bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantitative measurement of HER2 expression and HER2 homo-dimerization in formalin-fixed paraffin-embedded (FFPE) breast cancer tissues using a novel proximity-based assay
Authors: Huang W. , Tan Y. , Jin X. , Mukherjee A. , Sperinde J. , Pannu H. , Prasad U. , Penuel E. , Winslow J.
Published: March 2020

21023

Background: The best method to assess HER2 status remains controversial. Here we describe a novel assay that provides reliable quantitation of total HER2 (H2T) and HER2 homodimer (H22D) in FFPE tissues. The assay was cross-validated with conventional HER2 tests - immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Characteristics of the new assay and its potential application as predictive test were explored. Methods: Electrophoretic Tag (eTag) is a proprietary proximity-based technology that measures gene and protein expression. We have developed a novel application of the technology to quantify H2T and H22D in FFPE tissues. The validity of the assay was evaluated by analyzing its performance in cell lines and FFPE breast cancers. IHC (clone CB-11, Ventana) was performed in 174 breast cancers, scored according to standard IHC criteria and Histoscore (H-score), and HER2 gene amplification was evaluated by FISH (PathVysion, Vysis) in 19 breast cancers. eTag assays were performed on the same specimens and the results were compared with those of IHC and FISH. Results: H2T and H22D were proportional to the known expression levels in cell lines. H2T demonstrated a continuous measurement over a wide dynamic range (>2 logs), in contrast with conventional IHC (0, 1+, 2+, 3+). The correlation between H2T and IHC categories was significant (correlation=0.84, p<0.0001 by the Jonckheere-Terpstra test for trend), but overlap of H2T values in adjacent IHC categories was observed. H-score showed good correlation within the lower range of H2T, but plateaued at higher range of H2T. HER2 gene amplification (HER2/CEP17 ratio and gene copy #) by FISH was generally correlated with IHC categories and H2T values. There was a good correlation between H22D and H2T (r2= 0.7, P < 0.001). Conclusions: eTag reliably measures H2T and H22D in FFPE tissues. The continuous measure of H2T over a wide dynamic range and the novel H22D measure provide data superior to conventional HER2 tests by IHC and FISH, but clinical utility of the eTag assay remains to be investigated. eTag has potential as a predictive test for targeted HER2 therapy in breast cancer.

No significant financial relationships to disclose.
Overexpression of claudin-11 decreases the invasive potential of bladder cancer cells in vitro, but has no effect on their electrical resistance
Authors: Awsare N. S. , Martin T. A. , Kynaston H. G. , Mansel R. E. , Matthews P. N. , Jiang W. G. ,   Metastasis & Angiogenesis Research Group
Published: March 2020

21038

Background: An increasing body of evidence suggests that tight junctions (TJ) play an important role in invasion and metastasis. Claudins (Cl), a group of integral membrane proteins play an important role in maintaining TJ structure and function. Hepatocyte growth factor (HGF) has been shown to disrupt TJ structure. We investigated the effect of forced overexpression of Cl-11 on TJ function and invasive potential of T24 bladder cancer cells, in response to HGF. Methods: Expression of Cl-11 in bladder cancer cells was determined by RT-PCR. Cl-11 expression construct was made from full length human Cl-11 obtained from normal human cDNA bank, using pcDNA 3.1/ NT-GFP-TOPO expression vector. T24 cells were transfected with the resultant expression cassette (T24Cl-11) or an empty plasmid control (T24GFP). Change in TJ function of stably transfected cells was assessed by trans-urothelial resistance (TUR). In- vitro matrigel adhesion and invasion assays were used to determine the malignant potential of the cells. Cells were treated with HGF at 50 ng/ml for TUR and invasion assay. Immunofluorescence was used to localise Cl-11 within the cell. Results: Successful transfection of T24 cells was confirmed by endogenous GFP fluorescence and by an enhanced Cl-11 mRNA signal in T24Cl-11 compared to wild- type (T24WT) or T24GFP. There was no difference in TUR between the three cell types. Adhesion was significantly higher in T24Cl-11 than in T24GFP [median (IQR); 0.11 (0.096–0.137) vs 0.095 (0.089- 0.115), p=0.045]. T24Cl-11 cells had significantly reduced invasiveness in response to HGF, compared to T24GFP [mean (95% CI); 2.4 (1.8–3.01) vs 3.31 (2.89–3.71), p=0.032]. Immunoflourescence staining with Cl-11 showed redistribution of Cl-11 protein to the cytoplasm and perinuclear regions. Conclusion: Cl-11does not appear to be involved in the TJ function in T24 bladder cancer cells; however, its cytoplasmic location and its effect on the metastatic potential of these cells suggests that it may have a role in modulating the cytoskeletal or signalling network of the cell. Further studies are required to elucidate the exact mechanisms involved.

No significant financial relationships to disclose.
Clinical significance of proliferative activity evaluated by MIB-1 in the treatment and postoperative follow-up of early breast cancer
Authors: Nishimura R. , Arima N.
Published: March 2020

21054

Background: To evaluate a clinical significance of proliferative activity in breast cancer, we studied relationships between proliferative activity and recurrence rate, the time of recurrence or adjuvant therapy. Methods: We analyzed 2448 patients with primary breast cancer between 1987 and 2004 in the Kumamoto City Hospital, and 437 cases out of the patients developed recurrence. Furthermore, the rate of recurrence before and after 1999 when postoperative adjuvant therapy (such as CEF or Taxanes) was started as standard treatment was investigated. Proliferative activity was judged by immunostaining for MIB-1. The fraction of proliferating cells was classified into 3 degrees (=19%, 20–49%, 50%=). Median observation period was 70 months. Results: 1) Distribution of patients by proliferation was as follows; =19%:1215 cases(50%), 20–49%: 870 cases(35%), or 50%=: 363 cases(15%). There was a significant relationship between proliferative activity and tumor size, nodal status, ER, PgR, p53 or HER2 status. 2) Multivariate analysis for disease-free survival revealed that a proliferative activity was one of significant factors in node-negative and positive cases. Recurrence rate was 11.6% in cases with low proliferation and 31.0% in high proliferation. The mean period from operation to recurrence in cases with low proliferation was 50.2 months, whereas 19.9 months in high proliferation (p<0.0001). Moreover, 74% of recurrent cases with high proliferation recurred within 2 years after operation, and there were few recurrences from the fifth year. 3) Patients with low proliferation frequently developed bone metastasis. In local recurrence, diffuse skin recurrence was often seen in cases with high proliferation. 4) The prognosis of patients in the later period (standard therapy group) was significantly better than that of patients in the earlier period, especially in high proliferation group. Conclusions: Proliferative activity might reflect aggressive behavior of breast cancer and predict the time of recurrence. The standard adjuvant therapy was effective in inhibiting early recurrence with high proliferation. It is important to take proliferative activity into consideration in the treatment and follow-up of breast cancer.

No significant financial relationships to disclose.
Relevance of circulating tumor cells (CTC) in the progression of metastatic breast cancer
Authors: Altimari A. , Quercia S. , Benedettini E. , Rosati M. , Capizzi E. , Bernardi A. , Fiorentino M. , Zamagni C. , D'Errico Grigioni A. , Martoni A. A.
Published: March 2020

21066

Background: metastatic breast cancer is an incurable disease. Molecular tumor staging methods are required for a better therapeutic approach. Patients and Methods: eight mL blood samples were drawn from 20 patients (pts) (mean age 61.9±9) with metastatic breast cancer at the time of the beginning of a new chemo- or hormonal treatment line. Median follow-up was 7±4.5 months. Twenty- five female healthy blood donor volunteers were used as controls. Blood samples were screened for the presence of circulating tumor cells (CTC) with a quantitative PCR method using molecular probes for human mammaglobin (hMAM) and cytokeratin 19 (CK19). Relative quantification of hMAM and CK19 RNA was obtained using a blood sample infected with known concentrations of MDA-MB453 cells as calibrator. Results: none of the healthy controls was hMAM positive while the cut-off for CK19 was calculated as the mean value of the controls plus two standard deviations. Nine of 20 (45%) pts were hMAM positive, 15/20 (75%) CK19 positive, while 18/20 (90%) pts were positive for at least one marker (CTC positive). Among the 14 (70%) pts who had a disease progression 7 died. Seven of 9 hMAM positive (78%) and 11/15 (73%) CK19 positive pts had disease progression. All the 14 pts who had disease progression were CTC positive while the only 2 CTC negative pts were free from progression at the time of last follow-up. Conclusions: (1) Multiple (hMAM, CK19) rather than single marker detection should be preferred for CTC blood screening in breast cancer. (2) Combined hMAM and CK19 evaluation might identify pts at higher risk of tumor progression and might be useful for stratification and decision making in metastatic breast cancer pts.

No significant financial relationships to disclose.
Comparison between epidermal growth factor receptor (EGFR) gene in primary non-small cell lung cancer (NSCLC) and in fine needle aspirates from metastatic sites
Authors: Bozzetti C. , Tiseo M. , Lagrasta C. , Nizzoli R. , Leonardi F. , Gasparro D. , Spiritelli E. , Franciosi V. , Rindi G. , Ardizzoni A.
Published: March 2020

21081

Background: Epidermal growth factor receptor (EGFR) gene copy number obtained by fluorescence in situ hybridization (FISH) has been recently proposed to predict which non-small cell lung cancer patients (NSCLC) are expected to benefit from EGFR tyrosine kinase inhibitors. However, it is still unknown whether EGFR status differs in metastases compared to primary NSCLC. In all studies, FISH have been performed on histological material. The possibility to perform FISH analysis on cytological material obtained by fine-needle aspiration from superficial and deep metastases would allow to know the real EGFR status when the metastatic site is not accessible for biopsy. Methods: EGFR gene copy number was analyzed by FISH on fine-needle aspirates (FNAs) obtained from 18 patients with metastatic NSCLC (11 lymphnod, 2 liver, 1 abdomen, 2 skin, 2 pleural effusion) and results were compared with those obtained on corresponding paraffin histological sections from the primary tumor. Results: The feasibility of EGFR-FISH on cytology was 89%; 2/18 samples were not evaluable because of lack of hybridization. EGFR-FISH was positive (= 4 EGFR copy number; Cappuzzo F. et al, JNCI 2005) in 69% (11/16) of the metastases and in 38% (6/16) of the primary tumors. Five of the 16 cases were EGFR positive on both primary tumor and metastatic site and 4 were negative on both primary tumor and metastasis. Seven cases (44%) showed primary tumor vs. metastasis discordance: in 6 cases EGFR was positive in the metastatic site but not in the primary tumor, while in one sample EGFR was positive in the primary tumor but not in the metastasis. Conclusions: EGFR-FISH can be reliably assessed on FNAs obtained from NSCLC metastases. Possible changes in EGFR status during the metastatic progression as well as cancer heterogeneity may account for discrepancies observed between primary tumor and metastatic sites. These findings should be considered in future studies which will be design to better elucidate the predictive role of EGFR-FISH in NSCLC.

No significant financial relationships to disclose.
Relationship between BRCA1 promoter methylation and sensitivity of breast cancer cell lines to cisplatin and paclitaxel
Authors: Collins C. , Huo D. , Xu J. , Bleibel W. K. , Dolan M. E. , Olopade O. I. , Nanda R.
Published: March 2020

21083

Background: While BRCA1 germline mutations are uncommon, and contribute to fewer than 5% of breast cancer cases, epigenetic alterations in BRCA1 occur more frequently. BRCA1 promoter methylation has been detected in 10–30% of breast tumors. Given the role of BRCA1 in DNA repair and cell cycle regulation, we hypothesize that cells with decreased expression of BRCA1 secondary to promoter methylation will be sensitive to DNA damaging agents and resistant to microtubule inhibitors, as has previously been shown for cells deficient in BRCA1 secondary to mutation. Methods: BRCA1 methylation was determined using methylation specific PCR (MSP) as previously described (Wei et al, Cancer Research 2005). The relative sensitivities of BRCA1 methylated, mutated and competent cells to cisplatin and paclitaxel were determined in five representative breast cancer cell lines using the AlamarBlue cytotoxicity assay. Exponentially growing cells were treated with increasing concentrations of cisplatin and paclitaxel for 96 hours. IC50 values and 95% confidence intervals (CI) were calculated from sigmoidal dose response curves fitted with SAS 9.1 Proc NLIN. Western blot analysis for BRCA1 was performed on each cell line. Results: Conclusions: Only one of the two BRCA1 methylated cell lines studied (UACC3199) was sensitive to cisplatin and resistant to paclitaxel, as hypothesized. While both cell lines are methylated, western blot analysis revealed that both express BRCA1, but to a lesser degree than unmethylated cells. BRCA1 methylation, as assessed by non-quantitative MSP, does not correlate with sensitivity to cisplatin and resistance to paclitaxel. Quantification of BRCA1 promoter methylation may better predict chemosensitivity. Identification of the degree of BRCA1 methylation which does correlates with sensitivity to cisplatin and resistance to paclitaxel could improve treatment selection for patients with breast cancer. This work was supported by the US Army Grant W81XWH-04–1-0545.

[Table: see text]

No significant financial relationships to disclose.
Expression of periostin in human breast cancer: Biological and clinico-pathological correlations
Authors: Puglisi F. , Minisini A. , Andreetta C. , Russo S. , Pegolo E. , Pascoletti G. , Mansutti M. , Fasola G. , Damante G. , Di Loreto C.
Published: March 2020

21090

Background: Mesenchyme-specific genes are highly expressed by various types of human cancers. Recent lines of evidence suggest that periostin, a myoepithelial/basal gene, may play a role in the biology of breast cancer. Periostin is involved in metastatic process by taking part in mechanisms of adhesion and migration of epithelial cells. Furthermore, periostin seems to have a role in tumor angiogenesis through the up-regulation of vascular endothelial growth factor receptors in endothelial cells. We aimed at investigating the immunohistochemical expression of periostin in breast cancer and its correlation with established biological and prognostic factors. Methods: We performed immunohistochemical analysis of periostin in a consecutive series of 206 tumor samples from 200 patients with early breast carcinoma. To this aim, we used a specific antiperiostin antibody (Biovendor Laboratory Medicine, Inc., Palackeho 56, 612 00 Brno, Czech Republic). The intensity of immunoreactivity was scored as 0, 1, 2 or 3 denoting negative, weak, moderate and strong staining, respectively. Therefore, for statistical analysis, the periostin expression level for each case was putatively defined as positive if the predominant intensity was =1. We also analyzed immunohistochemical expression of Ki-67 (MIB-1), HER-2/neu, VEGF, VEGFR-1 and VEGFR- 2. Results: Periostin was found to be highly expressed by carcinoma cells, whereas it was absent in normal breast tissues. The pattern of expression was mainly cytoplasmic, although in some cases (11%) a nuclear reactivity was observed. A cytoplasmic expression was found in 108 out of 189 (57%) evaluable cases. Interestingly, a significant correlation was found between periostin expression and VEGF and VEGFR-1 (Spearman's rank test rho =0.37, p <0.0001 and rho=0.26, p=0.0005, respectively). Conclusions: These results strengthen the hypothesis of a relationship between periostin and vascular endothelial growth factor system. The role of periostin in angiogenesis and in other relevant molecular pathways in breast carcinoma deserves to be further investigated.

No significant financial relationships to disclose.
Cancer incidence and mortality in the Caribbean
Authors: Phillips A. A. , Jacobson J. S. , Magai C. , Consedine N. , Horowicz-Mehler N. C. , Neugut A. I.
Published: March 2020

21110

Background: Nearly 10% of immigrants to the United States come from the Caribbean region. In this paper, we analyzed incidence and mortality rates of the major cancers in the Bahamas, Barbados, Cuba, the Dominican Republic, Haiti, Jamaica, Puerto Rico, and Trinidad and Tobago, and compared them with US patterns. Methods: We obtained age-standardized, sex-specific cancer incidence and mortality rates for cancers of the bladder, breast, cervix, esophagus, large bowel, liver, lung, pancreas, prostate, and stomach for eight Caribbean countries and the US from the GLOBOCAN program of the International Agency for Research in Cancer (IARC) and for the US population from the Surveillance, Epidemiology, and End Results (SEER) Program of the NCI. Results: GLOBOCAN incidence and mortality rates for the overall US were lower than but correlated with overall SEER rates. Based on GLOBOCAN data, the incidence and mortality rates of cancers of the breast, prostate, large bowel, and lung, and, among males, bladder cancer were lower in the Caribbean countries than the US. Caribbean countries had higher rates of cancers of the cervix, esophagus, liver, and stomach. Haiti had the highest incidence and mortality rates of cervix and liver cancers. Jamaica and Haiti had the highest rates of stomach cancer. Conclusions: Cancer incidence and mortality in the Caribbean generally follow known patterns of association with economic development, infectious agents, and racial/ethnic origin. Studying these patterns and how immigration changes them may yield clues to cancer etiology. A better understanding of cancer incidence and mortality rates may help health policymakers to implement state-of-the-art treatment and preventive services for people of Caribbean descent both in their native countries and in immigrant communities in the US.

[Table: see text]

No significant financial relationships to disclose.
Receptor for advanced glycation end-products (RAGE) - soluble form (sRAGE) and gene polymorphisms in patients with breast cancer
Authors: Tesarova P. , Kalousova M. , Jachymova M. , Mestek O. , Petruzelka L. , Zima T.
Published: March 2020

21113

Background: Receptor for advanced glycation end products (RAGE) may be involved in the pathogenesis of the cancer progression and metastasis. Pathological effects mediated via RAGE are physiologically inhibited by soluble RAGE (sRAGE), so the higher sRAGE levels may confer the patients with cancer with better outcome.. Our aim was to study sRAGE and RAGE gene polymorphisms in patients with breast cancer. Methods: We studied sRAGE and RAGE polymorphisms in 120 patients with breast cancer (subdivided based on the clinical stage, histologic grading, expression of hormonal and C-erb B2 receptors) and in 92 healthy controls. Results: Despite higher serum concentrations of AGEs, serum concentrations of sRAGE were lower in patients with breast cancer compared to healthy controls (1581 ± 777 vs. 1803 ± 632 ng/ml, p < 0.05). Serum levels of sRAGE were higher in patients with advanced breast cancer (stage III), lower grade and positive estrogen receptors and intermediate positivity of C-erb B2 (Her-neu) receptors and were also influenced genetically (G82S and 2184 AG polymorphisms of the RAGE gene). Conclusions: Decreased sRAGE levels in patients with breast cancer may contribute to the progression of the disease. Patients with better outcome (with low grade and positive estrogen receptors) have higher sRAGE levels. Progression of the disease, may, however, increase sRAGE levels, possibly as a compensatory mechanism to counteract further progression.

No significant financial relationships to disclose.
Obesity at diagnosis increases relapse rate and shortens time to relapse in breast cancer patients
Authors: Hussain S. , Quispe D. , Quispe D. , Herrington C. , Shi R. , Sun A.
Published: March 2020

21123

Objective: Breast cancer is the most common cancer in US women. One in eight women will develop breast cancer in their lifetime. Obesity, one of the 10 leading US health indicators, is associated with breast cancer risk and outcome in various studies. Louisiana is one of the three states with obesity prevalence above 30%. Feist-Weiller Cancer Center (FWCC) in Shreveport serves a large area of Louisiana as far as Baton Rouge. There is a large population of African American patients who are followed in FWCC. The objective of this study is to examine the association of obesity with breast cancer in our patient population. Study Design: A retrospective study from single institution. Medical records of the breast cancer patients in FWCC electronic data management system are reviewed. National Institutes of Health criteria are used to stratify patients: normal or underweight (NW, body mass index or BMI < 25kg/m2, overweight (OW, BMI 25–29.9), and obese (OB, BMI > = 30). Relapse and time to relapsed are compared among three groups. Result: In analysis using multivariant Cox proportional regression model, BMI at diagnosis is a statistical significant predictor of time to relapse. In univariant analysis, increased BMI at diagnosis is associated with 3.3% risk of disease relapse per year. The results demonstrates a positive association of obesity and disease course in breast cancer patients treated at FWCC.

No significant financial relationships to disclose.
Human herpes virus 8 (HHV8): Detection in peripheral blood mononuclear cells (PBMC) from Venezuelan patients with human immunodeficienccy virus-1 (HIV-1) infection with/without Kaposi‘s sarcoma (KS)
Authors: Hernandez-Morales D. E. , Riera J. , Pinto J. , Marin M. E. , Lopez J. L.
Published: March 2020

21124

Background: The nucleic acid of HHV8 is present in the PBMCs of between 50% and 90% of KS patients,7% and 10% of HIV-1 infected patients without KS.We studied the prevalence of HHV8 in PBMCs from venezuelan patients with HIV-1 infection with/without KS. Methods: Seventy-six patients with HIV-1 infection without KS and 15 patients with KS associated with HIV-1 infection were included. Socioepidemiologic characteristics of HIV-1 infected patients were as follows: mean age (36 years, range 19–69 years); 79% of patients were male, 93% were heterosexuals, 9% were treated with antiherpetic drugs and 74% were on HAART; mean T-CD4 count was 362 cel/mm3. Socioepidemiologic characteristics of patients with KS associated with HIV-1 infection were as follows: mean age 39 years (range, 20- 69 years); 93% of patients were male, 87% were homosexuals, 93% belonged to a ‘high risk group‘, 7% were treated with antiherpetic drug and 80% were on HAART; mean T-CD4 count was 86 cel/mm3. PBMCs were isolated on a Fycoll Hypaque gradient and then stored at -70°C until processed. DNA was extracted from the samples by a standard phenol/chloroform extraction procedure.All DNA samples were confirmed to be amplifiable by PCR primers specific for a conserved region of the human beta-globin gen. Positive (DNA from KS biopsy) and negative controls were included. DNA was PCR amplified using the KS1 and KS2 primers specific for the HHV8 ORF 26. PCR reactions were considered positive only if the PCR products hybridized in the expected 233 bp region. Results: None of HIV-1 infected patients showed the presence of HHV8 in the PBMCs, and after a follow-up of two years, none has developed KS. HHV8 was detected in the PBMCs from 20 % of patients with KS. All patients belonged to a ‘high risk group‘, were male and homosexuals. None received blood transfusion. Conclusions: These preliminary data suggest that the prevalence of HHV8 in PBMCs from venezuelan HIV-1 infected patients with/without KS is probably low in comparison with patiens from USA and Europe.

No significant financial relationships to disclose.
Hypoxia-induced p21waf and p27 regulation in c-myc immortalized cells
Authors: Rosati M. , Raimondi C. , Di Seri M.
Published: March 2020

21125

Background: Hypoxia is an adaptative response to tissue damage whose mechanisms have not been yet characterized. From a clinical viewpoint, tumours with more necrosis, an indicator of severe hypoxic stress, are often resistant to conventional treatment. Moreover, numerous tumours overexpressed c-myc which strongly enforces proliferation in oxygen deprived conditions. Evidences showed that c-myc blocked cyclin-dependent kinase inhibitors (CDKI) through a complex network of interactions inducing proliferation and G0-S transition. We examined whether Rat-1 immortalized fibroblasts underwent cell cycle arrest p21waf- and p27- mediated in response to O2-deprivation. Materials and Methods: c-myc null cells (-/-) were derived by gene targeting from an immortalized but otherwise non- transformed Rat-1 fibroblast cell line. Oxygen deprivation conditions (0.2% and 1% O2) were achieved in a humidified anaerobic workstation at 37 °C for 6 or 24 hours. Protein concentration was determined by the Lawry assay method. Immunoblots for c-myc and p21waf and p27 were performed. Results: c-myc (+/+) samples collected after 6 hours of hypoxia, which were supposed to be slowly proliferating, showed lower p21waf and p27 levels than c-myc (-/-). Over 24 hours of hypoxia, cell cultures were supposed to be oxygen-dependent and we found higher CDKI levels in c-myc (+/+) cells. Discussion: Our data could explain same resistance mechanisms of tumours cells. In fact, 6 hours O2-deprived-cells, which are unable to supply autonomous O2 support (neo-angiogenesis, in vivo), downregulated p21waf and p27 expression to overcome CDKI cell-cycle arrest. When the cells acquired O2-dependent growth mechanism, low O2 level induced c-myc mediated p21waf and p27 up-regulation to induce cell cycle arrest. Despite the up-regulation of CDKI, PS 341 (a proteasome inhibitors) has been demonstrated to induce apoptosis. Our data kindly encouraging trials on the use of p21waf and p27 stabilizers (like PS 341) in those tumours which overexpressed c-myc.

No significant financial relationships to disclose.
Breast cancer care in Latin America and the Caribbean (LAC)
Authors: Cazap E. L. , Buzaid A. , Chacon R. , Garbino C. , de la Garza J. , Guercovich A. , Mickiewicz E. , Orlandi F. , Schwartsmann G. , Vallejos C.
Published: March 2020

21140

Background: This study was designed to evaluate breast cancer care (BCC) in LAC trough a survey of 65 questions. Methods: We surveyed 96 opinion leaders (OL) from 12 countries that were first contacted by a researcher explaining the project and methodology. A phone interview was done by a specialist in epidemiology surveys. Answers were analyzed by center or country with Intercooled State 8 software (State Corp.) Results: 92 % OL confirm that there is no country law or guidelines making mandatory mammographyc screening. Nearly 75% of the OL stated that some type of cancer registry was available. The first consultation is done by gynecologists or breast cancer surgeons (83%), clinicians (13%) and surgeons (4%).Time lapsed from consultation until pathologic diagnosis was less than 3 months in 62% (country) and 91% (centers). Accessibility for hormone receptor and molecular markers is very good in specialized centers: 90% and 83% respectively but it is only available to 52% and 5% of country patients. Conservative surgery is widely accepted (87%) and 71% OL are able to perform sentinel node biopsies (centers). Systemic treatment is mainly based in Anthracyclines and Tamoxifen. The treatment coverage at centers is through medical insurance companies (53%), government (28%) and patient (19%) while 67% of country patients are government covered. Radiation treatment is mainly indicated by oncologists and 62% consider that radiotherapy centers in their countries are insufficient. There is adequate availability of morphine for 93% (centers) and 82% (countries).The choice of the chemotherapy or hormonal adjuvant treatment is free for 74% of those surveyed at their centers and in 23% is pre-established by the coverage. Majority of opinions are that all types of research are deficient. It is mainly organized in public institutions and sponsored by pharmaceutical companies (76%). Full results will be presented. Conclusions: We obtained data about the reality of BCC in the region. There is a general lack of prevention plans. Time to diagnosis and first treatment is similar to developed countries. Treatment according to stage is similar to international standards. Radiotherapy availability is poor. Based on this data a strategic plan for BCC in LAC will be developed. Supported by a grant from The Breast Cancer Research Foundation

No significant financial relationships to disclose.
Characteristics of a high-risk minority population
Authors: Jooma N. , Elledge R. , Sexton K. , Kalidas M. , Rimawi M. , Osborne C. , Chang J.
Published: March 2020

21141

Background: Black and Hispanic breast cancer patients have a worse outcome when compared to Caucasians. This could be due to socioeconomic, cultural or biologic factors. We hypothesized that host and tumor biologic characteristics associated with a poor outcome may be found more often in minority women. Methods: Race/ethnicity, menopausal status, tumor histological features, and patient characteristics including age and body mass index (BMI) were reviewed from a prospective neoadjuvant trial of docetaxel vs. doxorubicin/cyclophosphamide at Baylor College of Medicine Breast Center, from September 2002 to September 2006. The data were analyzed using Chi-square and Fisher's exact tests, while the Kruskal-Wallis method was used to analyze BMI. Results: Of the 167 patients, 63% (n=105) were Caucasian, 15% (n=26) were Hispanic and 22% (n=36) were Black. The mean age was 47.6 years (range: 30–72). Fifty-nine percent were premenopausal. Overall, mean BMI was 29, with Caucasians having a mean BMI of 27.5, Hispanics with 29.8 and Blacks with a BMI of 34.6 (P<0.001). Sixty-five percent of the Caucasians and 58% of Hispanics were ER+ or PR+ versus 44% of Blacks (P=0.09). Sixteen percent of Caucasians were HER-2 positive compared to 4% of Hispanics and 9% of Blacks (p=0.25). In addition, 22% of Caucasians and 38% of Hispanics were ER-, PR-, HER-2- compared to 50% of tumors from Blacks (p=0.007). There was a trend linking BMI and triple negative status in breast cancers, which did not achieve statistical significance (p=0.21). Conclusion: In this study we found that black and Hispanic women were more likely to be obese and have ER-, PR-, HER-2- tumor phenotypes, both of which have been associated with poorer outcomes. Ongoing studies are being performed to elucidate the link between clinical and biological characteristics and understand the underlying molecular mechanisms associated with these findings.

No significant financial relationships to disclose.
13-cis-retinoic acid (CRA) and interferon-alpha (IFN) combination with or without radiation has a greater in vitro biological effect in reducing bcl-2 expression and inducing apoptosis in prostate cancer cells (LNCaP) than in normal human colorectal (Co-18) and normal human lung fibrolast (IMR-91) cells: Rationale for a clinical trial
Authors: Kumar P. , Hill C.
Published: March 2020

21157

Background: Over expression of bcl-2 is a major cause of radioresistance and recurrence in prostate cancer patients treated with RT. In order to determine whether CRA/IFN could down-regulate bcl-2 expression, induce apoptosis and reduce radioresistance, we conducted several experiments in LNCaP (which naturally express bcl-2), Co-18 (to mimic radiation effects on rectum) and IMR-91 (to confirm findings in Co-18 cells) cell lines to determine any differential selectivity by CRA/IFN with or without radiation. Methods: LNCaP, Co-18 and IMR-91 cells were treated with CRA (200 nmolar) and IFN (1000 U/ml) for 48 hours to determine bcl-2 expression and apoptosis at various time points (0, 6, 12, 24 & 48 hours) post-drug removal. For determining bcl-2 expression, cells were suspended in trypsin, centrifuged, washed with PBS, pelleted, and sonicated with RIPA buffer and re-centrifuged followed by Western blot analysis. For determining apoptosis, cells were washed and fixed in paraformaldehyde, and stained with Roche Chemical fluorescent apoptosis kit. The number of fluorescing cells vs. total number of cells were then counted in 3 wells using 3 microscope fields per well to determine percent of apoptosis. LNCaP, Co-18 and IMR-91 cells were also treated with radiation (400 cGy) after 48 hours of CRA/IFN exposure to measure bcl-2 expression and apoptosis. Results: In LNCaP cells, CRA/IFN significantly reduced bcl-2 expression with a maximum increase in apoptosis (70%) at 48 hours. In Co-18 and IMR-91 cells, CRA/IFN marginally decreased bcl-2 expression with no induction of apoptosis. Following CRA/IFN exposure and radiation, apoptosis was measured to be at least 90%, 22% and 0% at 48 hours in LNCaP, Co-18 and IMR-91 cells, respectively. Conclusions: CRA/IFN with or without radiation selectively reduces bcl-2 expression and induces apoptosis in LNCaP cells as compared to Co-18 and IMR-91 cells. Our findings provide a therapeutic rationale for clinically evaluating CRA/IFN with RT in patients with high risk prostate cancer.

No significant financial relationships to disclose.
Breast cancer experience in Uruguay: A 21-year follow up of 1,906 patients in the same institution
Authors: Krygier G. D. , Barrios E. , Cataldi S. , Vazquez A. , Alonso R. , Estellano F. , Folle E. , Laviña R. , Delgado F. , Pressa C. , Vazquez T.
Published: March 2020

21163

Background: Breast cancer is the most common tumor arising in Uruguaian women accounting for 1,930 patients/year (adjusted incidence ratio 83.1/100,000) with 637 death/year (adjusted mortality ratio 24.1/100,000). Both incidence and mortality rank Uruguay at the top of the latinamerican countries ( IARC-GloboCan 2002). We are presenting our final results with 1,906 patients followed during a 21 year period in the biggest private Institution in our country (CENDIMA) and probably amongst all other latin-american countries. Methods: Although this study was initially designed to find a relationship between prognostic factors and survival parameters: OS (overall survival) and DFS (disease free survival) it also describes the epidemiological features of a big breast cancer population in the top ranked country for breast cancer incidence and mortality in Latin America. Statistical analysis was calculated with SPSS (11.0 version) and SAS (6.0 version) programs. OS and DFS results were obtained through Kaplan Meier method. Log rank test was implemented for univariate analysis and Cox proportional hazard rates were used for multivariate analysis. Results: The median age at diagnosis was 61.0 (SD 13.5). Ductal infiltrating carcinoma (DIC) accounted for more than 80% of patients and 56% were node negative (N0) patients at diagnosis. Stratification was: Stage 0: 8.6%, Stage I: 31.5%, Stage II: 41.8%, Stage III: 16.6%, Stage IV: 1.5%. For OS, the axillary status and hystologic grade showed the highest relative ratio (RR) value: 2.49 and 2.40. The nodal status was the main prognostic factor related to DFS with a 2.2 RR. The five and ten year survival rate was: 0.96 and 0.92 (stage I), 0.84 and 0.71 (stage II), 0.71 and 0.56 (stage III) and 0.39 and 0.29 (stage IV) respectively. Conclusions: This is the final analysis of our population in Uruguay representing the biggest report in breast pathology in a latin-american country with a long follow up period (more than 20 years). Our “good” survival results may reflect the initially low risk population at diagnosis (56% node negative, 40.1% stage 0-I ). Nodal status, histologic grade and staging at diagnosis were independent prognostic factors in univariate and multivariate analysis.

No significant financial relationships to disclose.
Evaluation of the feasibility of expression microarray analysis in endoscopically obtained biopsies of gastric carcinoma and their clinical applicability
Authors: Jhawer M. P. , Qin L. , Gerdes H. , Klimstra D. , Schattner M. , Viale A. , Gonen M. , Schwartz G. , Kelsen D. , Shah M.
Published: March 2020

21164

Background: The feasibility of extracting high quality RNA for expression microarray analysis from endoscopic biopsy in gastric carcinoma has not been previously established. Methods: Patients with histologically confirmed locally advanced gastric or gastroesophageal junction adenocarcinoma were screened for enrollment in an NCI-sponsored trial of neoadjuvant irinotecan and cisplatin chemotherapy (NC1–5917). All patients underwent a repeat endoscopic biopsy for the procurement of fresh tumor tissue. Gross microdissection was performed to enrich the sample to at least 80% malignancy. RNA was isolated from the tumor specimens using RNeasy columns (Qiagen) and its quality verified by RNA 6000 NanoAssay and Bioanalyzer 2100 (Agilent). Gene expression profiling was performed on Human Genome U133A GeneChip (Affymetrix) which contained 22,215 oligonucleotide-base probe-sets. Differential gene expression profiles for Lauren's classification were assessed using empirical Bayes t test, a threshold p < 0.001 was considered statistically significant. Results: Of 36 patients with previous biopsy confirmed gastric cancer, repeat endoscopic biopsy identified carcinoma in 28 patients (78%, 95%CI 61–90%). Adequate RNA for microarray analysis was obtained from 21 patients-representing 58% of those who presented for the procedure and 75% in whom endoscopic biopsies confirmed malignancy. This yield improved with increasing number of samples taken. Lauren's classification was available on 26 patients who underwent resection. From the total 54,613 gene probe-sets on the arrays, comparison of the expression profiles of diffuse-type and intestinal-type identified 167 genes that were differentially expressed. Diffuse gastric cancer demonstrated altered expression of genes related to cell-matrix interaction whereas intestinal gastric cancer expression analysis showed enhancement of cell growth. Conclusions: Endoscopic biopsy for expression analysis of gastric cancer is feasible with increasing yield with each core taken. Expression analysis at the time of endoscopic biopsy can differentiate Lauren's histology, a characteristic not routinely evaluable by pathologic review.

No significant financial relationships to disclose.
Down-regulation of bbc3, flt1 and gstm3 is associated with lymph node metastases in breast carcinoma
Authors: Saavedra Villarroel E. , Gutierrez J. , Risueño C. , Gonzalez P. , Solis L. , Corvalan A.
Published: March 2020

21171

Background: Background: Axillary lymph node metastasis is the most significant marker for the pathologic staging of breast cancer. However a proportion of lymph node-negative breast cancer will develop metastatic disease. Therefore, molecular markers of invasion in these patients are needed Methods: We selected 10 primary breast cancer cases, 5 lymph node-negative (T1N0) and 4 lymph node-positive (T1N1). In these cases we searched for gene expression of 8 genes (bbc3, cegp1, fgf18, flt1, cffm4, gstm3, hec, tgfb3) selected from previous studies as a good candidates for metastasis prediction. A quantitative Real-Time PCR was performed using beta-2- microglobulin gene expression to normalized gene expression of each gene. The expression average of beta-2-microglobulin was 303,291 among T1N0 and 342,533 among T1N1 cases (ratio 0.88). The expression average of these 8 genes was 2.11 and 0.002 at T1N0 and T1N1 respectively (ratio 1,055). At least 3 genes were significantly down-regulated in T1N1 (bbc3, flt1, gstm3) in comparison with T1N1 breast carcinomas Results: Computational analysis reveals that these 3 genes (bbc3, flt1, gstm3) contain CpG islands in their promoter regions. Although preliminary data, we found group of genes that are down-regulated in T1N1 tumor Conclusions: The finding that these genes are epigenetically regulated, suggest that could be a good candidates for metastasis prediction, by methylation approach (MethyLight System). Since this down-regulation occurs in primary tumor, the analysis of these genes might be useful to predict metastasis in lymph node-negative breast cancer.

No significant financial relationships to disclose.
A new variant of the heat shock protein GRP78 as target for antibody- treatment of pancreatic cancer
Authors: Vollmers H. , Rauschert N. , Rasche L. , Hensel F. , Brändlein S.
Published: March 2020

21173

Background: Pancreatic malignancies belong to the top-five killers among all cancers worldwide. The 5-year survival rate with conventional therapy is below 5%. This shows that there is a big need for new therapeutical approaches. The fully human monoclonal antibody SAM-6 is a germ-line coded IgM, isolated from a cancer patient by TRIOMA technology. SAM-6 antibody binds to a modified O-linked carbohydrate moiety expressed on a membrane-bound variant of GRP78, which is a member of the HSP70 family. Heat-shock proteins (HSPs) are critical components of a cell's defense mechanism against injury associated with adverse stresses. They can protect cells against subsequent, otherwise lethal, outcome. Although HSPs are very beneficial to the normal cell, cancer cells often over-express HSPs on the membrane. They use them in response to stresses associated with various therapies, diminishing the treatment effects. Methods: In vitro and in vivo assays were used to investigate the apoptotic effects of antibody SAM-6 on pancreas cancer cells. Results: Binding of SAM-6 antibody to GRP78 induces an overfeeding of malignant cells with oxidized LDL. The cancer cells over-accumulate depots of cholesterol and triglyceride esters and finally undergo apoptosis. The deadly effect of SAM-6 could be demonstrated in vitro and in vivo in experimental animal models. Conclusions: These data show that cancer-specific modifications of cell surface protection molecules are ideal targets for immuno-therapeutical approaches.

No significant financial relationships to disclose.
Hospital discharge analysis of oncology patients from thirteen acute general hospitals which belong to the City of Buenos Aires Government (CBAG)
Authors: Koliren L. , Otero S. , Bianconi M. , Rossi M. , O'Leary K. , Mendoza Padilla J. , Jankilevich G.
Published: March 2020

21183

Background: Statistical report which considers the discharge of oncology patients from thirteen acute general Hospitals from the CBAG in order to determine how to allocate founds and propose epidemilogy, preventive and/or therapeutics trials. Methods: Review of the information given by the HSD of the CBAG Ministry.The variables taken into account were: type of cancer (CIE-10-OMS), sex, age and area of residency. Results: During 2005, in the 13 acute care hospitals of CBAG there were 132,431 disc; among these 6,896 were oncology patients (5%). From the total number of hospital beds used that year (1,074,495), 90,352 were oncology patients (9%). The malignant tumor diagnosis were; Gynecologic 23% (cervix 689 + in situ 134, ovarian 479, uterine 120 and other 188); digestive 15% (colorectal 529, pancreatic 149, stomach 134, esophagus 188 and others 34); hematologic 15% (lymphomas 500, leukemias 410, myelomas 77 and others 46); breast 12% (849); lung 10% (681); urologic 9% (bladder 228, prostate 187, kidney 115, testicle 43 and others 22); miscellaneus 15% (1,065). Sex: Female (F) discharges were 4,158 and male (M) 2,738; the relationshionship F/M was 1.5/1. The group mean age was 56.1± 16.6 years. Area of residence: 53% belonged to the City of Buenos Aires and 40 % to suburban areas. Conclusions: The diagnosis of the pathologies found could help determine epidemiology and therapeutic trials. Hospitalizacions due to cancers that can be ‘prevented by screening‘, such as breast, cervical and colon cancer, support the need to redefine prevention campaigns.

No significant financial relationships to disclose.
Multi-institutional phase I trials involve more patients and longer accrual time compared to single institution trials
Authors: Dowlati A. , Manda S. , Patrick L. , Remick S. , Gibbons J. , Fu P.
Published: March 2020

2500

Background: There has been a suggested increase in the number of multi-institutional phase I trials over the past decade. Methods: We reviewed all published phase I studies between 1/98 and 12/05 from the Journal of Clinical Oncology and Clinical Cancer Research. 452 phase I studies were identified. The following data were obtained from each study: sponsor (NIH/foreign equivalent vs. pharma), year published, number of participating institutions, mechanism of drug action (8 categories; most common are cytotoxic and targeted therapies), country, number of patients accrued, accrual time and study endpoint (maximum tolerated dose-MTD vs. optimal biological dose- OBD). Results: 55% of phase I trials were single institutional and 21% accrued patients from = 3 institutions. There was no increase over time in the number of multi-institutional studies and no significant association was seen between sponsor and number of institutions. No association was seen between mechanism of drug action and number of participating institutions. There was a highly significant association between number of institutions and number of patients enrolled with multi-institutional studies having higher number of patients per trial (p=0.0003). Pharmaceutical sponsored studies are associated with a greater number of patients per trial (mean 32.8±0.9) as compared to government sponsored (28.4±1) (p<0.05). Only 34% of trials report accrual time. Accrual time is increased in multi-institutional studies (= 3 centers) as compared to single institutional studies (mean 25 vs 22.5 mos) but does not reach statistical significance (p=0.613). No correlation was seen between endpoint of the phase I trial (MTD vs OBD) and number of institutions. OBD studies were strongly associated with agents defined as “targeted”. Studies of cytotoxic agents defined the MTD in 99% of trials versus only 64% of agents categorized as targeted therapies (p<0.0001). Conclusions: Although there has been no increase in the number of published multi-institutional phase I studies, these multi- institutional trials accrue more patients only to reach the same study endpoint but at a cost of greater accrual time. The clinical value of multi- institutional phase I studies is not apparent. Supported by K23 CA109348–01

No significant financial relationships to disclose.