Broccoli sprout supplementation in patients with advanced pancreatic cancer is difficult despite positive effects-results from the POUDER pilot study.

Pancreatic ductal adenocarcinoma is a highly aggressive malignancy with short survival and limited therapeutic options. Broccoli sulforaphane is a promising new treatment due to the results of recent epidemiological, experimental and patient studies. Upon approval from the ethics committee and registration at ClinicalTrials.gov, 40 patients with palliative chemotherapy were placed into a placebo and treatment group in an unblinded fashion. Fifteen capsules with pulverized broccoli sprouts containing 90 mg/508 µmol sulforaphane and 180 mg/411 µmol glucoraphanin or methylcellulose were administered daily for up to 1 year. Twenty-nine patients were included in the treatment group and 11 patients were in the placebo group; these patients were followed for up to 1 year. The patient characteristics, overall survival and feasibility were assessed. Compared to those of the placebo group, the mean death rate was lower in the treatment group during the first 6 months after intake (day 30: 0%/18%, day 90: 0%/25%, and day 180: 25%/43%), and Kaplan-Meier analysis revealed a higher survival rate. There was a high drop-out rate (72% in the treatment group and 55% in the placebo group) after 1 year. We concluded from the Karnofsky index that the broccoli sprouts did not impact patient's self-care and overall abilities severely. The intake of 15 capsules daily was difficult for some patients, and the broccoli sprouts sometimes increased digestive problems, nausea and emesis. We did not obtain statistically significant results (p = 0.291 for the endpoint at day 180), but the knowledge about the feasibility is the basis for the development of new sulforaphane drugs.

Glycine protects partial liver grafts from Kupffer cell-dependent ischemia-reperfusion injury without negative effect on regeneration.

Donor preconditioning with glycine prevents Kupffer cell-dependent reperfusion injury to liver grafts. Partial liver grafts need to regenerate and grow in size after transplantation; however, glycine inactivates Kupffer cells, which are important for hepatic regeneration. Thus, this study was designed to evaluate the impact of donor preconditioning with glycine after partial liver transplantation (pLTx). PLTx was performed in 28 female Sprague-Dawley rats. Glycine (1.5 ml, 300 mM; i.v.) was given to 14 live donors before organ procurement. Liver enzymes and histology were investigated 8 h after reperfusion to index liver injury and leukocyte infiltration. Hepatic microperfusion and leukocyte-endothelium interaction were assessed using the in vivo fluorescence microscopy method. Ki-67 and TNF-α were detected by immunohistochemistry for regeneration and Kupffer cell activation. Glycine significantly increased survival from 0% in controls to 40%, while both liver enzyme levels and necrosis were decreased to about 50% of controls (p < 0.05). Sinusoidal blood flow increased by 40-80%, while leukocyte-endothelium interaction decreased to 30% of control values (p < 0.05). While Kupffer cell-derived TNF-α decreased to 70% of controls, there was no difference between groups in Ki-67 expression. Data presented here clearly demonstrate that glycine protects partial liver grafts from reperfusion injury without effects on regeneration.

Intraductal papillary mucinous neoplasm of the pancreas rapidly xenografts in chicken eggs and predicts aggressiveness.

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas has a high risk of progressing to invasive pancreatic ductal adenocarcinoma (PDA), but experimental models for IPMN are largely missing. New experimental systems for the molecular characterization of IPMN and for personalized prognosis and treatment options for IPMN are urgently needed. We analyzed the potential use of fertilized chicken eggs for the culture of freshly resected IPMN tissue. We transplanted 49 freshly resected IPMN tissues into eggs and compared the growth characteristics to IPMN tissues transplanted into mice; this was followed by an analysis of histology, morphology, and marker expression. Of the IPMN tissues transplanted into eggs, 63% formed tumor xenografts within 4 days, while none of the 12 IPMN tissues transplanted into immunodeficient mice engrafted. In the eggs, the grafting efficiency of high-grade (n = 14) and intermediate-grade (n = 17) dysplasia was 77% and was significantly higher than the 39% grafting efficiency of low-grade dysplasia (n = 18). According to mucinous expression, 46 IPMN tissues were classified into gastric (n = 6), intestinal (n = 3), oncocytic (n = 23), and pancreatobiliary (n = 14) subtypes. The grafting efficiency was highest for the pancreatobiliary subtype (86%), followed by the oncocytic (70%), gastric (33%) and intestinal (33%) subtypes. The morphology and expression patterns of mucins, progression markers and pancreatic ductal markers were comparable between the primary IPMN tissues and their xenograft copies. The individual tumor environment was largely maintained during subtransplantation, as evaluated upon passage 6. This new IPMN model may facilitate experimental studies and treatment decisions for the optimal personalized management of IPMN.

Quercetin-induced miR-200b-3p regulates the mode of self-renewing divisions in pancreatic cancer.

BACKGROUND: Cancer stem cells are suggested to contribute to the extremely poor prognosis of pancreatic ductal adenocarcinoma and dysregulation of symmetric and asymmetric stem cell division may be involved. Anticancer benefits of phytochemicals like the polyphenol quercetin, present in many fruits, nuts and vegetables, could be expedited by microRNAs, which orchestrate cell-fate decisions and tissue homeostasis. The mechanisms regulating the division mode of cancer stem cells in relation to phytochemical-induced microRNAs are poorly understood. METHODS: Patient-derived pancreas tissue and 3 established pancreatic cancer cell lines were examined by immunofluorescence and time-lapse microscopy, microRNA microarray analysis, bioinformatics and computational analysis, qRT-PCR, Western blot analysis, self-renewal and differentiation assays. RESULTS: We show that symmetric and asymmetric division occurred in patient tissues and in vitro, whereas symmetric divisions were more extensive. By microarray analysis, bioinformatics prediction and qRT-PCR, we identified and validated quercetin-induced microRNAs involved in Notch signaling/cell-fate determination. Further computational analysis distinguished miR-200b-3p as strong candidate for cell-fate determinant. Mechanistically, miR-200b-3p switched symmetric to asymmetric cell division by reversing the Notch/Numb ratio, inhibition of the self-renewal and activation of the potential to differentiate to adipocytes, osteocytes and chondrocytes. Low miR-200b-3p levels fostered Notch signaling and promoted daughter cells to become symmetric while high miR-200b-3p levels lessened Notch signaling and promoted daughter cells to become asymmetric. CONCLUSIONS: Our findings provide a better understanding of the cross talk between phytochemicals, microRNAs and Notch signaling in the regulation of self-renewing cancer stem cell divisions.

Melatonin promotes sorafenib-induced apoptosis through synergistic activation of JNK/c-jun pathway in human hepatocellular carcinoma.

Melatonin has been shown to exert anticancer activity on hepatocellular carcinoma (HCC) through its antiproliferative and pro-apoptotic effect in both experimental and clinical studies, and sorafenib is the only approved drug for the systemic treatment of HCC. Thus, this study was designed to investigate the combined effect of melatonin and sorafenib on proliferation, apoptosis, and its possible mechanism in human HCC. Here, we found that both melatonin and sorafenib resulted in a dose-dependent growth inhibition of HuH-7 cells after 48 hours treatment, and the combination of them enhanced the growth inhibition in a synergistic manner. Colony formation assay indicated that co-treatment of HuH-7 cells with melatonin and sorafenib significantly decreased the clonogenicity compared to the treatment with single agent. Furthermore, FACS and TUNEL assay confirmed that melatonin synergistically augmented the sorafenib-induced apoptosis after 48 hours incubation, which was in accordance with the activation of caspase-3 and the JNK/c-jun pathway. Inhibition of JNK/c-jun pathway with its inhibitor SP600125 reversed the phosphorylation of c-jun and the activation of caspase-3 induced by co-treatment of HuH-7 cells with melatonin and sorafenib in a dose-dependent manner. Furthermore, SP600125 exhibited protective effect against apoptosis induced by the combination of melatonin and sorafenib. This study demonstrates that melatonin in combination with sorafenib synergistically inhibits proliferation and induces apoptosis in human HCC cells; therefore, supplementation of sorafenib with melatonin may serve as a potential therapeutic choice for advanced HCC.

Engineered adenoviruses combine enhanced oncolysis with improved virus production by mesenchymal stromal carrier cells.

Oncolytic viruses have demonstrated in pre-clinical and clinical studies safety and a unique pleiotropic activity profile of tumor destruction. Yet, their delivery suffers from virus inactivation by blood components and sequestration to healthy tissues. Therefore, mesenchymal stromal cells (MSCs) have been applied as carrier cells for shielded virus delivery to tumors after ex vivo infection with oncolytic viruses. However, infection and particle production by MSCs have remained unsatisfying. Here, we report engineered oncolytic adenoviruses (OAds) for improved virus production and delivery by MSCs. OAds are uniquely amenable to molecular engineering, which has facilitated improved tumor cell destruction. But for MSC-mediated regimens, OAd engineering needs to achieve efficient infection and replication in both MSCs and tumor cells. We show that an Ad5/3 chimeric OAd capsid, containing the adenovirus serotype 3 cell-binding domain, strongly increases the entry into human bone marrow-derived MSCs and into established and primary pancreatic cancer cells. Further, we reveal that OAd with engineered post-entry functions-by deletion of the anti-apoptotic viral gene E1B19K or expression of the death ligand TRAIL--markedly increased virus titers released from MSCs, while MSC migration was not hampered. Finally, these virus modifications, or viral expression of FCU1 for local 5-FC prodrug activation, improved tumor cell killing implementing complementary cytotoxicity profiles in a panel of pancreatic cancer cell cultures. Together, our study establishes post-entry modification of OAd replication for improving virus delivery by carrier cells and suggests a panel of optimized OAds for future clinical development in personalized treatment of pancreatic cancer.

Triptolide reverses hypoxia-induced epithelial-mesenchymal transition and stem-like features in pancreatic cancer by NF-κB downregulation.

Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal malignancies characterized by an intense tumor stroma with hypoperfused regions, a significant inflammatory response and pronounced therapy resistance. New therapeutic agents are urgently needed. The plant-derived agent triptolide also known as "thunder god vine" has a long history in traditional Chinese medicine for treatment of rheumatoid arthritis and cancer and is now in a clinical phase II trial for establishing the efficacy against a placebo. The authors mimicked the situation in patient tumors by induction of hypoxia in experimental models of pancreatic cancer stem cells (CSCs) and evaluated the therapeutic effect of triptolide. Hypoxia led to induction of colony and spheroid formation, aldehyde dehydrogenase 1 (ALDH1) and NF-κB activity, migratory potential and a switch in morphology to a fibroblastoid phenotype, as well as stem cell- and epithelial-mesenchymal transition-associated protein expression. Triptolide efficiently inhibited hypoxia-induced transcriptional signaling and downregulated epithelial-mesenchymal transition (EMT) and CSC features in established highly malignant cell lines, whereas sensitive cancer cells or nonmalignant cells were less affected. In vivo triptolide inhibited tumor take and tumor growth. In primary CSCs isolated from patient tumors, triptolide downregulated markers of CSCs, proliferation and mesenchymal cells along with upregulation of markers for apoptosis and epithelial cells. This study is the first to show that triptolide reverses EMT and CSC characteristics and therefore may be superior to current chemotherapeutics for treatment of PDA.

Multi-Algorithm Analysis Reveals Pyroptosis-Linked Genes as Pancreatic Cancer Biomarkers.

Pancreatic ductal adenocarcinoma (PDAC) is often diagnosed at late stages, limiting treatment options and survival rates. Pyroptosis-related gene signatures hold promise as PDAC prognostic markers, but limited gene pools and small sample sizes hinder their utility. We aimed to enhance PDAC prognosis with a comprehensive multi-algorithm analysis. Using R, we employed natural language processing and latent Dirichlet allocation on PubMed publications to identify pyroptosis-related genes. We collected PDAC transcriptome data (n = 1273) from various databases, conducted a meta-analysis, and performed differential gene expression analysis on tumour and non-cancerous tissues. Cox and LASSO algorithms were used for survival modelling, resulting in a pyroptosis-related gene expression-based prognostic index. Laboratory and external validations were conducted. Bibliometric analysis revealed that pyroptosis publications focus on signalling pathways, disease correlation, and prognosis. We identified 357 pyroptosis-related genes, validating the significance of BHLHE40, IL18, BIRC3, and APOL1. Elevated expression of these genes strongly correlated with poor PDAC prognosis and guided treatment strategies. Our accessible nomogram model aids in PDAC prognosis and treatment decisions. We established an improved gene signature for pyroptosis-related genes, offering a novel model and nomogram for enhanced PDAC prognosis.

[Retracted] Sulforaphane sensitizes human cholangiocarcinoma to cisplatin via the downregulation of anti­apoptotic proteins.

Following the publication of the above article and a corrigendum that was published in October 2023 to address the issue of misplaced control ß­actin western blots comparing between Figs. 3 and 4A (doi: 10.3892/or.2023.8646), an attentive reader drew to the authors' attention that the first author had apparently made additional unreported corrections to the revised version of Fig. 4 presented in the corrigendum. Although these image discrepancies did not alter the study's primary conclusions, they were such that they did cast doubt on the data's integrity. Consequently, the authors have decided to retract the paper and the Editor of Oncology Reports has agreed to the authors' request. The authors deeply regret any confusion or inconvenience this retraction may cause, and offer their sincere apologies to the Editor of Oncology Reports and the readership. [Oncology Reports 37: 3660­3666, 2017; DOI: 10.3892/or.2017.5622].

Corrigendum: Establishment of tumor treating fields combined with mild hyperthermia as novel supporting therapy for pancreatic cancer.

[This corrects the article DOI: 10.3389/fonc.2021.738801.].

Nitric oxide and glucocorticoids synergize in inducing apoptosis of CD4⁺8⁺ thymocytes: implications for 'Death by Neglect' and T-cell function.

Thymic epithelial cells (TECs) play a central role in T-cell development by presenting self-antigens on MHC proteins. Double-positive (DP) thymocytes that fail to interact with TEC via their TCR die by 'Death by Neglect'. We demonstrated a role for TEC-derived glucocorticoids (GCs) in this process. In a previous study, we used an in vitro system recapitulating Death by Neglect, to demonstrate the involvement of nitric oxide (NO) and inducible NO synthase (iNOS) in this process. In this study, we show that NO synergizes with GCs to induce apoptosis of DP thymocytes in a fetal thymic organ culture. Also, DP thymocytes from iNOS⁻/⁻ mice are less sensitive to GC-induced apoptosis. Furthermore, the number of DP thymocytes in iNOS⁻/⁻ mice is higher than in wild-type mice, suggesting a role for NO in Death by Neglect. This phenomenon effects T-cell function profoundly: iNOS⁻/⁻ T cells do not respond to TCR-mediated activation signals, measured by up-regulation of CD69, IL-2R and IFNγ secretion. This failure to activate is a result of TCR incompetence because iNO⁻/⁻ T cells respond to TCR-independent stimuli (phorbol myristate acetate and calcium ionophore). This study suggests that NO and GCs synergize to execute TEC-induced death of DP thymocytes.

Autophagy mediates survival of pancreatic tumour-initiating cells in a hypoxic microenvironment.

Involvement of dysregulated autophagy in cancer growth and progression has been shown in different tumour entities, including pancreatic ductal adenocarcinoma (PDA). PDA is an extremely aggressive tumour characterized by a small population of highly therapy-resistant cancer stem cells (CSCs) capable of self-renewal and migration. We examined whether autophagy might be involved in the survival of CSCs despite nutrition and oxygen deprivation typical for the hypoxic tumour microenvironment of PDA. Immunohistochemistry revealed that markers for hypoxia, CSCs and autophagy are co-expressed in patient-derived tissue of PDA. Hypoxia starvation (H/S) enhanced clonogenic survival and migration of established pancreatic cancer cells with stem-like properties (CSC(high)), while pancreatic tumour cells with fewer stem cell markers (CSC(low)) did not survive these conditions. Electron microscopy revealed more advanced autophagic vesicles in CSC(high) cells, which exhibited higher expression of autophagy-related genes under normoxic conditions and relative to CSC(low) cells, as found by RT-PCR and western blot analysis. LC3 was already fully converted to the active LC3-II form in both cell lines, as evaluated by western blot and detection of accumulated GFP-LC3 protein by fluorescence microscopy. H/S increased formation of autophagic and acid vesicles, as well as expression of autophagy-related genes, to a higher extent in CSC(high) cells. Modulation of autophagy by inhibitors and activators resensitized CSC(high) to apoptosis and diminished clonogenicity, spheroid formation, expression of CSC-related genes, migratory activity and tumourigenicity in mice. Our data suggest that enhanced autophagy levels may enable survival of CSC(high) cells under H/S. Interference with autophagy-activating or -inhibiting drugs disturbs the fine-tuned physiological balance of enhanced autophagy in CSC and switches survival signalling to suicide.

Sulforaphane and related mustard oils in focus of cancer prevention and therapy.

The plant family Brassicaceae, formerly Cruciferae, contains mustard oil glycosides, from which mustard oils are enzymatically hydrolyzed. Mustard oils offer protection from pests, microorganisms and fungi. More than 120 different mustard oils with various biological functions are known. Since ancient times, these substances are used as natural antibiotics, antiviral drugs and antimycotics. The antioxidative effect of mustard oils contributes to protection from DNA damage. Epidemiological and experimental studies have shown preventive and therapeutic effects of crucifers or isolated substances thereof. Particularly well studied is the mustard oil sulforaphane, which is contained in high concentrations in broccoli and its sprouts. As has been shown in mice recently, sulforaphane also targets the most malignant cancer stem cells, which are not affected by conventional cancer treatments. Based on these promising results, the first prospective clinical studies with cancer patients and sulforaphane-enriched broccoli sprouts have now been initiated in the United States.

[Corrigendum] Establishment of hypoxia induction in an in vivo animal replacement model for experimental evaluation of pancreatic cancer.

Subsequently to the publication of the above paper, an interested reader drew to the authors' attention that, on p. 156, the data panels shown to represent the 'CoCl2' and 'TRIP' data panels in Fig. 3 for the DAPI experiments were apparently the same, even though different experiments were being depicted here.  The authors were able to re­examine their original data files, and realized that this figure had been assembled incorrectly: there was an inadvertent mix­up of a pair of the DAPI control images. The revised version of Fig. 3, containing the correct DAPI data for the 'TRIP' experiment, is shown opposite. Note that the revisions made to this figure do not affect the overall conclusions reported in the paper. The authors are grateful to the Editor of Oncology Reports for allowing them the opportunity to publish this Corrigendum, and apologize to the readership for any inconvenience caused. [Oncology Reports 32: 153­158, 2014; DOI: 10.3892/or.2014.3196].

[Corrigendum] Sulforaphane sensitizes human cholangiocarcinoma to cisplatin via the downregulation of anti­apoptotic proteins.

Following the publication of this article, an interested reader drew to the authors' attention that, in Figs. 3 and 4A on p. 3664, the respective ß­actin controls for the cell lines TFK­1 and HuCCT­1 appeared to have mixed up, comparing the western blots between the two figures. After re­examining their data, the authors have realized that the control blots in Fig. 4A were inadvertently presented the wrong way around. The corrected version of Fig. 4, showing the correctly presented western blotting data in Fig. 4A, is shown on the next page. Note that this error did not grossly affect the results or the conclusions reported in this paper. The authors sincerely apologize for the error that was introduced during the preparation of this figure, and thank the Editor of Oncology Reports for allowing them the opportunity to publish a corrigendum. Furthermore, they regret any inconvenience caused to the readership. [Oncology Reports 37: 3660­3666, 2017; DOI: 10.3892/or.2017.5622].

[Corrigendum] Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-ß-driven progression of pancreatic cancer.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that two pairs of the culture plate images in Fig. 4A-C on p. 60 appeared to be the same, although the images were shown in different orientations; moreover, the 'NC/0 and DEX+miR132' and 'DEX and miR132' pairings of images in the scratch-wound assay experiments shown in Fig. 4B also appeared to be overlapping, such that these were apparently derived from the same original source where the results of differently performed experiments were intended to have been portrayed. After re­examining their original data, the authors have realized that some of the data in Fig. 4A and B were inadvertently assembled incorrectly. The revised version of Fig. 4, showing all the correct data for the culture plate images in Fig. 4A-C (specifically, the images fifth along on the right for Fig. 4B and C have been revised) and the correct images for 'NC/0' and 'DEX/0' in Fig. 4D is shown on on the next page. The authors are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a Corrigendum, and all the authors agree with its publication. Furthermore, the authors apologize to the readership for any inconvenience caused. [International Journal of Oncology 54: 53­64, 2019; DOI: 10.3892/ijo.2018.4616].

Targeting of pancreatic and prostate cancer stem cell characteristics by Crambe crambe marine sponge extract.

Cancer stem cells (CSCs) are suggested as reason for resistance of tumors toward conventional tumor therapy including pancreatic and advanced prostate cancer. New therapeutic agents are urgently needed for targeting of CSCs. Marine sponges harbor novel and undefined compounds with antineoplastic activity but their potential to eliminate CSC characteristics is not examined so far. We collected 10 marine sponges and one freshwater sponge by diving at the seaside and prepared crude methanolic extracts. The effect to established pancreatic and prostate CSC lines was evaluated by analysis of apoptosis, cell cycle, side population, colony and spheroid formation, migratory potential in vitro and tumorigenicity in vivo. While each sponge extract at a 1:10 dilution efficiently diminished viability, Crambe crambe marine sponge extract (CR) still strongly reduced viability of tumor cells at a dilution of 1:1,000 but was less toxic to normal fibroblasts and endothelial cells. CR inhibited self-renewal capacity, apoptosis resistance, and proliferation even in gemcitabine-selected pancreatic cancer cells with acquired therapy resistance and enhanced CSC characteristics. CR pretreatment of tumor cells diminished tumorigenicity of gemcitabine-resistant tumor cells in mice and totally abolished tumor take upon combination with gemcitabine. Our data suggest that CR contains substances, which render standard cancer therapy more effective by targeting of CSC characteristics. Isolation of bioactive metabolites from CR and evaluation in mice are required for development of new CSC-specific chemotherapeutic drugs from a marine sponge.

Sulforaphane increases drug-mediated cytotoxicity toward cancer stem-like cells of pancreas and prostate.

Despite intense efforts to develop treatments against pancreatic cancer, agents that cure this highly resistant and metastasizing disease are not available. Considerable attention has focused on broccoli compound sulforaphane (SF), which is suggested as combination therapy for targeting of pancreatic cancer stem cells (CSCs). However, there are concerns that antioxidative properties of SF may interfere with cytotoxic drugs-as suggested, e.g., for vitamins. Therefore we investigated a combination therapy using established pancreatic CSCs. Although cisplatin (CIS), gemcitabine (GEM), doxorubicin, 5-flurouracil, or SF effectively induced apoptosis and prevented viability, combination of a drug with SF increased toxicity. Similarly, SF potentiated the drug effect in established prostate CSCs revealing that SF enhances drug cytotoxicity also in other tumor entities. Most importantly, combined treatment intensified inhibition of clonogenicity and spheroid formation and aldehyde dehydrogenase 1 (ALDH1) activity along with Notch-1 and c-Rel expression indicating that CSC characteristics are targeted. In vivo, combination treatment was most effective and totally abolished growth of CSC xenografts and tumor-initiating potential. No pronounced side effects were observed in normal cells or mice. Our data suggest that SF increases the effectiveness of various cytotoxic drugs against CSCs without inducing additional toxicity in mice.

Machine-Learning-Based Bibliometric Analysis of Pancreatic Cancer Research Over the Past 25 Years.

Machine learning and semantic analysis are computer-based methods to evaluate complex relationships and predict future perspectives. We used these technologies to define recent, current and future topics in pancreatic cancer research. Publications indexed under the Medical Subject Headings (MeSH) term 'Pancreatic Neoplasms' from January 1996 to October 2021 were downloaded from PubMed. Using the statistical computing language R and the interpreted, high-level, general-purpose programming language Python, we extracted publication dates, geographic information, and abstracts from each publication's metadata for bibliometric analyses. The generative statistical algorithm "latent Dirichlet allocation" (LDA) was applied to identify specific research topics and trends. The unsupervised "Louvain algorithm" was used to establish a network to identify relationships between single topics. A total of 60,296 publications were identified and analyzed. The publications were derived from 133 countries, mostly from the Northern Hemisphere. For the term "pancreatic cancer research", 12,058 MeSH terms appeared 1,395,060 times. Among them, we identified the four main topics "Clinical Manifestation and Diagnosis", "Review and Management", "Treatment Studies", and "Basic Research". The number of publications has increased rapidly during the past 25 years. Based on the number of publications, the algorithm predicted that "Immunotherapy", Prognostic research", "Protein expression", "Case reports", "Gemcitabine and mechanism", "Clinical study of gemcitabine", "Operation and postoperation", "Chemotherapy and resection", and "Review and management" as current research topics. To our knowledge, this is the first study on this subject of pancreatic cancer research, which has become possible due to the improvement of algorithms and hardware.