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Introduction: Pancreatic cancer (PC) demonstrates very poor prognosis and its incidence continues to increase, despite developments in chemotherapy, radiotherapy, and targeted therapies. Surgical resection is currently the only curative approach for PC. The role of radiotherapy in adjuvant and locally advanced PC continues to be increasingly contro...
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... may be used to clarify images regarding invasion of local structures. PET/CT does not provide the anatomical detail of CT or MRI, but can be useful in certain situations, such as for the identification of involved nodes (Table 3). N staging is normally assessed with ultrasound (US), CT, or PET (Table 3). ...
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... does not provide the anatomical detail of CT or MRI, but can be useful in certain situations, such as for the identification of involved nodes (Table 3). N staging is normally assessed with ultrasound (US), CT, or PET (Table 3). ...
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Pancreatic cancer is one of the leading causes of cancer death worldwide. Its high mortality rate has remained unchanged for years. Radiotherapy and surgery are considered standard treatments in early and locally advanced stages. Chemotherapy is the only option for metastatic patients. Two treatment regimens, i. e. the association of 5-fluorouracil...
Citations
... Therapeutic options for PDAC, include surgical intervention, radiotherapy, chemotherapy treatment, target therapies, and combination therapies [25][26][27][28][29]. However, the best treatment choice for a single patient is still limited, and the clinical outcome not predictable even in the case of operable patients. ...
Simple Summary
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest cancers worldwide, with an overall survival rate of <10% at 5 years. For most patients with unresectable or recurrent PDAC, few therapeutic options are available, with limited efficacy. Furthermore, there is an almost complete absence of validated predictive factors. At present, microRNAs represent a promising diagnostic, prognostic, and predictive method for the clinical management of patients, avoiding inappropriate treatments.
Abstract
Pancreatic ductal adenocarcinoma (PDAC), a neoplasm of the gastrointestinal tract, is the most common pancreatic malignancy (90%) and the fourth highest cause of cancer mortality worldwide. Surgery intervention is currently the only strategy able to offer an advantage in terms of overall survival, but prognosis remains poor even for operated patients. Therefore, the development of robust biomarkers for early diagnosis and prognostic stratification in clinical practice is urgently needed. In this work, we investigated deregulated microRNAs (miRNAs) in tissues from PDAC patients with high (G3) or low (G2) histological grade and with (N+) or without (N−) lymph node metastases. miRNA expression profiling was performed by a comprehensive PCR array and subsequent validation by RT-qPCR. The results showed a significant increase in miR-1-3p, miR-31-5p, and miR-205-5p expression in G3 compared to G2 patients (** p < 0.01; *** p < 0.001; *** p < 0.001). miR-518d-3p upregulation and miR-215-5p downregulation were observed in N+ compared to N− patients. A statistical analysis performed using OncomiR program showed the significant involvement (p < 0.05) of two miRNAs (miR-31 and miR-205) in the histological grade of PDAC patients. Also, an expression analysis in PDAC patients showed that miR-31 and miR-205 had the highest expression at grade 3 compared with normal and other tumor grades. Overall, survival plots confirmed that the overexpression of miR-31 and miR-205 was significantly correlated with decreased survival in TCGA PDAC clinical samples. A KEGG pathway analysis showed that all three miRNAs are involved in the regulation of multiple pathways, including the Hippo signaling, adherens junction and microRNAs in cancer, along with several target genes. Based on in silico analysis and experimental validation, our study suggests the potential role of miR-1-3p, miR-31-5p, and miR-205-5p as useful clinical biomarkers and putative therapeutic targets in PDAC, which should be further investigated to determine the specific molecular processes affected by their aberrant expression.
... Therapeutic options for PDAC, include surgical intervention, radiotherapy, chemotherapy treatment, target therapies, and combination therapies [25][26][27][28][29]. However, the best treatment choice for a single patient is still limited, and the clinical outcome not predictable even in the case of operable patients. ...
Citation: Caputo, C.; Falco, M.; Grimaldi, A.; Lombardi, A.; Miceli, C.C.; Cocule, M.; Montella, M.; Pompella, L.; Tirino, G.; Campione, S.; et al. Identification of Tissue miRNA Signatures for Pancreatic Ductal Adenocarcinoma. Cancers 2024, 16, 824. https://doi. Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and deadliest cancers worldwide, with an overall survival rate of <10% at 5 years. For most patients with unresectable or recurrent PDAC, few therapeutic options are available, with limited efficacy. Furthermore , there is an almost complete absence of validated predictive factors. At present, microRNAs represent a promising diagnostic, prognostic, and predictive method for the clinical management of patients, avoiding inappropriate treatments. Abstract: Pancreatic ductal adenocarcinoma (PDAC), a neoplasm of the gastrointestinal tract, is the most common pancreatic malignancy (90%) and the fourth highest cause of cancer mortality worldwide. Surgery intervention is currently the only strategy able to offer an advantage in terms of overall survival, but prognosis remains poor even for operated patients. Therefore, the development of robust biomarkers for early diagnosis and prognostic stratification in clinical practice is urgently needed. In this work, we investigated deregulated microRNAs (miRNAs) in tissues from PDAC Cancers 2024, 16, 824. https://doi.org/10.3390/cancers16040824 https://www.mdpi.com/journal/cancers Cancers 2024, 16, 824 2 of 21 patients with high (G3) or low (G2) histological grade and with (N+) or without (N−) lymph node metastases. miRNA expression profiling was performed by a comprehensive PCR array and subsequent validation by RT-qPCR. The results showed a significant increase in miR-1-3p, miR-31-5p, and miR-205-5p expression in G3 compared to G2 patients (** p < 0.01; *** p < 0.001; *** p < 0.001). miR-518d-3p upregulation and miR-215-5p downregulation were observed in N+ compared to N− patients. A statistical analysis performed using OncomiR program showed the significant involvement (p < 0.05) of two miRNAs (miR-31 and miR-205) in the histological grade of PDAC patients. Also, an expression analysis in PDAC patients showed that miR-31 and miR-205 had the highest expression at grade 3 compared with normal and other tumor grades. Overall, survival plots confirmed that the overexpression of miR-31 and miR-205 was significantly correlated with decreased survival in TCGA PDAC clinical samples. A KEGG pathway analysis showed that all three miRNAs are involved in the regulation of multiple pathways, including the Hippo signaling, adherens junction and microRNAs in cancer, along with several target genes. Based on in silico analysis and experimental validation, our study suggests the potential role of miR-1-3p, miR-31-5p, and miR-205-5p as useful clinical biomarkers and putative therapeutic targets in PDAC, which should be further investigated to determine the specific molecular processes affected by their aberrant expression.
... The lack of cardinal symptoms leads to late diagnosis, as most patients present with unresectable disease due to locally advanced involvement (30%) or metastatic disease (50%) at the time of diagnosis [5]. For metastatic pancreatic cancer (MPC), treatment with systemic chemotherapy plays an important role, as it remains the best management option to increase survival, alleviate symptoms, and ensure better quality of life (QoL) [6,7]. The management of MPC represents one of the main challenges for clinical oncologists and the need for new strategies is more evident in the context of molecular target-driven medicine. ...
Pancreatic cancer is one of the most lethal neoplasms worldwide; it is aggressive in nature and has a poor prognosis. The overall survival rate for pancreatic cancer is low. Most patients present non-specific symptoms in the advanced stages, which generally leads to late diagnosis, at which point there is no option for curative surgery. The treatment of metastatic pancreatic cancer includes systemic therapy, in some cases radiotherapy, and more recently, molecular targeted therapies, which can positively impact cancer control and improve quality of life. This review provides an overview of the molecular landscape of pancreatic cancer based on the most recent literature, as well as current treatment options for patients with metastatic pancreatic cancer.
... The pathological entity with which pancreatic HC is related is PAC, which is one of the leading causes of cancer-related mortality worldwide, mainly presenting at advanced stages, frequently metastatic, with limited conventional treatment efficacy (9,10). As the fourth most lethal form of cancer in the USA, PAC is associated with high mortality and poor survival rates. ...
... As the fourth most lethal form of cancer in the USA, PAC is associated with high mortality and poor survival rates. The incidence of pancreatic carcinoma is increasing worldwide and in western countries (9,11), with its annual incidence having been reported as high as 50,000 patients (12). PAC is estimated to be the eleventh most reported cancer in 2018 (13) or the fourteenth most common cancer, as reported in 2021 (14); however, it is the third or the seventh leading cause of cancer-related mortality, as reported in 2018 (13) and 2021 (14), respectively, mainly affecting older adults. ...
... PAC is estimated to be the eleventh most reported cancer in 2018 (13) or the fourteenth most common cancer, as reported in 2021 (14); however, it is the third or the seventh leading cause of cancer-related mortality, as reported in 2018 (13) and 2021 (14), respectively, mainly affecting older adults. The incidence of PAC is expected to increase further (9), and it is predicted to become the second leading cause of cancer-related mortality in western countries by the year 2030. The median age of diagnosis is 71 years in the USA, with only <1% of diagnoses performed prior to the age of 50. ...
In rare cases, metastatic adenocarcinomas of different origin may exhibit the features of hepatoid carcinoma (HC), a rare malignant epithelial tumor, most commonly occurring in the ovaries and stomach, as well as in the pancreas and biliary ducts. A case of a 72-year-old female patient who developed a highly aggressive, poorly differentiated pancreatic ductal adenocarcinoma with peritoneal carcinomatosis, demonstrating hepatoid differentiation upon conventional hematoxylin and eosin staining is reported in the present study. The patient presented with severe abdominal pain, and the radiological investigations performed revealed ovarian and hepatic tumor masses and peritoneal lesions, which were surgically removed. The gross examination of the peritoneum and omentum revealed multiple solid, firm, grey-white nodules, diffusely infiltrating the adipose tissue. The microscopic examination revealed a malignant epithelial proliferation, composed of polygonal cells with abundant eosinophilic cytoplasm and irregular, pleomorphic nuclei. Certain cells presented with intracytoplasmic mucus inclusions, raising suspicion of a HC with an uncertain histogenesis. Immunohistochemical staining was performed, and the tumor cells were found to be positive for cytokeratin (CK)7, CK18 and mucin 5AC, whereas negative staining for CK20, caudal-type homeobox transcription factor 2, α-fetoprotein, paired box gene 8, GATA-binding protein 3 and Wilms tumor 1 were documented. Thus, the diagnosis of metastatic pancreatic adenocarcinoma was established. The main aim of the present study was to provide further knowledge concerning poorly differentiated metastatic adenocarcinoma resembling HC, emphasizing the histopathological and immunohistochemical features of these malignant lesions and raising awareness of the diagnostic difficulties that may arise, as well as the importance of the use immunohistochemistry in differentiating carcinomas of uncertain histogenesis.
... Pancreatic adenocarcinoma is the top ten leading cause of death from cancer in the world [1]. About 80% of pancreatic adenocarcinoma patients present with locally advanced findings or metastasis at the time of diagnosis, and the median survival time is less than 1 year. ...
Metabolome profiles are largely unknown for pancreatic head cancers, in which the predominant anatomical feature is the exosure of bile, pancreatic juice, and duodenal juice. In this research, 30 head and 30 body/tail cytological samples acquired by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) of pancreatic adenocarcinoma were delivered for liquid chromatography coupled with mass spectrometry (LC-MS). Transcriptome analysis was performed using the sequencing data from The Cancer Genome Atlas (TCGA) cohort. LC-MS obtained 4,857 features in EUS-FNA cytological samples, and 586 metabolites were certified. Among them, 30 differential metabolites were identified. In the TCGA cohort, 247 differential metabolism genes were selected from 1,583 differential genes. The integrated analysis identified the top three enriched metabolic pathways as follows: branched chain amino acid (BCAA) biosynthesis; glycerophospholipid metabolism; and phenylalanine metabolism. In cell line, BCAA promoted pancreatic cancer proliferation and inhibited Oxaliplatin-induced apoptosis. In conclusion, metabolomic analysis with the EUS-FNA sample is feasible for pancreatic cancer. The integrated analysis can identify key metabolites and enzyme-coded genes between pancreatic head and body/tail adenocarcinoma. Anti-BCAA metabolism therapy may exert promising effect, especially for the body/tail cancer.
... Tumors are considered 'operable' if there is no invasion into the circulatory system and no metastases. Surgery usually entails either (i) a pancreaticoduodenectomy (removal of part of the pancreas, stomach, duodenum and gall bladder) for tumors found at the head of the pancreas or (ii) a pancreatectomy (removal of the pancreas partially or wholly) for those with tumor in the main body or tail [42]. Despite recent improvements in perioperative care, morbidity post-surgery is still around 40%. ...
... Despite recent improvements in perioperative care, morbidity post-surgery is still around 40%. Resection is often combined with radio-and/or chemotherapy, aiming to eliminate micro-metastases and improve survival in an adjuvant setting [42][43][44]. ...
... It may be applied systemically if the cancer has metastasized or may be combined with surgery in a neo-adjuvant or adjuvant setting [1,46]. Chemotherapy with gemcitabine is the first-line treatment against PDAC and is well tolerated with low side effects [42]. Gemcitabine (Gemzar®) is an 'antimetabolite' pro-drug which becomes active once phosphorylated into gemcitabine-P (diphosphate or triphosphate) inside cells. ...
Simple Summary
Pancreatic ductal adenocarcinoma is a devastating disease that is very hard to treat. Here, we advance and evaluate the notion that the best possible management currently would be possible by combining clinical procedures with evidence-based complementary measures. We evaluate three categories of such complementary measures: Diet (background and specific), nutraceutical agents and lifestyle factors. Altogether, these include alkalinity, low-glycemic index, low-cholesterol, red meat, fish, fruit/vegetables, dairy, honey, coffee, vitamins A, C, D, E, genistein and curcumin (dietary issues); propolis, triptolide and cannabidiol (nutraceuticals); and obesity, diabetes, smoking, alcohol and exercise (lifestyle factors). The available evidence is considered by four criteria: clinical trials, meta-analyses and in vivo and in vitro data. A total of nine agents satisfy these criteria. These are combined and divided into two groups. Finally, a scheme is proposed for integrating the two groups with gemcitabine chemotherapy on a weekly cycle.
Abstract
The most common form of pancreatic cancer is pancreatic ductal adenocarcinoma (PDAC), which comprises some 85% of all cases. Currently, this is the fourth highest cause of cancer mortality worldwide and its incidence is rising steeply. Commonly applied clinical therapies offer limited chance of a lasting cure and the five-year survival rate is one of the lowest of the commonly occurring cancers. This review cultivates the hypothesis that the best management of PDAC would be possible by integrating ‘western’ clinical medicine with evidence-based complementary measures. Protecting the liver, where PDAC frequently first spreads, is also given some consideration. Overall, the complementary measures are divided into three groups: dietary factors, nutraceutical agents and lifestyle. In turn, dietary factors are considered as general conditioners, multi-factorial foodstuffs and specific compounds. The general conditioners are alkalinity, low-glycemic index and low-cholesterol. The multi-factorial foodstuffs comprise red meat, fish, fruit/vegetables, dairy, honey and coffee. The available evidence for the beneficial effects of the specific dietary and nutraceutical agents was considered at four levels (in order of prominence): clinical trials, meta-analyses, in vivo tests and in vitro studies. Thus, 9 specific agents were identified (6 dietary and 3 nutraceutical) as acceptable for integration with gemcitabine chemotherapy, the first-line treatment for pancreatic cancer. The specific dietary agents were the following: Vitamins A, C, D and E, genistein and curcumin. As nutraceutical compounds, propolis, triptolide and cannabidiol were accepted. The 9 complementary agents were sub-grouped into two with reference to the main ‘hallmarks of cancer’. Lifestyle factors covered obesity, diabetes, smoking, alcohol and exercise. An integrative treatment regimen was devised for the management of PDAC patients. This involved combining first-line gemcitabine chemotherapy with the two sub-groups of complementary agents alternately in weekly cycles. The review concludes that integrated management currently offers the best patient outcome. Opportunities to be investigated in the future include emerging modalities, precision medicine, the nerve input to tumors and, importantly, clinical trials.
... While a number of chemotherapeutics have looked promising against PDAC cells in vitro, these agents have failed to provide durable clinical benefit; the treatment algorithm for patients in the palliative or adjuvant setting often consists of nab-paclitaxel and gemcitabine (GEM), but relapse and drug resistance are common [2]. For patients with a good performance score, in the neoadjuvant setting of borderline resectable tumors or in patients with metastatic disease Folfirinox, a combination drug regimen, became the first choice with even more toxic side effects, that extend the median survival only 2 to 4 months [4]. A lack of chemotherapeutic efficacy has been at least partially attributed to the desmoplastic and hypo-vascular microenvironment of PDAC tumors, which can limit drug access to the cancer cells. ...
Current therapies for treating pancreatic ductal adenocarcinoma (PDAC) are largely ineffective, with the desmoplastic environment established within these tumors being considered a central issue. We established a 3D spheroid co-culture in vitro model using a PDAC cell line (either PANC-1 or Capan-2), combined with stellate cells freshly isolated from pancreatic tumors (PSC) or hepatic lesions (HSC), and human type I collagen to analyze the efficiency of the chemotherapeutic gemcitabine (GEM) as well as two novel drug candidates derived from natural products: pseudopterosin (PsA-D) and O-methyltylophorinidine (TYLO). Traditional 2D in vitro testing of these agents for cytotoxicity on PANC-1 demonstrated IC 50 values of 4.6 (±0.47) nM, 34.02 (±1.35) µM, and 1.99 (± 0.13) µM for Tylo, PsA-D, and GEM, respectively; these values were comparable for Capan-2: 5.58 (±1.74) nM, 33.94 (±1.02) µM, and 0.41 (±0.06) µM for Tylo, PsA-D, and GEM, respectively. Importantly, by assessing the extent of viable cells within 3D co-culture spheroids of PANC-1 with PSC or HSC, we could demonstrate a significant lack of efficacy for GEM, while TYLO remained active and PsA-D showed slightly reduced efficacy: GEM in PANC-1/PSC (IC 50 = >100 µM) or PANC-1/HSC (IC 50 = >100 µM) spheroids, TYLO in PANC-1/PSC (IC 50 = 3.57 ± 1.30 nM) or PANC-1/HSC (IC 50 = 6.39 ± 2.28 nM) spheroids, and to PsA-D in PANC-1/PSC (IC 50 = 54.42 ± 12.79 µM) or PANC-1/HSC (IC 50 = 51.75 ± 0.60 µM). Microscopic 3D rendering supported these cytotoxicity outcomes, showing little or no morphological spheroid structure change during this period of rapid cell death. Our results support the use of this 3D spheroid Bioengineering 2020, 7, 57 2 of 20 co-culture in vitro model having a desmoplastic microenvironment for the identification of possible novel chemotherapeutic drug candidates for PDAC, such as TYLO and PsA-D.
... PC, a fatal disease, is one of the most common and aggressive malignant tumors occurring in the digestive system around the world and characterized by rapid and uncontrolled growth [1,2]. Owing to the lack of early detection and effective interventions, PC is usually diagnosed at an advanced stage and has the poorest prognosis in cancer malignancy, with a low 5-year survival rate of 7.7% [3][4][5]. Some measures including surgery, chemotherapy and targeted therapy, radiotherapy, and traditional Chinese medicine have been taken for the treatment of PC; however, its incidence and mortality rate are still increasing [1,3,5]. ...
Pancreatic cancer (PC), highly malignant, is one of the most lethal cancers. Interferon-induced transmembrane protein 1 (IFITM1) has recently been regarded as a new molecular marker in human cancers. However, the role of IFITM1 in PC remains unclear. In this study, a short hairpin RNA (shRNA) was constructed to assess the effect of IFITM1 on PANC-1 and ASPC-1 cells. The level of IFITM1 was downregulated in cells transfected with shRNA targeting IFITM1 (sh-IFITM1). Silencing of IFITM1 significantly decreased cell viability, downregulated the level of Ki-67, arrested cell at G1/S phase, reduced the number of cells in S phase, and decreased cyclinD1, cyclinE, CDK2, and CDK4 levels. Moreover, Hoechst staining and Western blotting analysis showed that cell apoptosis was induced by IFITM1. IFITM1 knockdown suppressed the MAPK signaling pathway by downregulation of p-ERK, p-P38, and p-JNK levels. These findings suggested that IFITM1 could be considered a potential therapeutic target for PC.
... Currently, only a limited number of chemotherapeutic agents have been demonstrated to be effective against PDAC, including gemcitabine and fluorouracil (5). Despite advancements in the treatment of pancreatic cancer, therapies for PDAC are inadequate and the prognosis of PDAC remains unoptimistic due to late detection, drug resistance, and high recurrence and metastatic rates (6,7). Thus, there is a critical need to improve survival rates by identifying novel treatment targets and prognostic factors for patients with PDAC. ...
Pancreatic ductal adenocarcinoma (PDAC) remains a major cause of cancer-associated mortality, with poor patient outcome. The present study aimed to identify key candidate genes and investigate the potential molecular mechanisms associated with the progression of PDAC. The GSE46234 dataset was downloaded from the Gene Expression Omnibus database, in order to identify the upregulated differentially expressed genes (DEGs) in PDAC. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to determine the biological functions and pathways of the upregulated DEGs, and a protein-protein interaction (PPI) network was subsequently constructed to screen the hub genes. Subsequently, survival analyses of the hub genes were undertaken in patients with PDAC, using The Cancer Genome Atlas dataset. Reverse transcription-quantitative (RT-q)PCR analysis was performed to assess the mRNA expression levels of the hub genes associated with the prognosis of patients with PDAC. In the present study, 65 upregulated DEGs were identified. GO analysis suggested that the DEGs were enriched in response to hypoxia, calcium ion and negative regulation of catecholamine. KEGG analysis demonstrated that the DEGs were enriched in gastric acid secretion, the ECM-receptor interaction and the cGMP-PKG signaling pathway. Among the 18 hub genes determined by module screening of the PPI network, upregulation of three key genes, abnormal spindle-like microcephaly-associated protein (ASPM), mitotic checkpoint serine/threonine-protein kinase BUB1 β (BUB1B) and protein spindly (SPDL1), was significantly associated with worse overall survival and disease-free survival time in patients with PDAC. Furthermore, ASPM, BUB1B and SPDL1 were demonstrated to be associated with advanced tumor stage, and their upregulation in PDAC tumor tissues was validated using RT-qPCR analysis. Taken together, the results of the present study demonstrate that ASPM, BUB1B and SPDL1 may have the potential to function as prognostic markers and therapeutic targets for PDAC.
... Ductal adenocarcinomas account for most pancreatic malignancies. Despite recent advances in imaging and management strategies, pancreatic adenocarcinoma continues to be one of the most common causes of cancer-related mortality worldwide [1,2]. Due to the lack of early specific symptoms and tendency of pancreatic adenocarcinoma to invade adjacent structures or to metastasize at an early stage, many patients with pancreatic cancer already have advanced disease at the time of diagnosis resulting in a high mortality rate [3]. ...
The accurate determination of resectability in patients with pancreatic cancer is a main goal of preoperative imaging after diagnosis. With advances in surgical techniques, the definition of resectability is in evolution, and it is crucial for radiologists to have an understanding of findings that are relevant to the determination of resectability. The parallel advancements in imaging technology are aiming to improve the ability of imaging modalities to predict resectability. Fifty patients with pancreatic ductal adenocarcinoma (PDAC) were analyzed for capability of apparent diffusion coefficient (ADC) values to predict possible tumor resectability. The patients were classified into resectable and unresectable groups based on magnetic resonance (MR) imaging criteria. Logistic regression analysis was used. Receiver operator characteristic (ROC) curve was reconstructed. Out of different prognostic variables, tumor size was the only significant predictor of tumor resectability. ROC curve analysis showed that ADC value is not a discriminator of tumor resectability (area under the curve (AUC) = 0.5, P value = 0.452). In patients with pancreatic adenocarcinoma, ADC values might be unreliable for prediction of tumor resectability in clinical practice. Low ADC value in such tumors is more attributed to fibrotic nature rather than grade of the tumor.
