bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of Serum Dna Integrity as a Screening and Prognostic Tool in Patients with Hepatitis C Virus-Related Hepatocellular Carcinoma
Authors: El-Shazly Sherien F. , Eid Manal A. , El-Sourogy Hesham A. , Attia Gehan F. , Ezzat Sherif A.
Published: March 2018

Background

Hepatocellular carcinoma (HCC) is a common malignancy in Egypt due to the high frequency of hepatitis C virus (HCV) infection among the general population. Circulating free DNA is a potential molecular marker for the diagnosis and prognosis of malignant tumors. DNA released from apoptotic cells usually consists of short uniform fragments while DNA released from cancer cells is longer. The ratio of long DNA fragments to total DNA (DNA integrity) may be a potential marker for early detection of HCC and its progression in HCV patients.

Methods

Sera from 25 patients with HCV-related HCC, 25 patients with chronic HCV infection, and 15 healthy volunteers were examined for Alu repeats by quantitative real-time PCR (qPCR) using 2 sets of primers of 115 and 247 base pairs. DNA integrity was calculated as the ratio of 247-bp to 115-bp Alu fragments.

Results

Compared with healthy volunteers and HCV patients, significantly higher DNA integrity was found in HCC patients. DNA integrity was associated with tumor size, TNM stage, vascular invasion, lymph node involvement, and distant metastasis. DNA integrity had a higher sensitivity and specificity in discriminating HCC from HCV patients than total DNA. Patients with high DNA integrity had a significantly shorter overall survival and high DNA integrity was shown to be an independent prognostic factor for survival in HCV-related HCC.

Conclusions

DNA integrity is a promising molecular biomarker for detecting HCC in patients with chronic HCV infection; it reflects the progression and metastatic potential of the tumor, and high DNA integrity is associated with short overall survival in HCV-related HCC.
Analysis of Methylation Patterns and Expression Profiles of P14Arf Gene in Patients with Oral Squamous Cell Carcinoma
Authors: Kordi-Tamandani Dor Mohammad , Moazeni-Roodi Abdolkarim , Ladez Mohammad Ayoub Rigi , Hashemi Mohammad , Birjandian Elnaz , Torkamanzehi Adam
Published: March 2018

Aims

To analyze the promoter methylation profile and mRNA expression of the p14ARF gene in oral squamous cell carcinoma (OSCC).

Methods

Promoter methylation of the p14ARF gene was investigated by methylation-specific polymerase chain reaction in paraffin-embedded tissues from 76 patients with OSCC and 57 oral tissues used as healthy controls. Expression of p14ARF mRNA was also determined using real-time quantitative reverse-transcription PCR. The methylation status and mRNA level profile of the gene and their relationship with clinical data were analyzed.

Results

Methylation of the p14ARF gene in OSCC was significantly increased compared to normal control tissues (χ2 = 16.73, p<0.0001). The relative expression of p14ARF mRNA in OSCC was not significantly different from that in healthy control samples.

Conclusion

Promoter methylation of p14ARF may be an important mechanism in OSCC, and its determination may be considered an important tool in the early diagnosis and treatment of OSCC.
Predictive and Prognostic Role of P53 According to Tumor Phenotype in Breast Cancer Patients Treated with Preoperative Chemotherapy: A Single-Institution Analysis
Authors: Guarneri Valentina , Barbieri Elena , Piacentini Federico , Giovannelli Simona , Ficarra Guido , Frassoldati Antonio , Maiorana Antonino , D'Amico Roberto , Conte PierFranco
Published: March 2018

Introduction and aims

The p53 protein is a mediator of the cellular response to DNA damage. The aim of this study was to evaluate the predictive and/or prognostic value of p53 expression in relation to the molecular subtypes of breast cancer in patients treated with preoperative chemotherapy.

Patients and methods

Patients with stage II-III breast cancer were included in the study. The expression of p53 was evaluated by immunohistochemistry on the diagnostic core biopsy specimen. Patients received 4–6 courses of preoperative chemotherapy. Pathological complete response (pCR) was defined as complete disappearance of invasive tumor in the breast and axillary lymph nodes.

Results

154 patients were included in the study and the molecular subtypes of their tumors were classified as follows: triple negative 18.2%, hormone receptor positive 60.4%, and HER2 positive 21.4%. p53 was expressed in 43.5% of the patients. A significant association between p53 expression and breast cancer molecular subtypes, tumor differentiation, and proliferation was observed. pCR was achieved in 8 patients (5.2%). p53 expression, molecular subtype, and nuclear grading were significant predictors of pCR (odds ratio for pCR in patients with p53-expressing tumors 10.03, p=0.0077). In univariate analysis, the expression of p53 as well as high proliferation and lymph node involvement after preoperative chemotherapy were predictors of a worse disease-free survival. Patients with p53 positivity also had a worse overall survival. In multivariate analysis, both p53 expression and nodal status after preoperative chemotherapy were significantly associated with disease-free and overall survival: the hazard ratios for relapse and death in patients with p53-expressing versus non-p53-expressing tumors were 2.29 (p=0.015) and 7.74 (p=0.002), respectively. The hazard ratios for relapse and death in node-positive versus node-negative patients were 3.63 (p=0.003) and 3.64 (p=0.041), respectively.

Conclusions

In this series of patients, p53 expression was significantly associated with markers of aggressive tumor biology, and with a higher likelihood of attaining pCR. p53 expression was a negative prognostic parameter for disease-free and overall survival in univariate and multivariate analysis.
Identification of a Novel Biomarker Signature Associated with Risk for Bone Metastasis in Patients with Renal Cell Carcinoma
Authors: Paule Bernard , Deslandes Emmanuelle , Le Mouel Stéphane E. , Bastien Laurence , Podgorniak Marie-Pierre , Allory Yves , de la Taille Alexandre , Menashi Suzanne , Calvo Fabien , Mourah Samia
Published: March 2018

When renal cell carcinoma (RCC) metastasizes to bone (a frequent site of systemic spread of this cancer) it becomes highly resistant to radiation therapy and chemotherapy. A better understanding of the biology of bone metastasis in RCC may permit to identify biomarkers for early detection of subclinical disease and better stratification of patients prior to treatment. We therefore investigated in this study, using a multiplex real-time RT-PCR assay, the expression of a panel of 16 biomarkers involved in angiogenesis and tumor invasion; the panel was applied to primary tumors and normal tissues obtained from clear-cell RCC patients with and without bone metastases. We identified a novel combination of biomarkers associated with the risk of bone metastasis. Among the transcripts of the genes studied, VEGFR-1, VEGFR-2, HIF-1α, uPA, and PAI-1 overexpression in tumor tissues was significantly associated with the presence of bone metastasis (p=0.02, p=0.02, p<0.0001, p=0.04, and p=0.03, respectively). No differences were found in the expression of these transcripts in the corresponding normal tissues. This preliminary study provides a promising tool that may help in the management of RCC patients with bone metastasis. Indeed, these predictive markers could be useful to identify subclinical disease, improve staging, and guide treatment decisions.
Significance of Serum Tumor Necrosis Factor-Alpha and its Combination with Her-2 Codon 655 Polymorphism in the Diagnosis and Prognosis of Breast Cancer
Authors: Papadopoulou Evropi , Tripsianis Gregory , Anagnostopoulos Konstantinos , Tentes Ioannis , Kakolyris Stylianos , Galazios Georgios , Sivridis Efthimios , Simopoulos Konstantinos , Kortsaris Alexandros
Published: March 2018

Purpose

The present study was conducted to clarify the diagnostic and prognostic significance of TNF-alpha and its combination with HER-2 Ile655Val SNP in breast cancer.

Methods

In this case-control study, 56 consecutive patients with primary breast cancer were prospectively evaluated. The control group consisted of 45 healthy women. Serum concentrations of TNF-alpha were measured by quantitative sandwich enzyme immunoassay (ELISA). HER-2 SNP was genotyped using the PCR-RFLP method.

Results

Serum TNF-alpha was significantly increased in patients compared to controls. ROC analysis indicated a cutoff point of 11.00 pg/mL to classify breast cancer patients (sensitivity, 86%; specificity, 71%). Elevated TNF-alpha levels were associated with larger, poorly differentiated, invasive and advanced-stage tumors, and >3 positive lymph nodes. Regarding HER-2 SNP, patients with Ile-Val and Val-Val genotypes had significant TNF-α elevation compared with homozygous Ile-Ile patients. In multivariate analysis, high serum TNF-alpha remained an independent prognostic factor of worse overall survival; its combination with Val-Val genotype predicted a worse prognosis than high TNF-alpha alone.

Conclusions

Serum TNF-a could be used clinically as a useful tumor marker for diagnosis, disease extent and outcome of breast cancer. The negative impact on survival seems to be enhanced through the interaction with HER-2 Ile655Val SNP.
Expression of ERCC1 and Class III β-Tubulin in Resected Non-Small Cell Lung Cancer and its Correlation with Platinum-Based Adjuvant Chemotherapy
Authors: Zhang Shucai , Li Qi , Zhang Quan , Wang Jinghui , Zhang Haiqing , Zhang Zongde , Wang Qunhui , Yang Xinjie , Gu Yanfei , Zhang Hui
Published: March 2018

Objective

To explore the relationship between the expression of excision repair cross-complementation group 1 (ERCC1) and class III β-tubulin and the clinical characteristics and overall survival of patients with non-small cell lung cancer (NSCLC).

Methods

Immunohistochemical analysis was used to determine the protein expression of ERCC1 and class III β-tubulin in 160 completely resected NSCLC primary tumor samples, 50 of which were paired with adjacent normal tissue samples and another 40 benign lung lesion tissue samples as controls. Clinical data at baseline, disease-free survival and overall survival were also collected. Univariate and multivariate Cox models were used to analyze the risk factors.

Results

In 160 tumor samples, the ERCC1 and class III β-tubulin positive rates obtained with immunohistochemistry were 46.9% and 49.4%, respectively. Both biomarkers had a higher positive rate in male patients. For patients who did not receive adjuvant chemotherapy, ERCC1 positivity was associated with longer survival (median survival time 73 vs 53 months, p=0.041), while in patients treated with platinum chemotherapy, ERCC1 positivity tended to be associated with poor survival (median survival time 41 vs 54 months, p=0.014). Class III β-tubulin positivity was also associated with poor survival (median survival time 38 vs 58 months, p<0.001), but had no influence on the survival of patients who did not receive adjuvant chemotherapy.

Conclusions

ERCC1 and class III β-tubulin could be important survival predictors for completely resected NSCLC patients treated with adjuvant chemotherapy. Further prospective studies need to be performed to test this hypothesis in Chinese patients.
Impact of Cyp1A1 and Comt Genotypes on Breast Cancer Risk in Mexican Women: A Pilot Study
Authors: Moreno-Galván Mónica , Herrera-González Norma Estela , Robles-Pérez Vera , Velasco-Rodríguez Julio C. , Tapia-Conyer Roberto , Sarti Elsa
Published: March 2018

Background

Data suggest that estrogen-metabolizing genes may be involved in breast cancer carcinogenesis.

Objective

The aim of this study was to determine the association of CYP1A1 and COMT polymorphisms with this disease. Material and methods: A pilot case-control study was conducted with Mexican women. Ninety-one breast cancer patients and 94 healthy controls were selected. Epidemiological and clinical questionnaires were answered by all participants, and genotyping data were obtained. CYP1A1 3801 T>C (rs4646903), CYP1A1 4889 A>G (rs1048943) and COMT 1947 G>A (rs4680) polymorphisms were analyzed by PCR-RFLP.

Results

The results showed a high risk of breast cancer in women carrying the CYP1A1 (3801 T>C) m2/m2 genotype (OR=2.52; 95%CI=1.04–6.08). The risk was higher in postmenopausal women (OR=3.38; 95%CI=1.05–10.87). No association between COMT 1947 G>A (rs4680) or CYP1A1 4889 A>G (rs1048943) and breast cancer was found.

Conclusions

This study suggests that the CYP1A1 (3801 T>C) m2/m2 genotype may contribute to breast cancer susceptibility in Mexican women.
Comparison between Plasma and Serum Osteopontin Levels: Usefulness in Diagnosis of Epithelial Malignant Pleural Mesothelioma
Authors: Cristaudo Alfonso , Foddis Rudy , Bonotti Alessandra , Simonini Silvia , Vivaldi Agnese , Guglielmi Giovanni , Ambrosino Nicolino , Canessa Pier Aldo , Chella Antonio , Lucchi Marco , Mussi Alfredo , Mutti Luciano
Published: March 2018

Background

A potential role of serum osteopontin (OPN) and serum mesothelin-related peptide (SMRP) in the diagnosis of malignant pleural mesothelioma (MPM) has been recently reported. Although the most important data regarding the role of OPN in MPMs derive from the marker's measurement in serum samples, most commercial laboratory kits for OPN assay are suitable only for measuring plasma levels, as indicated by the manufacturers. Our study aimed to evaluate the influence of preanalytic variables on serum and plasma OPN, to compare serum and plasma OPN in the same population, and to assess whether OPN levels can aid in the diagnostic distinction of patients with MPM versus benign respiratory disease (BRD) and healthy subjects exposed to asbestos.

Methods

The influence of preanalytic variables such as the length of storage at different temperatures and the number of thawings of samples on serum and plasma OPN measurements were evaluated. We measured OPN in 239 plasma samples from 207 asbestos-exposed subjects including 94 healthy controls and 113 subjects with BRD, and 32 patients with epithelial MPM, employing a commercially available ELISA. Serum OPN was measured in 196 of the same 239 samples from 80 healthy subjects, 92 BRD patients and 24 MPM patients.

Results

We found that both serum and plasma OPN levels were influenced by storage at –80°C and by the number of thawings, while serum OPN was influenced also by storage at room temperature. Plasma and serum OPN levels were significantly higher (p<0.0001) in patients with epithelial MPM than in the healthy control group and the BRD group. The application of a ROC curve for plasma OPN resulted in an AUC value of 0.780 with a best cutoff of 878.65 ng/mL, with a sensitivity of 68.8% and a specificity of 84.5%. The AUC for sOPN was 0.725 with a best cutoff of 16.06 ng/mL, with a sensitivity of 62.5% and a specificity of 87.3%. Within the control group no significant correlation was observed between age, duration of asbestos exposure, pack-years in current smokers, lung function or imaging parameters and plasma or serum OPN.

Conclusions

These data suggest that plasm OPN and serum OPN are not influenced by confounding factors such as age, smoking habits and asbestos exposure. Plasma and serum OPN may be useful markers in the diagnosis of epithelial MPM in addition to traditional radiological exams. However, in our opinion plasma OPN is preferable to serum OPN because it is more stable and measurements of OPN in serum are less reliable.
Is Circulating D-Dimer Level a Better Prognostic Indicator than Cea in Resectable Colorectal Cancer? Our Experience on 199 Cases
Authors: Pedrazzani Corrado , Cerullo Guido , Marrelli Daniele , Fernandes Eduardo , Carlucci Filippo , Corso Giovanni , Bettarini Francesca , De Stefano Alfonso , Roviello Franco
Published: March 2018

Purpose

To evaluate the clinical impact of D-dimer (DD) as a tumor marker in patients with colorectal cancer (CRC). The prognostic value of preoperative DD measurement was assessed in relation to carcinoembryonic antigen (CEA) levels.

Methods

DD and CEA levels were measured preoperatively in 199 patients who underwent resection for CRC and the results were analyzed statistically.

Results

The preoperative mean (±SD) levels of DD and CEA were 347.5 (±940.1) ng/mL and 106.4 (±1099.2) ng/mL. The DD level was significantly correlated with the nature of surgery (emergency vs. elective; p=0.002), presence of residual tumor (R1–2 vs R0; p=0.037), and tumor diameter (p<0.001). Conversely, DD was not correlated with tumor grade, pT, pN and M stages, and stage according to the Dukes classification. The 5-year survival rates were 80% and 64% for patients with negative and positive DD values, respectively (p=0.156). CEA was significantly related to all major prognostic factors (resection category, pT, pN and M stages as well as Dukes stage). A significantly worse prognosis was observed for patients with positive CEA levels. Multivariate analysis confirmed CEA as an independent prognostic factor (p=0.005), whilst DD was not (p=0.796).

Conclusions

The possible clinical usefulness of preoperative assessment of DD suggested by previous studies has not been confirmed by our data. CEA was confirmed to be the most reliable and valid indicator of prognosis.
Possible Utility of Serum Determinations of CA 125 and CA 27.29 in Breast Cancer Management
Authors: Jensen J.L. , Maclean G.D. , Suresh M.R. , Almeida A. , Jette D. , Lloyd S. , Bodnar D. , Krantz M. , Longenecker B.M.
Published: March 2018

The utility of measurement of serum levels of the tumor associated antigens CA 125 and CA 27.29 in detecting the presence of disease and in monitoring changes in disease status was examined in 63 patients with breast cancer. In patients with clinically detectable disease the CA 125 level was elevated in 59%, the CA 27.29 level in 59.5% and one or both markers in 84.6%. Specificity for presence of disease was 83.6% for CA 125, 88% for CA 27.29, and 69.1% for the two markers combined. Changes in marker levels of more than 50% correlated with clinical changes in disease status in 58% of cases for either CA 125 or CA 27.29 alone. In 87.5% of cases with clinically progressive disease one or both marker levels increased by more than 50% from the previous levels. In no case with greater than 50% increase in a marker level was there regression of disease. Thus, the use of these markers in combination might have utility in cases where diagnosis of recurrent disease is difficult or where monitoring of response to treatment is hampered by lack of measurable disease.
Preliminary Study on Serum Levels of Mucinous like Cancer Antigen (MCA) in Patients with Breast Disease: Comparison with CEA
Authors: Boccardo F. , Bombardieri E. , Zanardi S. , Valenti G. , Zanaboni F. , Valtolina M. , Seregni E. , Crippa F.
Published: March 2018

MCA (mucinous-like cancer antigen) can be measured in the biological fluids of patients by means of a solid phase enzyme immunoassay. This study describes the results of MCA determination in sera of 230 patients with benign (99) and malignant (131) breast diseases. MCA levels were significantly higher in breast cancer patients than in non cancer patients and in healthy subjects (p < 0.001). MCA concentrations tended to increase as the stage of the disease advanced. The 95th percentile of MCA value distribution in normal subjects showed a diagnostic sensitivity in breast cancer patients of 16.3% at stage I,26.2% at stages II-III and 52% at stage IV. In a group of 118 cancer patients, MCA and CEA were tested simultaneously. The diagnostic sensitivity and specificity of MCA and CEA assays was very similar; nevertheless the association of the two tests showed 11 cases with high levels of MCA and low levels of CEA and 9 patients with high levels of CEA and low levels of MCA. Seventy-four out of 118 patients were negative for both markers and in 22 out of 118 patients markers were positive. The new marker MCA appeared to correlate with breast cancer and gave different information complementary to CEA.
Clinical Evaluation of a New Two-Site Assay for CA125 Antigen
Authors: Capstick V. , Maclean G.D. , Suresh M.R. , Bodnar D. , Lloyd S. , Shepert L. , Longenecker B.M. , Krantz M.
Published: March 2018

As appropriate surgery and chemotherapy can improve both quality of life and survival of patients with ovarian adenocarcinoma, there has been a pressing need for “serodiagnostic” assays to enable close patient monitoring. CA 125 antigen has previously been described as a useful tumor marker of ovarian cancer. This is the first clinical evaluation of a radioimmunoassay using two new monoclonal antibodies, B27.1 and B43.13, that react with separate sites on the glycoprotein marker CA 125. Using the new assay, the majority of patients with clinically or radiologically detectable disease had serum CA 125 antigen levels well above the upper limit seen with random apparently healthy donors, while only three patients who were believed free of disease had elevated levels. Disease progression was associated with increasing values of serum CA 125 antigen, while response to therapy was associated with a steady decline in serum CA 125 antigen levels. Seven patients had steadily rising serum CA 125 antigen levels after initially having normal levels. The mean lead time between rise above normal and clinical or radiological evidence of relapse was 5 months (range 2 to 12 months). The merits of further surgical intervention are illustrated by the serial values of two patients followed after chemotherapy.

The assay appears to have value in monitoring response to therapy and in detecting disease relapse at a time when appropriate therapeutic intervention is still possible or likely to be beneficial. Furthermore, monitoring CA 125 antigen was shown to be of benefit in assessing response to chemotherapy in a few patients with metastatic adenocarcinoma of unknown primary, and may be useful in this group of patients in determining those likely to benefit from aggressive chemotherapy.
CA 549 as a Marker in Breast Cancer
Authors: Dnistrian A.M. , Schwartz M.K. , Greenberg E.J. , Smith C.A. , Dorsa R. , Schwartz D.C.
Published: March 2018

CA 549 is one of several carcinoma associated mucin antigens proposed as a breast cancer tumor marker. In this study, the performance characteristics of the CA 549 assay were validated and the clinical utility of the test was compared with that of other breast cancer markers including CA 15-3, CA M26, CA M29 and carcinoembryonic antigen. The upper limit of normal was established as 15.5 U/ml based on data for 250 control subjects apparently free of disease. Overall, CA 549 had a low negative predictive value (0.51) due to a low sensitivity in the detection of early breast cancer. However, the test had a high positive predictive value (0.93) reflecting a high specificity for the disease. In 56 patients with advanced breast cancer, the sensitivity was 0.71 for CA 549 alone and 0.79-0.84 for CA 549 combined with any of the other markers studied.
Estrogen, Progesterone Receptors and Proliferating Activity Evaluated by Immunocytochemistry in Breast Cancer
Authors: Campani D. , De Negri F. , Fabbri R. , Martini L. , Giani C. , Squartini F. , Sarnelli R.
Published: March 2018

The correlation of the most important prognostic indicators was evaluated in 75 breast cancer cases. Estrogen-progesterone receptors and proliferating activity were analyzed by immunocytochemical methods (ER-ICA, PR-ICA, Ki-67). Both steroid receptors were inversely correlated with the proliferating activity (ER-ICA vs Ki-67, p < 0.003; PR-ICA vs. Ki-67, p < 0.0001). No correlation was found between steroid receptors or cell kinetics and tumor size or lymph node status. These findings confirm the relevance of biochemical and kinetic parameters as independent markers in breast cancer and suggest a routine use of the simple immunocytochemical methods in assessing the biological behavior of tumors.
Demonstration of Mucinous-Like Carcinoma-Associated Antigen in Bone Marrow and Lymph Node Biopsies from Patients with Breast Carcinoma
Authors: Jotti G. Saccani , Grassi C. , Fontanesi M. , Becchi G. , Tardini A.
Published: March 2018

Two hundred and fifty bone marrow and 140 lymph nodal biopsies were analyzed immunocytochemically, using a mouse monoclonal antibody b-12 (MAb b-12), which reacts with MCA (mucinous-like carcinoma-associated antigen). The presence of MCA in bone marrow specimens was demonstrated in 102 out of 105 (97.1%) breast cancer metastases, 5 out of 8 (62.5%) gastric cancers, 5 out of 6 (83.3%) colon cancers, 3 out of 5 (60%) prostate cancers, 11 out of 26 (42.3%) lung cancers and 25 out of 30 (83.3%) unknown primary cancers, while no positivity to anti-MCA antibody was found in 30 cases of normal bone marrow biopsies, 5 cases of non epithelial malignancies and 30 cases of hemolymphoproliferative disease. Normal lymph nodes and non-epithelial lymph node metastases did not show any reaction to MAb b-12; on the contrary MCA positive staining was observed in 75 out of 75 (100%) lymph nodal metastases in breast cancer. These results suggest that application of MAb b-12 in immunohistochemistry is valid for the detection of bone marrow and lymph nodal micrometastases of epithelial origin.
CA 15.3 in Nonmalignant Liver Diseases
Authors: Collazos J. , Genollá J. , Ruibal A.
Published: March 2018

CA 15.3 is a recent tumor marker for a wide range of cancers that is usually used for monitoring breast carcinoma patients. This study was performed to evaluate CA 15.3 behaviour in 161 patients with benign diffuse hepatic diseases who underwent thorough clinical and biochemical evaluation. Abnormal serum levels of this antigen were found in 8.7% of the 161 patients, 11.6% of the 86 cirrhotics, and 5.3% of the 75 noncirrhotic patients. The correlation between CA 15.3 and certain parameters characteristic of liver diseases was checked. IgA showed the most relevant correlation (r = 0.39, p < 0.00001) and in our series a normal level of IgA was practically determinant of normal CA 15.3 levels. Our results also support the role played by hepatocellular dysfunction in increasing levels of this antigen in spite of the low number of false-positive results. CA 15.3 can be used as a tumor marker in these patients at levels used for healthy subjects.
Radioimmunotherapy for Breast Cancer: Treatment of a Patient with I-131 L6 Chimeric Monoclonal Antibody
Authors: Denardo S.J. , Warhoe K.A. , O'grady L.F. , Hellstrom I. , Hellstrom K.E. , Mills S.L. , Macey D.J. , Goodnight J.E. , Denardo G.L.
Published: March 2018

We report the first treatment of metastatic breast cancer by systemic radioimmunotherapy. The serial therapy doses were chosen based on quantitative imaging data in a treatment planning approach. A terminally ill patient with aggressive, locally advanced breast cancer who had failed radiation treatment and chemotherapy was injected intravenously with radiolabeled I-131 chimeric L6, a human-mouse chimeric IgG1 monoclonal antibody to adenocarcinoma. Initially, an imaging 10 mCi dose of 1-131 chimeric L6 (dose 1) deposited 8.8% of the injected dose in her chest wall tumor at 48 hours. Ten days later the patient was given a 150 mCi I-131 chimeric L6 dose (dose 2) followed three weeks later by a 100 mCi dose (dose 3). Tumor uptake and retention were comparable for doses 1 and 2, and decreased for dose 3. Following dose 3 the patient developed a manageable thrombocytopenia and transient Grade IV granulocytopenia. The tumor was observed to decrease in size with peak tumor regression occurring two weeks after dose 3. This partial response (PR) was achieved by radioimmunotherapy at a time when conventional therapy had been unable to impact the growth of the patient's massive and aggressive tumor.
Serum AFP, hCG and CEA in the Management of Patients with Testicular, Ovarian and Extragonadal Germ Cell Tumors
Authors: Motawy M.S. , Szymendera J.J. , Al-Jazzaf H. , Behbehani A.E. , Foudeh M.O. , Ebraheem A.K. , Nasralla M. Y. , Ali M.A.A.
Published: March 2018

Serum levels of AFP, hCG and CEA were initially and serially measured in 59 patients with testicular germ cell tumors, and serially in 37 with ovarian and 3 with extragonadal germ cell tumors. Patients with seminoma/dysgerminoma or mature teratoma had normal serum AFP and sporadically slightly elevated hCG. Some patients with embryonal carcinoma, pure or with admixture of seminoma, had serum AFP elevated to maximum 100 U/ml, yet its use for monitoring therapy was limited. Patients with yolk sac tumors had elevated AFP and sometimes CEA levels, those with choriocarcinoma had elevated hCG, and those with compound tumors had one or more of the markers highly elevated. High AFP and/or hCG levels indicated the presence of the relevant tumor cells both in the primary and in residual tumor and/or metastases, also those missed in histological material, and thus were useful in restaging. Unfortunately, their absence in serum did not exclude the presence of marker-negative subpopulations of tumor cells. Changes in marker values paralleled the effects of treatment: the level increasing from any nadir heralded recurrence in patients in remission; elevated or increasing levels during therapy implied resistance to the therapy; decreasing levels indicated regression even though a return to the normal range did not mean eradication of all tumor cells.
Growth Fraction of Colorectal Carcinoma (Ki67): A Comparative Study
Authors: Benetti A. , Berenzi A. , Grigolato P.
Published: March 2018

We studied the growth fraction of55 resected colorectal adenocarcinomas by means of a three-step immunoperoxidase technique (avidin-biotin-peroxidase) using the monoclonal antibody Ki67 directed against a cell proliferation-associated nuclear antigen.

The percentage of Ki67-positive cells was evaluated independently by two observers, and a Ki67 score was obtained for each case.

No correlation was observed between Ki67 staining and patient's age and sex, tumor size and localization or grading and staging according to Dukes’ method (modified by Astler-Coller and Turnbull).

The growth fraction showed extreme heterogeneity in the cases examined, within each grade of differentiation.
Preliminary Study of Alpha-Fetoprotein in Nonmalignant Liver Diseases. A Clinico-Biochemical Evaluation
Authors: Collazos J. , Genolla J. , Ruibal A.
Published: March 2018

This preliminary study was carried out to evaluate the behavior of AFP in 155 patients with benign diffuse liver diseases who underwent thorough clinical and laboratory evaluation. We found correlations between AFP and some clinical and biochemical parameters characteristic of liver diseases; serum glutamic oxalacetic transaminase (GOT) proved the most relevant (r = 0.27 p = 0.0004) and most reliable marker to predict AFP levels. 22.6% of the patients as a whole, 25.6% of the 86 cirrhotics and 18.8% of the 69 non-cirrhotics, had increased levels of AFP. Patients with active liver disease as measured by increased GOT, had higher AFP levels than patients with quiescent liver diseases (p = 0.0048), suggesting that cytolysis and/or regeneration plays a role in the increase in AFP. Elevation of the cutoff level was necessary to improve the specificity of AFP as a tumor marker. In our series, the cutoff of 9 ng/ml was exceeded by only 10% of the patients.
Clinical Significance of Tumor Necrosis Factor in Patients with Bronchogenic Carcinoma and Benign Lung Diseases: A Comparative Study
Authors: Rapellino M. , Pecchio F. , Aimo G. , Priolo G. , Baldi S. , Ruffini E. , Cianci R.
Published: March 2018

Tumor Necrosis Factor (TNF) was determined in the serum of 72 lung carcinoma patients. Twenty-four healthy subjects younger than 50 years and 10 healthy subjects older than 70 years were considered as control group. TNF was also measured in 20 patients with stage I sarcoidosis and in 15 patients with pulmonary fibrosis. The marker was detected in 32% of cases in the neoplastic group, in 37.5% of disease confined to the chest and in 25% of advanced disease cases. A large proportion of TNF-positive samples was found in sarcoidosis (30%), and even larger in pulmonary fibrosis (66.6%).

TNF was also present in healthy subjects older than 70 (40%). We conclude that TNF is not specific of malignancy, being demonstrable in other benign pulmonary diseases and even in the course of physiological aging.
Preliminary evaluation of HER-2/neu oncogene and epidermal growth factor receptor expression in normal and neoplastic human ovaries
Authors: Mileo A.M. , Fanuele M. , Battaglia F. , Scambia G. , Benedetti-Panici C. , Mattei E. , Mancuso S. , Delpino A.
Published: March 2018

The HER-2/neu oncogene (a member of the Erb-like oncogene family) is distinct from but closely related to the c-erb B gene which encodes the epidermal growth factor receptor (EGFr). HER-2/neu gene amplification was found in a large number of mammary carcinomas and there was a strong correlation between this phenomenon and poor prognosis. In our study HER-2/neu oncogene expression was determined in 16 malignant ovarian tumors, 2 ovarian lymphomas and 5 normal ovaries. The HER-2/neu gene was found both in normal ovaries and malignant tumors, without any apparent difference among the various histological types. In all the specimens examined, HER-2/neu expression did not seem to be related to EGF binding capacity.
Introduction to the CEA Family: Structure, Function and Secretion
Authors: Von Kleist S.
Published: March 2018

Due to the phenomenal progress in the field of tumor immunology that took place during the last twenty years, we dispose today of highly specific and sensitive techniques and reagents like monoclonal antibodies (MAbs). In this context the discovery in human carcinomas of tumor-associated antigens, such as CEA, was of primary importance, especially since the latter was found to have clinical relevance as a tumor marker. Based on animal models, a new in vivo technology for the detection of tumors and metastases was developed in recent years, that uses anti-CEA MAbs, or fragments of them, coupled to radio-isotopes. This technique, called radioimmunodetection (RAID), also paved the way for immunotherapeutic procedures, where again CEA served as the target-antigen. This new technique holds great promise, provided the epitope-specificity of the MAbs is well-controlled: it has been shown that CEA belongs to a large gene-family of at least 22 members, which can be subdivided into two subgroups (i.e., the CEA- and the PSG-subgroup) and which in turn belongs to the immunoglobulin-supergene family. Great structural similarities render the distinction of the various cross-reactive molecules by immunological means rather difficult.
Cost/Effectiveness Ratio of Carcinoembryonic Antigen - Importance of Adequacy of Routine Requests of Tumor Markers
Authors: Gion M. , Rampazzo A. , Mione R. , Bruscagnin G.
Published: March 2018

Since 1987 we have been evaluating the cost/effectiveness ratio of tumor markers using carcinoembryonic antigen (CEA) as a leading indicator. Preliminary to the evaluation of cost/effectiveness ratio we verified the fitness of CEA requests to the proper clinical problems in order to identify any bias of cost due to inadequate CEA use. 2677 CEA orders were evaluated in 1987. The percentage of inadequate requests was very high (43%). Therefore, it seemed not advisable to carry out the evaluation of cost/effectiveness ratio, while educational actions (divulgation of informative material, service of telephone consultation) were addressed to the physicians of the geographic area of laboratory users. In 1991 the adequacy of CEA requests was reevaluated. The percentage of inadequate requests on 2647 orders was 29.4%. This result, although not yet satisfactory, suggests that proper educational programs may probably improve the fitness of tumor marker requests to correct clinical problems. Additional educational actions are mandatory to futher reduce the rate of inadequate tumor marker orders.
Pilot, Multicenter and Prospective Trials with an Anti-CEA Antibody
Authors: Buraggi G.L. , Gasparini M. , Seregni E. , Bombardieri E. , Regalia E. , Maffioli L.
Published: March 2018

In this paper we summarize the investigations performed by our group utilizing an anti-CEA monoclonal antibody (F023C5) labelled with different radionuclides in humans. Since 1983 radioimmunoscintigraphy (RIS) was performed on 51 patients with 64 localizations of colorectal carcinoma (pilot study). A multicenter clinical trial in a large number of patients (509 pts of which 284 with gastrointestinal cancer) was subsequently carried out in collaboration with ten nuclear medicine centres. High sensitivity and specificity values were obtained by these studies and many unsuspected lesions were recorded. In order to better define the clinical role of RIS, a prospective study was performed on 59 patients with suspected local relapses of colorectal cancer. A comparative evaluation of RIS, CT scan, US and MRI was done. RIS and MRI had the highest accuracy (86%) followed by CT scan (68%) and US (54%).
Application of Genetically-Engineered Anti-CEA Antibodies for Potential Immunotherapy of Colorectal Cancer
Authors: Hardman N. , Murray B. , Zwickl M. , Kolbinger F. , Pluschke G.
Published: March 2018

Hitherto anti-CEA monoclonal antibodies (MAbs), normally of mouse origin, have been used primarily for clinical diagnosis of colorectal cancer, either as a tumor marker in serum to monitor tumor recurrence, or latterly as a means to localize in vivo CEA-bearing tumors and metastases in patients. In vivo diagnosis using mouse anti-CEA MAbs has so far had limited clinical utility because the antibodies elicit a strong anti-mouse immunoglobulin immune response on repeated administration in man. This problem has been addressed by the development of various strategies for “humanization” of mouse anti-CEA MAbs by genetic manipulation of immunoglobulin genes. Such humanized, engineered antibodies markedly attenuate the antigenic response directed against the MAb, such that safe, repeated administration to patients has become feasible. Such humanized anti-CEA antibodies can thus be radioactively-labelled and applied for in vivo monitoring and detection of recurrent malignant disease, or used for therapeutic strategies which similarly take advantage of the ability of the antibodies to target cytotoxic agents selectively to tumor cells. The application of these novel procedures for manipulating MAb structure presents entirely new opportunities for diagnosis and treatment of human colorectal cancer.
Simultaneous Determination of Urinary CEA, Ferritin and TPA in Egyptian Bladder Cancer Patients
Authors: Halim A.-B. , El-Ahmady O. , Hamza S. , Aboul-Ela M. , Oehr P.
Published: March 2018

Urinary carcinoembryonic antigen (CEA), ferritin (Fer) and tissue polypeptide antigen (TPA) were determined in 328 cases (106 with blader cancer, 152 with non-malignant urinary tract disease and 70 healthy controls). CEA was determined by the kit supplied by Roche Diagnostica (CEA EIA Doumab 60), ferritin by the Tandem-E Fer kit supplied by Hybritech and TPA by the Prolifigen TPA-IRMA kit supplied by Sangtec Medical. The results of this work revealed that combined determination of urine CEA and Fer, CEA and TPA or Fer and TPA showed higher sensitivity than determination of the individual markers. There was no significant difference between combined and individual marker determination with respect to false positivity in non-malignant urinary tract diseases. At 97% specificity, the sensitivities of urine CEA, Fer and TPA were 82.1%,71.7% and 90.6%, respectively, while combined urine CEA & Fer, CEA & TPA and Fer & TPA showed sensitivities of 92.5%, 99.1% and 98.1%, respectively. When the specificity was related to the entire non-cancer group (patients with benign urinary tract diseases and normal controls), some reduction in the sensitivities of the combined markers was noted compared to the normal group only.

In conclusion, combined determination of urine markers is superior to determination of individual markers in the diagnosis of bladder cancer
Plasmatic Fibronectin in Malignancies
Authors: Gallurt P. , Rodriguez P. , Lorenzo A. , Saez J.J.B. López , Senra A. , Millán J.
Published: March 2018

Plasmatic fibronectin has been studied in tumor patients on the basis of the role that unspecific opsonin may play in tumor growth and spreading. Alterations in fibronectin levels might be used as a biological marker and our purpose has been to evaluate the significance of this test in the biological diagnosis of cancer. When comparing the levels found in the control group (22.86 ± 1.40 mg/dl) and in tumor patients (23.80 ± 1.90 mg/dl), we observed no difference in the overall group. However, in relation to the localization of tumors, a significant increase was found in breast cancer (31.83 ± 3.83 mg/dl) and a significant decrease in squamous cell carcinoma of the head and neck (9.56 ± 1.68 mg/dl). These results suggest that plasmatic fibronectin could be useful as a biomarker in some types of tumors. Our conclusion was confirmed by analysis of ROC curves related to every one of the studied tumors.
Ki-67 Antibody Immunostaining in Benign and Malignant Human Prostatic Disease
Authors: Lloyd S.N. , Brown I.L. , Leake R.E.
Published: March 2018

Indices of mitotic potential may improve prognostic discrimination in patients with malignant disease. Ki-67 is a monoclonal antibody directed against an unknown proliferation antigen which has been shown to be a measure of mitotic potential. Sixty-four benign and eighty malignant prostatic biopsies were stained with the Ki-67 antibody. Nuclear and cytoplasmic staining was identified in benign and malignant biopsies using immunoalkaline phosphatase and immunoperoxidase staining reactions. Nuclear staining was identified in 14 benign and 44 malignant biopsies. Nuclear staining for Ki-67 was seen in 36% of biopsies with Gleason histological score (GHS) 2-4, 71% with GHS 5-7 and 62%> with GHS 8-10. Nuclear staining was associated with advanced local disease stage, but not with metastatic disease stage. Clinical follow-up is required to establish the value of Ki-67 immunostaining as a prognostic determinant in prostatic cancer.
Serum Tumor Markers in Non-Hodgkin's Lymphomas and Chronic Lymphocytic Leukemia
Authors: Pavlidis A.N. , Kalef-Ezra J. , Bourantas L.C. , Lambrou A. , Mavridis A.
Published: March 2018

The levels of soluble interleukin-2 receptors (sIL-2R), beta-2 microglobulin (β-2M), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured in the serum of 50 previously untreated patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL) as well as in 25 age and sex-matched normal controls. Compared to normal controls, mean serum levels of sIL-2R and β-2M were significantly increased in both NHL and CLL (p < 0.001) while the increase in ESR and CRP was less marked (p < 0.01 and p < 0.05, respectively). Comparison of these tumor markers with histologic grading showed statistically significant differences only for CRP between low, intermediate and high-grade lymphomas (p < 0.001 and p < 0.05). More advanced stages exhibited higher mean values of all serum markers than early stages (p < 0.001 for sIL-2R, β-2M and ESR and p < 0.05 for CRP). An association with the presence of b-symptoms was observed only for sIL-2R (p < 0.05). In addition, sIL-2R as well as β-2M were able to predict time to progression in patients with diffuse large-cell lymphomas.

We conclude that of the four tumor markers tested sIL-2R and β-2M more frequently showed increased serum levels and were associated with clinical stage and/or presence of b-symptoms. Both sIL-2R and β-2M were also found to have prognostic significance for survival.
Chronic Effects of Subcutaneous Interleukin-2 Therapy on Soluble Interleukin-2 Receptors in Advanced Small Cell Lung Cancer
Authors: Viviani S. , Salvini P.M. , Bidoli P. , Camerini E. , Spinazzé S. , Arienti F. , Rivoltini L. , Motta V.
Published: March 2018

The increase in IL-2 receptor serum levels is one of the most typical changes in immune parameters during IL-2 cancer immunotherapy. To better define the effects of prolonged IL-2 injection on SIL-2R levels, we evaluated 7 advanced small cell lung cancer patients who received IL-2 subcutaneously at a daily dose of 9x106 IU/m2/12h for two days followed by 3x106 IU/m2/12h for 18 days (5 days/week for 4 weeks). Moreover, four patients were also evaluated during the second IL-2 cycle. Venous blood samples were drawn before and at weekly intervals during IL-2 therapy. Mean SIL-2R serum levels rapidly increased with the start of IL-2 injection, and they were signicantly higher than the baseline levels throughout the immunotherapy cycle. The increase in mean SIL-2R levels was higher in patients with progressive disease than in those with response or stable disease, but the difference was not significant. Finally, the increase in mean SIL-2R concentrations during the second IL-2 cycle was not significantly different from that seen during the first one. The present study confirms that IL-2 administration determines an evident increase in SIL-2R levels; moreover, it would demonstrate that re-exposure to IL-2 after a rest period does not induce a more pronounced SIL-2R release.
Serum CEA, CA125, and SCC antigens and tumor recurrence in resectable non-small cell lung cancer
Authors: Diez M. , Gomez A. , Hernando F. , Ortega M.D. , Maestro M.L. , Torres A. , Mugüerza J.M. , Gutierrez A. , Granell J. , Balibrea J.L.
Published: March 2018

Carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), and CA125 were determined pre- and postoperatively in non-small cell lung cancer patients (NSCLC) to assess the relationship between serum levels and postoperative recurrent disease. Ninety-five patients who underwent curative surgical resection were included (TNM stages I, II, IIIa). CEA and CA125 were determined by solid-phase enzyme-immunoassay, SCC by radio-immunoassay. Tumor relapse was detected in 41 patients (43%): 16 (39%) with locoregional disease and 25 (61%) with disseminated disease. The overall 36-month disease-free survival rate was 42%. The sensitivity for recurrence was 58% for CEA, 53.6% for CA125, and 51.2% for SCC; 87.8% of patients showed at least one elevated marker. The sensitivity of CEA and CA125 increased significantly in patients with preoperative serum concentrations above the cut-off: 86.6% versus 42.3% (p < 0.01), and 93% versus 18% (p < 0.01), respectively. Preoperative CA125 above 15 U/ml identified a high-risk group of patients: a lower 36-month disease-free survival rate (0%) versus 56%) (p < 0.001), a 3.02-fold higher risk of recurrence (p < 0.05), and a 6.22-fold higher risk of disseminated failure (p < 0.001). The identification of CEA and CA125 producer-tumors, based on preoperative serum values, enhances the clinical performance of a postoperative surveillance program in surgically treated NSCLC. Preoperative serum CA125 is a prognostic factor to identify patients at high risk of postoperative tumor recurrence.