-
EBioMedicine Jun 2024Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC,...
BACKGROUND
Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking.
METHODS
We screened fourteen patient-derived PDAC cultures which reflect the intra- and intertumoural heterogeneity of PDAC for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H-1PV. Live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays and titration of viral progeny were conducted. Transcriptome profiling was employed to identify potential predictive biomarkers for response to OV treatment.
FINDINGS
Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the classical molecular subtype, the quasi-mesenchymal or basal-like subtype of PDAC was found to be more sensitive to H-1PV, jin-3, and T-VEC. Generally, expression of viral entry receptors did not correlate with sensitivity to OV treatment, with one exception: Expression of Galectin-1 (LGALS1), a factor involved in H-1PV entry, positively correlated with H-1PV induced cell killing. Rather, cellular pathways controlling immunological, metabolic and proliferative signaling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas low cyclic GMP-AMP synthase (cGAS) expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures and cells overexpressing cGAS were found to be less sensitive to MV oncolysis.
INTERPRETATION
Considering the heterogeneity of PDAC and the complexity of biological therapies such as OVs, no single biomarker can explain the spectrum of response patterns. For selection of a particular OV, PDAC molecular subtype, ISG expression as well as activation of distinct signaling and metabolic pathways should be considered. Combination therapies can overcome resistance in specific constellations. Overall, oncolytic virotherapy is a viable treatment option for PDAC, which warrants further development. This study highlights the need for personalised treatment in OVT. By providing all primary data, this study provides a rich source and guidance for ongoing developments.
FUNDING
German National Science Foundation (Deutsche Forschungsgemeinschaft, DFG), German Cancer Aid (Deutsche Krebshilfe), German National Academic Scholarship Foundation (Studienstiftung des deutschen Volkes), Survival with Pancreatic Cancer Foundation.
PubMed: 38941955
DOI: 10.1016/j.ebiom.2024.105219 -
Artificial Intelligence in Medicine Jun 2024Pancreatic cancer does not show specific symptoms, which makes the diagnosis of early stages difficult with established image-based screening methods and therefore has...
Pancreatic cancer does not show specific symptoms, which makes the diagnosis of early stages difficult with established image-based screening methods and therefore has the worst prognosis among all cancers. Although endoscopic ultrasonography (EUS) has a key role in diagnostic algorithms for pancreatic diseases, B-mode imaging of the pancreas can be affected by confounders such as chronic pancreatitis, which can make both pancreatic lesion segmentation and classification laborious and highly specialized. To address these challenges, this work proposes a semi-supervised multi-task network (SSM-Net) to leverage unlabeled and labeled EUS images for joint pancreatic lesion classification and segmentation. Specifically, we first devise a saliency-aware representation learning module (SRLM) on a large number of unlabeled images to train a feature extraction encoder network for labeled images by computing a contrastive loss with a semantic saliency map, which is obtained by our spectral residual module (SRM). Moreover, for labeled EUS images, we devise channel attention blocks (CABs) to refine the features extracted from the pre-trained encoder on unlabeled images for segmenting lesions, and then devise a merged global attention module (MGAM) and a feature similarity loss (FSL) for obtaining a lesion classification result. We collect a large-scale EUS-based pancreas image dataset (LS-EUSPI) consisting of 9,555 pathologically proven labeled EUS images (499 patients from four categories) and 15,500 unlabeled EUS images. Experimental results on the LS-EUSPI dataset and a public thyroid gland lesion dataset show that our SSM-Net clearly outperforms state-of-the-art methods.
PubMed: 38941908
DOI: 10.1016/j.artmed.2024.102919 -
Nature Medicine Jun 2024Metastasis occurs frequently after resection of pancreatic cancer (PaC). In this study, we hypothesized that multi-parametric analysis of pre-metastatic liver biopsies...
Metastasis occurs frequently after resection of pancreatic cancer (PaC). In this study, we hypothesized that multi-parametric analysis of pre-metastatic liver biopsies would classify patients according to their metastatic risk, timing and organ site. Liver biopsies obtained during pancreatectomy from 49 patients with localized PaC and 19 control patients with non-cancerous pancreatic lesions were analyzed, combining metabolomic, tissue and single-cell transcriptomics and multiplex imaging approaches. Patients were followed prospectively (median 3 years) and classified into four recurrence groups; early (<6 months after resection) or late (>6 months after resection) liver metastasis (LiM); extrahepatic metastasis (EHM); and disease-free survivors (no evidence of disease (NED)). Overall, PaC livers exhibited signs of augmented inflammation compared to controls. Enrichment of neutrophil extracellular traps (NETs), Ki-67 upregulation and decreased liver creatine significantly distinguished those with future metastasis from NED. Patients with future LiM were characterized by scant T cell lobular infiltration, less steatosis and higher levels of citrullinated H3 compared to patients who developed EHM, who had overexpression of interferon target genes (MX1 and NR1D1) and an increase of CD11B natural killer (NK) cells. Upregulation of sortilin-1 and prominent NETs, together with the lack of T cells and a reduction in CD11B NK cells, differentiated patients with early-onset LiM from those with late-onset LiM. Liver profiles of NED closely resembled those of controls. Using the above parameters, a machine-learning-based model was developed that successfully predicted the metastatic outcome at the time of surgery with 78% accuracy. Therefore, multi-parametric profiling of liver biopsies at the time of PaC diagnosis may determine metastatic risk and organotropism and guide clinical stratification for optimal treatment selection.
PubMed: 38942992
DOI: 10.1038/s41591-024-03075-7 -
Scientific Reports Jun 2024Telocytes are closely associated with the regulation of tissue smooth muscle dynamics in digestive system disorders. They are widely distributed in the biliary system...
Telocytes are closely associated with the regulation of tissue smooth muscle dynamics in digestive system disorders. They are widely distributed in the biliary system and exert their influence on biliary motility through mechanisms such as the regulation of CCK and their electrophysiological effects on smooth muscle cells. To investigate the relationship between telocytes and benign biliary diseases,such as gallbladder stone disease and biliary dilation syndrome, we conducted histopathological analysis on tissues affected by these conditions. Additionally, we performed immunohistochemistry and immunofluorescence double staining experiments for telocytes. The results indicate that the quantity of telocytes in the gallbladder and bile duct is significantly lower in pathological conditions compared to the control group. This reveals a close association between the decrease in telocyte quantity and impaired gallbladder motility and biliary fibrosis. Furthermore, further investigations have shown a correlation between telocytes in cholesterol gallstones and cholecystokinin-A receptor (CCK-AR), suggesting that elevated cholesterol levels may impair telocytes, leading to a reduction in the quantity of CCK-AR and ultimately resulting in impaired gallbladder motility.Therefore, we hypothesize that telocytes may play a crucial role in maintaining biliary homeostasis, and their deficiency may be associated with the development of benign biliary diseases, including gallstone disease and biliary dilation.
Topics: Telocytes; Cholelithiasis; Humans; Gallbladder; Female; Male; Bile Ducts; Middle Aged; Aged; Dilatation, Pathologic
PubMed: 38942924
DOI: 10.1038/s41598-024-65776-w -
Cellular & Molecular Immunology Jun 2024Recent studies reveal a critical role of tumor cell-released extracellular vesicles (EVs) in pancreatic cancer (PC) progression. However, driver genes that direct EV...
Recent studies reveal a critical role of tumor cell-released extracellular vesicles (EVs) in pancreatic cancer (PC) progression. However, driver genes that direct EV function, the EV-recipient cells, and their cellular response to EV uptake remain to be identified. Therefore, we studied the role of Bcl-2-associated-anthanogene 6 (BAG6), a regulator of EV biogenesis for cancer progression. We used a Cre recombinase/LoxP-based reporter system in combination with single-cell RNA sequencing to monitor in vivo EV uptake and tumor microenvironment (TME) changes in mouse models for pancreatic ductal adenocarcinoma (PDAC) in a Bag6 pro- or deficient background. In vivo data were validated using mouse and human organoids and patient samples. Our data demonstrated that Bag6-deficient subcutaneous and orthotopic PDAC tumors accelerated tumor growth dependent on EV release. Mechanistically, this was attributed to mast cell (MC) activation via EV-associated IL33. Activated MCs promoted tumor cell proliferation and altered the composition of the TME affecting fibroblast polarization and immune cell infiltration. Tumor cell proliferation and fibroblast polarization were mediated via the MC secretome containing high levels of PDGF and CD73. Patients with high BAG6 gene expression and high protein plasma level have a longer overall survival indicating clinical relevance. The current study revealed a so far unknown tumor-suppressing activity of BAG6 in PDAC. Bag6-deficiency allowed the release of EV-associated IL33 which modulate the TME via MC activation promoting aggressive tumor growth. MC depletion using imatinib diminished tumor growth providing a scientific rationale to consider imatinib for patients stratified with low BAG6 expression and high MC infiltration. EVs derived from BAG6-deficient pancreatic cancer cells induce MC activation via IL33/Il1rl1. The secretome of activated MCs induces tumor proliferation and changes in the TME, particularly shifting fibroblasts into an inflammatory cancer-associated fibroblast (iCAF) phenotype. Blocking EVs or depleting MCs restricts tumor growth.
PubMed: 38942797
DOI: 10.1038/s41423-024-01195-1 -
Biochemistry Jun 2024Protein advanced glycation end products (AGEs) can be formed via nonenzymatic glycation and accumulated intracellularly to disrupt cellular homeostasis for protein...
Protein advanced glycation end products (AGEs) can be formed via nonenzymatic glycation and accumulated intracellularly to disrupt cellular homeostasis for protein clearance. Here, we investigated the formation particulars of intracellular protein AGEs and sought to elucidate the molecular events implicated in the impact of cellular clearance systems. The formation and accumulation of intracellular protein AGEs increased protein aggregation and protease resistance, potentially overwhelming the ubiquitin-proteasome system (UPS). At high levels of protein AGEs, the abundance of many E3 ligases decreased and the overall ubiquitination level was reduced, all of which indicated decreased UPS activity. On the other hand, autophagy activity was stimulated, as evidenced by the upregulation of autophagy marker LC3II and important proteins in autophagosome and autolysosome formation, as well as downregulation of mTOR. Understanding the functional impacts of intracellular protein AGEs on the UPS and autophagy could pave the way for the future development of pharmaceutical agents targeting AGE-related diseases.
PubMed: 38941592
DOI: 10.1021/acs.biochem.4c00250 -
Medicine Jun 2024Acute pancreatitis (AP) is a common emergency condition with high morbidity, mortality, and socio-economic impact. Soluble urokinase plasminogen activator receptor...
BACKGROUND
Acute pancreatitis (AP) is a common emergency condition with high morbidity, mortality, and socio-economic impact. Soluble urokinase plasminogen activator receptor (suPAR) is a potential biomarker for AP prognosis. This study systematically reviews the literature on suPAR's prognostic roles in assessing AP severity, organ failure, mortality, and other pathological markers.
METHODS
A comprehensive search of 5 databases up to March 19, 2023, was conducted, selecting cohort studies that examined suPAR's relationship with AP outcomes. Outcome variables included AP severity, organ failure, mortality, hospital stay length, and suPAR's association with other inflammatory markers. Our paper has been registered on Prospero (ID: CRD42023410628).
RESULTS
Nine prospective observational studies with 1033 AP patients were included. Seven of eight studies found suPAR significantly elevated in severe acute pancreatitis (P < .05). Four studies showed suPAR effectively predicted organ failure risk, and 4 studies concluded suPAR significantly predicted mortality (P < .05). The review had no high-risk studies, enhancing credibility.
CONCLUSION
suPAR is a valuable prognostic marker in AP, significantly predicting severity, organ failure, hospital stay length, and mortality. Further large-scale studies are needed to explore suPAR's role in other clinical outcomes related to AP disease course, to establish it as a mainstay of AP prognosis.
Topics: Humans; Pancreatitis; Receptors, Urokinase Plasminogen Activator; Prognosis; Biomarkers; Systematic Reviews as Topic; Severity of Illness Index; Length of Stay; Acute Disease
PubMed: 38941433
DOI: 10.1097/MD.0000000000037064 -
Magyar Sebeszet Jun 2024Bevezetés: A posztoperatív pancreasfistula mind proximalis, mind distalis pancreatectomia után a legjelentősebb sebészi szövődménynek számít. A...
Bevezetés: A posztoperatív pancreasfistula mind proximalis, mind distalis pancreatectomia után a legjelentősebb sebészi szövődménynek számít. A szakirodalomban nincs egyértelműen ajánlott, megbízható módszer ezen probléma kiküszöbölésére, emiatt történnek újítások szerte a világon. Jelen közleményünkben a technikai innovációinkról számolunk be. Anyag és módszerek: 2013. január 1-jétől 2023. november 30-ig terjedő időszakban 205 Whipple-műtétet végeztünk nyitottan, mely során a pancreatojejunalis anastomosist az általunk módosított dohányzacskó-öltéses módszerrel készítettük el. 2019. január 1. és 2023. november 30. között pedig 30 betegnél történt nyitott distalis pancreatectomia, amikor a pancreascsonkot az általunk kifejlesztett technikával, szabad rectus fascia-peritoneum grafttal fedtük, majd azt cirkuláris öltéssel rögzítettük. Közleményünkben ezen két módszerrel elért eredményeket ismertetjük. Eredmények: a demográfiai adatok megfeleltek a betegségnél szokásosnak. A posztoperatív ápolási idő és a transzfúzió igény terén észlelt különbségek tükrözték a kétféle beavatkozás eltérő invazivitását. A releváns pancreasfistula kialakulási rátája kedvező képet mutatott, Whipple-műtét után 7,3% volt, míg distalis pancreatectomát követően nem fejlődött ki. A reoperációs és a halálozási arányok megfeleltek az elvártaknak és korreláltak a műtétek kiterjedtségével. Következtetés: pancreas resectiók utáni komplikációk csökkentésére tett törekvéseink során a módosított dohányzacskó-öltéses pancreatojejunostomia és a pancreascsonk fedésére kidolgozott módszerünk egyaránt kedvező eredményekkel járt.
Topics: Humans; Pancreatic Fistula; Postoperative Complications; Female; Male; Pancreatectomy; Middle Aged; Pancreaticojejunostomy; Aged; Pancreaticoduodenectomy; Treatment Outcome; Adult
PubMed: 38941151
DOI: 10.1556/1046.2024.20002 -
JAMA Network Open Jun 2024While most patients with acute pancreatitis (AP) fulfill diagnostic criteria with characteristic abdominal pain and serum lipase levels of at least 3 times the upper...
IMPORTANCE
While most patients with acute pancreatitis (AP) fulfill diagnostic criteria with characteristic abdominal pain and serum lipase levels of at least 3 times the upper limit of normal (reference range) at presentation, early imaging is often used for confirmation. A prior prediction model and corresponding point-based score were developed using nonimaging parameters to diagnose AP in patients presenting to the emergency department (ED).
OBJECTIVE
To evaluate the performance of the prediction model to diagnose AP in a prospective patient cohort.
DESIGN, SETTING, AND PARTICIPANTS
This prospective diagnostic study included consecutive adult patients presenting to the ED between January 1, 2020, and March 9, 2021, at 2 large academic medical centers in the northeastern US with serum lipase levels at least 3 times the upper limit of normal. Patients transferred from outside institutions or with malignant disease and established intra-abdominal metastases, acute trauma, or altered mentation were excluded. Data were analyzed from October 15 to October 23, 2023.
EXPOSURES
Participants were assigned scores for initial serum lipase level, number of prior AP episodes, prior cholelithiasis, abdominal surgery within 2 months, presence of epigastric pain, pain of worsening severity, duration from pain onset to presentation, and pain level at ED presentation.
MAIN OUTCOME AND MEASURES
A final diagnosis of AP, established by expert review of hospitalization records.
RESULTS
Prospective scores in 349 participants (mean [SD] age, 53.0 [18.8] years; 184 women [52.7%]; 66 Black [18.9%]; 199 White [57.0%]) demonstrated an area under the receiver operating characteristics curve of 0.91. A score of at least 6 points achieved highest accuracy (F score, 82.0), corresponding to a sensitivity of 81.5%, specificity of 85.9%, positive predictive value of 82.6%, and negative predictive value of 85.1% for AP diagnosis. Early computed tomography or magnetic resonance imaging was performed more often in participants predicted to have AP (116 of 155 [74.8%] with a score ≥6 vs 111 of 194 [57.2%] with a score <6; P < .001). Early imaging revealed an alternative diagnosis in 8 of 116 participants (6.9%) with scores of at least 6 points, 1 of 93 (1.1%) with scores of at least 7 points, and 1 of 73 (1.4%) with scores of at least 8 points.
CONCLUSIONS AND RELEVANCE
In this multicenter diagnostic study, the prediction model demonstrated excellent AP diagnostic accuracy. Its application may be used to avoid unnecessary confirmatory imaging.
Topics: Humans; Pancreatitis; Female; Male; Prospective Studies; Middle Aged; Adult; Lipase; Emergency Service, Hospital; Aged; Predictive Value of Tests; Acute Disease; Abdominal Pain
PubMed: 38941094
DOI: 10.1001/jamanetworkopen.2024.19014 -
Annals of Surgery Jun 2024We aimed to establish global benchmark outcomes indicators for L-RPS/H67.
OBJECTIVE
We aimed to establish global benchmark outcomes indicators for L-RPS/H67.
BACKGROUND
Minimally invasive liver resections has seen an increase in uptake in recent years. Over time, challenging procedures as laparoscopic right posterior sectionectomies (L-RPS)/H67 are also increasingly adopted.
METHODS
This is a post hoc analysis of a multicenter database of 854 patients undergoing minimally invasive RPS (MI-RPS) in 57 international centers in 4 continents between 2015 and 2021. There were 651 pure L-RPS and 160 robotic RPS (R-RPS). Sixteen outcome indicators of low-risk L-RPS cases were selected to establish benchmark cutoffs. The 75th percentile of individual center medians for a given outcome indicator was set as the benchmark cutoff.
RESULTS
There were 573 L-RPS/H67 performed in 43 expert centers, of which 254 L-RPS/H67 (44.3%) cases qualified as low risk benchmark cases. The benchmark outcomes established for operation time, open conversion rate, blood loss ≥500 mL, blood transfusion rate, postoperative morbidity, major morbidity, 90-day mortality and textbook outcome after L-RPS were 350.8 minutes, 12.5%, 53.8%, 22.9%, 23.8%, 2.8%, 0% and 4% respectively.
CONCLUSIONS
The present study established the first global benchmark values for L-RPS/H6/7. The benchmark provided an up-to-date reference of best achievable outcomes for surgical auditing and benchmarking.
PubMed: 38939972
DOI: 10.1097/SLA.0000000000006418