General Tumor Marker Research Articles

Chromogranin A as surveillance biomarker in patients with carcinoids: CASPAR.

e16242 Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare cancers with highly heterogeneous growth rates, yielding very broad ranges of radiographic imaging intervals in standard guidelines, with a multitude of risk for patients. Better tools are needed to reduce risks for these patients. Chromogranin A (CgA) is released by GEP-NET cells and has been associated with increased tumor burden. The European Neuroendocrine Tumor Society (ENETS) considers CgA to be the most practical and useful general serum tumor marker in patients with NETs. However, clinical utility has been limited by the lack of prospective validation studies and by different sensitivity of CgA according to NET tumor type and volume. Accordingly, expert consensus guidelines have offered varying advice regarding the use of CgA to practicing clinicians. The aim was to evaluate the performance of the B·R·A·H·M·S CgA II KRYPTOR immunoassay to monitor the course of disease in patients with well-differentiated GEP-NETs (grade 1 and grade 2). This is the first prospective validation of a clinical algorithm for the interpretation of CgA values in patients with advanced GEP-NETs. Methods: This prospective, multi-center, observational study was designed to validate the performance of the B·R·A·H·M·S CgA II KRYPTOR assay in monitoring disease progression in a defined population of GEP-NET patients with minimal confounding from end organ dysfunction or concomitant medications (e.g. PPIs). Patients were followed for up to 36 months including the evaluation of tumor burden with RECIST 1.1 categorization by imaging (CT/MRI scans). A clinical cut-off for changes in CgA levels over time to indicate the risk that a tumor progression occurred was derived from a retrospective, bicentric observational pilot study. A change in CgA levels between visits was considered positive, if the CgA concentration increased by more than 50% to an absolute value of >100 ng/ml. Results: A total of 175 adult patients were enrolled, and 153 patients had measurable disease at baseline and ≥1 follow-up visit. Using the cut-off for CgA increase defined above resulted in a sensitivity of 34.4% (95%-CI: 25.6% - 44.3%, p < 0.001) and a specificity of 93.4% (95%-CI: 90.4% – 95.5%, p < 0.001). Positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio (LR+) and negative likelihood ratio (LR-) to diagnose whether a tumor progression occurred according RECIST 1.1 criteria were 57.9% (95% CI: 45.0-69.8), 84.3% (95% CI: 80.5-87.6), 5.20 (95% CI: 3.23-8.36), and 0.70 (95% CI: 0.61-0.81), respectively. The AUC was estimated at 0.731 (95% CI: 0.670-0.793). Conclusions: B·R·A·H·M·S CgA II KRYPTOR can be used in conjunction with other clinical methods as an aid in monitoring of disease progression during the course of disease and treatment in patients with gastroentero-pancreatic neuroendocrine tumors (GEP-NETs, grade 1 and grade 2).

Fusion of CT images and clinical variables based on deep learning for predicting invasiveness risk of stage I lung adenocarcinoma.

To develop a novel multimodal data fusion model by incorporating computed tomography (CT) images and clinical variables based on deep learning for predicting the invasiveness risk of stage I lung adenocarcinoma that manifests as ground-glass nodules (GGNs) and compare the diagnostic performance of it with that of radiologists. A total of 1946 patients with solitary and histopathologically confirmed GGNs with maximum diameter less than 3cm were retrospectively enrolled. The training dataset containing 1704 GGNs was augmented by resampling, scaling, random cropping, and so forth, to generate new training data. A multimodal data fusion model based on residual learning architecture and two multilayer perceptron with attention mechanism combining CT images with patient general data and serum tumor markers was built. The distance-based confidence scores (DCS) were calculated and compared among multimodal data models with different combinations. An observer study was conducted and the prediction performance of the fusion algorithms was compared with that of the two radiologists by an independent testing dataset with 242 GGNs. Among the whole GGNs, 606 GGNs are confirmed as invasive adenocarcinoma (IA) and 1340 are non-IA. The proposed novel multimodal data fusion model combining CT images, patient general data, and serum tumor markers achieved the highest accuracy (88.5%), area under a ROC curve (0.957), F1 (81.5%), F1weighted (81.9%), and Matthews correlation coefficient (73.2%) for classifying between IA and non-IA GGNs, which was even better than the senior radiologist's performance (accuracy, 86.1%). In addition, the DCSs for multimodal data suggested that CT image had a stronger influence (0.9540) quantitatively than general data (0.6726) or tumor marker (0.6971). This study demonstrated that the feasibility of integrating different types of data including CT images and clinical variables, and the multimodal data fusion model yielded higher performance for distinguishing IA from non-IA GGNs.

PCA, K-PCA, ICA ve Random Forest Kullanarak Yumurtalık Kanserinin Tahmini

Ovarian cancer, which is the most common in women and occurs mostly in the post-menopausal period, develops with the uncontrolled proliferation of the cells in the ovaries and the formation of tumors. Early diagnosis is very difficult and in most cases, it is a type of cancer that is in advanced stages when first diagnosed. While it tends to be treated successfully in the early stages where it is confined to the ovary, it is more difficult to treat in the advanced stages and is often fatal. For this reason, it has been focused on studies that predict whether people have ovarian cancer. In our study, we designed a RF-based ovarian cancer prediction model using a data set consisting of 49 features including blood routine tests, general chemistry tests and tumor marker data of 349 real patients. Since the data set containing too many dimensions will increase the time and resources that need to be spent, we reduced the dimension of the data with PCA, K-PCA and ICA methods and examined its effect on the result and time saving. The best result was obtained with a score of 0.895 F1 by using the new smaller-sized data obtained by the PCA method, in which the dimension was reduced from 49 to 6, in the RF method, and the training of the model took 18.191 seconds. This result was both better as a success and more economical in terms of time spent during model training compared to the prediction made over larger data with 49 features, where no dimension reduction method was used. The study has shown that in predictions made with machine learning models over large-scale medical data, dimension reduction methods will provide advantages in terms of time and resources by improving the prediction results.

Serum Endocan Levels Can Predict Malignancy Of Thyroid: A Prospective Clinical Study

Aim: The differential diagnosis of benign and malignant diseases of the thyroid is important in borderline malignancies and malignancies that have not been diagnosed with biopsy. This study aimed to determine endocan molecule levels in patients with thyroid cancer, nodular goiter and thyroiditis. Thus, it was aimed to determine the availability of the endocan molecule in the differential diagnosis of thyroid diseases. Material and Method: The study was conducted between March 1, 2018 and August 1, 2018. During this period, patients who were scheduled for surgery due to thyroid disease and wanted to participate in the study voluntarily were included in the study. A prospective, cross-sectional clinical trial was designed. Patients included in the study were divided into four groups, according to their pathology report results; Group 1: Papillary thyroid cancer (PTC), Group 2: Multinodular goiter on thyroiditis background, Group 3: Multinodular goiter (MNG), Group 4: Follicular thyroid cancer (FTC). Results : A total of 72 patients were included in the study. Multiple analysis comparing the four groups, showed no statistically significant difference between the groups (p>0.050). When the benign and malignant patient groups were compared, endocan levels were found to be statistically significantly higher in the malignant group (p=0.0375). When thyroid carcinoma groups were compared among themselves, the endocan level was detected to be higher in FTC, compared to PTC (p=0.047). Conclusion: The level of “endocan” was observed to increase in malignant thyroid diseases. This was particularly so in FTC, which shows spreading via the hematogenous route. This is an encouraging sign that the "endocan" molecule can be used as a general tumor marker. However, prospective additional studies with large randomized series are needed.

Urinary CE-MS peptide marker pattern for detection of solid tumors

Urinary profiling datasets, previously acquired by capillary electrophoresis coupled to mass-spectrometry were investigated to identify a general urinary marker pattern for detection of solid tumors by targeting common systemic events associated with tumor-related inflammation. A total of 2,055 urinary profiles were analyzed, derived from a) a cancer group of patients (n = 969) with bladder, prostate, and pancreatic cancers, renal cell carcinoma, and cholangiocarcinoma and b) a control group of patients with benign diseases (n = 556), inflammatory diseases (n = 199) and healthy individuals (n = 331). Statistical analysis was conducted in a discovery set of 676 cancer cases and 744 controls. 193 peptides differing at statistically significant levels between cases and controls were selected and combined to a multi-dimensional marker pattern using support vector machine algorithms. Independent validation in a set of 635 patients (293 cancer cases and 342 controls) showed an AUC of 0.82. Inclusion of age as independent variable, significantly increased the AUC value to 0.85. Among the identified peptides were mucins, fibrinogen and collagen fragments. Further studies are planned to assess the pattern value to monitor patients for tumor recurrence. In this proof-of-concept study, a general tumor marker pattern was developed to detect cancer based on shared biomarkers, likely indicative of cancer-related features.

A noninvasive cancer detection strategy based on gold nanoparticle surface-enhanced raman spectroscopy of urinary modified nucleosides isolated by affinity chromatography

The search for tumor biomarkers in the urine for cancer diagnosis is currently a hot topic in clinical oncology, with potential for cancer screening and diagnosis. Modified nucleosides excreted through the urine are considered to be a general tumor marker for various cancer types. Herein, we explore a new method that utilizes surface-enhanced Raman scattering (SERS) spectroscopy to obtain a complete biochemical profile of urinary modified nucleosides. In our method, modified nucleosides are first isolated from urine sample utilizing the excellent separation ability of affinity chromatography; then supplemented with gold (Au) nanoparticles as substrate for SERS spectroscopy analysis. The obtained SERS spectra present rich diagnostic and fingerprinting type signatures of urinary modified nucleosides. The utility of this new method in cancer detection was evaluated by analyzing urine samples from three groups of subjects: nasopharyngeal cancer patients (n=62), esophageal cancer patients (n=55), and healthy volunteers (n=52). Partial least squares and linear discriminant analysis (PLS-DA) were used to analyze and classify the SERS spectra of urinary modified nucleosides from nasopharyngeal cancer, esophageal cancer, and the normal group, achieving diagnostic sensitivities of 95.2%, 90.9% and 98.1% and specificities of 97.2%, 98.2% and 95.7%, respectively. These results demonstrated great potential of this novel method for non-invasive and label-free cancer detection and screening.

Widespread Expression of γ-Glutamyl Cyclotransferase Suggests It Is Not a General Tumor Marker

γ-Glutamyl cyclotransferase (GGCT) contributes to the γ-glutamyl cycle that regulates glutathione metabolism. Although GGCT has been implicated in several studies as a possible cancer marker, little is known about its distribution in cells and tissues. The authors investigated GGCT expression in normal tissues and tumors using Western blots and immunohistochemistry with a novel anti-GGCT monoclonal antibody. GGCT was detected in most organs and was mainly found in epithelial cells. Although the intracellular distribution was mainly cytoplasmic, in some situations, nuclear staining was strong. A significant increase in the expression of GGCT was found in tumors of the lung, esophagus, stomach, bile duct, and uterine cervix. In contrast, there was a significant decrease in expression in renal and urothelial tumors. These results suggest that GGCT may be a biomarker of tumors in a limited range of organs.

Biomarkers and Molecular Imaging in Gastroenteropancreatic Neuroendocrine Tumors

Neuroendocrine gastrointestinal and pancreatic tumors (GEP-NETs) are a heterogenous group of cancers with various clinical expressions. All tumors produce and secret various amines and peptides, which can be used as tissue and circulating markers. Chromogranin A (CgA) is a general tumor marker stored in secretory granules within the tumor cell and released upon stimulation. CgA is the best general tumor marker at the moment, expressed in 80-90% in all patients with GEP-NETs. CgA and NSE are used as tissue markers for the delineation of the neuroendocrine features of the tumors, but recently also the proliferation marker Ki-67 has been included in the standard procedure for evaluation of the proliferation. GEP-NETs are classified into well differentiated neuroendocrine tumors (Ki-67<2%), well-differentiated neuroendocrine carcinoma (Ki-67 2-20%), poorly differentiated neuroendocrine carcinoma (Ki-67>20%). The molecular imaging of NETs is based on the ability of these tumor cells to express somatostatin receptors as well as the APUD features. Octreoscan has been applied for imaging and staging of the disease for more than 2 decades and will nowadays be replaced by 68Ga-DOTA-Octreotate, with higher specificity and sensitivity. 18Fluoro-DOPA and 11C-5HTP are specific tracers for NETs with high specificity and selectivity. A new potential biomarker is auto-antibodies to paraneoplastic antigen MA2, which might indicate early recurrence of carcinoids after surgery with a curative intent. Circulating tumor cells (CTC) have been applied in GEP-NETs quite recently. There is still an unmet need for new markers.

English

Midkine (MK) is a heparin-binding growth factor and was found to be highly expressed in many types of human carcinomas. MK may become a novel tumor marker.&nbsp;In this study, we used&nbsp;the rabbit specific antibodies against human MK to establish a double antibody sandwich enzyme-linked immunosorbent assay (ELISA) of MK system and applied it to detect serum MK levels in different types of cancer patients. The standard curve, precision and recovery rate were tested, respectively, and serum MK concentration of 102 cancers patients and 102 normal individuals were detected using this method. The detection range of this method was 0.2 to 10 ng/ml (R2&nbsp;= 0.97). The average intra and intro-assay&nbsp;coefficients of variation&nbsp;(CVs) were 3.6 and 7.9%, respectively. The average recovery rate was 89.9% when some standard antigens were added into the serum. The medians (25th and 75th percentiles) of serum MK levels were 1.35 ng/ml (0.96 and 1.64) in cancer patients and 0.30 ng/ml (0.23 and 0.38) in the controls; the MK levels of the patients were significantly higher than those of the controls (P&lt;0.05). Moreover, 87.2% of the patients showed more than 0.6 ng/ml levels of MK. Serum MK could serve as a general tumor marker with a good potential for clinical application. &nbsp; Key words:&nbsp;Midkine, rabbit monoclonal antibody, sandwich ELISA, tumor marker.

The GNAS1 T393C Polymorphism Predicts Survival in Patients with Clear Cell Renal Cell Carcinoma

G proteins mediate signaling from cell surface receptors to specific intracellular proteins. In vitro cancer cell line studies revealed a link between the Galphas protein and proapoptotic processes. We have recently shown that TT genotypes of the GNAS1 T393C polymorphism display increased transcription of Galphas and a more favorable clinical course in bladder and colorectal cancer patients compared both with TC or CC genotypes. In the present study, 150 patients with clear cell renal cell carcinoma surgically treated by nephrectomy with curative intent were retrospectively genotyped to elucidate a potential association between T393C genotypes and clinical outcome. The C-allele frequency in the renal cell carcinoma patient group was 0.51, which is not significantly different from that of a healthy blood donor group. Kaplan-Meier curves for tumor progression, development of metastasis, and tumor-related death showed a significant association of the T393C polymorphism with outcome (5-year cancer-specific survival rates: TT, 91%; TC, 81%; CC, 69%; P = 0.015). Multivariate Cox proportional analysis of a 10-year follow-up confirmed the T393C polymorphism as an independent prognostic factor in clear cell renal cell carcinoma. Homozygous CC patients were at highest risk for progression (hazard ratio, 2.48; P = 0.009) or tumor-related death (hazard ratio, 3.15; P = 0.018) compared with T-allele carriers. Our results show that besides tumor stage, lymph node status, and tumor grade, the GNAS1 T393C status is a novel independent host factor for disease progression in patients with clear cell renal cell carcinoma and provides further evidence for the T393C polymorphism as a general prognostic tumor marker.

Carcinoid tumors: molecular genetics, tumor biology, and update of diagnosis and treatment.

Carcinoid tumors are rare neoplasms which, by tradition, have been divided into foregut, midgut, and hindgut tumors. Although they share many features, they seem to have different molecular backgrounds. Foregut tumors very often show involvement of the MEN1 gene with deletions and mutations, whereas midgut carcinoids display genetic changes on chromosome 18. Hindgut tumors in general show rather low proliferation capacity, and transforming growth factor-alpha/epidermal growth factor receptor autocrine mechanism may play a role in the tumor development. Sometimes it might be a problem to delineate the location of the primary carcinoid tumor, but analyzing thyroid transcription factor-1 can be of help, because this factor is only expressed in foregut carcinoid and not in midgut or hindgut tumors. Chromogranin A is an important general tumor marker for all types of carcinoid tumors. Somatostatin receptor scintigraphy is a cornerstone in staging and localization of carcinoid tumors, but newer techniques such as positron emission tomography will challenge its position in the future. Although surgical cure is not obtainable, a more aggressive surgery has emerged during the last decade. Debulking and other cytoreductive procedures are quite common today. Somatostatin analogues have been the treatment of choice in symptomatic patients with carcinoid tumors, but more recent studies have indicated a cytostatic effect of somatostatin analogues. Tumor-targeted radioactive treatment based on somatostatin analogues is now under clinical evaluation. Preliminary data indicate interesting clinical potentials.

Serum Immunoreactive Calcitonin: Useful as a General Tumor Marker?

Serum Immunoreactive Calcitonin: Useful as a General Tumor Marker?

The fibrinolytic system. A key to tumor metastasis?

Neither histologic nor clinical staging reliably correlates with patient survival or the time course of tumor metastatic spread. There is no general biologic tumor marker which is able to distinguish those patients with microscopic residual cancer who may benefit from adjuvant anticancer treatment from those patients cured by their primary treatment who do not require additional anticancer therapy. Our data suggest that tumor activation and inhibition of fibrinolysis are related to the likelihood of tumor spread. Calculation of mean activation/inhibition ratios (A/I ratios) in groups of tumors with and without metastatic spread demonstrated a statistically significant difference between their respective A/I ratios (p less than 0.001). In addition, the mean activation/inhibition ratios for secondary or "metastatic" lesions were significantly different from the mean activation/inhibition ratios of the original tumors from which they metastasized (p less than 0.001). Therefore, tumor activation/inhibition ratios would appear to have clinical reliability as biologic markers for the presence or absence of tumor metastases. These data may have important therapeutic implications that would permit the use of activation/inhibition ratios as a biologic marker for the presence or absence of tumor spread at the time of primary surgical excision of the tumor. These observations warrant further investigation into the mechanisms of tumor interaction with the fibrinolytic system.