bluuebunny/crossref_metadata_2025 huggingface dataset:
Early CYFRA 21-1 Variation Predicts Tumor Response to Chemotherapy and Survival in Locally Advanced Non-Small Cell Lung Cancer Patients
Authors: Merle P. , Janicot H. , Filaire M. , Roux D. , Bailly C. , Vincent C. , Gachon F. , Tchirkov A. , Kwiatkowski F. , Naamé A. , Escande G. , Caillaud D. , Verrelle P.
Published: January 2018

We have evaluated CYFRA 21-1 serum level variations as an indicator of tumor response and survival in 44 consecutive patients with locally advanced non-small cell lung cancer (NSCLC) treated with induction chemotherapy (IC). Irrespective of the initial CYFRA 21-1 serum concentration, a more than 65% decrease in the serum level after the first chemotherapy course was significantly predictive of an objective tumor response (p=0.0022). In addition, a more than 80% decrease in this level significantly predicted a better disease-free survival (p=0.039). In patients with initial CYFRA 21-1 serum levels >3.3 ng/mL (n=29), a more than 80% decrease after the first IC course was the most significant predictor of overall survival (p=0.025) in a Cox analysis including initial staging, tumor response and surgery. We conclude that early monitoring of CYFRA 21-1 serum levels may be a useful prognostic tool for tumor response and survival in stage III NSCLC patients treated by induction chemotherapy.
Increased Levels of Albumin in Bronchial Washing Fluid of Patients with Bronchial Carcinoma. Could Albumin be Considered as a Tumor Marker?
Authors: Charokopos N. , Leotsinidis M. , Tsiamita M. , Kalofonos H.P. , Vasillakos P. , Christofidou M. , Spiropoulos K.
Published: January 2018

Background

The aim of this study was to evaluate the significance of albumin in bronchial washing fluid (BWF) and its relationship to three tumor markers (CEA, CA 19–9 and NSE).

Methods

Serum and BWF samples were collected in a group of 60 patients. Albumin and tumor markers in the BWF and serum of three groups: a control group (CG), a chronic bronchitis group (CBG) and a lung cancer group (CaG), were analyzed in a prospective cross-sectional study. The diagnostic yields of the tests in each environment (serum and BWF) were evaluated by using as cutoff points the values of the corresponding 90th percentile of CG and CBG taken together.

Results

A significant difference in albumin level (p<0.001) was noted in the BWF of patients with cancer compared with the other two groups. In addition, a significant difference in CEA level (p<0.001) was observed in the serum of cancer patients compared with the other two groups. The cutoff values for CEA in serum and albumin in BWF were 2.20 ng/mL and 2.00 g/dL, respectively. The areas under the corresponding ROC curves were 93% and 97%. Combination of CEA-serum and albumin-BWF by logistic regression analysis increased their diagnostic value.

Conclusion

Measurement of albumin levels in BWF could be a useful additional diagnostic tool to differentiate malignant from non-malignant lung diseases. Moreover, the combined measurement of CEA in serum and albumin in BWF could be of aid in the follow-up of lung cancer patients.
Clinical Significance of Urinary N1,N12-Diacetylspermine Levels in Patients with Hepatocellular Carcinoma
Authors: Enjoji M. , Nakamuta M. , Arimura E. , Morizono S. , Kuniyoshi M. , Fukushima M. , Kotoh K. , Nawata H.
Published: January 2018

Background/aim

N1,N12-diacetylspermine (DiAcSpm), a diacetylpolyamine which was recently identified in urine, appeared to be a useful tumor marker for urogenital cancers. Here we examined the clinical significance of urinary DiAcSpm as a tumor marker for hepatocellular carcinoma (HCC).

Methods

Urine samples were collected from patients with HCC and benign liver diseases. Urinary levels of DiAcSpm were measured by ELISA, which was newly developed in order to analyze large numbers of samples.

Results

The appropriate threshold value was set at 325 nM/g·creatinine. The sensitivity of the DiAcSpm assay for HCC was 65.5% and the specificity calculated between HCC and liver cirrhosis was 76.0%. The percentage of DiAcSpm-positive HCC patients was similar to that for AFP or PIVKA-II. At more advanced clinical stages, the positive percentage of these three markers increased but the DiAcSpm levels appeared to move independently of AFP and PIVKA-II. In HCC patients, the DiAcSpm levels reflected the progression of disease or the effect of treatment.

Conclusions

DiAcSpm levels were found to reflect the severity, activity or viability of HCC. Urinary DiAcSpm can therefore be considered one of the useful indexes for patients with HCC.
Quantitative Expression of TEL in Childhood Acute Lymphoblastic Leukemia
Authors: Timson G. , Gutiérrez M.I. , Bhatia K.
Published: January 2018

Loss of heterozygosity of chromosome 12p in human precursor B-cell ALL invariably results in loss of TEL coding sequences. Accompanied by a 12;21 translocation, such loss of heterozygosity ensures complete loss of the wild-type TEL. No inactivating mutations of the retained TEL allele have been reported in leukemias with hemizygous deletion. However, only minimal data reported the expression of the wild-type TEL in ALL. We now demonstrate that quantitative real-time RT-PCR from leukemic RNA samples could be indicative of compromised TEL expression in childhood ALL and therefore loss of TEL function.
Genetic Heterogeneity of Variable Number Tandem Repeats in Thymidylate Synthase Gene in Colorectal Cancer Patients
Authors: Agostini M. , Pucciarelli S. , Calandra P. , Villani F. , Lise M. , Nitti D.
Published: January 2018

Purpose

To analyze the genetic variability in a variable number of tandem repeats (VNTR) in the thymidylate synthase (TS) enhancer promoter region and assess the influence of functional alterations in mismatch repair genes by analyzing constitutional and tumoral DNA from patients with colorectal adenocarcinoma with a high microsatellite instability (MSI-H) or microsatellite stability (MSS) status.

Patients and methods

Patients who underwent surgery for colorectal adenocarcinoma were selected from the colorectal database of our institute and, on the basis of MSI status, assigned to a study group and a control group: group A, MSI-H; group B, MSS. Microsatellite status was investigated using the Bethesda recommended panel (BAT-26, BAT-25, D2S123, D5S346, D17S250). In MSI-H patients an additional analysis was made of the microsatellite loci D18S61 and D18S58, both mapping in the region containing the TS gene (18p11.2–11.32). Based on the number of altered microsatellites (≥2, 1, or 0), tumors were considered as having high (MSI-H) or low (MSI-L) instability or microsatellite stability (MSS), respectively. Genotyping for thymidylate synthase promoter polymorphism was carried out on constitutional and tumor DNA of each patient by PCR amplification of the polymorphic region.

Results

MSI-H was found in 55 patients (group A) and MSS in 50 patients (group B). In none of the MSI-H patients was microsatellite instability found in the additional D18S61 and D18S58 loci. In five group A and ten group B cases the analysis was not performed because constitutional DNA and/or tumoral DNA were not amplifiable. Homozygotes for the triple repeat variant (3R/3R) displayed only the large PCR product, homozygotes for the double repeat variant (2R/2R) displayed only the smaller PCR product, while heterozygotes (2R/3R) displayed both the larger and smaller PCR products. In 3/50 (6%) group A patients and 5/40 (12%) group B patients repeat variations were found in tumoral DNA.

Conclusion

Our findings demonstrate that there is genetic homogeneity between constitutional and tumoral DNA but do not support the hypothesis that mismatch repair genes are involved in VNTR recombinant events in TS gene variability.
Evaluation of the Prevalence of Human Papillomavirus and Epstein-Barr Virus in Esophageal Squamous Cell Carcinomas
Authors: Lyronis I.D. , Baritaki S. , Bizakis I. , Tsardi M. , Spandidos D.A.
Published: January 2018

The aim of this study was to determine the possible involvement of human papillomavirus and Epstein-Barr virus in esophageal squamous cell cancer (ESCC) carcinogenesis in the Greek population. DNA was extracted from 30 ESCC and 27 normal esophageal specimens and screened for HPV type-specific or EBV infection by PCR-based assay. Seventeen out of 30 ESCC specimens (56%) were found positive for HPV DNA, of which 15 (88%) were typed as HPV-18 infected, one (5.9%) as HPV-16 infected, and one (5.9%) as infected by an HPV type different from the studied HPV-6, 11, 16, 18 and 33 subtypes. Six of the 27 normal esophageal specimens (22.2%) were positive for HPV infection, five typed as HPV-18 (83.3%) and one as HPV-16 (16.7%). All samples were negative for EBV genome detection as assessed by the PCR assay. No statistically significant correlation was found between the HPV status of the tumor samples and clinical parameters including sex, age of the patients, tobacco or alcohol use, differentiation grade of the lesions and stage of the disease. In conclusion, our findings indicate a statistically significant (p<0.001) overall association between ESCC and HPV infection, mostly related to the HPV-18 subtype, in the Greek population.
Tyrosinase mRNA RT-PCR Analysis as an Additional Diagnostic Tool for the Identification of Melanoma Cells in Biological Fluid Samples other than Blood: A Preliminary Report
Authors: Savoia P. , Quaglino P. , Osella-Abate S. , Comessatti A. , Nardò T. , Bernengo M.G.
Published: January 2018

Reverse transcription polymerase chain reaction (RT-PCR) of tyrosinase mRNA has been applied for the detection of melanoma cells in the peripheral blood, lymph nodes and bone marrow of melanoma patients. We evaluated the diagnostic accuracy of RT-PCR in comparison to standard cytology and immunocytochemistry (ICC) for the identification of melanoma cells in biological fluids other than blood. Tyrosinase expression was evaluated together with standard cytology and ICC (anti-S100, HMB-45 and Melan-A antibodies) in biological fluid samples collected from 17 melanoma patients according to the site of metastatic involvement or clinical suspicion (eight cerebrospinal fluid (CSF) samples; three pleural effusions; four ascites; one bile sample, one pericardial effusion); 17 samples collected from patients with non-melanoma metastatic cancer were used as controls. Tyrosinase expression in the biological fluid sample was compared with the expression determined at the same time in peripheral blood. Positive tyrosinase expression was found in 12/17 melanoma and 3/17 non-melanoma cancer patients. Cytology/ICC showed the presence of neoplastic cells in only 7/12 melanoma samples with positive tyrosinase expression: radiological evidence of disease involvement was found in all these patients (three meningeal, two pleural, two peritoneal). Clear-cut radiological evidence of disease involvement at the sampling site was found in the five patients with negative cytology/ICC and positive RT-PCR (one CSF; four serous membrane effusions); all patients died of disease progression within four months of sampling. The five patients who were negative for both cytology/ICC and RT-PCR did not show any clinical evidence of disease recurrence at the sampling site. Only five of the 12 metastatic patients with positive tyrosinase expression in biological fluid showed positivity for tyrosinase in the peripheral blood. These preliminary results suggest that the analysis of biological fluids other than blood could be considered as a new potential clinical field of application for the tyrosinase mRNA assay.
Comparison of Four Different Assays for Determination of Serum S-100B
Authors: Smit L.H.M. , Korse C.M. , Bonfrer J.M.G.
Published: January 2018

Background

S-100B determination has been shown to be clinically useful in the management of melanoma patients. After the development of a test for determination of the isoforms S100-A1B and S100-BB in serum (S-100B), several sensitive assays for the detection of serum S-100B have become available. We compared four S-100B assays, two automated (LIAISON®Sangtec®100 and Elecsys®S100) and two manual ones (Sangtec®100 ELISA and CanAg S100 EIA), with respect to clinical data, reference values and correlation.

Methods

In a total of 280 samples from 155 melanoma patients and 98 healthy individuals S-100B values were measured simultaneously with the different assays.

Results

The inter and intra coefficients of variation were best for the automated assays. The functional sensitivity of both manual assays was 0.15 μg/L. Method comparison revealed satisfactory correlation coefficients of 0.9 or higher, but the slopes ranged from 0.29 to 3.36. Except for the Sangtec®100 ELISA, the linearity between the assays was acceptable. The overall sensitivity for melanoma ranged from 37% (Elecsys®S100) to 47% (LIAISON®Sangtec®100) and the sensitivity increased with stage. ROC curves showed the best accuracy for the LIAISON®Sangtec®100 assay.

Conclusions

All assays gave satisfactory results, but it is advisable to improve the performance of the manual assays for better sensitivity. Agreement about an international reference standard is needed.
Diagnostic Utility of Cyfra 21-1 and Cea Assays in Pericardial Fluid for the Recognition of Neoplastic Pericarditis
Authors: Szturmowicz M. , Tomkowski W. , Fijalkowska A. , Kupis W. , Cieślik A. , Demkow U. , Langfort R. , Wiechecka A. , Orlowski T. , Torbicki A.
Published: January 2018

A positive cytology result in pericardial fluid is the gold standard for recognition of malignant pericardial effusion. Unfortunately, in 30–50% of patients with malignant pericardial effusion cytological examination of the pericardial fluid is negative. Tumor marker assessment in pericardial fluid may help to recognize malignant pericardial effusion. The aim of our study was to estimate the value of CYFRA 21-1 and CEA measurement in pericardial fluid for the recognition of malignant pericardial effusion. To our knowledge this is the first study on CYFRA 21-1 assessment in pericardial effusion. The examined group consisted of 50 patients with malignant pericardial effusion and 34 patients with non-malignant pericardial effusion. Median CEA concentrations in malignant pericardial effusion and non-malignant pericardial effusion were 80 ng/mL (0–317) and 0.5 ng/mL (0–18.4), respectively (p<0.001). Median CYFRA 21-1 concentrations in malignant pericardial effusion and non-malignant pericardial effusion were 260 ng/mL (5.3–10080) and 22.4 ng/mL (1.87–317.6), respectively (p<0.001). The optimal cutoff value for CYFRA 21-1 in pericardial effusion was 100 ng/mL. CYFRA 21-1 >100 ng/mL or CEA >5 ng/mL were found in 14/15 patients with malignant pericardial effusion and negative pericardial fluid cytology. We therefore strongly recommend the use of CYFRA 21-1 and/or CEA in addition to pericardial fluid cytology for the recognition of malignant pericardial effusion.
Cathepsins B and L and Their Inhibitors Stefin B and Cystatin C as Markers for Malignant Progression of Benign Meningiomas
Authors: Trinkaus M. , Vranič A. , Dolenc V.V. , Lah T.T.
Published: January 2018

Meningiomas are, in general, slowly growing benign tumors attached to the dura mater and composed of neoplastic meningothelial (arachnoidal) cells. They have a wide range of histopathological appearances and are classified, according to the aggressiveness of their growth and the risk of recurrence, as WHO grade I (benign) meningiomas, WHO grade II (atypical) meningiomas and WHO grade III anaplastic (malignant) meningiomas. As invasion of normal tissue may occur in all grades, independent biological markers are needed to identify the more aggressive and recurrent meningiomas. The lysosomal cysteine proteinases, cathepsins B and L, have been associated with tumor invasiveness and the aim of this study was therefore to evaluate them, together with their endogenous inhibitors stefin B and cystatin C, as potential markers for the aggressiveness of meningiomas. The expression of cathepsins B and L and their inhibitors stefin B and cystatin C in 21 benign (grade I) and 9 atypical (grade II) meningiomas has been compared by immunohistochemical staining, QRT-PCR and Northern blot analysis. The protein levels of cathepsins B (p=0.050) and L (p=0.019) were found to be significantly higher in atypical than in benign meningiomas. In contrast, their mRNA levels did not differ, indicating that the synthesis of cathepsins was accelerated at the translational level. Protein and mRNA levels of stefin B (p= 0.007), but not cystatin C, were significantly lower in atypical compared with benign meningiomas. The expression of cathepsins and inhibitors was not different between central and peripheral meningioma tissue or between histological subtypes of meningiomas, with the exception of cathepsin L, the level of which was significantly lower in transitional meningiomas. We conclude that higher protein levels of cathepsins B and L and lower mRNA levels of stefin B are potential diagnostic markers for invasive and aggressive behavior of meningiomas. The diagnostic and prognostic value for relapse of meningioma needs to be confirmed in a larger population of patients.
Altered Expression of the Dna Mismatch Repair Proteins Hmlh1 and Hmsh2 in Cutaneous Dysplastic Nevi and Malignant Melanoma
Authors: Shpitz B. , Klein E. , Malinger P. , Osmolovsky G. , Gochberg S. , Bomstein Y. , Bernheim J.
Published: January 2018

Molecular alterations in the mismatch repair system suggest that this mechanism may be important in the evolution of cutaneous melanoma. Our current study evaluated the expression of two mismatch repair proteins, hMLH1 and hMSH2, in dysplastic nevi (DN) and cutaneous melanoma (CM). Immunohistochemical staining of these proteins was performed on 55 CM and 30 DN specimens. The staining results were divided into three groups: negative, partially positive and strongly positive. Normal adjacent skin cells served as an internal control for positive immunostaining. Altered immunoreactivity of one of the proteins was found in four (13.4%) DN and seven (12.7%) CM. Lack of staining for hMLH1 was observed in two (6.7%) cases of DN and five (9.1%) cases of CM; staining for hMSH2 was absent in two (6.7%) of the DN and two (3.6%) of the CM specimens. Partially positive staining was found in 33.3% and 53.3% for hMLH1 and hMSH2, respectively, in DN, and in 54.5% and 69.1%, respectively, in CMM. Our study shows that complete or partial loss of MMR protein expression occurs in a subset of both DN and CM and may represent a distinct pathway in the development of some DN and CM.
Glutathione S-Transferase M1, T1 and P1 Polymorphisms and Bladder Cancer Risk in Egyptians
Authors: Saad A.A. , O'Connor P.J. , Mostafa M.H. , Metwalli N.E. , Cooper D.P. , Povey A.C. , Margison G.P.
Published: January 2018

Previous studies suggest that bladder cancer risk may vary with GST genotype but these results are inconsistent. The aim of this study was to explore whether GSTM1, GSTT1 and GSTP polymorphisms were associated with increased bladder cancer risk in an Egyptian population. GSTM1, GSTT1 and GSTP1 genotype frequencies were determined in bladder cancer cases (n=72) and healthy controls with no history of malignancies (n=82) using PCR-based techniques. The GSTT1*2 genotype was particularly associated with increased risk (OR 2.71, 95%CI 1.27–5.73) and the GSTM1*2 genotype to a lesser extent (OR 1.63, 95%CI 0.85–3.10). 18.1% of cases but only 7.3% of controls were GSTP1*B*B homozygotes (OR 2.38, 95%CI 0.83–6.87). The presence of two or more a priori at-risk genotypes was associated with increased bladder cancer risk (OR 2.42; 95%CI 1.47–3.97). These results suggest that polymorphisms in the GST genes are associated with increased risk of bladder cancer among Egyptians.
Clinical Significance of Cathepsin D Concentration in Tumor Cytosol of Primary Breast Cancer
Authors: Rodríguez J. , Vízquez J. , Corte M.D. , Lamelas M. , Bongera M. , Corte M.G. , Alvarez A. , Allende M. , Gonzalez L. , Sínchez M. , Vijande M. , Muñiz J. Garcia , Vizoso F.
Published: January 2018

Background

Cathepsin D is the proteolytic enzyme most frequently implicated as a prognostic factor in primary breast cancer. In the present study we evaluated by means of an immunoradiometric assay the tumor content of this protease in primary breast cancer, its relationship with tumor-related clinical and pathological parameters, and its prognostic significance in a large series of breast cancer patients.

Method

The study comprised 1033 women with histologically established invasive breast cancer. Cathepsin D was measured in cytosol samples by means of an immunoradiometric assay to determine the total amount of cathepsin D (52 kDa, 48 kDa and 34 kDa). Evaluation of relapse-free survival and cause-specific survival was performed in the group of 1003 patients without evidence of metastasis at the time of initial diagnosis. The median follow-up of the patients who were free of recurrence was 54 months.

Results

Cathepsin D levels showed a wide range among the studied tumors (n=1033; median (range) 41 (0.9–2504) pmol/mg protein). Statistical analysis showed that the median cathepsin D levels were considerably higher in large tumors (T2–4) than in smaller ones (T1) (p=0.017), as well as in node-positive than in node-negative tumors (p=0.004). Cathepsin D levels were also higher in ductal tumors than in the other histological types (p=0.001), as well as in moderately or poorly differentiated tumors (p<0.001). Likewise, the median value of the protease was significantly higher in ER or PgR-positive tumors than in hormone receptor-negative ones (p=0.011 and p=0.004, respectively), as well as in aneuploid tumors than in diploid tumors (p=0.029). Multivariate analysis demonstrated that elevated cathepsin D levels (>59 pmol/mg protein) were notably associated with a shorter cause-specific survival in the whole group of patients with breast cancer, as well as in the subgroup of node-positive patients (p<0.05).

Conclusions

This study suggests that elevated intratumoral cathepsin D levels may identify a subset of node-positive breast cancer patients showing a high probability of earlier death.
Behavior of free Testosterone in Patients with Prostate Cancer on Androgen Deprivation Therapy
Authors: Morote J. , Esquena S. , Abascal J.M. , Trilla E. , Cecchini L. , Raventós C.X. , Catalín R. , Reventós J.
Published: January 2018

Objectives

Determination of free testosterone (FT) serum level is an efficient method to evaluate bioavailable testosterone. We analyzed the behavior of serum FT in patients with prostate cancer receiving androgen deprivation therapy (ADT) and correlated FT with total testosterone (TT). We also analyzed the efficiency of both isoforms in the evaluation of the ADT.

Methods

Serum levels of TT and FT were determined in 191 patients with prostate cancer in a cross-sectional study. A subset of 56 patients submitted only to radical prostatectomy served as control group. The remaining 135 patients with advanced prostate cancer on three-month LHRH agonist treatment comprised the study group. The median age of the population was 73 years (range, 53–86 years) and the median time on ADT was 42 months (6–198).

Results

A significant correlation and linear regression between TT and FT was observed (r2 0.948). The efficiency of TT and FT to discriminate patients with and without ADT was similar (AUC: 0.993 and 0.995, respectively, p>0.05). A castration level of serum FT established at 1.7 pg/mL had a sensitivity of 85.9% and a specificity of 100%, which are similar to the sensitivity and specificity of 50 ng/dL of TT. All patients without ADT had levels of serum TT and FT above the castration level. In 19 of the 135 (14.1%) patients on ADT serum TT was above 50 ng/dL. In 12 of these 19 patients (63.2%) serum FT was below 1.7 pg/mL while in seven patients (5.2%) FT was also above the castration level.

Conclusions

The castration level of FT was established at 1.7 pg/mL. Serum TT and TF correlated very well; however, they seemed to provide complementary information in the evaluation of ADT efficiency. 14.1% of the patients on ADT failed to reach the castration level of serum TT; determination of serum FT in these patients would reduce this rate to 5.2%.
Usefulness of Bone Formation Markers in Breast Cancer
Authors: Palma M.A. , Body J.-J.
Published: January 2018

The skeleton is the main site affected by metastases and breast cancer is the most frequent tumor to invade bone. The assessment of bone metastases is difficult and biochemical markers of bone formation (BFMs) could be a promising alternative. Although the essential role of osteoblasts in the metastatic process of bone destruction is now well established, little attention has been paid to BFMs. We conducted a Medline search for studies about BFMs in breast cancer. Our review allows us to conclude that BFMs have high specificity but low sensitivity for the diagnosis of bone metastases. The available biochemical markers cannot replace imaging techniques for the diagnosis of bone metastases. Several studies indicate that BFM serum levels reflect total tumor burden in the skeleton. BFM levels are higher in patients with blastic lesions compared to those with lytic lesions. Serial measurements of BFMs could be useful for the clinical assessment of response to antineoplastic treatment or to bisphosphonate therapy. Besides markers of bone resorption, biochemical markers of bone formation are a promising alternative for the assessment of metastatic bone disease, but large prospective studies are needed to address this important issue.
Plant-Based Diet, Serum Fatty Acid Profile, and Free Radicals in Postmenopausal Women: The Diet and Androgens (DIANA) Randomized Trial
Authors: Colombo C. , Muti P. , Pala V. , Cavalleri A. , Venturelli E. , Locardi M. , Berrino F. , Secreto G.
Published: January 2018

High calorie and fat consumption and the production of free radicals are two major mechanistic pathways between diet and disease. In this study we evaluated the effect of a plant-based diet poor in animal fat and rich in (n-3) fatty acids on fatty acids of serum phospholipids and on the production of reactive oxygen metabolites (ROMs). One hundred and four healthy female postmenopausal volunteers were recruited and randomized to a dietary intervention or a control group. Dietary intervention included a program of food education and biweekly common meals for 18 weeks. When the intervention and control groups were compared, it was seen that dietary intervention resulted in a significant reduction of saturated fatty acids (-1.5%) and a significant increase in (n-3) fatty acids (+20.6%), in particular docosahexaenoic acid (+24.8%). We observed that arachidonic acid decreased (–7.7%), while (n-6) fatty acids did not, and the (n-3)/(n-6) polyunsaturated ratio increased significantly (+24.1%). As expected, ROMs decreased significantly in the intervention group (-6%). The results indicated that a plant-based diet can improve the serum fatty acid profile and decrease ROMs production. These results suggest that a plant-based diet may reduce the body's exposure to oxidative stress.
Interobserver Reproducibility of Immunohistochemical Her-2/Neu Assessment in Human Breast Cancer: An Update from INQAT round III
Authors:   Italian Network for Quality Assurance of Tumor Biomarkers (INQAT) Group, Paradiso A. , Marubini E. , Verderio P. , Cortese M.E. , Pizzamiglio S. , De Paola F. , Silvestrini R. , Simone G. , Sarotto I. , Carcangiu M.L. , Menard S. , Tagliabue E. , Mottolese M. , Benevolo M. , Bisceglia M. , Giardina E. , Maiorano E. , Napoli A. , Querzoli P. , Nenci I. , Pedriali M. , Rinaldi R. , Bianchi S. , Vezzosi V. , Collecchi P. , Bevilacqua G. , Colombari R. , Caneva A. , Gasparin P. , Rucca V. , Morigi F.P. , De Paola F. , Dubini A. , Gaudio M. , Medri L. , Padovani F. , Saragoni L. , Volpi A. , Granato A.M. , Marinaro E. , Folicaldi S. , Ghidoni D. , Cortecchia S. , Veronese S. , Galli C. , Gambacorta M. , Stella M. , Rizzo A. , Nizzoli R. , Bozzetti C. , Guazzi A.M. , Naldi N. , Sidoni A. , Bucciarelli E. , Ludovini V. , Pistola L. , Bernardi L. , Ghisolfi G. , Pecchioni C. , Sapino A. , Bussolati G. , Barbareschi M. , Dalla Palma P. , Leonardi E.
Published: January 2018

The clinical interest in HER-2/neu is related to trastuzumab, a drug used to treat patients with invasive breast carcinoma overexpressing the HER-2/neu protein. It is very important to correctly identify those patients who may benefit from trastuzumab by accurate assessment of the HER-2/neu status. Of the various methods available, the Dako Herceptest for immunohistochemical assay is considered the most reliable to reach this goal. The aim of this study was to investigate within a group of Italian laboratories the reproducibility of the results of HER-2/neu assessment by means of the Dako scoring system on slides stained with the Herceptest kit. This study was also conceived as the continuation of one of our previous studies, which was similar in its aims but different in the classification criteria adopted. Our results show that, whereas the intra-observer reproducibility was generally satisfactory, the interobserver reproducibility was not. Moreover, our findings confirm that the two extreme classes (0 and 3+) are more easy to identify than the other two and that the Herceptest does not allow to discriminate optimally between scoring classes 2+ and 3+. These findings are relevant in clinical practice where the treatment choice is based on categories defined by this assay, suggesting the need of adopting educational programs and/or new reference materials to improve the assay performance.
Neuroendocrine Phenotype of Non-Small Cell Lung Carcinoma: Immunohistological Evaluation and Biochemical Study
Authors: Slodkowska J. , Zych J. , Szturmowicz M. , Demkow U. , Rowinska-Zakrzewska E. , Roszkowski-Sliz K.
Published: January 2018

Aims and methods

The prevalence and distribution of neuroendocrine differentiation in non-small cell lung cancer (NSCLC) was estimated by assays for synaptophysin (SYN), chromogranin A (CgA), Leu7 and neuron-specific enolase (NSE). Serum NSE and CgA were determined in parallel to find the values of these markers for distinguishing neuroendocrine differentiation in NSCLC. Fifty-eight resected NSCLC specimens and 34 sera of NSCLC patients entered the study. Neuroendocrine differentiation was graded according to the percentage of neuroendocrine tumor cells as NE0 – 0%, NE1–NE4 – 1%->76%. Serum NSE <12.5 ng/mL and serum CgA <46 U/L were taken as cutoff levels.

Results

63.8% (37/58) of NSCLC were scored as NE1–NE4 according to the SYN, CgA and Leu7 levels; 34.5% as NE1; 29.3% as NE2–NE4. 56.8% of tumors were positive for SYN, 34.4% for CgA, 22.4% for Leu7, and 79.3% for NSE. A significant relationship was found between tumor SYN and tumor CgA expression, and between tumor SYN expression and tumor stage. Adenocarcinomas showed a significantly higher rate of neuroendocrine differentiation than squamous cell carcinomas. All normal serum CgA levels corresponded to a lack of CgA expression in the tumors. The increased serum NSE levels presented by 26% of NSCLC patients (mainly <16 ng/mL) did not correlate with tumor NSE expression.

Conclusions

The prevalence of neuroendocrine differentiation in NSCLC varies and depends on the immunohistochemical criteria used; this warrants standardization of the immunohistochemical criteria for neuroendocrine differentiation in NSCLC. NSE expression in the tumor and a mild increase in serum NSE are poor markers for distinguishing neuroendocrine differentiation in NSCLC.
Collagenase-3 (MMP-13) Expression in Cutaneous Malignant Melanoma
Authors: Corte M.D. , Gonzalez L.O. , Corte M.G. , Quintela I. , Pidal I. , Bongera M. , Vizoso F.
Published: January 2018

Background

Matrix metalloproteases (MMPs), enzymes with the ability to degrade the extracellular matrix, play an important role in tissue invasion by cutaneous malignant melanoma (CMM). One specific MMP, collagenase-3 (MMP-13), is thought to have a key function in the activation of MMP.

Aims

To evaluate the expression of MMP-13 in CMM and assess its possible relationship to clinical and pathological parameters.

Methods

MMP-13 expression was analyzed in 51 paraffin-embedded tumor samples from patients with invasive CMM, ten samples from in situ melanomas, and in eight samples from benign lesions (three dermal melanocytic nevi, three compound melanocytic nevi and two atypical melanocytic nevi) using immunohistochemical techniques. The median follow-up period in patients with invasive CMM was 50 months.

Results

Benign lesions were consistently negative for MMP-13, whereas three of the ten in situ melanomas (30%) and 23 of the 51 invasive CMMs (45%) showed positive immunostaining for MMP-13. The percentage of MMP-13-positive tumors correlated significantly and positively with the mitotic index (p=0.002) in invasive CMM. However, our results did not show any significant association between tumoral MMP-13 expression and relapse-free survival in patients with invasive CMM.

Conclusions

MMP-13 appears to be a factor associated with tumor aggressiveness in CMM. It seems to eliminate an important barrier not only against tumoral invasion but also against proliferation.
Prognostic Biomarkers in Renal Cell Carcinoma: Relevance of DNA Ploidy in Predicting Disease-Related Survival
Authors: Pinto A.E. , Monteiro P. , Silva G. , Ayres J.V. , Soares J.
Published: January 2018

Objective

To investigate the prognostic value of DNA ploidy, Ki-67 index and p53 expression in relation to disease-related survival in a consecutive series of patients with renal cell carcinoma (RCC).

Material and methods

The study group consisted of 64 RCC patients treated by radical nephrectomy. Histological type, pathological staging and nuclear anaplasia were assessed according to the WHO classification, TNM system and Fuhrman grading criteria, respectively. Ploidy was determined by DNA flow cytometry using two sampling methods (frozen vs paraffin-embedded tissue). Ki-67 and p53 were evaluated by immunohistochemistry techniques using two cutoff points (10% vs mean value) for staining interpretation. Kaplan-Meier and Cox regression analyses were used for prognostic evaluation.

Results

Thirty-one tumors (48.4%) showed DNA diploidy and 33 (51.6%) were DNA aneuploid. Concordance between both ploidy measurement methods was found in 85.5% of cases (p=0.0455). The mean values for Ki-67 and p53 immunostaining were 3.65% (0–23.5%) and 5.90% (0–55.9%), respectively. DNA ploidy significantly correlated with staging, tumor size (pT), nuclear grading, and Ki-67 (mean value cutoff). Ki-67 (10% cutoff) correlated with staging and pT, while p53 (mean value cutoff) was associated with Ki-67 (mean value cutoff). There were significant differences between survival curves for pathological stage, pT, nuclear grade, ploidy, Ki-67 (both cutoffs), and p53 (10% cutoff). By univariate regression analysis, stage III and stage IV, pT3, aneuploidy, high Ki-67 (both cutoffs), and p53 overexpression (10% cutoff) showed significant correlations with worse disease-related survival. In addition, DNA aneuploidy significantly correlated with poor prognosis within stages I/II (p=0.0355) and stages III/IV (p=0.0138) of the disease.

Conclusion

The results indicate that DNA ploidy has relevant prognostic value in RCC, adding useful information to the classic histopathological indicators of clinical outcome.
Individualized Survival and Treatment Response Predictions for Breast Cancers Using Phospho-EGFR, Phospho-ER, Phospho-HER2/neu, Phospho-IGF-IR/In, Phospho-MAPK, and Phospho-p70S6K Proteins
Authors: Guo L. , Abraham J. , Flynn D.C. , Castranova V. , Shi X. , Qian Y.
Published: January 2018

The development and progression of breast cancer involves the activation of numerous protein kinases, and the change in phosphorylation is a hallmark of protein kinase activation. In this study, we identified a comprehensive profile to predict individual breast cancer patients’ survival and treatment responses using the Random Committee algorithm. The profile incorporated a subset of phosphorylated signal protein expressions and several selected clinical factors of breast cancer. The parameters of our profile were identified by supervised feature selection algorithms, Gain Ratio Attribute Evaluation and Relief. The results showed that the overall accuracy of survival prediction reached 92.3% for individual breast cancer patients with the use of the expression profiles of phospho-EGFR, phospho-ER, phospho-HER2/neu, phospho-IGF-IR/In, phospho-MAPK, and phospho-p70S6K plus the selected clinical factors. The results also indicated that the overall accuracy of treatment response prediction was 92.6% with the use of the level of phospho-EGFR, phospho-ER, phospho-HER2/neu, phospho-MAPK, and phospho-p70S6K plus the selected clinical information. The prediction system combines multiple signal protein activation profiles and relevant clinical information, and provides a unique guideline to aid individualized decision-making in the clinical management of breast cancer.
Clinical Usefulness of Bisphosphonates in Oncology: Treatment of Bone Metastases, antitumoral Activity and Effect on Bone Resorption Markers
Authors: Verì A. , D'Andrea M.R. , Bonginelli P. , Gasparini G.
Published: January 2018

The present article overviews the role of bisphosphonates for the treatment and prevention of bone metastases and their antiangiogenic effects and antitumoral activity. The skeleton is a frequent and clinically relevant site of metastasis in cancer patients. The major events related to bone metastases include bone pain, bone loss, hypercalcemia, spinal cord compression, and fractures. On the basis of their radiographic features, bone metastases are classified as osteoblastic, osteoclastic, or mixed. The primary goals of treatment of bone metastases are reduction of the risk of pathological fractures and other skeletal-related events, and pain control. Bisphosphonates are used to prevent pathological fractures by inhibition of osteoclasts. Recent studies suggest that bisphosphonates have some direct antitumoral activity, mainly mediated through the blockade of angiogenic pathways. Further clinical studies are needed to determine the optimal treatment duration, timing and schedule of bisphosphonates, assess their role as adjuvant therapy for the prevention of bone metastases, and establish their antiangiogenic activity in association with standard cytotoxic and hormonal drugs for treatment of patients with advanced disease.
Levels of Circulating Cell-Free Serum DNA in Benign and Malignant Breast Lesions
Authors: Zanetti-Dällenbach R.A. , Schmid S. , Wight E. , Holzgreve W. , Ladewig A. , Hahn S. , Zhong X.Y.
Published: January 2018

Purposes of the study: We analyzed circulating cell-free DNA in the serum of patients with benign and malignant breast disease and in healthy individuals to determine its diagnostic value.

Basic procedures: Serum samples were obtained from 50 healthy individuals, 33 patients with malignant breast disease and 32 patients with benign breast disease. Circulatory DNA was extracted from serum samples. Cell-free DNA was quantified by real-time quantitative PCR for the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene. Tissue samples from patients with malignant and benign breast lesions were histopathologically examined.

Main findings: The mean levels of circulating cell-free DNA in serum samples were 41,149 genome equivalents (GE)/mL in patients with malignant disease, 30,826 GE/mL in patients with benign disease, and 13,267 GE/mL in healthy individuals. Healthy individuals had significantly lower levels of cell-free DNA than patients with malignant or benign breast disease (p=0.001, p=0.031). No significant difference was observed between malignant and benign disease. There was a correlation between cell-free DNA levels and tumor size but not with other tumor characteristics.

Principal conclusion: Our results suggest that levels of circulating cell-free DNA in serum could have diagnostic value to discriminate between healthy individuals and patients with breast lesions but not between patients with malignant and benign breast lesions.
Cytoplasmic Localization of BAG-1 in Leukoplakia and Carcinoma of the Tongue: Correlation with p53 and C-Erbb2 in Carcinoma
Authors: Vora H.H. , Mehta S.V. , Shah K.N. , Brahmbhatt B.V. , Desai N.S. , Shukla S.N. , Shah P.M.
Published: January 2018

Background

The present study evaluated the clinical significance of BAG-1, an antiapoptotic protein, in leukoplakia and carcinoma of the tongue.

Methods

BAG-1 expression was evaluated by immunohistochemistry in paraffin-embedded tissues of leukoplakia (n=25) and carcinoma of the tongue (n=61).

Results

Cytoplasmic expression was predominantly seen in 80% and 70% of patients with leukoplakia and carcinoma, respectively. BAG-1 expression was found to be significantly lower in tobacco users than in non-tobacco users. BAG-1 expression in tobacco-using leukoplakia and carcinoma patients was compared by grouping the carcinoma patients according to lymph node status and disease stage. Carcinoma patients with tumor-positive lymph nodes had significantly lower BAG-1 expression than patients with negative lymph nodes and leukoplakia. Further, a trend towards an inverse correlation was observed with p53 and c-erbB2. In univariate and multivariate survival analysis, patient subgroups with 2+ or 3+ marker positivity (BAG-1 negativity, p53 and c-erbB2 positivity) had a reduced overall survival compared with patient subgroups with 1+ marker positivity or negativity.

Conclusion

BAG-1 negativity in association with p53 and c-erbB2 positivity identified a subgroup of tongue cancer patients with an aggressive phenotype. Hence, an antiapoptotic protein, BAG-1, was found to be down-regulated in chewing-tobacco-mediated tongue carcinogenesis.
Basic Helix-Loop-Helix Transcription Factor Profiling of Lung Tumors Shows Aberrant Expression of the Proneural Gene Atonal Homolog 1 (ATOH1, HATH1, MATH1) in Neuroendocrine Tumors
Authors: Westerman B.A. , Breuer R.H.J. , Poutsma A. , Chhatta A. , Noorduyn L.A. , Koolen M.G.J. , Postmus P.E. , Blankenstein M.A. , Oudejans C.B.M.
Published: January 2018

Microarray-based expression profiling studies of lung adenocarcinomas have defined neuroendocrine subclasses with poor prognosis. As neuroendocrine development is regulated by members of the achaetescute and atonal classes of basic helix-loop-helix (bHLH) transcription factors, we analyzed lung tumors for expression of these factors. Out of 13 bHLH genes tested, 4 genes, i.e., achaetescute complex-like 1 (ASCL1, HASH1, Mash1), atonal homolog 1 (ATOH1, HATH1, MATH1), NEUROD4 (ATH-3, Atoh3, MATH-3) and neurogenic differentiation factor 1 (NEUROD1, NEUROD, BE-TA2), showed differential expression among lung tumors and absent or low expression in normal lung. As expected, tumors that have high levels of ASCL1 also express neuroendocrine markers, and we found that this is accompanied by increased levels of NEUROD1. In addition, we found ATOH1 expression in 9 (16%) out of 56 analyzed adenocarcinomas and these tumors showed neuroendocrine features as shown by dopa decarboxylase mRNA expression and immunostaining for neuroendocrine markers. ATOH1 expression as well as NEUROD4 was observed in small cell lung carcinoma (SCLC), a known neuroendocrine tumor. Since ATOH1 is not known to be involved in normal lung development, our results suggest that aberrant activation of ATOH1 leads to a neuroendocrine phenotype similar to what is observed for ASCL1 activation during normal neuroendocrine development and in lung malignancies. Our preliminary data indicate that patients with ATOH1-expressing adenocarcinomas might have a worse prognosis.
Association of Human Papillomavirus Type 16 E7 and HLA Class I Antigen Expression in Cervical Premalignant and Malignant Lesions
Authors: Wang J.-F. , Wang C.-X. , Wang L.-S. , Zhang J. , Yang X.-J. , Liu M. , Zheng G.-X.
Published: January 2018

In the present experiment we studied the correlation between HPV16 infection and expression of HLA-I antigen in cervical premalignant and malignant lesions (cervicitis, CIN, cervical squamous carcinomas and adenocarcinoma samples). The HPV16 E7 DNA load and the expression of HLA-I antigen in the samples were measured by real-time fluorescence quantitative polymerase chain reaction (RFQ-PCR) and immunohistochemical S-P staining, respectively. Our data indicate that HPV16 E7 load was highly and positively associated with the development of cervical lesions (Spearman's correlation coefficient r=0.848, p<0.001), the negative rate of HLA-I antigen was significantly distinguished among groups (p<0.001), and HPV16 E7 infection and downregulation of HLA-I antigen were highly correlated in cervical lesions (Pearson's correlation coefficient r=-0.487, p<0.001). HPV16 E7 may play an important role in the downregulation of HLA-I antigen in cervical lesions, which results in the immune escape of the virus and the occurrence, development, invasion and metastasis of cancer. Furthermore, quantitative PCR for HPV16 E7 may play an important role in the early detection of cervical diseases and in guiding future therapy toward prevention.
Development of ELISAs for Quantification of HMFG1-Specific Human Anti-Mouse IgG and IgM Antibodies
Authors: Oei A.L.M. , Boerman O.C. , Geurts-Moespot A. , van Eerd J.E. , van Tienoven D. , Courtenay-Luck N. , Thomas C.M.G. , Massuger LF.A.G. , Sweep F.C.G.J.
Published: January 2018

The aim of this study was to develop and validate ELISAs for quantification of HAMA-IgM and HAMA-IgG in serum of patients with ovarian cancer who enrolled in a large international randomized phase III trial of intraperitoneal Yttrium-90-labeled HMFG1 murine monoclonal antibody therapy. The capture antibody of these 2 assays was the murine antibody HMFG1, while mouse anti-human IgM-HRP or mouse anti-human IgG(Fc)-HRP served as tracer antibodies. A pool of HAMA-positive serum samples was used to prepare a series of assay standards and another pool served as reference preparation. The analytical sensitivity of the HAMA-IgM assay was 2.5 arbitrary units per mL (AU/mL) and 4.7 AU/mL for the HAMA-IgG ELISA. Diluted serum samples showed good parallelism with the HAMA-IgM and HAMA-IgG standard dose-response curves. Within-assay coefficient of variation was 7.5% for HAMA-IgM and 6.5% for HAMA-IgG. Between-assay variation was 14.2% for HAMA-IgM and 15.3% for HAMA-IgG. The developed HAMA-IgM and HAMA-IgG ELISAs show satisfactory reliability criteria (sensitivity, parallelism and precision) and are suitable for monitoring of HAMA-IgM and HAMA-IgG responses in ovarian cancer patients. These ELISAs will be used to monitor the development of HAMAs in patients who received radioimmunotherapy with murine HMFG1.
Nuclear and Cytoplasmic Expression of ErbB-4 in Prostate Cancer
Authors: Ben-Yosef R. , Sarid D. , Vexler A. , Lidawi G. , Inbar M. , Marmor S. , Starr A. , Hahoshen N. Yaal
Published: January 2018

Purpose

To evaluate cytoplasmic and nuclear ErbB-4 expression in prostate cancer specimens and its association with outcome.

Basic procedures

Specimens of 50 prostate cancer patients were investigated for ErbB-4 overexpression using immunohistochemistry staining. Cytoplasmic and nuclear staining was graded as 0–3 according to its intensity. The prognostic parameters were tumor stage, PSA level, Gleason score, probability of positive lymph nodes (Partin's tables and Roach equation), and 5-year disease free survival (Kattan nomogram).

Main findings

Overexpression of ErbB-4 (≥1) was detected in 30 (60%) patients and overexpression using cytoplasmic and nuclear staining was ≥2 in 19 (38%) and 17 (34%) patients, respectively. In only one third of the specimens was there any similarity between the 2 types of staining. Advanced tumor stage, high pretreatment PSA levels and high Gleason scores were evenly distributed among the patients with low (≤1) and intermediate/high (≥2) ErbB-4 expression. The probability of lymph node involvement and 5-year disease free survival were similar in both types of staining.

Principal conclusions

ErbB-4 was overexpressed (cytoplasmic and nuclear staining) in approximately one third of prostate cancer patients. The rate of similarity between the 2 staining types was only 33%: overexpression was evenly distributed among intermediate/high and low risk prostate cancer patients with both staining methods.