bluuebunny/crossref_metadata_2025 huggingface dataset:
Blood-Borne Cancer Cells – Quo Vadis?
Authors: Brandt B. , Schmitt H. , Feldner J.C. , Lellé R.J. , Semjonow A. , Beckmann A.
Published: March 2018

The detection of blood-borne cancer cells may help in clinical staging and further understanding of cancer metastasis. We developed a cytokeratin-based immunomagnetic method to isolate epithelium-derived cells from the circulating blood of patients. The number of cell clusters positive for cytokeratin/prostate-specific antigen (PSA) from the peripheral blood of prostate cancer patients and cytokeratin/p185c-erbB-2 from the peripheral blood of breast cancer patients has been related to stage of the disease. Breast cancer patients who presented cytokeratin/p185c-erbB-2-positive cell clusters showed a decrease in such cells under adriamycin adjuvant therapy with Further molecular characterization by a highly sensitive microsatellite multiplex-PCR enabled reproducible detection of microsatellite alterations. The impact of these individually targeted results may contribute to an individual diagnostic and therapeutic strategy.
Neural Network Analysis of Follow-Up Data in Primary Breast Cancer
Authors: Harbeck N. , Kates R. , Ulm K , Graeff H. , Schmitt M.
Published: March 2018

This paper reports on the performance of a recently developed neural network environment incorporating likelihood-based optimization and complexity reduction techniques in the analysis of breast cancer follow-up data with the goal of building up a clinical decision support system. The inputs to the neural network include classical factors such as grading, age, tumor size, estrogen and progesterone receptor measurements, as well as tumor biological markers such as PAI-1 and uPA. The network learns the structural relationship between these factors and the follow-up data. Examples of neural models for relapse-free survival are presented, which are based on data from 784 breast cancer patients who received their primary therapy at the Department of Obstetrics and Gynecology, Technische Universität München, Germany. The performance of the neural analysis as quantified by various indicators (likelihood, Kaplan-Meier curves, log-rank tests) was very high. For example, dividing the patients into two equally sized groups based on the neural score (i.e., cutoff = median score) leads to an estimated difference in relapse-free survival of 40% or better (80% vs. 40%) after 10 years in Kaplan-Meier analysis. Evidence for factor interactions as well as for time-varying impacts is presented. The neural network weights included in the models are significant at the 5% level. The use of neural network analysis and scoring in combination with strong tumor biological factors such as uPA and PAI-1 appears to result in a very effective risk group discrimination. Considerable additional comparison of data from different patient series will be required to establish the generalization capability more firmly. Nonetheless, the improvement of risk group discrimination represents an important step toward the use of neural networks for decision support in a clinical framework and in making the most of biological markers.
The Clinical Significance of Thymidine Kinase 1 Measurement in Serum of Breast Cancer Patients Using Anti-TK1 Antibody
Authors: He Q. , Zou L. , Zhang P.A. , Lui J.X. , Skog S. , Fornander T.
Published: March 2018

The activity of total thymidine kinase in serum (S-TK) has been used as a tumor maker for decades. To date such activity has been determined using [125]I-iodo-deoxyuridine as a substrate. The aim of this study was to develop a new, antibody-based technique for the measurement of cytoplasmic thymidine kinase (TK1) in serum. Both mono- and polyclonal antibodies against S-TK1 were used in dot blot assay. S-TK1 was characterized by SDS and IEF techniques. Sixty-five breast cancer patients were studied, including 17 preoperative and 38 postoperative tumor-free patients and 10 patients with metastases to the lymph nodes (N1–2). They were compared to patients with benign tumors (n=21) and healthy volunteers (n=11). S-TK1 was low (0–1.0 pM) in healthy volunteers, while in preoperative patients the level was increased 6–110-fold. Significant differences were observed between preoperative patients and healthy volunteers (p=0.005), preoperative patients and patients with benign tumors (p<0.001), and preoperative patients and postoperative patients without metastases (p<0.001). No significant difference was observed between preoperative patients and postoperative patients with metastases (p=0.191). The S-TK activity in preoperative patients was also high in serum, but no decrease was observed following surgery. In conclusion, the anti-TK1 antibody could be a good marker for monitoring the response of breast cancer patients to therapy.
Prognostic Value of CA125 Kinetics and Half-Life in Advanced Ovarian Cancer
Authors: Čolaković S. , Lukiç V. , Mitroviç L. , Jeliç S. , Susnjar S. , Marinkoviç J.
Published: March 2018

This retrospective study was undertaken in order to assess the prognostic value of prechemotherapy serum CA125 level, CA125 kinetics, and CA125 half-life compared to the ten common clinicopathological variables in patients with advanced ovarian cancer (AOC). CA125 serum levels were determined before and during induction cisplatin polychemotherapy in 222 patients. A prechemotherapy CA125 level higher than 35 U/mL was found in 134 patients. Blood samples were further obtained before each course of chemotherapy (CT). CA125 half-life values were calculated in 112 patients with CA125 levels above 60 U/mL using van der Burg's exponential regression model. The prechemotherapy CA125 level had no prognostic value for survival. However, the median survival time of patients with CA125 levels below the upper normal limit of normality after two courses of CT was 101 months compared to a median survival of 21 months in patients without CA125 normalization (p=0.0000). Half-life calculation showed a significant correlation with survival. The median survival times of patients with T 1/2 <20 days and T 1/2 >20 days were 101+ and 18 months, respectively (p=0.0003). In a survival analysis using the Cox proportional hazard model, independent prognostic variables for survival included therapeutic response (p<0.0001), Karnofsky index (p<0.0001), residual disease (p<0.0001), tumor grade (p=0.0002), CA125 half-life (p=0.007), and CA125 kinetics (p=0.04). As a consequence, the possibility to predict treatment response by the CA125 half-life during chemotherapy and the time needed for normalization of CA125 levels can divide patients into good and poor prognostic groups early during chemotherapy.
Optimizing Efficacy of Quick Parathyroid Hormone Determination in the Operating Theater
Authors: Mengozzi G. , Baldi C. , Aimo G. , Mullineris B. , Salvo R. , Biasiol S. , Pagni R. , Gasparri G.
Published: March 2018

The usefulness of intraoperative parathyroid hormone (PTH) monitoring has been extensively documented in primary hyperparathyroidism (HPT), whereas few data have been published on its use in reoperations or in secondary and tertiary HPT. We report our initial experience with a rapid (12 min response) PTH immunochemiluminometric assay performed in the operating room during surgery in 12 patients with primary HPT, 16 end-stage renal disease patients with secondary HPT and five kidney transplanted subjects with tertiary HPT. Blood samples were taken at baseline, within 10 min after resection and subsequently at various intervals whenever needed. The mean PTH levels before and after parathyroidectomy were 230.5 pg/mL (range 69–842) and 47.3 pg/mL (range 5–184), respectively, in primary HPT, 855.0 pg/mL (416–1655) and 202.2 pg/mL (53–440) in secondary HPT, and 205.6 pg/mL (116–301) and 45.4 pg/mL (18–97) in tertiary HPT. All patients but one had a significant percentage decline from pre-excision values (mean 76.9%, 76.0%, and 76.1% in primary, secondary and tertiary HPT, respectively). While a reduction of more than 50% was observed in 30 out of 33 patients after the first intraoperative sampling, additional measurements were performed in 10 cases. On-site PTH monitoring with this user-friendly and reliable system has proved helpful in targeting PTH tests to give the surgeon a rapid and accurate assessment of the intervention. The development of optimal PTH sequence strategies with decision-focused analytical and clinical limits will improve the efficacy of “point-of-care” PTH assay and resource utilization.
Anticancer Drug Action on Poly(A) Polymerase Activity and Isoforms during Hela and Wish Cell Apoptosis
Authors: Balatsos N.A.A. , Havredaki M. , Tsiapalis C.M.
Published: March 2018

Poly(A) polymerase (PAP; EC 2.7.7.19) catalyzes mRNA polyadenylation. Its activity and isoform levels vary during cell cycle transformation and apoptosis. It has become widely accepted that cell death after DNA damage by anticancer agents is primarily the result of apoptosis and that cells able to evade apoptosis will be resistant to cell killing. The therapeutic agents interferon (IFN), 5-fluorouracil (5-FU) and tamoxifen (Tam) with different mechanisms of action mediate both partial dephosphorylation and inactivation of PAP, detected by immunoblotting analysis and PAP enzyme assay, respectively. We examined the apoptotic tendencies of HeLa and WISH cell lines caused by one of the drugs used, 5-FU. The trend in the cells examined, observed by DAPI and/or DNA fragmentation assay, was found to be accompanied by and reversibly related to PAP activity levels and PAP lower mobility phosphorylated forms of 106 and 100 kDa isoforms. Moreover, a cell type-modulated, differential response of HeLa (chemosensitive cells) versus WISH (drug-resistant diploid cells) has been revealed. This finding yields information on the possible use of PAP as a tumor marker involved in cell commitment and/or induction of apoptosis and may help to improve our understanding of tumor cell sensitivity to anticancer agents.
EORTC Receptor and Biomarker Study Group Report: A Sandwich Enzyme-Linked Immunosorbent Assay for Vascular Endothelial Growth Factor in Blood and Tumor Tissue Extracts
Authors: Span P.N. , Grebenchtchikov N. , Geurts-Moespot J. , Westphal J.R. , Lucassen A.M.J. , Sweep C.G.J.
Published: March 2018

A four-antibody sandwich enzyme-linked immunosorbent assay (ELISA) for vascular endothelial growth factor (VEGF) for application in blood (serum and plasma) and tumor tissue extracts was set up within the framework of the EORTC Receptor and Biomarker Study Group (RBSG). Polyclonal antibodies against VEGF165 were raised in chickens and rabbits, and used in a previously described assay format. The assay was validated and characterized for use in serum, plasma and tumor tissue extracts. The resulting VEGF ELISA was found to be specific for VEGF165 and VEGF121, the main isoforms of VEGF. The assay showed good precision and parallelism in serial dilutions of samples. The assay was not susceptible to interference by heterophilic antibodies because avian antibodies (duck anti-chicken and chicken anti-VEGF) were used in the pre-analyte stage and mammalian antibodies (rabbit anti-VEGF and goat anti-rabbit) in the post-analyte stage. In conclusion, a sensitive, robust and specific VEGF ELISA has been developed. Research into the prognostic value of VEGF employing this assay is currently underway.
Cholestasis is the Main Determinant of Abnormal CA 19–9 Levels in Patients with Liver Cirrhosis
Authors: Giannini E. , Borro P. , Botta F. , Chiarbonello B. , Fasoli A. , Malfatti F. , Romagnoli P. , Testa E. , Risso D. , Lantieri P.B. , Antonucci A. , Boccato M. , Milone S. , Testa R.
Published: March 2018

Background/Aims

Altered CA19–9 levels are commonly found in patients with liver cirrhosis though a clear explanation for this finding has not yet been given. The aim of this study was to investigate whether CA19–9 levels might be related to alterations in biochemical parameters and/or to functional impairment in cirrhotic patients with and without hepatocellular carcinoma. Methods: We studied 126 patients with liver cirrhosis, 60 of whom also had hepatocellular carcinoma. CA19–9 values were related to clinical, biochemical and functional parameters. In half of the patients CA19–9 levels were related to the monoethylglycinexylidide test, which is a dynamic liver function test.

Results

In more than half the cases CA19–9 values were above the upper limit. Liver function worsening as assessed by Child-Pugh's score and monoethylglycinexylidide test did not seem to influence the alteration of the marker. By contrast, in univariate analysis CA19–9 correlated with aminotransferases, γ-glutamyltransferase and alkaline phosphatase. Multivariate analysis showed that besides alkaline phosphatase also the presence of hepatocellular carcinoma might influence the alteration of CA19–9, although the marker was of no use for the diagnosis of liver cancer in patients with altered though not diagnostic α-fetoprotein levels.

Conclusions

In our study we confirmed the correlation of CA19–9 levels with cholestasis and cytolysis parameters. Moreover, we found no association between CA19–9 levels and impaired liver function as assessed by means of the Child-Pugh's score and the monoethylglycinexylidide test, which is cholestasis-independent and explores liver metabolic and clearance activities. The cholestatic picture that characterizes liver cirrhosis might enhance the expression and passage of the marker from the bile to the blood. The addition of CA19–9 assessment is not useful for the diagnosis of hepatocellular carcinoma in patients with non-diagnostic levels of α-fetoprotein. Caution should therefore be used when evaluating CA19–9 in cirrhotic patients with cholestasis, since false positive results may occur.
The Role of Blood Tumor Marker Measurement (Using a Biochemical Index Score and C-Erbb2) in Directing Chemotherapy in Metastatic Breast Cancer
Authors: Cheung K.L. , Pinder S.E. , Paish C. , Sadozye A.H. , Chan S.Y. , Evans A.J. , Blamey R.W. , Robertson J.F.R.
Published: March 2018

The role of blood tumor markers in monitoring response in advanced breast cancer is established in endocrine therapy and standard chemotherapy. This study examines marker levels in patients receiving new chemotherapy regimens. Thirty patients were recruited into two multicenter trials in which docetaxel-based regimens were used in 15 patients. The other 15 received doxorubicin-based regimens. Biochemical response calculated from a score using CA15.3, CEA and ESR was compared with UICC response. Marker changes at 2, 4 and 5 months correlated with UICC response at 3, 41/2 and 6 months, respectively (p < 0.03). Eleven patients achieved both clinical/radiological and biochemical response at the end of treatment; markers had not yet returned to below cutoffs in seven, suggesting a possible advantage to continue chemotherapy. No patient showed a biochemical response whilst judged clinically/radiologically progressive. Nineteen patients had progressed either clinically/radiologically or biochemically at six months; of these, eight showed progression assessed earlier by markers so that a median of four cycles of chemotherapy could have been saved. Measurements of serum c-erbB2 showed a correlation with tissue c-erbB2 staining in the primary tumor (p < 0.003). Among the patients with positive tissue staining, sequential changes in serum c-erbB2 completely paralleled initial response.
Chemotherapy and Angiogenesis in Advanced Cancer: Vascular Endothelial Growth Factor (VEGF) Decline as Predictor of Disease Control during Taxol Therapy in Metastatic Breast Cancer
Authors: Lissoni P. , Fugamalli E. , Malugani F. , Ardizzoia A. , Secondino S. , Tancini G. , Gardani G.S.
Published: March 2018

Angiogenesis is essential for tumor growth. Since vascular endothelial growth factor (VEGF) represents the main angiogenic factor, the control of VEGF secretion could constitute the most important mechanism to achieve the inhibition of angiogenesis-related processes. High blood concentrations have been proven to correlate with poor prognosis in advanced cancer. In experimental conditions, chemotherapeutic agents such as taxol appeared to inhibit VEGF-induced angiogenesis, while at present there are no data about the influence of chemotherapy on VEGF secretion in cancer patients. This preliminary study was performed to evaluate the effect of taxol therapy on VEGF secretion in advanced cancer patients in relation to the clinical response. The study included 14 patients with metastatic breast cancer who were treated with taxol monochemotherapy (175 mg/m2 i.v. every 21 days for three cycles). Serum levels of VEGF were measured by ELISA in blood samples collected before therapy and at 21-day intervals. The clinical response consisted of partial response (PR) in three and stable disease (SD) in six patients, whereas the other five patients had progressive disease (PD). Abnormally high pre-treatment levels of VEGF were seen in 8/14 patients. VEGF mean values significantly decreased during taxol therapy in patients with PR or SD, whereas no decline was observed in patients with PD. Moreover, the percent of normalization or decline greater than 50% in VEGF levels was significantly higher in patients with PR or SD than in those with PD (5/9 vs. 0/5). This preliminary study would suggest that the efficacy of taxol therapy in metastatic breast cancer - at least in terms of disease stabilization - may be associated with a decrease in VEGF blood levels followed by potential inhibition of cancer-related neovascularization.
Monitoring Therapy by Serum HER-2/Neu
Authors: Schwartz M.K. , Smith C. , Schwartz D.C. , Dnistrian A. , Neiman I.
Published: March 2018

We have evaluated the performance of the Bayer Immuno 1™ serum HER-2/neu assay. The precision is excellent and varied between 1.7% and 2.1% at values of HER-2/neu ranging from 16.8 ng/mL to 108.6 ng/mL. In normal women who were followed on a monthly basis the average deviation was 6%. The concentration (mean ± SD) in normal women was 8.7 ± 3.2 ng/mL. There was no difference between pre and postmenopausal women. The normal/abnormal cutoff was defined as greater than 15 ng/mL. In normal women and those with benign disease the specificity varied between 95% and 100%. In women with breast cancer the sensitivity was 1.7% in stage I disease, 3.0% in stage II, 16.7 in stage III and 35.5% in stage IV. There were 56 elevations (14.7%) in the total group of 285 women with breast cancer. There was an excellent correlation with a microtitre plate method (r=0.9944). Longitudinal studies showed clearly that women who expressed HER-2/neu in their tissue had elevated serum levels and these levels reflected the clinical course of the patient. More extensive control studies are required to establish the role of HER-2/neu assays in the management of women with breast cancer.
Surrogate Markers of Tumoral Angiogenesis
Authors: Byrne G.J. , Bundred N.J.
Published: March 2018

Background

Angiogenesis is a prerequisite for tumor growth and metastasis. Vascular cell adhesion molecule-1 (VCAM-1) is expressed on endothelial cells as a result of vascular endothelial growth factor (VEGF) stimulation.

Purpose

To determine if measurement in serum of VEGF or VCAM-1 provides an accurate measure of tumor angiogenesis.

Methods

VCAM-1 and VEGF were measured in the serum of women with early and advanced breast cancer by ELISA. Levels were compared to levels of VCAM-1 and VEGF in women with normal breasts and levels of the endothelial glycoprotein von Willebrand factor. Levels of VEGF and VCAM-1 in women with early breast cancer were correlated with established clinicopathological prognostic markers and intratumoral microvessel density (IMD).

Results

In early breast cancer serum VCAM-1 correlated closely with the microvessel density in tumors (r=0.61, p<0.001). Women with lymph node-positive and high-grade tumors had higher levels of serum VCAM-1 than women with lymph node-negative and low-grade tumors. Serum VEGF demonstrated no correlation with established prognostic features or IMD. Levels of VCAM-1 and VEGF were raised in women with advanced breast cancer.

Conclusion

Serum VCAM-1 is a surrogate marker of angiogenesis in breast cancer and its measurement may help in the assessment of antiangiogenic drugs currently in phase II trials.
Use of a Variety of Biological Parameters in Distinguishing Cirrhotic from Malignant Ascites
Authors: Alexandrakis M.G. , Moschandrea J. , Kyriakou D.S. , Alexandraki R. , Kouroumalis E.
Published: March 2018

Twenty-two different protein measurements were taken in the serum and ascitic fluid of fifty consecutive patients in an attempt to investigate which tests are the most reliable for the differential diagnosis of ascites. Serum and ascitic fluid total proteins (TPR), albumin (ALB), lactate (LAC), ferritin (FER), C3 and C4 complement factors, C-reactive protein (CRP), ceruloplasmin (CER), α2-macroglobulin (α2MG), haptoglobin (HAP), α1-antitrypsin (α1AT), α1-acid glycoprotein (α1AG), transferrin (TRF), immunoglobulins IgG, IgA, IgM and cytokines such as interleukin-1α (IL-1α), interleukin-1α (IL-1α), interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-α) were measured to distinguish between malignant and cirrhotic ascites. Correlations and non-parametric Mann-Whitney tests were used for ascitic fluid:serum ratio comparisons between the two groups. Multivariate analyses were used to determine the most significant biochemical ratio predictors for the differential diagnosis and a recursive partitioning model was constructed. Highly positive correlations (r>0.50) were found between the ratios IgA, IgG, IgM, CER, α2 MG, HAP, α1AT, α1AG and TRF. There was evidence that TPR, ALB, LAC, FER, IgG, CER, α2MG, α1AT, α1AG, TRF and IL-8 ascitic fluid:serum ratios are significnatly higher in patients with malignant neoplasms than in cirrhotics. In the recursive partitioning model the most significant parameters were found to be the ratios of albumin and IL-1a. The model fitted allowed for 100% correct classification of ascites. In conclusion, we have shown that a simple and very accurate model based on two ascitic fluid: serum measurements is able to differentiate between malignant and non-malignant ascites.
Immunoradiometric Assay of Chromogranin a in the Diagnosis of Small Cell Lung Cancer: Comparative Evaluation with Neuron-Specific Enolase
Authors: Giovanella L. , Ceriani L. , Bandera M. , Garancini S.
Published: March 2018

The aims of our work were 1) to determine the diagnostic performance of an immunoradiometric assay of chromogranin A (CgA) in smal cell lung cancer and 2) to compare its discriminatory power with that of neuron-specific enolase (NSE), the marker currently used for SCLC. We selected 166 cases of small cell (64) and non-small cell (102) lung cancer and 106 cases of non-malignant lung diseases as controls. Both CgA and NSE were assayed by immunoradiometric methods and cutoff values were established on the basis of a pre-fixed specificity of 95% in non-malignant lung diseases. The CgA assay showed better diagnostic sensitivity than NSE in SCLC (61% versus 57%), especially in limited disease, and a low positivity rate in NSCLC with respect to NSE (14% versus 22%). By contrast, NSE reflected disease extent more accurately than CgA (U test: CgA p<0.05, NSE p<0.001). Finally, we found that the CgA assay was not affected by hemolysis whereas NSE serum levels greatly increased in hemolyzed sera. In conclusion, CgA assaying by an IRMA method is a reliable procedure in the diagnosis of SCLC. NSE remains the marker of choice in staging and monitoring of the disease. Further studies are needed to evaluate the prognostic significance of the marker and its role in therapy monitoring and patient follow-up.
Serum Tumor Markers: Past, State of the Art, and Future
Authors: Thomas C.M.G. , Sweep C.G.J.
Published: March 2018

Serum determinations of tumor markers are indispensable in the diagnosis and management of cancer, and therefore play an important role in clinical practice. After a short historical survey, we systematically review a number of contemporary aspects of serum tumor markers related to various organ systems, and briefly indicate possible future developments.
Validation of Blood Collection Procedures for the Determination of Circulating Vascular Endothelial Growth Factor (VEGF) in Different Blood Compartments
Authors: Dittadi R. , Meo S. , Fabris F. , Gasparini G. , Contri D. , Medici M. , Gion M.
Published: March 2018

Aims of the study.

Studies on circulating VEGF have reported mixed results, possibly due to a lack of standardization of the pre-analytical phase. The aim of our investigation was to standardize the sampling procedure for the determination of VEGF in different blood fractions.

Basic procedures.

We evaluated various clotting times for obtaining serum in 30 subjects, as well as different procedures for the preparation of plasma Edinburgh anticoagulant mixture (EDTA, PGE1, theophylline) and CTAD. VEGF was also assayed in lysed whole blood. In vitro platelet activation was monitored by measuring the levels of PF4. VEGF and PF4 were measured using commercially available enzyme-linked immunoassays.

Main findings.

Clotting time increased the release of VEGF, which reached a plateau between 2 and 4 hours. The percent increase of VEGF at 2 hours ranged from 118% to 4515% (median 327%) compared to samples centrifuged within 10 min from withdrawal. VEGF was not different and PF4 was very low or undetectable in Edinburgh plasma and CTAD plasma, while it was significantly higher in sodium citrate plasma. VEGF in CTAD plasma was not correlated with platelet count or leukocytes. Serum VEGF did not correlate with the leukocyte number, but it correlated significantly with the platelet count.

Principal conclusions.

The procedures for sample collection described above are highly standardized and easy to perform in a routine setting. We therefore suggest systematic evaluation of VEGF in CTAD plasma, in serum (clotting for 2 hours at room temperature) and in whole blood, until prospective controlled clinical studies will have clarified in which blood compartment(s) VEGF provides clinically relevant information.
Prognostic Significance of DNA Aneuploidy and p21ras Oncoprotein Expression in Colorectal Cancer and Their Role in the Determination of Treatment Modalities
Authors: Karelia N.H. , Patel D.D. , Desai N.S. , Mehta H.V. , Yadav P.K. , Patel S.M. , Kothari K.C. , Shah P.M.
Published: March 2018

The purpose of the present study was to investigate the prognostic significance of DNA ploidy, S-phase fraction and p21ras oncoprotein expression in patients with colorectal cancer and to correlate these factors with the clinical behavior of the tumors and their response to therapy. Of 79 patients with colorectal cancer 57% (45/79) had early stage disease. Forty-one percent (32/79) had aneuploid tumors while 30% (24/79) of the tumors had a high (>10%) S-phase fraction. p21ras oncoprotein expression was detected in 38% (30/79) of tumors. Patients with aneuploid tumors had a worse prognosis than patients with diploid tumors (p=0.0002). Similarly, patients with high S-phase fraction tumors had a shorter survival than those with low S-phase fraction tumors (p=0.005). No such difference was found between p21ras-positive and p21ras-negative tumor subgroups. In early stage colorectal cancer, aneuploidy was closely correlated with disease outcome (p=0.029). Early stage patients with diploid tumors who received radiotherapy and chemotherapy had a better prognosis than patients with aneuploid tumors. In conclusion, DNA ploidy is a significant and independent prognostic factor in colorectal cancer. Aneuploidy and genetic alteration of the p21ras oncoprotein are important in determining the biological aggressiveness of colorectal cancer. Furthermore, DNA ploidy may identify those subgroups of patients with early stage disease who may benefit from more aggressive treatment.
Serum Levels of Interleukin-18 and sICAM-1 in Patients Affected by Breast Cancer: Preliminary Considerations
Authors: Merendino R.A. , Gangemi S. , Ruello A. , Bene A. , Losi E. , Lonbardo G. , Purello-D'Ambrosio F.
Published: March 2018

Interleukin-18 (IL-18), a cytokine that plays an important role in the T-cell-helper type 1 response, acts as an angiogenesis and tumor suppressor. Intercellular adhesion molecule-1 (ICAM-1) has a potential role in immunoregulation by mediating immune cell infiltration into the tissue. The aim of this study was to evaluate IL-18 and soluble (s) ICAM-1 serum levels in breast cancer (BCa) patients with liver (BCaM1h) or bone (BCaM1b) metastases compared to BCa patients without metastases (BCaM0) and healthy donors (HDs). Furthermore, since IL-18 enhances ICAM-1 expression, we investigated whether there was a direct correlation between sICAM-1 and IL-18 serum levels. Serum IL-18 and sICAM-1 levels were assayed by immunoenzymatic methods. The serum sICAM-1 levels in the three groups of cancer patients were significantly higher (p<0.05) than those of HDs. Serum IL-18 levels were significantly higher (p<0.05) in BCaM1h and BCaM1b patients compared to BCaM0 patients and HDs. sICAM-1 proved to be closely correlated with serum IL-18 levels in HDs, whereas a weaker correlation was found in BCaM1h, BCaM1b and BCaM0 patients. The defective correlation between sICAM-1 and IL-18 found in cancer patients may contribute to our understanding of the immunity upset occurring in cancer. Our data suggest that IL-18, irrespective of its biological activity, could represent a marker for metastatic breast cancer.
Cytokeratins as Serum Markers in Egyptian Bladder Cancer. A Comparison of CYFRA 21–1, TPA and TPS
Authors: Mady Essam A.
Published: March 2018

Cytokeratins (CKs) have been shown to be overexpressed in bladder cancer and to be valuable as tumor markers. The present study was designed to evaluate the single and combined use of three cytokeratin fragments, CYFRA 21–1, TPA, and TPS, in serum of Egyptian bladder cancer patients. The study subjects comprised 40 healthy controls, 30 patients with benign bladder diseases, and 60 patients with histologically confirmed primary bladder cancer. The cutoff was set at 95% specificity versus benign bladder diseases, resulting in cutoff values of 2.93 ng/mL for CYFRA 21–1, 158 U/L for TPA and 143.7 ng/mL for TPS. With 41% true positive results CYFRA 21-1 had a higher sensitivity than TPA (32%) and TPS (27%). Evaluation by histological findings revealed a highest sensitivity of CYFRA 21-1 (46%) in transitional cell carcinoma (TCC) followed by TPA (27%) and TPS (21%). Also in adenocarcinoma CYFRA 21-1 showed the highest sensitivity (38%) followed by TPA (32%) and TPS (28%). A high percentage (41.6%) of Egyptian bladder cancers is represented by squamous cell carcinoma (SCC). In this population TPS showed the highest sensitivity (69%), followed by CYFRA 21-1 (54%) and TPA (41%). The sensitivity of each of the three markers increased with advancing tumor stage and increasing tumor grade. Combined use of two of the three markers did not raise the sensitivities obtained by single determination of CYFRA 21-1. The present study suggests that serum CYFRA 21-1 could be a marker of choice in bladder cancer.
Role of Coactivators and Corepressors in Steroid and Nuclear Receptor Signaling: Potential Markers of Tumor Growth and Drug Sensitivity
Authors: Cottone E. , Orso F. , Biglia N. , Sismondi P. , De Bortoli M.
Published: March 2018

Nuclear receptors regulate target gene expression in response to steroid and thyroid hormones, retinoids, vitamin D and other ligands. These ligand-dependent transcription factors function by contacting various nuclear cooperating proteins, called coactivators and corepressors, which mediate local chromatin remodeling as well as communication with the basal transcriptional apparatus. Nuclear receptors and their coregulatory proteins play a role in cancer and other diseases, one leading example being the estrogen receptor pathway in breast cancer. Coregulators are often present in limiting amounts in cell nuclei and modifications of their level of expression and/or structure lead to alterations in nuclear receptor functioning, which may be as pronounced as a complete inversion of signaling, i.e. from stimulating to repressing certain genes in response to an identical stimulus. In addition, hemizygous knock-out of certain coactivator genes has been demonstrated to produce cancer-prone phenotypes in mice. Thus, assessment of coactivator and corepressor expression and structure in tumors may turn out to be essential to determine the role of nuclear receptors in cancer and to predict prognosis and response to therapy.
Predicting Prostate Biopsy Outcome by Findings at Digital Rectal Examination, Transrectal Ultrasonography, PSA, PSA Density and Free-To-Total PSA Ratio in a Population-Based Screening Setting
Authors: Ciatto S. , Bonardi R. , Lombardi C. , Cappelli G. , Castagnoli A. , D'Agata A. , Zappa M. , Gervasi G.
Published: March 2018

The study offers a retrospective analysis of the positive predictive value (PPV) of several variables, i.e. digital rectal examination (DRE), transrectal ultrasonography (TRUS), PSA value, PSA density (PSAD), and free/total PSA ratio (F/T), for the histologic outcome of 179 prostate biopsies performed within a population-based screening trial. The ratio of spared benign biopsies to missed cancers (SBB/MC) if biopsy results had been decided on the basis of single variables was also evaluated. PPV was 82.9% for DRE, 56.3% for TRUS, 26.6% for PSA (cutoff ≥4 ng/mL), 47.4% for PSA (cutoff ≥10 ng/mL), 42.0% for PSAD (cutoff 0.15), 59.2% for PSAD (cutoff 0.20), 34.9% for F/T (cutoff 0.20) and 40.0% for F/T (cutoff 0.15). SBB/MC was 121/23 for DRE, 96/12 for TRUS, 11/10 for PSA (cutoff ≥4 ng/mL), 107/34 for PSA (cutoff ≥10 ng/mL), 87/23 for PSAD (cutoff 0.15), 109/26 for PSAD (cutoff 0.20), 45/8 for F/T (cutoff 0.20) and 70/14 for F/T (cutoff 0.15). Multivariate analysis of the association with biopsy outcome showed the highest odds ratio for TRUS (13.24, 95% CI=4.4–30.7), and considerably lower values for DRE (4.17, 95% CI=2.0–8–9), PSAD (cutoff 0.20: 3.24, 95% CI=–1.8–5.7) and F/T (cutoff <0.15: 3.16, 95% CI =1.7–1.8). None of the possible variable combinations was clinically useful: the highest PPV (83.3%) was obtained with a combination of suspicious DRE/TRUS, PSAD >0.20 and F/T <0.15, which nevertheless missed 20 of 52 cancers.
Clinical Significance of Epidermal Growth Factor Receptor Content in Gastric Cancer
Authors: García I. , Vizoso F. , Andicoechea A. , Raigoso P. , Vérez P. , Alexandre E. , García-Muñiz J.L. , Allende M.T.
Published: March 2018

The objective of this work was to evaluate the epidermal growth factor receptor (EGFR) content in gastric cancer, its possible relationship with clinicopathological parameters of tumors and its prognostic significance. Membranous EGFR levels were examined by radioligand binding assays in 110 patients with gastric cancer. The mean follow-up period was 30.7 months. EGFR levels of tumors ranged widely, from 0.3 to 510 fmol/mg protein. EGFR levels were significantly higher (p<0.0005) in neoplastic tissue than in paired adjacent mucosa samples (median) (n= 84; 8.7 vs. 3.9 fmol/mg protein). Intratumoral EGFR levels were significantly correlated with tumor stage (p<0.05), and were higher in patients with stage III tumors (median) (7.6, 6.4, 12.3 and 7.5 fmol/mg protein for stages I, II, III and IV, respectively). In addition, the tumor/mucosa ratios of the EGFR content were significantly higher (p<0.05) in patients with stage III tumors (1, 1.8, 3.9, and 0.92, respectively). Although there was no significant relationship between EGFR levels of tumors and overall survival, the results suggest a role for EGFR in tumor progression of gastric cancer.
Immunohistochemistry and Reverse Transcriptase Polymerase Chain Reaction on Sentinel Lymph Nodes can Improve the Accuracy of Nodal Staging in Breast Cancer Patients
Authors: Péley G. , Tóth J. , Csuka O. , Sinkovics I. , Farkas E. , Köves I.
Published: March 2018

In this study the nodal staging sensitivity of sentinel lymph node biopsy (SLNB) with detailed pathological and molecular biological examination has been investigated and compared to that of axillary lymph node dissection (ALND) with routine histological evaluation. Sentinel lymph nodes (SLNs) were removed by the dual-agent injection technique in 68 patients with primary, clinically node-negative breast cancer. Forty-seven patients had negative SLNs according to hematoxylin and eosin (H&E) staining. These H&E-negative SLNs were serially sectioned and examined at 250 μm levels by anticytokeratin immunohistochemistry (IHC). In 14 patients the SLNs were also investigated by cytokeratin 20 (CK20) reverse transcriptase polymerase chain reaction (RT-PCR). SLNB with IHC increased the node-positive rate by 26% (by 40% in tumors less than or equal to 2 cm in size (pT1) and by 9% in tumors more than 2 cm but less than or equal to 5 cm in size (pT2)). The sensitivity of SLNB with IHC was superior to that of ALND with routine histology in pT1 tumors and identical in pT2 tumors. The concordance between histology and RT-PCR was only 21%, and in two of three cases with positive histological results RT-PCR was negative. In conclusion, SLNB with detailed pathological and/or molecular biological evaluation can improve the sensitivity of regional staging. ALND can probably be abandoned in patients with pT1 SLN-negative breast cancer. Further prospective studies are required to determine the clinical significance of these detailed SLN evaluation techniques, but at present these methods are still investigational.
C-erbB-2 Oncoprotein in Gastric Carcinoma: Correlation with Clinical Stage and Prognosis
Authors: Oshima C.T.F. , Lanzoni V. Pereira , Iriya K. , Forones N.M.
Published: March 2018

The aim of this study was to investigate the expression of the oncogene c-erbB-2 in gastric tumors. Immunohistochemical study of the expression of c-erbB-2 was performed in formalin-fixed, paraffin-embedded sections from 82 gastric adenocarcinomas using polyclonal antibody. c-erbB-2-positive immunostaining was observed in 37 (45%) tumors. Positive staining was detected in 63% of well differentiated, 46% of moderately differentiated and 80% of papillary adenocarcinomas. In poorly differentiated adenocarcinomas, positivity for c-erbB-2 was observed in 21%. According to the Lauren classification, a higher frequency of c-erbB-2 positive staining was observed in intestinal type tumors (70%). During the follow-up period 43% of the patients with c-erbB-2 oncoprotein-negative tumors and 45% of the patients with c-erbB-2 oncoprotein-positive tumors died. There was no significant association between c-erbB-2 staining and sex, age, clinical stage, tumor grade, histological type or survival rates. In conclusion, almost half of the gastric cancers were positive for c-erbB-2. Nonetheless, the expression of c-erbB-2 oncoprotein did not play a role in prognosis.
Evaluation of HER-2/neu in Serum and Tissue of Primary and Metastatic Breast Cancer Patients using an Automated Enzyme Immunoassay
Authors: Dittadi R. , Zancan M. , Perasole A. , Gion M.
Published: March 2018

Serum HER-2/neu concentrations were evaluated in 172 healthy subjects, 176 primary and 55 metastatic breast cancer patients, employing a new automated assay (Bayer Immuno 1™ serum HER-2/neu). Using 13 ng/mL as the cutoff, abnormal HER-2/neu serum levels were found in 8% (14/176) of primary and 50.9% (28/55) of metastatic breast cancer patients.

Both in primary and metastatic breast cancer a significant relationship was found with the stage of the disease when serum HER-2/neu was considered as a categorized variable (p=0.0003 and p=0.02, respectively), but not when it was taken as a continuous variable (p=0.247 and p=0.146, respectively). Moreover, we evaluated the correlation between Immuno 1™ HER-2/neu and Oncogene Research Products ELISA assay in 53 normal subjects, 46 primary and 34 metastatic breast cancer patients. The correlation was relatively good (p<0.0001), although substantial differences could be found in single cases. The Immuno 1™ assay was also evaluated for the first time in breast cancer tissue. The method, which showed good performance both in terms of imprecision and linearity, was used to measure HER-2/neu protein in 140 cytosol samples from primary breast cancer tissue and in homogenates from 40 matched cases. The correlation between the two matrixes was very close (p<0.0001). By contrast, no correlation was found between serum and matched cytosol (p=0.101) or ho-mogenate samples (p=0.511).
Can the Acute-Phase Reactant Proteins be Used as Cancer Biomarkers?
Authors: Pang Wei Wei , Abdul-Rahman Puteri Shafinaz , Wan-Ibrahim Wan Izlina , Hashim Onn Haji
Published: March 2018

The association between the acute-phase reactant proteins (APRPs) and cancer has long been established. There have been numerous reports correlating altered levels of various APRPs with different types of cancers. However, researchers are often quick to dismiss the use of these APRPs as potential biomarkers for the diagnosis and monitoring of cancer because alterations in APRP concentrations are observed in a wide range of diseases. Recent progress in proteomics studies which profiled the serum proteins of cancer patients and those of normal individuals indicated that the altered APRP expressions were different for distinct types, subtypes, and even stages of cancer. Interestingly, these data are in agreement with those observed earlier using immunochemical and biochemical assays. In view of this compelling association of different patterns of APRPs with various types of cancers and in an apparent shift of paradigm, we present in this review some indications that APRP fingerprinting may be used as complementary cancer biomarkers.
Human Kallikrein 14 (Klk14) Expression in Salivary Gland Tumors
Authors: Hashem Nelly N. , Mara Thomas W. , Mohamed Mohamed , Zhang Irene , Fung Kevin , Kwan Keith F. , Daley Thomas D. , Diamandis Eleftherios P. , Darling Mark R.
Published: March 2018

Objective

To analyze the expression of human kallikrein 14 (KLK14) in salivary gland tumors.

Methods

A standard immunoperoxidase staining technique was used to assess the expression profile of KLK14 in normal salivary glands and tumors including pleomorphic adenoma (PA; n=17), adenoid cystic carcinoma (ACC; n=13) and mucoepidermoid carcinoma (MEC; n=9). Tumor stage, grade, patient age and gender, and site of occurrence were recorded. These clinical parameters were correlated with KLK14 levels in malignant tumors. The expression profiles for KLK3, 5, 6, 8 and 13 were also retrieved.

Results

Normal salivary glands, PA, ACC and MEC showed strong expression of KLK14 in ductal and non-ductal cells. Both PA and ACC showed higher KLK14 levels than normal glands and MEC tissues. There were no statistically significant associations between levels of KLK14 and clinical parameters.

Conclusions

The differences in the levels of KLK14 suggest that KLKs may aid in the differential diagnosis of salivary gland tumors. The coexpression of KLKs suggests their possible involvement in an enzymatic pathway activated in salivary gland. KLK14 may be a promising new biomarker in salivary gland tumors.
No Mutation Detected in Five Hot Spot Codons of the Tp53 Gene by Restriction Site Mutation Analysis in Patients with Carcinoma of the Tongue
Authors: Vora Hemangini H. , Mehta Shalvi V. , Shukla Shilin N. , Shah Pankaj M.
Published: March 2018

The present study evaluated 5 of the 8 main TP53 mutation hot spots in cancer by restriction site mutation analysis and compared the results with p53 protein expression in patients with cancer of the tongue. Tumor samples from 49 patients with tongue cancer were screened for TP53 mutations in exons 5 through 8 by PCR restriction site mutation analysis and for p53 protein expression by immunohistochemistry using the DO-7 antibody. Nuclear accumulation of p53 protein was seen in 22% (11/49) of the tumors, whereas none of the patients exhibited TP53 mutations in exons 5 through 8. The observed data suggest that TP53 mutations alone are not responsible for abnormal accumulation of p53 protein in tobacco-chewing-mediated tongue carcinogenesis.
Analysis of Cytokine Pattern in Exhaled Breath Condensate of Patients with Squamous Cell Lung Carcinoma
Authors: Barta Imre , Kullmann Tamas , Csiszer Eszter , Antus Balazs
Published: March 2018

Exhaled breath condensate (EBC) analysis is a promising method for investigating airway pathology. In this study we compared the cytokine pattern of EBC of patients suffering from squamous cell lung carcinoma with that of healthy smokers. Breath condensates collected from 8 smoking lung cancer patients before receiving any anticancer treatment and 8 smokers without any clinical or radiological evidence of pulmonary tumors were used for antibody microarray analysis testing 120 cytokines simultaneously. Ninety-eight cytokines on the array gave a detectable signal in both groups. Cytokine levels were similar across the samples, and none of the cytokines exhibited a significant increase or decrease in cancer patients as compared to healthy subjects with similar smoking status, lung function, and airway inflammation. The results of this pilot study suggest that patients with squamous cell lung carcinoma cannot be distinguished from smokers with no pulmonary tumors based on EBC cytokine signals only.
Prognostic Value of Membrane Type 1 and 2 Matrix Metalloproteinase Expression and Gelatinase a Activity in Bladder Cancer
Authors: Mohammad Mohammad A. , Ismael Naglaa R. , Shaarawy Sabry M. , El-Merzabani Mahmoud M.
Published: March 2018

Purpose

To analyze the behavior of matrix metalloproteinases (MMPs) in their active state in patients with bladder cancer.

Method

A retrospective study of 50 patients with localized bladder cancer who underwent tumor resection between June 2006 and June 2007 at the National Cancer Institute in Cairo, Egypt was carried out. Tissue samples were collected and the expression of membrane type 1 (MT1) and type 2 (MT2) MMPs was determined by Western blotting. Gelatinase A (MMP-2) activity was estimated by zymographic analysis in tissue samples of each patient and the values were correlated with clinical tumor stage and lymph node status.

Result

The behavior of MMP-2 showed statistical significance in 90% of tumor tissues compared with 22% of adjacent normal tissues (p<0.001). MT1-MMP was expressed in 88% of tumor tissues compared with 24% of normal tissues (p<0.001); MT2-MMP was expressed in 74% of tumor tissues compared with 12% of normal tissues (p<0.001). While there was a highly significant association between MMP-2 activity and MT1-MMP expression in tumor tissues (p<0.001), there was a moderately significant association between MMP-2 activity and MT2-MMP expression (p=0.018). The results also revealed an association between MT1-MMP and MT2-MMP expression in tumor tissues (p<0.001). MMP-2 activity and MT2-MMP expression in tumor tissues were statistically associated with high tumor stage (p=0.039 and p=0.014, respectively), while the expression of MT1-MMP showed no association with tumor stage (p=0.139).

Conclusion

MMP-2 activity is associated with an increase in MT2-MMP expression and with lymph node metastasis. No association was found between MT1-MMP expression and lymph node metastasis.