI, 0.06-0.50; P=0.001). EUS-BD is comparable to ERCP for primary biliary drainage in DMBO patients with shorter procedural time and a significantly reduced risk of post-procedure pancreatitis.