Serum level of TSGF,CA242 and CA19-9 in pancreatic cancer

AIM:To establish a method to detect the expression of thetumor specific growth factor TSGF,CA242 and CA19-9 in serumand evaluate their value in diagnosis of pancreatic cancer.METHODS:ELISA and Biochemical colorimetric assay wereused to detect the serum content of TSGF,CA242 andCA19-9 in 200 normal cases,52 pancreatitis patients and96 pancreatic cancer patients.RESULTS:The positive likelihood ratios of TSGF,CA242and CA19-9 were 5.4,12.6 and 6.3,respectively,and theirnegative likelihood ratios were 0.10,0.19 and 0.17,respectively.With single tumor marker diagnosed pancreaticcancer,the highest sensitivity and specificity of TSGF were91.6% and 93.5%.In combined test with 3 markers,whenall of them were positive,the sensitivity changed to 77.0%and the specificity and the positive predictive value were100%.The levels of TSGF and CA242 were significantly higherin the patients with pancreatic cancer of head than those inthe patients with pancreatic cancer of body,tail and wholepancreas,but the expression of CA19-9 had no correlationwith the positions of the pancreatic cancer.The sensitivityof TSGF,CA242 and CA19-9 was increased with the progressin stages of pancreatic cancer.In stage Ⅰ,the sensitivity ofTSGF was markedly higher than CA242 and CA19-9.CONCLUSION:The combined use of TSGF,CA242 and CA19-9 expressions can elevate the specificity for pancreatic cancerdiagnosis.And it shows that it plays an important role todifferentiate positions and tissue typing.It is a forepartdiagnosis for the pancreatic cancer by combination checking.There is very important correlation between the three markersand the pancreatic cancer.     

Clinical value of serum tumor marker CA19-9 in pancreatic carcinoma

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CA 19–9 predicts resectability of pancreatic cancer even in jaundiced patients

Background

Surgical resection remains the only curative option for pancreatic adenocarcinoma. Despite recent improvements in medical imaging, unresectability is still often discovered at the time of surgery. It is essential to identify unresectable patients preoperatively to avoid unnecessary surgery. High serum CA 19-9 levels have been suggested as a marker of unresectability but considered inaccurate in patients with hyperbilirubinemia.

Prognostic impact of the ratio of preoperative CA19-9 to liver enzyme levels in pancreatic cancer patients with jaundice (predictability of combined CA19-9/AST and CA19-9/γ-GGT for jaundiced PDAC patients)

BackgroundCarbohydrate antigen 19–9 (CA19-9) has been reported as the most significant survival predictor of patients with pancreatic ductal adenocarcinoma (PDAC). However, the elevation of CA19-9 could interfere with obstructive jaundice and the predictive value of CA19-9 in PDAC patients with jaundice remains to be analyzed and elucidated to find possible adjustments.ObjectiveTo evaluate the predictability of preoperative CA19-9 and its adjustments for the overall survival (OS) of PDAC patients by analyzing the relationship between preoperative serum CA19-9 and total bilirubin (TBIL).MethodsA total of 563 consecutive patients who underwent surgery for primary pancreatic adenocarcinoma in our center between January 2015 and September 2018 were retrospectively reviewed. Clinicopathologic information was collected and preoperative parameters such as CA19-9, CEA, TBIL, γ-GGT, AST, ALT, and ALP were recorded as well as overall survival rates, which began from the date of operation to that of death or the last follow-up. Kaplan-Meier survival curves with log-rank test and Cox regression models were applied using SPSS and the survival and survminer packages in R software.ResultsUsing 39/390/1000 as the cut-off values for preoperative serum CA19-9, significant capability of OS stratification was found in the total cohort (p < 0.001, MST = 29.7/19.1/15.2/12.1 months) and patients with TBIL <102.6 μmol/L (p < 0.001, MST = 32.2/19.6/15.0/11.2 months). However, in the subgroup of TBIL≥102.6 μmol/L, this classification method was replaced by the combined scoring of CA19-9/AST and CA19-9/γ-GGT.ConclusionsAs an independent predictor of overall survival of PDAC patients, preoperative serum CA19-9 is defective in survival stratification when TBIL≥102.6 μmol/L but a positive survival prognosis could be achieved with the application of combined preoperative CA19-9/AST and CA19-9/γ-GGT.     

Relationship between serum calcium and CA 19-9 levels in colorectal cancer

AIM:To examine the calcium metabolism of colorectal cancer(CRC)in patients with colorectal cancer and control patients.METHODS:Seventy newly diagnosed CRC patients wereincluded.The healthy control group was age and gendermatched(n=32).Particular attention was devoted to therelationship between serum calcium of patients,and levelsof AFP,CEA,carbohydrate antigen 19-9(CA 19-9)(that couldbe considered as prognostic factors).Furthermore,theCa-sensing receptor(CaSR)gene A986S polymorphism wasinvestigated in these patients,as well as the relationshipbetween different CaSR genotypes and the data stated above.RESULTS:A lower level of ionized calcium(also correctedfor albumin)was found in the serum of CRC patients withnormal 25(OH)vitamin D levels.The ionized calciumconcentration was inversely correlated with the serum levelof CA.19-9.There was no difference in the distribution ofCaSR genotypes,between CRC patients and generalpopulation.The genotypes did not correlate with other dataexamined.CONCLUSION:Based on these results,lower levels ofserum calcium might be a pathogenic and prognostic factorin colorectal cancer.     

Usefulness of CA 19–9 for pancreatic cancer screening in patients with new-onset diabetes

Background: Generally, carbohydrate antigen 19–9(CA 19–9) is not useful for screening pancreatic cancer in the asymptomatic general population. This study aimed to evaluate the utility of CA 19–9 level as a screening indicator of pancreatic cancer in asymptomatic patients with new-onset diabetes.Methods: We retrospectively reviewed the medical records of patients who visited our health promotion center for health check-ups without cancer related symptoms from January 2005 to January 2014, and were newly diagnosed with diabetes mellitus(DM) within 2 years before their visit.Results: Of the 5111 asymptomatic patients with new-onset DM(2 years) selected for analyses, 87(1.7%) eventually developed pancreatic cancer after the health check-up. In the subgroup of 322 patients with high total bilirubin levels(1.7 mg/d L) at the screening time, 42(73.7%) of 57 patients with high CA19–9 levels(37 IU/m L) had been diagnosed as pancreatic cancer during follow-up period and 12(4.5%)of 265 patients with normal CA 19–9 levels had finally developed pancreatic cancer(OR = 16.3). In the subgroup of 4789 patients with normal bilirubin levels, pancreatic cancer had been detected in 20(3.8%)of 522 patients with high CA 19–9 level, while only 13(0.3%) in 4267 patients with normal CA 19–9 levels(OR = 12.6), respectively.Conclusion: CA 19–9 levels after a diagnosis of new-onset DM could be a useful biomarker of pancreatic cancer, especially in patients with high serum bilirubin.     

Clinical studies in the second line setting of advanced pancreatic cancer: are we making any progress?

Despite the enormous advances in clinical research in oncology, the prognosis of pancreatic carcinoma remains poor. The therapeutic options in this type of cancer are very limited, with modest results at present. In the 2012 American Society of Clinical Oncology (ASCO) Annual Meeting, four interesting trials on the second line treatment of pancreatic cancer were presented. The first study (Abstract #4017) with a phase II design suggested that maintenance therapy with sunitinib, after a complete course of standard first line treatment, was feasible and effective while the second phase I/II study (Abstract #4034) evaluated the role of trabedersen, an agent that inhibits TGF-β2 expression. Finally, the efficacy and toxicity of lapatinib combined with either FOLFOX (Abstract #e14533) or capecitabine (Abstract #e14569) were examined in the second line setting of pancreatic cancer.     

Utility of serum CA19-9 in diagnosis of cholangiocarcinoma： In comparison with CEA

AIM:The diagnosis of cholangiocarcinoma is often difficult,making management approaches problematic. A reliable serum marker for cholangiocarcinoma would be a useful diagnostic test. The aims of our study were to evaluate the usefulness of a serum CA19-9 determination in the diagnosis of cholangiocarcinoma.METHODS: We prospectively measured serum CA19-9 and CEA concentrations in patients with cholangiocarcinoma (n=35), benign biliary diseases (n=92), and healthy individuals (n=15). Serum CA19-9 and CEA concentrations were measured by an immunoradiometric assay without knowledge of the clinical diagnosis.RESULTS:The sensitivity of a CA19-9 value&gt;37KU&#183;L^-1 and a CEA value &gt;22μg&#183;L^-1 in diagnosing cholangiocarcinoma were 77.14% and 68.57%, respectively. When compared with the benign biliary diseases group,the true negative rates of serum CA19-9 and CEA were 84.78% and 81.52%,respectively. The false positive rates of serum CA19-9 and CEA were 15.22% and 18.48%, whereas the accuracy of serum CA19-9 and CEA were 82.68% and 77.95%,respectively. Serum CA19-9 and CEA concentrations were significantly elevated (P&lt;0.001 and P&lt;0.05) in patients with cholangiocarcinoma (290.31&#177;5.34KU&#183;L^-1 and 36.46&#177;18.03μg&#183;L^-1) compared with patients with benign biliary diseases (13.38&#177;2.59KU&#183;L^-1 and 13.84&#177;3.85μg&#183;L^-1) and healthy individuals (12.78&#177;3.69KU&#183;L^-1 and 11.48&#177;3.37μg&#183;L^-1). In 15 patients undergoing curative resection of cholangiocarcinoma,the mean serum CA19-9 concentration was decreased from a preoperative level of 286.41&#177;4.36KU&#183;L^-1 to a postoperative level of 62.01&#177;17.43KU&#183;L^-1 (P&lt;0.001), and the mean serum CEA concentration from 39.41&#177;24.35μg&#183;L^-1 to 28.69&#177;11.03μg&#183;L6-1(P&lt;0.05). In patients with cholangiocarcinoma,however, no correlation was found between serum CEA and CA19-9 concentrations (r=-0.036).CONCLUSION:These data suggest that the serum CA19-9 determination is a useful addition to the available tests for the differential diagnosis of cholangiocarcinoma. Serum CA19-9 is an effective tumor marker in diagnosing cholangiocarcinoma,deciding whether the tumor has been radically resected and monitoring effect of treatment.     

Utility of serum CA19-9 in diagnosis of cholangiocarcinoma:In comparison with CEA

AIM:The diagnosis of cholangiocarcinoma is often difficult,making management approaches problematic.A reliableserum marker for cholangiocarcinoma would be a usefuldiagnostic test.The aims of our study were to evaluate theusefulness of a serum CA19-9 determination in the diagnosisof cholangiocarcinoma.METHODS:We prospectively measured serum CA19-9 andCEA concentrations in patients with cholangiocarcinoma(n=35),benign biliary diseases (n=92),and healthyindividuals (n=15).Serum CA19-9 and CEA concentrationswere measured by an immunoradiometric assay withoutknowledge of the clinical diagnosis.RESULTS:The sensitivity of a CA19-9 value >37 KU·L~(-1)and a CEA value >22 μg·L~(-1) in diagnosing cholangiocarcinomawere 77.14% and 68.57%,respectively.When comparedwith the benign biliary diseases group,the true negativerates of serum CA19-9 and CEA were 84.78% and 81.52%,respectively.The false positive rates of serum CA19-9 andCEA were 15.22% and 18.48%,whereas the accuracy ofserum CA19-9 and CEA were 82.68% and 77.95%,respectively.Serum CA19-9 and CEA concentrations weresignificantly elevated (P<0.001 and P<0.05) in patients withcholangiocarcinoma (290.31±5.34 KU·L~(-1) and 36.46±18.03μg·L~(-1)) compared with patients with benign biliary diseases(13.38±2.59 KU·L~(-1) and 13.84±3.85 μg·L~(-1)) and healthyindividuals (12.78±3.69 KU·L~(-1) and 11.48±3.37 μg·L~(-1)).In 15patients undergoing curative resection of cholangiocarcinoma,the mean serum CA19-9 concentration was decreased froma preoperative level of 286.41±4.36 KU·L~(-1) to a postoperativelevel of 62.01±17.43 KU·L~(-1) (P<0.001),and the mean serumCEA concentration from 39.41±24.35 μg·L~(1) to 28.69±11.03μg·L~(-1)(P<0.05).In patients with cholangiocarcinoma,however,no correlation was found between serum CEA andCA19-9 concentrations (r=0.036).CONCLUSION:These data suggest that the serum CA19-9determination is a useful addition to the available tests for thedifferential diagnosis of cholangiocarcinoma.Serum CA19-9 isan effective tumor marker in diagnosing cholangiocarcinoma,deciding whether the tumor has been radically resected andmonitoring effect of treatment.     

Interaction of glibenclamide and metformin at the level of translation in pancreatic β cells

Sulfonylurea and metformin are used in the treatment of diabetes. Their chronic effects on β cells are not well known. We have shown that sustained exposure of rat β cells to glibenclamide increased their protein synthesis activity, while metformin caused an inhibition. The effect of glibenclamide was attributed to an activation of translation factors. This study examines whether both drugs interact at the level of protein translation in β cells. Purified rat β cells were cultured with and without glibenclamide and metformin before measurement of protein and insulin synthesis, abundance of (phosphorylated) translation factors, and cell viability. A 24?h exposure to metformin stimulated AMP-activated protein kinase (AMPK), suppressed activation of translation factors- both the mammalian target of rapamycin (mTOR; also known as mechanistic target of rapamycin, MTOR)-dependent ones (eukaryotic initiation factor 4E-binding protein 1 and ribosomal protein S6) and the mTOR-independent eukaryotic elongation factor 2-, and inhibited protein synthesis; a 72?h exposure resulted in 50% dead cells. These effects were counteracted by addition of glibenclamide, the action of which was blocked by the mTOR inhibitor rapamycin and the protein kinase A (PKA) inhibitor Rp-8-Br-cAMPs. In conclusion, metformin activates AMPK in β cells leading to suppression of protein translation through mTOR-dependent and -independent signaling. Glibenclamide antagonizes these metformin effects through activation of mTOR- and PKA-dependent signaling pathways.     

The epithelial-to-mesenchymal transition of human pancreatic β-cells: inductive mechanisms and implications for the cell-based therapy of type I diabetes

As a therapy for type I diabetes, islet transplantation provides clear benefits in terms of increased insulin-independence and a reduced risk of hypoglycemia. However, a critical shortage of donor pancreata means that few can benefit from this approach. The ex vivo expansion of human β-cells prior to transplantation could ameliorate this problem, however, attempts to grow large numbers of β-cells that retain their native phenotype have thus far failed. Recent lineage tracing studies suggest that this problem is due to the inherent tendency of cultured human β-cells to undergo a process reminiscent of epithelial-to-mesenchymal transition (EMT). EMT describes a highly complex process that culminates in a loss of epithelial cell polarity, severance of intercellular adhesive junctions and the acquisition of a highly motile mesenchymal phenotype. Interestingly, recent evidence suggests that a transient EMT-like process may also contribute to the delamination of endocrine progenitors and subsequent islet neogenesis. The inherent susceptibility of cultured human β-cells to EMT, and the potential involvement of this process during islet neogenesis, raises important questions as to how this process is triggered and subsequently regulated. The primary purpose of this review is to describe those factors, pathways or processes that are complicit in inducing or regulating the mesenchymal transition of human β-cells. This includes addressing the role of the extracellular matrix, the contribution of select signaling pathways, and the regulatory function of microRNAs. We propose that manipulation of these cues and pathways offers the greatest potential for restoring β-cell function after ex vivo expansion.     

What are the current and potential future roles for endoscopic ultrasound in the treatment of pancreatic cancer?

Pancreatic adenocarcinoma is the fourth leading cause of cancer-related death in the United States. Due to the aggressive tumor biology and late manifestations of the disease, long-term survival is extremely uncommon and the current 5-year survival rate is 7%. Over the last two decades, endoscopic ultrasound(EUS) has evolved from a diagnostic modality to a minimally invasive therapeutic alternative to radiologic procedures and surgery for pancreatic diseases. EUSguided celiac plexus intervention is a useful adjunct to conventional analgesia for patients with pancreatic cancer. EUS-guided biliary drainage has emerged as a viable option in patients who have failed endoscopic retrograde cholangiopancreatography. Recently, the use of lumen-apposing metal stent to create gastrojejunal anastomosis under EUS and fluoroscopic guidance in patients with malignant gastric outlet obstruction has been reported. On the other hand, anti-tumor therapies delivered by EUS, such as the injection of anti-tumor agents, brachytherapy and ablations are still in the experimental stage without clear survival benefit. In this article, we provide updates on well-established EUS-guided interventions as well as novel techniques relevant to pancreatic cancer.     

COVID-19 and myeloma: what are the implications for now and in the future?

The pandemic has affected every aspect of myeloma care. Immediate focus is minimising risk of contracting coronavirus disease 2019 (COVID-19) and the sequelae of infection. However, what does the future hold for our patients? What lessons will be taken forward to tackle myeloma in the fiscally constrained future? If we embrace the challenges that will emerge in the post-pandemic environment, the treatment delivered to patients could be more cost-effective and better tailored than before. Healthcare delivery post-COVID-19 will not return to how it was, and now is the time to invest in novel strategies to deliver the best possible outcomes for patients.     

Comment on “Prognostic value of preoperative enhanced computed tomography as a quantitative imaging biomarker in pancreatic cancer”

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies because of its high invasiveness and metastatic potential. Computed tomography (CT) is often used as a preliminary diagnostic tool for pancreatic cancer, and it is increasingly used to predict treatment response and disease stage. Recently, a study published in World Journal of Gastroenterology reported that quantitative analysis of preoperative enhanced CT data can be used to predict postoperative overall survival in patients with PDAC. A tumor relative enhancement ratio of ≤ 0.7 indicates a higher tumor stage and poor prognosis.     

Mechanisms of disease: chronic inflammation and cancer in the pancreas--a potential role for pancreatic stellate cells?

Late diagnosis and ineffective therapeutic options mean that pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer. The identification of genetic alterations facilitated the launch of the Pancreatic Intraepithelial Neoplasm nomenclature, a standardized classification system for pancreatic duct lesions, but the factors that contribute to the development of such lesions and their progression to high-grade neoplasia remain obscure. Age, smoking, obesity and diabetes confer increased risk of PDA, and the presence of chronic pancreatitis is a consistent risk factor for pancreatic cancer. It is hypothesized that chronic inflammation generates a microenvironment that contributes to malignant transformation in the pancreas, as is known to occur in other organs. Pancreatic stellate cells (PSCs) are the main mediator of fibrogenesis during chronic pancreatitis, but their contribution to the development of PDA has not been elucidated. Data now suggest that PSCs might assume a linking role in inflammation-associated carcinogenesis through their ability to communicate with inflammatory cells, acinar cells, and pancreatic cancer cells in a complicated network of interactions. In this Review, the role of PSCs in the process of inflammation-associated carcinogenesis is discussed and new potential treatment options evaluated.     

Clinical assessment and identification of immuno-oncology markers concerning the 19-gene based risk classifier in stage Ⅳ colorectal cancer

BACKGROUND Genomic profiling of tumors has contributed to the understanding of colorectal cancer(CRC), facilitating diagnosis, prognosis and selection of treatments,including targeted regimens. A report suggested that a 19-gene-based risk classifier(TCA19) was a prognostic tool for patients with stage III CRC. The survival outcomes in patients with stage IV CRC are still poor and appropriate selection of targeted therapies and immunotherapies is challenging.AIM To assess clinical implication of TCA19 in patients with stage IV CRC, and to identify TCA19 with involvement in immune-oncology.METHODS A retrospective review of the medical records of 60 patients with stage IV CRC was conducted, assessing clinicopathological variables and progression-free survival(PFS). TCA19 gene expression was determined by quantitative polymerase chain reaction(qPCR) in matched normal and tumor tissues taken from the study cohort. Expression of potential immune-oncology regulatory proteins and targets was examined by immunohistochemistry(IHC), western blot, immunofluorescence staining in tissues from a validation cohort of 10 patients, and in CRC cell lines co-cultured with monocyte in vitro.RESULTS In the patients with TCA19 score higher than the median, the PFS rates of eight patients who received the targeted regimens were significantly higher than the PFS rates of four patients who received 5-fluorouracil-based regimen(P = 0.041).In multivariate analysis, expression of signaling lymphocytic activation molecule family, member 7(SLAMF7) and triggering receptor expressed on myeloid cells 1(TREM1) was associated with PFS in the 60-patient cohort. After checking another 10 validate set, the expression of the IHC, the level of real-time qPCR,and the level of western blot were lower for SLAMF7 and higher for TREM7 in primary and metastatic tumors than in normal tissues. In CRC cells expressing SLAMF7 that were co-cultured with a monocytic cell line, levels of CD 68 and CD73 were significantly lower at day 5 of co-culture than at day 0.CONCLUSION The TCA19 score might be prognostic for target-regimen-specific PFS in stage IV CRC. Down-regulation of SLAMF7 and up-regulation of TREM1 occur in primary and metastatic tumor tissues.