bluuebunny/crossref_metadata_2025 huggingface dataset:
Lymphocyte Subpopulations in Lynch Syndrome Ii: An Immunocytochemical Study on Gastrointestinal Biopsies. Preliminary Report
Authors: Senatore Silvano , Jotti Gloria Saccani , Liguori Donata , Chetrì Maria , Attolini Annamaria , Cristofaro Giuseppe , Gabrielli Marzio
Published: April 2018

Gastrointestinal biopsies from 18 members of a family with Lynch Syndrome II were evaluated and immunocytochemical studies were made to characterize the phenotypic expression of the tissue's immune populations. The intestinal findings suggest polyclonal B-cell activation related to the T-helper distribution. Our evaluation provides no specific information so far on the management of patients with Lynch Syndrome II.
Evaluation of Specific Antigen and Prostatic Acid Phosphatase Specificity. Study of False Values
Authors: Morote Juan , Ruibal Alvaro , Palou Juan
Published: April 2018

We assayed prostatic specific antigen (PSA) and prostatic acid phosphatase (PAP) serum levels in 1305 subjects without malignant prostatic pathology by double antibody RIA I125 to evaluate their specifity. When we set a second upper normal limit of 10 ng/ml for PSA and 2.5 ng/ml for PAP there was a significant increase of specificity. There were 2 and 3.7% false positive results in non-prostatic benign pathologies, 1.8 and 7.9% in non-prostatic malignant, 3.5 and 4.7% in non-complicated benign prostatic hypertrophy (BPH) and 3.3% for both in chronic prostatitis. In patients with complicated BPH and acute prostatitis the results were 64.8 and 24% for PSA and 20 and 16% for PAP. In conclusion, PSA is more specific than PAP in patients without acute inflammatory pathology of the prostate; the high rate of false positive values in the latter excludes its usefulness in these patients as diagnostic tumoral markers.
Tumor Markers and Lung Cancer: Correlation between Serum and Bronchial Secretion Levels of Cea, Tpa, Canag Ca-50, Nse and Ferritin
Authors: Macchia Vincenzo , Mariano Angela , Cavalcanti Mariarita , Coppa Anna , Cecere Ciriaco , Fraioli Gaetano , Elia Stefano , Ferrante Giovanni
Published: April 2018

The levels of carcinoembryonic antigeny (CEA), tissue polypeptide antigeny (TPA), CanAg 50, neuron specific enolase (NSE) and ferritin were determined in bronchial secretion and serum of patients with neoplastic and non-neoplastic lung diseases. Simultaneous determination of two or three markers in the serum and in bronchoalveolar lavage (BAL) may be clinically useful for the diagnosis of lung cancer and even for the type of tumor. The positivity of CEA determined simultaneously in serum and in BAL of patients with lung cancer is higher than 80% whereas in patients with benign lung disease it is lower than 40%. The simultaneous assay of TP A in serum and in BAL showed 100% positivity in patients with oat-cell carcinoma, the frequencies of positivity were similar in patients with non-oat-cell carcinoma. For NSE and CanAg CA-50 patients with oat-cell carinoma showed 100% positivity. Simultaneous assay of ferritin in serum and in BAL gave 85% positivity in patients with oat-cell carcinoma and only 23% in patients with non-oat-cell carcinoma. We conclude that the simultaneous determination of CEA and CanAg CA-50 or NSE in serum and in BAL is a useful aid in the diagnosis of lung malignancy.
Diagnostic Interest of the Monoclonal Antibody Ca1 in Malignant Pleural Effusion
Authors: Font Pedro , Palacìn Antonio , Font José , Faus Ramón , Molina Rafael , Ballesta Antonio M. , Cardesa Antonio , Ingelmo Miguel
Published: April 2018

The Ca1 antibody was used in an immunohistochemical procedure on smears of cells from 40 patients with malignant pleural effusion. The control group consisted of 25 benign pleural effusions with a high percentage of reactive mesothelial cells. The Ca1 Me Ab was positive in 19 (79%) of the 24 pleural effusions with positive malignant cytology. In all the benign cases the Ca1 Mc Ab was negative (100% specificity). The Ca1 Mc Ab detected malignant mesothelial cells in two cases and was negative with reactive mesothelial cells and other nucleated cells present in the pleural effusion. We conclude that the Ca1 antibody offers a useful diagnostic method for malignant pleural effusions, when the morphological interpretation is doubtful.
Phosphohexose Isomerase and Carcinoembryonic Antigen in the Sera of Patients with Primary Lung Cancer
Authors: Santabárbara P. , Molina R. , Estapé J. , Ballesta A.M.
Published: April 2018

Phosphohexose isomerase (PHI) and carcinoembryonic antigen (CEA) were measured at the time of diagnosis in 300 patients with lung cancer. Serum levels were high in 75.7% and 53.0% of patients respectively. PHI levels were higher in large cell and small cell carcinomas (p < 0.001). CEA levels were higher in adenocarcinomas (p < 0.001). Metastatic carcinomas showed higher levels on PHI and CEA than localized cases. Survival was significantly longer in patients with normal PHI (p < 0.001) and normal CEA (p < 0.005) than in cases with elevated markers. The prognostic significance of PHI persisted in the different pathological types and stages, whereas CEA only had prognostic impact in non-small cell cases. Serial PHI determinations were useful for follow-up in 82.4% of cases with initial abnormal values and in 55.4% of cases with a normal value. Serial CEA was useful in 41% of cases with initially high value but in less than 15% of those with baseline normal. We conclude that PHI has prognostic significance independently of pathology and stage, whereas CEA was a prognostic indicator only in non-small cell cases; serial PHI determinations were useful more often than CEA for follow-up.
Value of ER-D5 Immunocytochemical Determination in Routine Tissue Sections of Human Breast Cancer
Authors: Giani C. , Campani D. , De Negri F. , Perpoli F. , Capotorti E. , Squartini F. , Pinchera A.
Published: April 2018

ER-D5 is a recently identified protein related to estrogen receptors (ER). Generally ER measurement requires fresh frozen tissue and for ER-D5 assay ethanol (E) fixation of the specimen is recommended. We evaluated the possibility of immunocytochemical detection of ER-D5 in routine formalin-fixed (F) sections in 51 breast cancers comparing the results with those obtained in the same specimens using E as fixative. The results of ER-D5 assay were expressed by the staining index (SI) taking values ≥5 as positive. In all tumors ER was also assayed by a biochemical method (DCCA). The sensitivity of ER-D5 detection in F was only 33.3%, while the specificity was 94.4%. A lower cut-off value of SI for F sections (≥2) increased the sensitivity to 66.6%, leaving the specificity unchanged. A strong correlation was found between the SI of ER-D5 in E and F (p<0.001). The SI of ER-D5 in F sections was also well correlated with ER concentrations (p<0.001). These results suggest that immunocytochemical determination of ER-D5 in routine sections may be useful in retrospective studies of hormone dependence in breast cancer.
Tumor Markers, Liver Function Tests and Symptoms in 115 Patients with Isolated Colorectal Liver Metastases
Authors: Lorenz M. , Baum R.P. , Oremek G. , Inglis R. , Reimann-Kirkowa M. , Hör G. , Seiffert U. , Hottenrott C.
Published: April 2018

Development of the hybridoma technique has made the identification of several new tumor antigens possible. Although it was hoped that they would be more tumor-specific, none of these markers are found exclusively in tumor or in serum of tumor patients. Compared with carcinoembryionic antigen (CEA) and liver function tests, the roles of these markers (CA 19-9, CA 125, CA 15-3) were prospectively evaluated in 115 patients with colorectal liver metastases. Patients were classified according to tumor volume (T1 <25%, T2 25-75%, T3 >75%), and the extension of infiltration (solitary/multiple/diffuse; unilateral, bilateral). Patients with benign liver or biliary disease served as a control group (n=63). Overall sensitivity was 87% for *1 , 50% for *2 and 38% for *3 , with a significant correlation with tumor size. CEA serum levels were elevated in 88% of all patients. CA 19-9 was less sensitive: positive in 59%. Because of some complementary elevations, the combined use of CEA, CA 19-9 and CA 125 raised sensitivity to 94%. CA 19-9 and LDH could be useful for confirmation because of their higher specificity; however, the specificity of CEA rose to 93% on using a cut-off of 10 ng/ml instead of 3 ng/ml. The results indicate that CEA and CA 19-9 as well as liver function tests are helpful for preoperative staging in conjunction with imaging procedures before liver resection or regional chemotherapy.
Prolactin Secretion in Testicular Cancer Patients
Authors: Lissoni P. , Crispino S. , Barni S. , Tancini G.
Published: April 2018

The role of prolactin (PRL) in testicular function and in its disorders is still obscure. To draw some preliminary conclusions on the relation between the PRL and testis cancer, we assessed the PRL response to thyrotropin-releasing hormone (THR) in 15 patients with testicular cancer (8 seminoma; 6 nonseminoma; 1 leydigioma), and in 11 healthy male subjects as controls. The results showed that 5/15 cancer patients gave no PRL response to TRH; 4 of them had a nonseminoma and the fifth a seminomatous testis carcinoma. Patients with nonseminoma had significantly lower mean peak values of PRL after TRH than controls or patients with seminoma. The biological significance of the altered PRL response to TRH in testicular carcinoma has still to be established.
Carcinoembryonic Antigen Levels in Germ Cell Tumours
Authors: Hitchins R.N. , Rustin G.J.S. , Mitchell H.D.C. , Newlands E.S. , Begent R.H.J. , Bagshawe K.D.
Published: April 2018

Elevated serum carcinoembryonic antigen (CEA) prior to specific treatment was noted in 3% (7/258) of assessable patients with testicular, extragonadal or ovarian germ cell tumours (GCT). In addition, persistently raised CEA was documented in 7% (26/385) of patients during or after cisplatin-based chemotherapy for metastatic GCT. Raised CEA did not appear associated with adverse prognosis. Among patients undergoing resection of residual tumour masses post-chemotherapy, 8 of 36 with mature differentiated teratoma excised had raised CEA compared with only one of 39 patients where no mature teratoma was found. However, CEA levels remained elevated in 6 of the 8 cases despite apparent complete resection of mature teratoma. Elevated CEA in treated GCT patients may be caused by hepatotoxicity from chemotherapy, intercurrent diseases, or other unknown factors. History of cisplatin-based chemotherapy may be a confounding factor in interpreting raised CEA levels. CEA measurements do not help in the management of patients with germ cell tumours.
Efficiency of Composite Laboratory Tests in the Diagnosis of Liver Malignancies
Authors: Pavesi F. , Lotzniker M. , Scarabelli M. , Garbagnoli P. , Moratti R.
Published: April 2018

The utility of the markers CEA, β-HCG, CA-50, alpha-fetoprotein (APF), ferritin, alkaline phosphatase (AP), its isoenzyme liver-1 (APL1), gamma-glutamyltransferase (gGT), its fast migrating isoenzyme (gGT1) and 5'nucleotidase (5'N) in differentiating liver malignancies and benign involvement was evaluated in, the sera of 85 patients with hepatocellular carcinoma (HCC), 157 with chronic liver disease (CLD) and 91 with liver metastases (LM) derived from different tumors. The mean concentrations of all the parameters except CEA and GGT1 were significantly different in HCC and CLD, but a broad overlap existed in the two groups, so different cut-offs were considered to assess the positive and negative predictive values and test efficiency (Eff). The best results were observed considering AFP > 100 IU/m (Eff0.86), ferritin > 800 ng/ml (Eff0.69), CA-50 > 100 U/ml (Eff 0.63), β-HCG > 10 mU/ml (Eff 0.61), AP > 300 IU/ml (Eff 0.66), the presence of APL1 (Eff 0.78), 5'N > 25mU/ml (Eff 0.70), gGT > 100 mlU/ml (Eff0.63). Among HCC patients 17% did not secrete AFP; in 26% the protein was < 100 IU/ml and in 36% < 400 IU/ml. Apart from AFP the most effective marker was APL1. At the above cut-offs more than three parameters were simultaneously positive in 71% of HCC and 9.9% of CLD. CEA, CA50, AFP were the only parameters that distinguished the HCC from the LM group; in the latter, APL1 was also a very sensitive marker (87%) for neoplastic involvement of the liver
Tumor Markers in Squamous Cell Carcinoma of Esophagus: Immunometric Assay in Cytosol and Membrane Fraction
Authors: Gion M. , Tremolada C. , Mione R. , Dittadi R. , Palma P. Della , Castoro C. , Ruol A. , Nosadini A. , Peracchia A. , Bruscagnin G.
Published: April 2018

Carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), ferritin, and the monoclonal antibody-detected tumor-associated antigens CA19.9 and CA50 were measured by radioimmunoassay in tissue fractions of carcinoma and normal esophageal mucosa from 59 patients with untreated primary squamous cell carcinoma of the esophagus. Tumor markers were measured in cytosol (118 samples) and in a membrane-enriched fraction (32 samples). CEA, TPA and ferritin were detected in almost all the cytosol samples evaluated, CA19.9 and CA50 in 66% and 50% of cases respectively. Ferritin was significantly higher in carcinoma than in normal mucosa. The cytosol concentrations of CEA, TPA, CA19.9 and CA50 were not significantly different in carcinoma and normal tissue. Concentrations of CEA, CA19.9 and CA50 in the membrane fraction tended to be higher in normal tissue than in carcinoma, whereas the cytosol-to-membrane ratio was significantly higher in carcinoma. For CEA, CA19.9 and CA50, the phenotypic pattern of the malignant transformation seems to involve a different intracellular distribution rather than a quantitative change. No correlations were found between tissue and serum concentrations of the tumor markers, the former being related to the phenotypic characteristics of the tumor, the latter to the tumor burden.
Immunoreactive Calcitonin: A Tumor Marker for Myelogenous Leukemias
Authors: Foa P. , Ortolani S. , Pogliani E.M. , Iurlo A. , Gualdonj A. , Maiolo A.T. , Polli E.E.
Published: April 2018

In a series of 59 patients with chronic or acute myelogenous leukemia (CML, AML) we investigated whether circulating immunoreactive human calcitonin (i-hCT) levels correlate with diagnosis, response to therapy and clinical course. I-hCT was detectable in plasma samples of 88% of patients with CML in the chronic phase and in 100% of patients with CML in blastic transformation. In the AML patients, a significant relation was observed between the cytological subtype and i-hCT levels at diagnosis. In sequentially studied patients the i-hCT plasma concentration was related to the overall mass of leukemic cells, being lower when complete remission was achieved than at diagnosis and increasing at time of recurrence. These data suggest that circulating i-hCT levels can serve as a “tumor marker” in human myelogenous leukemias.
Comparison between CEA, TPA, CA 15/3 and Hydroxyproline, Alkaline Phosphatase, Whole Body Retention of 99mTc MDP in the follow-up of Bone Metastases in Breast Cancer
Authors: Francini G. , Montagnani M. , Petrioli R. , Paffetti P. , Marsili S. , Leone V.
Published: April 2018

The development of bone metastases in cancer can be monitored easily using three markers: 24 h urinary hydroxyproline excretion (HOP) (an index of osteoclastic activity), serum alkaline phosphatase (Alk.Ph.) (an index of osteoblastic activity) and 24 h whole body retention of 99mTc-methylene diphosphonate (WBR%) (an index of bone turnover). To evaluate the effectiveness of this group of bone tumor markers in breast cancer we compared it with the following group of three markers which are commonly used in the monitoring of breast cancer and in the follow-up of advanced disease with or without bone metastases: carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA) and breast carcinoma antigen (CA 15/3).

In 48 patients with bone metastases CEA, TPA and CA 15/3 were shown to be sensitive (79%, 85%, 90% respectively), while HOP, Alk.Ph. and WBR%, which are commonly accepted as reliable markers of bone activity, showed a lower sensitivity (67%, 46%, 75% respectively).

These results may be explained by the lack of osteoclastic or osteoblastic (or both) activity at the time of diagnosis. This explanation is supported by the fact that the bone markers HOP, Alk.Ph. and WBR% were found to be more sensitive than the others in the subsequent follow-up study.

We conclude that in our study, CEA, TPA and CA 15/3 are at first more sensitive than Alk. Ph., HOP and WBR% but during the follow-up Alk.Ph., HOP and WBR% are possibly both more specific and more sensitive
Characterization of Primate Antibody Responses to Administered Murine Monoclonal Immunoglobulin
Authors: Milenic D.E. , Detrick B. , Reynolds J.C. , Colcher D.
Published: April 2018

Murine monoclonal antibodies (MAb) are currently being assessed for their utility as tools in cancer management. Anti-murine immunoglobulin responses have been observed in many patients receiving monoclonal antibody treatment. In this study, we evaluated the response of primates to the administration of a monoclonal antibody. MAb B6.2, an antibody generated against a human breast tumor metastasis, was used as a prototype MAb. Baboons were inoculated with MAb B6.2 whole IgG, Fab', or F(ab')2 fragments. Blood samples were drawn at periodic intervals post-inoculation and the sera collected. Anti-murine immunoglobulin responses were detected using a solid-phase radioimmunoassay. The specificity of the antibody response was analyzed to determine if the response was directed against the species of origin of the MAb (species specificity), against the class of the MAb (isotype specificity), or against the hypervariable region of the MAb (idiotype specificity). We found that primates develop a humoral immune response against all three forms of the monoclonal antibody [IgG, Fab', and F(ab')2]. Furthermore, this antibody response demonstrated a high degree of specificity for the antigen binding site suggesting an idiotypic specificity. Using a competitive radioimmunoassay, the antibody response was found to interfere with antigen binding of MAb B6.2. These studies suggest that monoclonal antibody treatment can generate an anti-idiotypic response which may alter the efficacy of this mode of treatment.
Activation of the Complement System during Immunotherapy of Cancer with Interleukin-2: A Possible Explanation of the Capillary Leak Syndrome
Authors: Lissoni P. , Barni S. , Cattaneo G. , Archili C. , Crispino S. , Tancini G. , D'Angelo L. , Magni S. , Fiorelli G.
Published: April 2018

The capillary leak syndrome, responsible for fluid loss into the interstitial space, represents one of the major cardiovascular toxicities of IL-2 during the immunotherapy of cancer. The mechanisms involved in the increased vascular permeability have still to be better understood. The present study was carried out to investigate the role of the complement system in mediating the IL-2 vascular toxicity. The study was performed in metastatic renal cancer patients, treated with IL-2 through a 24-hour i.v. infusion at a daily dose of 3 × 106 U/m2 for 5 consecutive days, corresponding to one IL-2 course. Six IL-2 courses were evaluated. C3 and C4 were measured daily during IL-2 infusion, and 2 and 5 days after its interruption. IL-2 administration induced a significant decrease in both C3 and C4 mean levels, which became within the normal range 5 days after the end of IL-2 infusion. These results show that IL-2 administration may directly activate the complement system through the classical pathway, which might play a role in determining the increased vascular permeability.
Mucin-Like Carcinoma-Associated Antigen (MCA) in Tissue and Serum of Patients with Breast Cancer: Clinical Applications in Prognosis and Disease Monitoring
Authors: Molina R. , Jo J. , Filella X. , Zanon G. , Grau J.J. , Joseph J. , Bedini J.L. , Biete A , Ballesta A.M.
Published: April 2018

Mucin-like Carcinoma-associated Antigen (MCA) has been associated with many breast cancers. The aim of this study was to evaluate MCA in tumor tissue and serum as a potential tumor marker for prognosis and disease monitoring. MCA levels were determined in the tissue of 196 patients with primary breast cancer, 25 with metastatic disease and 25 patients with benign diseases, in pellet and/or cytosol. MCA levels were also determined in the serum of 50 patients with benign diseases, 148 with primary breast cancer (Mo), 150 with metastatic breast cancer (MT), and 200 with no clinical evidence of disease (NED). MCA tissue concentrations in pellet and cytosol were similar: 66.7 + 251 U/mg and 41.1 + 53 U/mg, respectively. No relationship between MCA levels and tumor size or nodal involvement was found. Higher MCA levels were observed in patients with ER + or PgR + tumors than in those with ER- or PgR- tumors (p < 0.01). Patients with MCA pellet concentrations lower than 10 U/mg of protein had shorter disease - free intervals (DFI) than those with higher values (p < 0.05).

Abnormally high serum levels of MCA were found in 8% of patients with benign diseases, 4% of NED patients, 22% of Mo patients, and in 76% of MT cases. In primary breast cancer MCA values were related to tumor size and nodal involvement. A trend toward a lower DFI in patients with elevated presurgical MCA levels was observed but was of no statistical significance. These differences became statistically significant when patients were subdivided according to nodal status, with shorter DFI in those without nodal invasion (p < 0.05). In metastatic patients, changes in serum MCA were related to the tumor's response to treatment in 82% of cases. The highest MCA values were found in patients with liver or bone metastasis and the lowest values were found in those with locoregional recurrence. In conclusion, although MCA is not a specific tumor marker, it can be useful as a prognostic factor (tissue and serum) and in monitoring metastatic patients.
Monoclonal Antibodies by Genetic Engineering: Novel Reagents for in vivo Diagnosis and Therapy
Authors: Canevari S. , Furlan D. , Mossa A. , Figini M.
Published: April 2018

In only a few years, the technology of antibody engineering has demonstrated its power and a variety of recombinant monoclonal antibodies are now being developed.

Recent developments in gene manipulation have allowed the isolation of antibodies, including human antibodies, with or without immunization, by displaying functional antibody fragments on the surface of bacteriophage particles and directly selecting with antigen. In the present review some recent achievements in these areas are highlighted.
The Role of Cytokines in the Modulation of Cell Surface Antigens of Human Melanoma
Authors: Anichini A. , Mortarini R. , Parmiani G.
Published: April 2018

A number of different cytokines, including IL-1α. and ß, IL-2, IL-3, IL-4, IL-6, IL-7, IL-8, IFN-α, -ß and γ, TNF-α -ß, and TGF-ß1, can modulate the expression of distinct cell surface antigens of normal and neoplastic cells. Both induction/increase of expression and reduction of expression can be achieved depending on the antigen and on the cytokine. Antigens subjected to the modulating activity of cytokines include distinct families of cell surface structures such as the molecules coded by the major histocompatibility complex (MHC), the superfamily of adhesion receptors that regulate cell-cell and cell-matrix interaction, receptors for cytokines and growth factors and tumor-associated antigens. The modulating activity of cytokines is a consequence of their influence on gene expression, protein synthesis, membrane expression and shedding of antigens from the cell surface. The changes of phenotype due to the action of cytokines can influence the signalling pathways dependent on the expression and function of cell surf ace structures. Therefore, the antigen modulating activity of cytokines can thoroughly affect the biological behavior of normal and neoplastic cells. As described here, most of the modulating effects of cytokines on different cell surface structures and the functional consequences of antigenic modulation can be verified in human malignant melanoma cells.
Pretargeting of Carcinomas with the Avidin-Biotin System
Authors: Paganelli G. , Magnani P. , Fazio F.
Published: April 2018

Diagnosis and experimental therapy of cancer have been performed with encouraging results using radiolabelled monoclonal antibodies. However, the high background due to non-specific uptake by normal tissue and blood is a major drawback in antibody-guided tumor detection. Various strategies have been proposed to overcome this problem, such as computed background subtraction, use of a second antibody, and local delivery. An antibody is a slow “bullet” for tumor targeting, since in many lesions it requires two or three days to accumulate. The use of fragments such as F(ab’)2 or Fab, which display a faster blood clearance than whole antibody, improves tumor localization to a sufficient extent (hours) to allow the use of the most suitable radionuclides, e.g. 99m-Tc. In therapeutic applications we are still far away from the optimal condition in terms of the absolute amount of radioactivity delivered to the tumor. The high specificity of antibodies could be exploited at its best by delaying the delivery of the label to a time when the ratio tumor-bound to non-tumor-bound antibody has reached its maximum value. To obtain this goal, the label should display a fast clearance and should be captured by the antibody already targeted onto tumor cells. These considerations have led to strategies of tumor pretargeting where antibody and label are administered separately. One of these strategies, based on the avidin-biotin system, has already been used extensively for several years in immunohistochemistry and in ELISA. Due to the flexibility of this system, several alternative protocols are possible.

We describe a three-step and a two-step pretargeting protocol based on the avidin-biotin system.
Radionuclide Therapy of Tumors: General Aspects and Considerations
Authors: Hoefnagel C. A.
Published: April 2018

Therapeutic nuclear medicine is rapidly developing as an additional treatment modality in oncology. Its unique characteristics are the systemic, yet selective delivery of radiation doses in target tissues, its non-invasiveness, the relative lack of immediate and late side effects, and the advantage that uptake and retention in the tumor can be pre-assessed by tracer studies. Many different tumor seeking radiopharmaceuticals are being used for therapy by different routes and a variety of targeting mechanisms.

The current clinical role of radionuclide therapy is briefly reviewed, as well as more general aspects and considerations, such as mechanisms for tumor targeting, the choice of radionuclide labels, radiopharmacy, drug delivery, radiation protection, dosimetry and toxicity.
Radionuclides for Radioimmunotherapy: Criteria for Selection
Authors: Geerlings M. W.
Published: April 2018

In developing and designing radioimmunotherapy, the selection of the isotope is a major factor. This selection depends on a number of criteria and parameters, affecting usefulness and feasibility.

Usefulness is directly related to the radiological performance of the ionising radiation in relation to tissue and its morphology, with a major distinction between the effects of α and ß-particles (or rays). Usefulness is also directly related to the pharmacodynamic performance of the isotope-carrier (e.g. antibody) complex, where the proper choice of isotope radiodecay halflife is of major importance. Feasibility depends on availability of the components in the isotope-ligand-carrier complex, and also on convenience and safety aspects in the preparation and the handling of the materials as well as in their application in patients.

A comparison is made between the various properties of α-emitting isotopes that have been proposed over a number of years, concluding that the combination 225Ac- 213Bi deserves serious further attention.
Radioimmunotherapy of Gastrointestinal Cancer and Glioblastomas
Authors: Riva P. , Tison V. , Arista A. , Sturiale C. , Franceschi G. , Riva N. , Casi M. , Moscatelli G. , Campori F. , Spinelli A.
Published: April 2018

Two groups of patients with gastro-intestinal (GI) tumours (41) and recurrent glioblastoma (GBM), (17) underwent radioimmunotherapy after the failure of traditional treatments. A number of different MAbs were employed (anti-CEA and anti-Tenascin) which were labelled with I-131. The radiopharmaceuticals were administered by the intraperitoneal and intratumoral routes. As a rule the cycles were repeated to enhance the effectiveness of RIT. No significant early or late adverse effects were recorded. HAMA development was observed in all GI cases but only in a few GBM patients. The cumulative dose delivered to the target tumors was considerable (mean 8,900 cGy) in the GI group, and was much higher in the GBM patients (mean 51,700 cGy) owing to the particular modality of injection. Survival improved in both series of patients. The objective responses to RIT were promising: in the GI group 10 complete remissions (CR) and 6 partial remissions (PR) were observed, while in the GBM group 3 long-lasting CRs and 3 prolonged PRs were documented.
Serum TPS versus TPA in Egyptian Bladder Cancer Patients
Authors: Halim A.-B. , El-Ahmady O. , Hamza S. , Aboul-Ela M. , Oehr P.
Published: April 2018

This study included 328 cases (106 with bladder cancer, 152 with non-malignant urinary tract diseases and 70 healthy controls). Serum TPA was determined using the Prolifigen TPA IRMA kit supplied by AB Sangtec Medical, Bromma, Sweden and serum TPS was determined using the TPS IRMA kit supplied by Beki Diagnostics AB, Bromma, Sweden.

The results of this study revealed that serum TPA had better sensitivity than serum TPS while no marked difference was found in the false-positivity rates in the non-malignant urinary tract diseases, A correlation coefficient of 0.83 was found between serum TPA and TPS. No relation was found between either TPA or TPS and histopathological stage, grade or association of the tumor with bilharziasis. As regards the histopathological type of the tumor, serum TPS was slightly higher in squamous cell than transitional cell carcinoma but TPA showed no difference. In the follow-up of bladder cancer patients after surgery both TPA and TPS showed an excellent concordance with the clinial state of the patients.

In conclusion, TPS does not seem to be an optimal test in Egyptian patients with bladder cancer but serial determinations of one of the two markers can be used in the follow-up of these patients after surgery.
Immunohistochemical Detection of Carcinoembryonic Antigen (CEA) in non-neoplastic Lung Disease
Authors: Abbona G.C. , Papotti M. , Gugliotta P. , Pecchio F. , Rapellino M.
Published: April 2018

Carcinoembryonic antigen (CEA), though typically associated with malignant epithelial neoplasms, is known to be present at elevated levels even in the serum of normal individuals and of patients suffering from interstitial diseases of the lung. Few reports have addressed the question of the possible source of CEA immunoreactivity within the lung parenchyma. Two patients with elevated CEA serum levels were studied by immunohistochemistry on open lung biopsy specimens. Two different antibodies (one absorbed with non-specific cross-reacting antigen, NCA) were used. The results show that bronchiolar cells and type II pneumocytes are focally positive with both antibodies; the immunoreaction is preserved even after absorption with NCA. In agreement with experimental data on CEA synthesis in fetal bronchial cell lines, these findings indicate that interstitial lung disorders may induce abnormal CEA-like substance expression. In these cases, where no epithelial neoplasms subsequently develop, the cutoff level for CEA in serum should be raised. Bronchiolar and alveolar cells appear primarily responsible for CEA-like substance production.
Marker Determination for Response Monitoring: Radiotherapy and Disappearance Curves
Authors: Becciolini A. , Porciani S. , Lanini A.
Published: April 2018

This paper reports the results of studies on the possible role of biochemical markers in monitoring the effects of ionizing radiations and in the follow-up of cancer patients submitted to radiotherapy.

Three different case series were analyzed: patients with head and neck cancer, prostate carcinoma and residual thyroid tumors or uptaking metastases (131-Iodine therapy).

Serum TPA and amylase were serially determined in patients with head and neck or thyroid cancer to measure the radiation damage to the salivary glands. In the former group a statistically significant correlation between the increase of both molecules and the total dose administered after the first day of treatment (2, 3, 4 or 6 Gy) was observed. In patients treated for thyroid cancer the damage to the salivary glands was revealed by an increase in TPA and amylase serum levels, dependent on the dose of 131-Iodine administered. Moreover, an association was demonstrated between pretreatment values of TPA in patients with head and neck tumors and prognosis: patients with values below the cutoff have significantly higher survival rates than those with higher values.

In patients with prostate carcinoma PSA was confirmed to have better diagnostic and prognostic value than PAP. Patients with metastases show an inversion or lack of negative trend in PSA levels observed in the disease-free patients. This precedes the clinical diagnosis of metastases by 1 to 15 months.
Analytical Performance of Ca 19.9, Ca 125 and Ca 15.3 Assays as Observed through an External Quality Assessment Program
Authors: Zucchelli G.C. , Pilo A. , Chiesa M.R. , Masini S. , Clerico A.
Published: April 2018

Immunoassays of the tumor markers CA 19.9, CA125 and CA 15.3 are generally acknowledged to be a useful tool in the management of cancer patients. As a consequence, many methods developed by different companies are now commercially available. However, discrepancies have been described in the results of marker determinations even when the same monoclonal antibody was used. An external quality assessment (EQA) was carried out; starting from 1989 about 110 laboratories participated; since December 1991 the program was linked with the interlaboratory program Oncocheck organized by the Service de Radiopharmacie et Radioanalyse, University of Lyon. At present more than 200 laboratories of many European countries are involved: cumulatively 47 quality control samples have been prepared and sent to the participants. This manuscript is a report on data collected for CA 19.9, CA 125, and CA 15.3.
Quality Assessment of Tumor Marker Determinations: A Proposal for a Supraregional Scheme
Authors: Piffanelli A. , Giganti M. , Colamussi P. , Cittanti C. , Pelizzola D. , Barozzi R.
Published: April 2018

The use of tumor marker tests has increased progressively in the last decade concomitant with the advent of new monoclonal antibodies and their growing use in clinical oncology for various follow-up programs. External quality assessment (EQA) schemes widely adopted in clinical chemistry, have been extended in the last decade to immunoassays of hormones and tumor markers. EQA results can provide realistic information on the quality of the assays, performed under routine conditions. The goal of this article is to report the main results and discrepancies encountered so far in External Quality Assessment programs on tumor markers.
Lung Cancer-Associated Keratin 19 Fragments: Development and Biochemical Characterisation of the New Serum Assay Enzymun-Test® Cyfra 21–1
Authors: Bodenmüller H. , Ofenloch-Hähnle B. , Lane E.B. , Dessauer A. , Böttger V. , Donié F.
Published: April 2018

From a panel of 4 murine monoclonal antibodies directed against keratin 19 various antibody combinations were evaluated in solid-phase enzyme-linked sandwich immunoassays for detection of soluble keratin 19 fragments in patient sera. One of these antibody combinations, comprised of the monoclonal antibodies Ks 19.1 and BM 19.21, was selected for further development to a routine test (Enzymun-Test® CYFRA 21–1) because of its high diagnostic sensitivity and specificity for non-small cell lung carcinoma (NSCLC). Both antibodies are specific for keratin 19, no reactivity could be observed with cytokeratin 8 or 18. The epitopes of the two antibodies were determined to be within helix 2B of the rod romain. The epitope sequences lie within the sequence 311–335 for the catcher antibody Ks 19.1 and 346–367 for the detector antibody BM 19.21. These sequences are unique, as could be confirmed from sequence databases. The standard material for the assay was prepared from a cytoskeleton fraction of cultivated MCF-7 cells. Subsequent digestion of this fraction with chymotrypsin yielded a soluble and stable standard material. Both the standard material and the serum analyte appeared as oligomers when analysed on gel chromatography: the serum analyte appeared exclusively at a Mr of 100 ± 10 kD, whereas the standard material eluted in fractions corresponding to 100 ±10 kD and 450 kD. Due to the precise definition of the antigen and the localisation of the antibody binding sequences, Enzymun-Test® CYFRA 21–1 is one of the best characterised tumor markers so far.
Clinical Profile of a New Monoclonal Antibody-Based Immunoassay for Tissue Polypeptide Antigen
Authors: Correale M. , Arnberg H. , Blockx P. , Bombardieri E. , Castelli M. , Encabo G. , Gion M. , Klapdor R. , Martin M. , Nilsson S. , Reutgen H. , Ruggeri G. , Safi F. , Stegmuller M. , Vering A.
Published: April 2018

Our preliminary evaluation of a new monoclonal antibody-based assay for tissue polypeptide antigen (TPA) has shown it to be clinically equivalent to the polyclonal antibody-based assay for TPA. The new assay (TPA-M) employs three monoclonal antibodies to epitopes on cytokeratins 8, 18 and 19. This multicenter, multinational study included 266 patients with newly diagnosed carcinomas of the lung, breast, large bowel and urinary bladder. TPA values from the two assays were compared with three other cytokeratin markers (TPS, CYFRA 21–1 and TPACyk) and with the established reference markers for these malignancies (CEA and NSE for lung, CA 15–3 for breast, CEA and CA 19–9 for colorectal tumors). Analysis of receiver operating characteristic (ROC) curves in lung, colorectal and bladder cancer showed similar sensitivities for the two assays, ranging from 50% to 80% with a specificity of 95%. In breast cancer all the markers studied showed poor sensitivity. However, TPA determination by either method could discriminate advanced stage (stages III and IV) from early stage disease (stages 0 to II). TPA showed similar discriminating ability in bladder cancer. On the basis of the results obtained in our patient series, it seems that of the cytokeratin markers studied, TPA and TPA-M are the most sensitive and offer a wide range of clinical applications.
Oestrogen and Progesterone Receptors as Prognostic Variables in Hormonally Treated Breast Cancer
Authors: Robertson J. F. R. , Cannon P. M. , Nicholson R. I. , Blamey R. W.
Published: April 2018

This study directly compares ER status and PgR status of primary tumour tissue measured by enzyme immunoassays for prediction of response to therapy and survival in 99 women with breast cancer treated by hormone therapy. ER and PgR status alone both correlated with response to therapy (p=0.002 and p=0.02 respectively), time to progression (p<0.0001 and p=0.003 respectively) and survival (p<0.001 and p=0.01 respectively). 67% of tumours ER(+)/PgR(+) showed responsive or static disease compared to 25% of tumours ER(-)/PgR(-). Tumours of mixed phenotype (i.e. ER(+)/PgR(-) and ER(-)/PgR(+)) showed an intermediate response rate of 46%. Similar findings were observed when tumour phenotype was compared with overall survival. Combining ER and PgR allows more accurate prediction of clinical outcome but does not aid in selecting individual patients for endocrine therapy.
Serum Biochemical Markers of Bone Turnover in Healthy Infants and Children
Authors: Tommasi M. , Bacciottini L. , Benucci A. , Brocchi A. , Passeri A. , Saracini D. , D'Agata A. , Cappelli G.
Published: April 2018

Serum osteocalcin (OC), bone alkaline phosphatase (BAP), carboxyterminal propeptide of type I procollagen (PICP), carboxyterminal telopeptide of type I collagen (ICTP), parathyroid hormone (PTH) and 1,25 dihydroxyvitamin D [1,25(OH)2D] were measured in 241 normal infants and children (134 males and 107 females aged 1.9 months-14 years, 1.8 months-12 years, respectively). Regarding the analysis of data for children above 2 yrs, we chose data with the following normalization: data/body surface x standard body surface, to eliminate biological variations not exclusively related to chronological age. The increase in serum OC occurred at the expected age of growth spurts in both sexes: in the first year of life OC values (mean ± SD) were 82.6 ±34.3 and 60.2 ± 32.9 OC ng/ml in males and females, respectively; during puberty, peak values occurred at the age of 10–12 yrs in girls (76.6 ± 25.8) and at the age of 12–14 yrs in boys (113 ± 48.3). Furthermore, significant positive correlations with age were found for males from 2 to 14 yrs (p < 0.00001) and for females from 2 to 12 yrs (p < 0.001). Elevated levels of BAP occurred in the first year, 70.4 ± 28.2 and 71.8 ± 28.5, and in the second year, 69.4 ± 26.7 and 67.4 ± 33.8 ng/ml, for males and females, respectively. For children older than 2 yrs, a positive correlation with age (p < 0.01) was found for females only, with a peak value of 67.2 ± 13.9 at the age of 10–12 yrs. For ages 2–14 yrs the reference values (mean ± 2SD) were 15.5 – 90.3 and 17.2 – 95.2 ng/ml for males and females, respectively. The highest PICP levels (1354 ± 680 ng/ml in males and 1041 ± 766 in females) were observed in infants less than 1 year of age, decreasing by about 60% at the age of 2. There was no significant change in serum PICP for children older than 2 yrs with values covering a range (mean ± 2SD) of 52 – 544 and 18 – 546 ng/ml in males and females, respectively. Similarly, the highest ICTP values were seen in infants younger than 1 year (29.7 ± 11.7 and 29.5 ± 20.1 ng/ml in males and females, respectively). In the ages from 2 to 14 yrs there did not seem to be any systematic age-correlated changes, with values covering a range (mean ± 2SD) of 6.06 – 24.5 in boys and 6.84 – 22.9 ng/ml in girls. Serum PTH concentrations (mean ± SD) in infancy were 27.2 ± 19.3 pg/ml for males and 25.8 ± 10.8 for females. Normal ranges (mean ± 2SD) in the older group were 5.77 – 53.1 and 6.71 – 57.3 pg/ml for males and females, respectively. Serum 1,25(OH)2D presented values of 47.3 ± 28.1 and 38.7 ± 18.2 pg/ml under 2 yrs for males and females, respectively. The ranges (mean ± 2SD) in children above 2 yrs were 9.5 – 101 pg/ml in boys and 10.9 – 88.4 in girls. The results of this study contribute to the establishment of reference values in normal children for these biochemical assays; these reference values are needed when the above biological markers will be applied in the monitoring of metabolic bone diseases.
Production and Characterization of Monoclonal Antibodies Directed against the Laminin Receptor Precursor
Authors: Butò S. , Ghirelli C. , Aiello P. , Tagliabue E. , Ardini E. , Magnifico A. , Montuori N. , Sobel M.E. , Colnaghi M.I. , Ménard S.
Published: April 2018

The 67-kDa laminin receptor (67LR) is an important tumor marker whose molecular structure has not yet been fully elucidated. To shed new light on this molecule, we raised a series of eight new monoclonal antibodies, designated MPLR1 to 8, directed against the 37-kDa recombinant laminin receptor precursor (37LRP). Cross-competition experiments demonstrated that the epitopes recognized by MPLR2, 4 and 5 partially overlap, since MPLR4 and 5 compete with labelled MPLR2 for the binding to recombinant 37LRP. These three antibodies belong to the IgG1 class, whereas the other ones are all IgM. Presumably due to the fact that they are directed against partially unfolded antigenic determinants expressed on the recombinant protein, MPLRs did not recognize the native protein. Indeed, they showed no reactivity at the membrane level in cytofluorimetric analysis and they did not work in immunoprecipitation experiments. In contrast, these reagents are valuable tools in immunoblotting, since they clearly identify a 67-kDa protein (the mature laminin receptor) in addition to the 37-kDa precursor form. MPLRs are thus a new powerful tool which could help in the characterization of the still enigmatic 67LR molecule.
Serum Gonadotropin Levels in Patients with Germ-Cell Tumors of the Testis: Interrelations, Possible Cross-Reactions and Interpretation of Beta-Hcg Level
Authors: Kovčin V.N. , Jelić S.B. , Ivanović S.M. , Babović N.L.
Published: April 2018

The concentration of FSH, LH, LTH, testosterone and beta-hCG was estimated in 177 serum samples from 86 patients with malignant germ-cell tumors of the testis. The objectives of the investigation were the following: the detection of interrelations of hypophyseal gonadotropins at different beta-hCG levels; the determination of the significance of borderline values of beta-hCG; the analysis of the effect of elevated concentrations of beta-hCG on pituitary gonadotropins: the detection of possible cross-reactions during gonadotropin determinations. The RIA method was used to estimate levels of three gonadotropins. The results revealed that there was no cross-reaction between FSH and beta-hCG at RIA assays. When the serum level of beta-hCG of tumor origin exceeded 100 U/l a subtotal inhibition of FSH secretion was observed. Pathologically increased values of beta-hCG were found not only in serum with subnormal FSH levels, but also when FSH levels were excessively elevated (exceeding 50 U/l). In the latter case the elevated beta-hCG levels could possibly be the consequence of the secretion of beta subunits by the hypophysis or a cross-reaction with LH, and not of a tumor. With values of beta-hCG over 100 U/l cross-reaction with LH occurs, so the true LH levels cannot be assessed. For an adequate interpretation of elevated values of beta-hCG in the serum (i.e. whether they are tumor-derived or not), it is necessary to have values of FSH from the same serum sample.
A Controversial Problem: Is There a Relationship between Parathyroid Hormone Level and Parathyroid Size in Primary Hyperparathyroidism?
Authors: Locchi F. , Tommasi M. , Brandi M.L. , Tonelli F. , Meldolesi U.
Published: April 2018

The current study was undertaken with the aim of studying the relationship between parathyroid hormone and hyperfunctioning parathyroids by a sophisticated method of analysis. Our clinical study included 25 patients undergoing surgery for primary hyperparathyroidism. The measurement of basal circulating intact PTH (pg/ml) and the volume (mm3) of the removed gland(s) were recorded. It was essential for the distribution of the sample values to be normal before Pearson's correlation and regression analysis were performed. The Kolmogorov-Smirnov test showed sufficient sample data agreement (p>20%) with normal distribution after their transformation into natural logarithm (ln) and so statistical analysis was performed utilizing ln transformed data. The regression line between basal ln of iPTH levels (x) and ln of tumor volume (y) was highly significant (y=2.3828+1.0424 x, r=.72504, p<.0001). In our opinion, the above is a correct statistical procedure with reliable results.