bluuebunny/crossref_metadata_2025 huggingface dataset:
Production of Monoclonal Antibodies against a New Carcinoma-associated Marker in View of Developing a Serological Test
Authors: Tagliabue E. , Centis F. , Mastroianni A. , Martignone S. , Ménard S. , Pellegrini R. , Colnaghi M.I.
Published: April 2018

By immunizing a mouse with human metastatic breast tumor cells from patient effusions and infiltrated lymph nodes, a monoclonal antibody (MLuC2), which identifies a new carcinoma-associated marker, was raised. The reactivity of this reagent was studied by immunohistochemistry on live and fixed cells from tumor cell lines and on frozen sections from surgical specimens. Besides reacting with 73% of breast carcinomas, MLuC2 also reacted with 93% of non-small cell lung carcinoma (NSCLC) and with a few normal tissues. The MLuC2-recognized molecule (CaMLuC2), whose MW was 90 KDa according to immunoblotting experiments, was found to be detectable in the serum and could therefore be of particular interest for serological diagnostic applications. Since the CaMLuC2 epitope was not polyexpressed on the bearing molecule, we produced a new generation of MAbs in order to define epitopes coexpressed with CaMLuC2 on the same 90 KDa molecule, and which are therefore suitable to develop a double-determinant immunoradiometric assay (DDIRMA) for the detection of this marker in the sera of lung carcinoma patients. Different analyses by immunohistochemistry, binding inhibition tests and DDIRMA, proved that the two new reagents developed, MLuC8 and MLuC9, recognize the same or closely related epitopes, which are however different from CaMLuC2, but which are all present on the same molecule. Preliminary immunoradiometric tests performed on sera from lung cancer and control patients showed a good specificity but a low sensitivity. In fact, only 42% of the 28 tested sera samples from NSCLC patients scored positive despite the fact that more than 90% of the NSCLC expressed the relevant antigen
AFP, CEA, CA 19-9 and TPA in Hepatocellular Carcinoma
Authors: Maussier M.L. , Valenza V. , Schinco G. , Gallv G.
Published: April 2018

The present study is based on the assay of four markers (AFP, CEA, TPA, Ca 19-9) using IRMA methods in 36 normal subjects, 44 cirrhosis and 66 HCC patients.

Parametric and non parametric tests were used to test differences and correlations. ROC curves and discriminant functions were also elaborated.

Normal 95% “cut-off” was determined by the “boostrap” method yielding: CEA 3.4 ng/ml; Ca 19-9 55 U/ml; TPA 58U/l and AFP 5.2 ng/ml.

In HCC patients the values of the four markers were, on average, significantly different from those of normal subjects. However, only AFP and TPA exhibited high diagnostic accuracy (90%) for detection of the tumor.

Higher than normal mean values for all markers were, also observed in cirrhotic patients. Only AFP yielded effective discrimination between HCC and cirrhosis. The positive prediction for the presence of the tumor on cirrhotic ground was 95% for AFP values higher than 18.5 ng/ml, with a 78% negative predictive value with a 6 ng/ml threshold. Association of AFP with TPA showed only a marginal diagnostic improvement. Results were not improved at all by combining CEA and Ca 19-9 with AFP and/or TPA.

In conclusion, AFP is and remains the best marker for HCC and the only one effective in discriminating of HCC from cirrhosis. TPA may be considered a valid alternative if cirrhosis is not present. CEA and Cal9-9 are of no use.
Tumor Markers in Pancreatic Cancer: A Comparative Clinical Study between CEA, CA 19-9 and CA 50
Authors: Molina L.M. , Díez M. , Cava M.T. , Maestro M.L. , Ortega M.D. , Mendíz J.G. , Prego A. , De Diego J.A. , Balibrea J.L.
Published: April 2018

Seventy-eight patients were evaluated to ascertain the usefulness of markers CA 19-9 and CA 50 in diagnosing pancreatic cancer, using a less specific marker (CEA) as reference. Three groups were considered: a) 36 controls; b) 22 patients with benign obstructive jaundice; c) 20 patients with pancreatic cancer. Preoperative blood samples were obtained to ascertain CEA (E.I.A.), CA 19-9 (R.I.A.) and CA 50 (T.R.-F.I.A.). Serum concentrations of the various markers were significantly higher for patients with pancreatic cancer in comparison with the other groups, at cut-offs of l0ng/ml (CEA), 100ng/ml (CA 19-9) and 170 U/ml (CA 50). The sensitivity of CA 19-9 (94%) and CA 50 (88%) was much greater than that of CEA (30%). The specificity of the three markers in patients with pancreatic cancer, with respect to the control group, was 100% and this figure is reduced with respect to the group suffering from benign obstructive jaundice (CEA: 90%; CA 19-9: 88% and CA 50: 87%). Diagnostic results (sensitivity, specificity, positive predictive value (P.P. V.) and negative predictive value (N.P. V.)) did not significantly increase with respect to CA 19-9 and CA 50 when considered individually. It is concluded that the serum concentrations of CA 199 and CA 50 showed high sensitivity and specificity as markers of pancreatic cancer with respect to the other groups, pointing towards clinical routine clinical use of both markers. In addition, a comparative study of the literature has been made and prospects for short-term development and concrete applications for early and reliable diagnosis have been highlighted.
Localization of Mucinous - like Carcinoma Associated Antigen (MCA) in Breast Pathology: Comparison with Carcinoembryonic Antigen (CEA) and Tissue Polypeptide Antigen (TPA)
Authors: Saccani Jotti G. , Fontanesi M. , Colombo A. , Valtolina M. , Tardini A.
Published: April 2018

The topographic distribution of a mucinous-like cancer antigen (MCA) recognized by a monoclonal antibody b-12 (MAb b-12) was assessed in benign (38) and malignant (66) breast tissues. The reactivity of MAb b-12 showed a good selectivity for breast tissues, reacting both with normal tissues and breast cancer. The degree of MCA expression was evaluated in the various groups of breast pathology adopting quantitative criteria of assessment. With the criteria of evaluation adopted, strong staining was observed in 71.4% breast carcinomas. The most positive reaction was demonstrated in mucinous carcinoma.

MCA distribution in breast tissue was compared with the distribution of two other antigens, CEA and TPA. Reactivity of MAb b-12 was higher than the reactivity shown by the anti-CEA and anti-TPA antibodies.
Immunoscintigraphy with 131I or 111In Labelled OC 125 F(ab')2 Fragments in Patients with Ovarian Carcinoma
Authors: Jiménez-Vicioso A. , Torres M. , Jiménez-Heffernan A. , Grana M.D. , Latre J.M. , Llamas J.M. , Carreras J.L. , Mateo A.
Published: April 2018

To evaluate the clinical usefulness of immunoscintigraphy with OC 125 in ovarian carcinoma, we studied 25 patients suspected of having ovarian carcinoma or in follow-up after surgery. Fourteen patients were studied with 131I-OC 125 F(ab')2 and 11 with 111In-OC 125 F(ab')2. No differences were observed with the use of either radionuclide.

Global diagnostic indexes obtained were S = 100%, Sp = 44,5% and A = 81%. The low specificity obtained was remarkable: 5 false positive results in two uterine myomas, one abscess, one follicular cyst and one granulation tissue scar. On the other hand, all lesions of ovarian carcinoma were detected. Analysis of the evolution of tumor/background (T/B) uptake ratios from the first to the second day of exploration revealed a tendency for the ratio to diminish significantly (> 15%) in false positive cases with the exception of the abscess while this did not happen in true positive cases, with the exception of a regional recurrence. Analysis of T/B ratio variations could contribute towards elevating the test's specificity.
Serum NSE, CEA, CT, CA 15-3 Levels in Human Lung Cancer
Authors: Nutini S. , Cappelli G. , Benucci A. , Catalani C. , Nozzoli F.
Published: April 2018

The significance of neuron specific enolase (NSE) was investigated in comparison with other tumor markers (CEA, CT, CA 15-3) used in the diagnosis and treatment monitoring of lung cancer.

As previously described, the calcitonin assay proved to have very low sensitivity for small cell lung cancer (SCLC). The serum NSE assay was, however, shown to be a useful diagnostic aid for discrimination between histologically different lung cancers, and therefore this assay may be a valuable tool for treatment monitoring in SCLC patients.

CA 15-3, also an unspecific marker, showed similar sensitivity to the NSE assay in SCLC patients, the sensitivity being higher than CEA in non small cell lung cancer (NSCLC)
Cathepsin D in Breast Cancer Tissue
Authors: Gonzalez Gancedo P. , G-Casaus M.L. , Ruiz Cacho J. , Calero F. , Inocente J.M. , Gomez-Pastrana F. , Ramon N.
Published: April 2018

The cathepsin D concentration in 18 women with benign breast pathology has a cut-off value of 43 pmol/mg of protein. High values have been detected in two cases of chronic mastitis. These high values of cathepsin D were found in a study of 62 patients suffering from breast cancer and are independent of the hormone dependent state of the tumour. The cathepsin D concentration may have a prognostic function in breast cancer determination, as high concentrations are found in combination with other prognostic factors such as clinical stage, size of the tumour, state of the axillary lymph nodes and in the histological differentiation grade, where from a statistical point of view, the combination is important.
Immunoscintigraphy in Colorectal Cancer: Surgeon's Perspective
Authors: Doerr R.J. , Abdel-Nabi H.
Published: April 2018

External immunoscintigraphy (IS) is a new imaging tool to diagnose, stage and follow-up solid malignancies. Monoclonal antibodies are raised to tumor-associated antigens, radiolabeled and when injected in the patient localize to the tumor. Detection is with nuclear medicine gamma camera.

In colorectal cancer, immunoscintigraphy can be beneficial to the surgeon. With primary colorectal carcinoma, IS detects synchronous primaries, identifies lymph node metastasis, determines extent of disease and detects occult metastasis. Postoperatively, in high-risk patients (Dukes B2, B3 and C lesions) IS assists in the follow-up for recurrence. Particular advantage with IS is seen in pelvic, mesenteric and retroperitoneal recurrences. Rising serum CEA and negative conventional cross-sectional imaging can often be clarified as to site of disease with IS.

IS contributes significantly to surgical decision making with alterations in management based on radiolabeled monoclonal antibody scans in 25 - 32% of primary and recurrent colorectal cancer cases.
CEA and CA 15-3 in Pleural Effusion of Advanced Breast Cancer Patients: Clinical Relevance and Diagnostic Value
Authors: Nešković-Konstantinović Z. , Tasić S. , Vuletić L. , Branković M. , Ogrizović N. , Nikolić Z. , Vlajić M. , Josifovski J.
Published: April 2018

Serum and pleural effusion fluid were tested for CEA concentration in 83 advanced breast cancer patients, in 43 of whom CA 15-3 was also determined.

All pleural effusions were clinically malignant. The sensitivity of the CEA test for the presence of pleural metastases was closer to that of the CA 15-3 test in effusion (0.59 and 0.79, respectively) than the sensitivity of CEA compared to CA 15-3 in serum (0.43 vs. 0.79). The use of two markers combined with cytology increased the diagnostic rate from 48% (cytologically positive) to 88% (cytologically positive and/or with one or both markers increased in effusion). A high diagnostic rate in cytologically negative effusions (65%), and in effusions presented as the sole metastatic involvement (100%), points to the clinical value of these two markers. Our results show that markers produced by pleural metastases may be secreted either into the effusion fluid or into serum, or both. This finding, as well as some other observations, are discussed in the present paper.
Tissue Polypeptide Antigen Immunostaining in Fine Needle Aspirates from Solid Breast Nodules
Authors: Battistelli S. , Marcheggiani F. , Pecorella I. , Sessa M. , Malatesta M. , Ligori G. , Troccoli R.
Published: April 2018

the purpose of this study was to determine the role of Tissue Polypeptide Antigen (TPA) immunostaining in the evaluation of aspiration smears from solid breast nodules and to discuss its possible clinical applications. Seventy-one cytologic specimens were studied; 52 were carcinomas, 15 fibroadenomas and 4 fibrocystic dysplasia. TPA was visualized with the peroxidaseantiperoxidase method, using 3-3 ‘diaminobenzidine as chromogen and hematoxylin as counterstaining. The incidence of TPA-positive aspiration smears was 88.5% in the carcinomas and 26.7% in the fibroadenomas. The four cases of fibrocystic dysplasia showed variable behaviour. The intensity of the TPA staining varied from – to + + + and was most frequently high in the carcinomas. The results of this research show a good correlation between a diagnosis of carcinoma and TPA positivity in fine needle aspirates of solid breast nodules.
Rapid, Automated Enzyme Immunoassay for MCA with the Cobas® Core Roche Immunochemistry Analyser
Authors: Henne V. , Maurer A.
Published: April 2018

The breast cancer marker Mucin-like Carcinoma-associated Antigen (MCA) was evaluated in a version that has been adapted to a new enzyme immunoanalyser, the CobasR Core. The two-step sandwich assay has a short total assay time of less than 60 minutes. Standard curves are stable for at least 2 weeks. The coefficients of variation for the inter-assay precision ranged between 3.6% and 7.8%, but were mainly below 5%. Single determinations of patient values from different runs correlated also very closely (R = 0.99). The dilution linearity for a set of 14 sera exhibited recovery rates mostly ranging from 90% to 110%. From 165 blood donors investigated, more than 99% had values below the cut-off of 11 U/ml. As demonstrated for pathological sera, the automated and manual versions showed a high degree of accordance (R = 0.98). The investigation presents convincing evidence that the Cobas Core MCA EI A running on a CobasR Core analyser guarantees a high analytical reliability and reproducibility.
Enhancement of in vivo Monoclonal Antibody Targeting with Recombinant Interferon and Cytokines
Authors: Gasparini M. , Zampino M.G. , Maffioli L. , De Braud F. , Bombardieri E. , Buraggi G.L.
Published: April 2018

Up to now a number of studies have been performed to determine whether the combined use of cytokines and monoclonal antibodies (MAbs) directed against tumor-associated antigens (TAA) can increase the sensitivity of radioimmunoscintigraphy (RIS).

It well known that human natural and recombinant interferons can enhance the cell surface expression of HLA Class I and II antigens as well as some specific tumor antigens, but there is scanty and conflicting information about the expression and shedding of TAA.

Some authors reported that alpha-IFN enhances the expression of a melanoma-associated antigen (MAA), recognized by conventional antiserum. Other authors have found no changes in the expression of MAA identified by MAbs (17, 18).

In a pilot study on patients with malignant melanoma Rosenblum demonstrated an increase in tumor uptake of the anti-melanoma MAb 96.5 after IFN administration.

In our study we performed immunoscintigraphy with the anti-melanoma MAb 225.28S in the same patient before and after IFN administration in different doses. We point out the difference in biodistribution in different organs and in blood clearance and discuss the possibility to improve the sensitivity of RIS.
MCA Serum Determination in Breast Carcinoma Patients for the Diagnosis of Bone Metastases
Authors: Dominguez-Ġadea L. , Martin-Curto LM. , Crespo A. , Avila C.
Published: April 2018

Serum MCA levels were determined in 173 consecutive patients with breast cancer in order to assess the clinical utility of MCA for the detection of bone metastases. Bone pathology was diagnosed by scintigraphy, radiology and clinical follow-up. Metastases were found in 37 patients, benign lesions in 25, and in 111 no bone lesions were found. Eighteen of the 173 bone scans were considered indeterminate for metastases. Based on the receiver-operating characteristic curves (ROC) analysis, the cut-off level for MCA was set at 20 U/ml. Only in 4 of the 37 patients with bone metastases MCA was below 20 U/ml. All 4patients had completed their chemotherapy course within six months before MCA determination. Only in 6 patients of the 136 without bone metastases MCA levels were above 20 U/ml. Of the 18 patients with indeterminate bone scans, 15 had benign lesions and all of them had MCA levels below 20 U/ml.

MCA determination is a sensitive method for the detection of bone metastases in breast carcinoma. We encourage the use of this procedure for the selection of high-risk groups or as a complementary method for the interpretation of bone scintigraphy.
CA 15.3 with Urinary Calcium Excretion is Useful in the Diagnosis and Monitoring of Bone Metastases from Breast Cancer
Authors: Yadav G.C. , Rao A. , Motawy M.M. , Safadi N. , Ahmed M. Jameel
Published: April 2018

Serum levels of breast carcinoma antigen (CA 15.3) and urinary calcium excretion (UCa) were determined in 73 patients with breast cancer: 36 without bone metastases (stage I-IV) and 37 with bone metastases. The patients in the latter group were further investigated at 2,4 and 6 months from the start of treatment. Both markers showed significant elevations in the group with bone metastases (CA 15.3: P = 1.0×10–6, UCa: P = 8.6×10–9). The bone metastasis index (BMI), which represents the combination of the markers, had better diagnostic efficacy (90%) than CA 15.3 alone (84%) or UCa alone (82%).

During treatment of bone metastasis, the longitudinal levels of the markers showed a highly significant association with the therapeutic response assessed by the UICC criteria. For identifying progression of disease, the diagnostic efficacy of CA 15.3, UCa and a combination of both, the so-called Biochemical Index of Response (BIR), was 65%, 70% and 79%, respectively, at two months and 89%, 84% and 92% at four months.

Application of the tandem, CA 15.3 with UCa, was very useful for the detection of bone metastases and the prediction of response to therapy.
Modification of Soluble Immunological Parameters during Treatment with Interleukin-2
Authors: Abbate I. , Correale M. , Musci M.D. , Guida M. , Dragone C.D. , De Santis M. , De Lena M.
Published: April 2018

In the present study we tested numerous soluble immunological parameters (soluble Interleukin 2 receptor, Beta 2 microglobulin, Neopterin, soluble CD8 antigen, gamma Interferon and alpha Tumor Necrosis Factor) in sera obtained from 18 advanced cancer patients during subcutaneous treatment with recombinant Interleukin 2. The treatment cycles consisted of a dose of 9×106 IU/m2 twice daily for 2 days followed by 1.8×106 IU/m2 twice daily for 5 days/week during 6 weeks. Even before therapy, neoplastic patients had higher levels of soluble Interleukin 2 receptor than a group of healthy subjects. Moreover, basal soluble CD8 antigen levels showed significant differences (p<0.01) in patients with different clinical responses (responders and non-responders).

During treatment we observed a fast increase (in the first or second week) of all parameters considered; soluble Interleukin 2 receptor and soluble CD8 antigen were the markers that were best related to the course of immunotherapy.

In conclusion, monitoring recombinant Interleukin 2 immunotherapy with immunological parameters in serum seems to be of interest. However, more data are necessary to confirm the real value of the single markers.
Mathematical Model Application to the Kinetic Study of Tumor Markers
Authors: Cappelli G.
Published: April 2018

In order to overcome the inefficient cutoff criterion in the management of neoplastic patients after therapy, in follow-up, in recurrence and in monitoring treatment, we have analysed some mathematical models to evaluate serial determinations of tumor markers, with the aim to ascertain the radicality of surgery or the presence of recurrences.

Since a tracer study of the biological system of tumor markers is impossible, some information, such as rate factor and half-life, is obtained by determination of the marker after radical treatment.

In steady state with two or more samples in time it is possible with adequate statistical models to establish a significant increase in the marker.

In recurrence, if it is true that the secretion rate of the marker by a tumor is proportional to tumor mass, then increasing concentrations of the tumor marker would be a phenotypic expression of tumor growth.

Therefore some mathematical models are proposed to evaluate the kinetics of tumor growth.
In Vitro and in Vivo Regulation of Human Tumor Antigen Expression by Human Recombinant Interferons: A Review
Authors: Guadagni F. , Roselli M. , Schlom J. , Greiner J.W.
Published: April 2018

The ongoing development of monoclonal antibody technology may eventually lead to the selective targeting of human carcinoma lesions by MAbs conjugated with a variety of cytotoxic agents (i.e., radionuclides, drugs, etc.). The antigen phenotype of the carcinoma cell will play an important role in the efficacy of the MAbs. Clearly, the human tumor antigens that are expressed on all carcinoma cells, and with a high antigen density, should provide the optimal target for the MAbs. More often than not, however, the human tumor antigens whose expression is highly selective for human tumor cells will also exhibit a certain degree of heterogeneity. Therefore, the ability of interferon to augment the level of expression of human tumor antigens such as TAG-72 and CEA, may play an important role in an adjuvant setting for immunoscintigraphy and/or immunotherapy. More recent observations have demonstrated that interferon treatment can also enhance the amount of TAG-72 and CEA secreted by the tumor cell. The ability of interferon to enhance the shedding of both TAG-72 and CEA could be of particular importance since recent reports suggest that their presence in the sera of patients diagnosed with gastrointestinal adenocarcinoma may be complementary and that the ability to increase either marker may facilitate earlier diagnosis of recurrent disease. It is conceivable that in subsequent years effective approaches to monitoring and/or treating malignacies may include a new combination of biological/immunological therapy.
Cytokeratins in the Histological Diagnosis of Malignant Tumors
Authors: Moll R.
Published: April 2018

Cytokeratins, which comprise a multigene family of 20 related polypeptides (CKs 1–20), are constituents of the intermediate filaments of epithelial cells, in which they are expressed in various combinations depending on the epithelial type and the degree of differentiation. Of these, CK 19 (400 amino acids; 44.1 kilodaltons) is an example of a widely distributed CK, being expressed in various epithelia, including many simple epithelia. In contrast, the recently identified CK 20 (424 amino acids; 48.6 kilodaltons) is essentially confined to gastrointestinal epithelia, the urothelium and Merkel cells. The differential expression of individual CKs in various types of carcinomas makes them useful markers for histopathological carcinoma subtyping, providing relevant information concerning the differentiation and origin of carcinomas, especially when tumors first present as metastases. The CKs that are of particular value for differential diagnosis include CK 20, as it is mainly expressed in carcinomas derived from CK 20-positive epithelia; it is also found in bile-tract, pancreatic and mucinous ovarian adenocarcinomas, being absent in most other carcinomas. In certain carcinoma types, the changes in the expression of individual CKs that may occur during tumor progression could be of prognostic relevance. It remains to be established whether the serological detection of fragments of not only widely distributed but also more restrictedly expressed CKs may provide useful serological tumor markers in the future.
The Tumor Markers Tpa, Tps, TpaCyk and Cyfra 21–1 React Differently with the Keratins 8, 18 and 19
Authors: Bodenmüller H. , Donié F. , Kaufmann M. , Banauch D.
Published: April 2018

The commercially available tumor marker tests TPA, TPS, TPACYK and CYFRA 21–1 react with simple epithelium keratins. From clinical studies it can be deduced that the pattern of keratin recognition must be different for each of these tests. We therefore studied the reactivity of the keratin fragment combinations K8/K18 and K8/K19 in the different tests and determined the reactivity of the corresponding soluble antibodies with purified keratin 8, 18 and 19 in immunoblots. TPS and CYFRA 21–1 were found to distinguish clearly between the keratin fragment combinations K8/K18 (TPS) and K8/K19 (CYFRA 21–1). TPA and TPACYK reacted with both combinations, however, with different intensities. On immunoblots the CYFRA 21–1 antibodies reacted exclusively with K19, whereas the antibodies of the other assays reacted with at least 2 of the keratins investigated.
Cyfra 21–1 in Lung Cancer: Comparison with Cea, Ca 125, Scc and Nse Serum Levels
Authors: Molina R. , Agusti C. , Mañe J.M. , Filella X. , Jo J. , Joseph J. , Giménez N. , Estapé J. , Ballesta A.M.
Published: April 2018

CYFRA 21–1, CEA, CA 125, SCC and NSE serum levels were determined in 50 healthy subjects and in 189 patients with primary lung cancer (101 with locoregional disease, 68 with recurrence and 20 patients with no evidence of residual disease (NED). Abnormal CYFRA 21–1 serum levels were found in 53.6% (90/168) of the patients with active cancer. Neither healthy subjects nor NED patients had abnormal serum levels. CYFRa 21–1 serum concentrations were significantly higher in patients with active cancer than in healthy subjects or in NED patients (p < 0.0001). CYFRA 21–1 sensitivity was related to tumor histology with abnormal levels in 64.7% of patients with NSCLC and in 30% of patients with SCLC (P <0.0001). In NSCLC, serum CYFRA 21–1 concentrations were also related to histological type, the highest values being found in squamous cell carcinomas and LCLC and the lowest in adenocarcinomas (p < 0.04). There was also a clear relationship between CYFRA 21–1 and tumor extension, with significantly higher values in patients with metastases than in those without metastases (p < 0.0001). Abnormal CEA values were found in 49.1%, CA 125 in 39%, SCC in 27.8% and NSE in 21.3% of the patients with active cancer. With respect to histological type, CYFRA was elevated in 68.3% of squamous cell carcinomas (CEA: 46.7%, SCC: 50%, CA 125:31.7%, NSE: 11.7%), in 54.8% of adenocarcinomas (CEA: 62%, SCC: 26.2%, CA 125: 59.5%, NSE: 9.5%), in 78.6% of LCLC (CEA: 64.3%, SCC: 28.6%, CA 125: 78.6%, NSE: 7.1%) and in 30% of SCLC (CEA: 37.7%, SCC: 3.8%, CA 125:20.8%, NSE: 45.3%). In summary, CYFRA 21–1 is the most sensitive tumor marker in patients with lung cancer, especially in NSCLC patients.
Cytokeratins and Tissue Polypeptide Antigen
Authors: Sundström B.E. , Stigbrand T.I.
Published: April 2018

Cytokeratins (CKs), which are biochemically related to intermediate filaments (IFs), form an intracellular network of filaments that is believed to participate in maintaining the structural integrity of cells. Twenty individual polypeptides, divided into two groups, constitute the cytokeratin family.

Each type of epithelial cell can be characterized by its content of cytokeratin polypeptides since the expression pattern varies with the type of epithelium. During transformation of normal epithelial cells into malignant cells, the cytokeratin patterns are usually maintained. This property has enabled the use of cytokerations as histological tumor markers, especially for tumors that are not easily classified.

Cytokeratins 8, 18 and 19 are the most abundant cytokeratins in carcinomas. They are released into necrotic areas and can be found intratumorally and in blood, circulating as partially degraded complexes, and can as such be used as tumor markers. Cytokeratin deposits in tumors make these structures potential targets for radioimmunodetection and immunotherapy. The usefulness of tissue polypeptide antigen (TPA) as a serological tumor marker has been known for a long time. TPA is a molecular complex containing CK8, 18 and 19 and determinations of TPA in serum samples can be used in the follow-up of patients with many types of cancer.
Relationship between Cytosol Tps, Tpa and Cell Proliferation
Authors: Gion M. , Mione R. , Becciolini A. , Balzi M. , Correale M. , Piffanelli A. , Giovannini G. , Jotti G. Saccani , Fontanesi M.
Published: April 2018

The serological tumor marker tissue polypeptide antigen (TPA) and the more recently identified tissue-specific polypeptide antigen (TPS) have been reported to be indicators of the proliferation rate of the tumor. In the present investigation we compared the cytosol level of the two markers with the proliferative activity of the tumor measured using the 3H-thymidine labelling index. The preliminary results presented here show that higher TLI is associated with lower cytosol levels of both TPA and TPS. TPA and TPS in the cytosol were significantly associated. These findings are in agreement with the previously demonstrated association between high TPA cytosol levels and better prognosis in breast cancer. Further studies are ongoing in order to:

1. confirm these findings in a larger patient series;

2. investigate any possible prognostic indication provided by TPS;

3. evaluate any possible biological meaning of the negative association between TPA/ TPS and TLI in the cytosol of breast cancer.
Evaluation of Critical Differences of CEA and CA15.3 Levels in Serial Samples from Patients Operated for Breast Cancer
Authors: Gion M. , Cappelli G. , Mione R. , Pistorello M. , Meo S. , Vignati G. , Fortunato A. , Saracchini S. , Biasioli R. , Giulisano M.
Published: April 2018

In the present investigation we evaluated the variability of tumor marker levels in the follow-up of patients without evidence of disease after resection of primary breast cancer. CEA and CA15.3 were measured using commercially available methods in serial blood samples collected from 170 patients. The coefficient of variation among all samples from each patient, which accounts for the total variability (analytical variability + biological variability), was widely scattered (from 4 to 99% for CEA; from 4 to 52% for CA15.3). The critical difference was calculated using the formula designed by Eraser [CD = 2.77. (CVa2 + CVb2)1/2]. It ranged from 11 to 276 for CEA and from 11 to 144 for CA15.3. From the present findings we conclude that:

1) it is possible to identify individually tailored decision criteria to evaluate tumor marker variations in the follow-up of breast cancer patients;

2) in a considerable number of cases the non-tumor-related variability is too high to allow the early identification of minor tumor marker variations that are of clinical relevance.
Antigen “Suicide”: A Preliminary Study on the Induction of Specific Anti-Immunoglobulin Immunological Suppression in Vivo, Using Radiolabeled Immunoglobulin as “Lethal” Antigen
Authors: Sivolapenko G.B. , Paganelli G. , Epenetos A.A. , Ritter M.A.
Published: April 2018

The effectiveness of immunodiagnosis and immunotherapy is limited when xenogeneic antibodies are used, due to the host's anti-immunoglobulin response. We have attempted to specifically suppress the immune response to the immunogen (immunoglobulin) administered. The concept of antigen “suicide” was used, where the antigen (immunoglobulin) was suitably radiolabelled and administered to animals. The question asked was whether immunocompetent cells that specifically interact with the radiolabeled immunogen, would be lethally irradiated and thus become inactivated rather than stimulated. When mice where primed with 111Indium-labelled polyclonal human IgG (specific activity 15 mCi/mg), they responded 13% less than control animals (p = 0.0485). This suppression was IgG-specific, since all animals responded similarly to a control antigen (human albumin). However, a second boost of the same 111Indium-labelled preparation (specific activity 7 mCi/mg) did not show any statistically significant immunosuppression. In addition, rabbits primed with125 Iodine-labelled mouse monoclonal antibody (specific activity 180mCi/mg) and boosted with the same unlabelled monoclonal antibody, showed a similar anti-mouse antibody response with the ones that received only unlabelled preparation twice. We conclude that the concept of antigen “suicide” may be effective for the induction of specific unresponsiveness; when immunoglobulins are radiolabeled with 111Indium at high specific activities, the desired state of specific immune suppression may be induced.
Expression of Gst-Mu Transferase in Breast Cancer Patients and Healthy Controls
Authors: Paradiso A. , Vetrugno M.G. , Capuano G. , Longo S. , Sibilano L. , Schittulli F. , Correale M. , Barletta A. , Pelagio G. , De Lena M.
Published: April 2018

The expression of glutathione S-transferase mu was measured by a qualitative immunoenzymatic assay in the blood samples of 108 women (63 breast cancer patients and 45 healthy controls) in order to analyze the relationships of GST-mu phenotype and smoking habits with tumor characteristics of breast cancer patients, such as tumor extension, nodal status, hormone receptor status and DNA content by flow cytometry. GST-mu was expressed in 53/108 (49%) of cases without any significant difference between healthy or neoplastic subjects, smokers or non-smokers, pre or post-menopausal, younger or older subjects. Moreover, the percentages of the GST-mu phenotype did not differ significantly in patients with different ER and PgR tumor status, tumor extension or nodal status. By contrast, aneuploid DNA tumor content was shown to be significantly associated with GST-mu expression (24% and 76% GST-mu positive, respectively, in diploid and aneuploid cases; p < 0.003). The biological meaning of this association remains to be interpreted.
Total Sialic Acid as a Tumor Marker for Oral Cancer
Authors: Xing R.D. , Wang Z.S. , Li C.Q. , Tang Q.Y. , Jiang C.B. , Zhang Y.Z.
Published: April 2018

Serum sialic acid levels were measured in 80 healthy subjects, in 60 patiens with benign tumors and in 110 patients with oral cancer. It was shown that these levels were significantly elevated in oral cancer patients compared to healthy controls and patients with benign tumors (p < 0.01); they were higher in patients with stage III and stage IV disease than in those with stage I and II disease (p < 0.01). However, no difference was observed between healthy controls and stage I and II cancer patients. The results of this study suggest that the determination of sialic acid levels may be of value in the diagnosis of oral cancer, but its usefulness as an adjunct in clinical staging is limited.
Usefulness of PSA Density and PSA Excess in the Differential Diagnosis between Prostate Cancer and Benign Prostatic Hypertrophy
Authors: Diaz F. , Morell M. , Rojo G.
Published: April 2018

The usefulness of PSA density (PSAD) was evaluated in relation to the volume of the transitional zone (PSAT) and PSA excess. With this purpose we conducted a study including 27 patients diagnosed as having prostatic cancer (PC) and 46 patients with benign prostatic hypertrophy (BPH). In all of them, the PSA concentration in the serum was determined as well as the total prostatic volume and the transitional zone volume; digital rectal examination (DRE) was also performed. The major diagnostic efficacy was obtained with the excess of PSA (73%, cutoff = -13 ng/ml), followed by DRE (68%), PSAT (64%, cutoff = 0.5), PSAD (64%, cutoff = 0.2), and lastly PSA and ultrasonography (60%). Multivariate analysis (logistic regression) demonstrated PSA excess and DRE to be the best predictors. The model obtained by regression shows the best positive predictive value, and PSA excess the best negative predictive value. Consequently, PSA excess could be relevant in prostate cancer diagnosis.
Preliminary Clinical Evaluation of free/total PSA Ratio by the IMMULITE® system
Authors: Correale M. , Pagliarulo A. , Donatuti G. , Sturdà F. , Capobianco A.M.L. , Stigliani V. , Rizzello M. , Circhietta S. , Pignatelli F. , Leone L. , Frusciante V. , Modoni S. , Schittulli F.
Published: April 2018

The role of free (F) and complexed serum PSA is now under investigation. In the present study, we evaluated the clinical significance of F-PSA and F/Total (T) PSA ratio in a preliminary series of samples from 88 patients with prostate cancer (PC), 113 with benign prostatic disease (BPD), and 98 with non-prostatic disease (NP). We used the F-PSA and third generation T-PSA (DPC, Los Angeles, USA) chemiluminescent enzyme immunometric assays with the IMMULITE automated system. At the 10 ng/ml cutoff for T-PSA levels, we obtained a sensitivity of 83% with a specificity of 100% in NP and 80% in BPD. The addition of the FIT ratio –rather than F-PSA levels – was useful to better discriminate PC and BPD in the cases erroneously classified by T-PSA alone: 44/68 samples (65%) were correctly diagnosed. Moreover, the FIT ratio was particularly effective in the critical T-PSA range between 4.1-9.9 ng/ml; 26/40 cases (65%) were correctly evaluated. In conclusion, the FIT ratio seems to be an interesting auxiliary test to T-PSA, to be reserved for selected cases where additional diagnostic information is necessary.
Immunoglobulin Ihhibiting Reagent®: Evaluation of a New Method for Eliminating Spurious Elevations in CA125 Caused by HAMA
Authors: Nicholson S. , Fox M. , Epenetos A. , Rustin G.
Published: April 2018

Cancer therapy utilising radiolabelled murine monoclonal antibodies frequently leads to the production of Human Anti-Mouse Antibodies (HAMA) in the recipient. HAMA interferes with “sandwich” immunoassays, such as those for tumour markers, rendering results unreliable. Published methods for eliminating HAMA from serum are not suitable for use in a laboratory which is processing a large number of assays using an automated system. We report on the use of Immunoglobulin Inhibiting Reagent (IIR) in CA125 assays from recipients of intraperitoneal radioimmunotherapy who had spuriously elevated results due to HAMA. IIR was found to be comparable to the admixture of mouse serum as a way of eliminating the effect of HAMA. IIR is ideally suited to use with an automated assay process.
Cathepsin D versus Other Prognostic Factors in Breast Cancer. Results and Controversies of a Multicenter Study on 2575 Cases
Authors: Pelizzola D. , Gion M. , Paradiso A. , Dittadi R. , Correale M. , Mione R. , Piffanelli A. , Paradiso A. , Correale M. , Ruggeri G. , Piffanelli A. , Giovannini G. , Messeri G. , Amadori D. , Riccobon A. , Di Fronzo G. , Cocconi G. , Camisa R. , Saccani-Iotti G. , Zibera C. , Gion M.
Published: April 2018

The aim of this study was the survey of cathepsin D determination in a large group of patients enrolled at several centers, under the coordination of the Italian Committee for Quality Control in the Oncological Laboratory. Cathepsin D was measured with the same method-ology, under control of an intra and interlaboratory quality control program, in order to verify the comparability of cathepsin D results from different institutions and to analyze the frequency of cathepsin D positive cases in subgroups of patients stratified according to other prognostic parameters. This retrospective study included 2575 patients with primary breast cancer evaluat-ed in 10 institutions. Cytosol from tumor tissue was the substrate for biochemical cathepsin D, estrogen receptor and progesterone receptor determination, with an interlaboratory quality control survey provided by the E.O.R.T.C. Receptor Group and the Italian Committee for Quality Control in the Oncological Laboratory.

The results of the present study can be summarized as follows:

1) Cathepsin D is independent of menopausal status;

2) In spite of standardization of tissue handling and assay methods, different results may be obtained by different institutions. It is therefore essential that each laboratory calculates its own positive/negative cutoff values prior to any routine clinical use of the parameter. This should be a serious consideration when a multicenter study is planned.
Serum CA 125 as a Marker of Hepatocellular Carcinoma
Authors: Lopez J.B. , Balasegaram M. , Thambyrajah V.
Published: April 2018

This study was undertaken to investigate whether serum CA 125 could complement alpha-fetoprotein (AFP) to improve the diagnosis of hepatocellular carcinoma (HCC). CA 125 showed a sensitivity of 92% for HCC against the 58.8% sensitivity of AFP at the cutoff value of 200 ng/ml. However, the former was less specific (48.5% versus 97.4%) in relation to benign liver diseases (BLD). CA 125 had a higher negative predictive value (NPV) of 84.6% compared to 69.2% for AFP; when both markers were combined, however, the NPV rose to 91.7%. Overall, AFP was more efficient than CA 125 for the diagnosis of HCC. While a positive AFP result was highly indicative of HCC, a negative result did not rule out the disease; however, negative AFP and CA 125 meant that the likelihood of the disease was low. In situations of low HCC prevalence, CA 125 could serve as a first-line screening test followed by confirmation of positives by AFP.
ΔIK17: An Antigen Expressed on Human Lymphocytes
Authors: Sotiriadou R. , Kokkinopoulos D. , Stinios J. , Dimas C. , Trangas T. , Perez S.
Published: April 2018

Anti-ΔIK17 monoclonal antibody was produced by fusing SP2/0/Ag14 myeloma with spleen cells of BALB/c mice immunized with normal human thymocytes. AΔIK17 antibody recognizes a 44kD cell surface protein detected on human lymphocytes. ΔIK17 is expressed on human thymocytes, CD4+ and CD8+ T cell subsets, B, NK cells, as well as on activated cells. The antigen is detected on cells during the early, indermediate and late stages of lymphocyte maturation. In addition, the expression of the antigen is correlated with ontogenesis. A T+ ΔIK17+ subpopulation responded poorly to TPA stimulation and provided a better helper signal for PWM-induced IgM synthesis than T+ ΔIK17- cells. In addition, different levels of ΔIK17 expression were detected in several hematological diseases tested.
ΔIK17 Antigen: A Possible Early Marker of Cancer Development
Authors: Perez S. , Sotiriadou R. , Missitzis G. , Trangas T. , Giannoulis N. , Mavroudeas D. , Apostolikas N. , Kokkinopoulos D.
Published: April 2018

ΔIK17 is a 44 kD molecule located on the surface of T, B and NK cells in normal peripheral blood mononuclear cells (PBMC) (1). The portion of PBMC expressing ΔIK17 was determined in 52 patients with benign breast diseases, 182 patients with breast malignancies and 132 healthy individuals. The percentage of ΔIK17'-positive cells was significantly lower in the early stages (I-IIA) of malignancy compared to that of healthy donors. However, the percentage of PBMC expressing ΔIK17 tended to increase as the stage of the disease advanced. ΔIK17 seems to be the only antigen among the other cellular markers tested (CD2, CD4, CD8, HLA-DR) with a statistically significant correlation between a low percentage of positive cells and the early stages of malignancy and between a high expression and advanced disease. Its potential use as a tumor marker in breast cancer is discussed here.
CA549 and TPS Patterns in the Diagnosis and Staging of Patients with Breast Carcinoma
Authors: Vibert H.G. , Houston A.S. , Wilkins G.P. , Kemp P.M. , Macleod M.A.
Published: April 2018

This study compares the clinical value of the breast cancer tumour markers CA549 and TPS, and their tandem use when one or both markers indicate abnormality. For 144 patients presenting with active disease, 33 were classified as Stage I, 37 as Stage II, 40 as Stage III and 34 as Stage TV. For these patients the sensitivity of CA549 using a cut-off of 10 U/ml was 27%, 32%, 42% and 79%, respectively. The sensitivity of TPS for each stage using a cut-off of 100 U/l was 12%, 22%, 28% and 73%, respectively. At these cut-off levels, 36%, 46%, 63% and 91% of patients, respectively, have either CA549 or TPS or both markers raised. For 161 patients with diagnosed benign breast disease, the specificity of marker levels was 96% for CA549, 88% for TPS and 84% for tandem use. CA549 is shown to be superior to TPS and this was confirmed by Receiver Operating Characteristic (ROC) analysis using variable threshold levels, with the areas under the curves for all stages combined being 0.74 ± 0.03 (1SD) and 0.66 ± 0.03, respectively. The corresponding area under the curve for tandem use (0.75 ± 0.03) is marginally greater than for either individual marker, although the difference with respect to CA549 is statistically insignificant.
False Positive Tumor Markers: Elevation in Patients with Breast Cancer on FAC-type Chemotherapy and Correlation with the Development of Hand-foot Syndrome
Authors: Tyshler L.B. , Longton G.M. , Ellis G.K. , Livingston R.B.
Published: April 2018

Breast cancer patients on dose-intensive chemotherapy often have elevated tumor markers during the course of treatment. Our objective was to estimate the incidence of a “false positive” tumor marker screen and to determine whether hand-foot epithelial damage was correlated.

Data from 53 patients with high risk primary breast cancer who had undergone adjuvant or neoadjuvant 5FU-containing chemotherapy (FAC or FAC plus G-CSF) for 3 to 12 months were reviewed. The relationship between tumor marker elevation and disease recur- rence, regimen intensity, and the occurrence of hand-foot syndrome was examined.

Thirty-three of the 53 patients had elevated tumor markers in the absence of recurrent disease. The false positive rate was higher in patients who underwent FAC plus G-CSF chemotherapy than in patients who underwent FAC chemotherapy (92% vs 55%, p = .01). A false positive marker screen was associated with the occurrence of hand-foot syndrome even when the effect of regimen was accounted for by stratification (p=.01).

Tumor marker screening of breast cancer patients on this type of adjuvant chemotherapy has poor specificity for recurrent malignancy. These data suggest tumor marker elevation may be an indicator of epithelial toxicity during chemotherapy, manifested clinically as hand-foot syndrome.
Generation of Human Monoclonal Anti-idiotypic Antibodies with Specificity to the Murine Monoclonal Anti-CA 125 Antibody B43.13
Authors: Oltrogge J.B. , Donnerstag B. , Baum R.P. , Noujaim A.A. , Träger L.
Published: April 2018

Two human monoclonal antibodies, HID-7E7 and ROB-6F2, were produced by EBV transformation of peripheral blood lymphocytes (PBL). PBL were obtained from a patient with ovarian cancer who had been exposed several times to a Tc-99m labeled murine monoclonal anti-CA 125 antibody (B43.13, Biomira, Edmonton) for immunoscintigraphy. The HID-7E7 and ROB-6F2 producing B-cells were cloned with a limiting dilution technique and have shown stable immunoglobulin secretion within a period of three years. The human monoclonal antibodies HID-7E7 and ROB-6F2 are of the IgG isotype, and bind with significant affinity to the murine monoclonal antibody B43.13, which was used for immunoscintigraphy. Binding affinity of ROB-6F2 to other murine antibodies could not be detected. Cross reactivity of HID-7E7 to a murine anti-CEA monoclonal antibody was observed. In order to verify the anti-idiotypic character of the generated human antibodies, the ability of HID-7E7 and ROB-6F2, respectively, to inhibit the formation of the CA125/B43.13 complex is demonstrated via an enzyme-linked immunosorbent assay. These human anti-idiotypic antibodies are possible candidates for immunotherapy of ovarian cancer in patients with a small tumor burden following surgery and/or chemotherapy.