bluuebunny/crossref_metadata_2025 huggingface dataset:
Correlation between the expression of hypoxia-inducible factor-1α or histone deacetylase 1/metastasis-associated protein 1 complex and poor prognosis on human pancreatic carcinoma
Authors: Miyake K. , Shimada M. , Imura S. , Sugimoto K. , Batmunkh E. , Ikemoto T. , Morine Y. , Yoshizumi T.
Published: March 2020

21012

Background: Hypoxia-inducible factor-1a (HIF-1a) is a transcription factor that plays an important role in tumor growth and metastasis by regulating energy metabolism and inducing angiogenesis. Inhibition of histone deacetylase shows a marked inhibition of HIF-1a expression, however, the association between HIF-1a and histone deacetylase 1 (HDAC1) / metastasis-associated protein 1 (MTA1) is not fully understood. Here, we explored the involvement of HIF-1a and HDAC1/MTA1 in human pancreatic carcinoma. Methods: HIF-1a, HDAC1 and MTA1 expressions were detected by immunohistochemistry in surgical specimens obtained from 39 patients with pancreatic carcinoma. The correlations between the expression of HIF-1a, HDAC1 or MTA1 and clinical features, and the prognosis of patients with pancreatic carcinoma were then analyzed. Results: HIF-1a, HDAC1 and MTA1 positive stainings were found in 16 of 39 cases (41%), 22 of 39 cases (56%) and 12 of 39 cases (31%), respectively. There was no correlation between HIF-1a, HDAC1 or MTA1 expression levels and any of the clinical parameters examined. The five-year survival rate for pancreatic carcinoma patients with HIF-1a and HDAC1 positive stainings were significantly lower than for those patients with HIF-1a and HDAC1 negative stainings (P = 0.0243 and 0.0433). The MTA1 positive stainings group did not have a significantly worse prognosis than the MTA1 negative stainings group (P = 0.9694). In addition, the five-year survival rate for the HDAC1/MTA1 positive stainings group was statistically significantly worse than for the other groups (P = 0.0386). Conclusions: These results suggest that HIF-1a expression may be regulated through HDAC1/MTA1, which is associated with a poor prognosis on human pancreatic carcinoma, and indicate that HIF-1a and HDAC1/MTA1 is a promising therapeutic target in pancreatic carcinoma treatment.

No significant financial relationships to disclose.
Plasma DNA: A molecular marker for the pattern of dissemination of esophageal cancer
Authors: Banki F. , Hagen J. A. , Mason R. J. , DeMeester S. R. , Oh D. , Yacoub W. N. , Danenberg P. V. , DeMeester T. R.
Published: March 2020

21015

Background: We previously showed that free DNA is present in blood of normal subjects and that the plasma DNA level is higher in patients with esophageal cancer compared to normal subjects. These observations suggest that the plasma DNA level may be a useful molecular marker in the diagnosis of esophageal cancer. We hypothesize that lymphatic and hematogenous spread may result in different plasma DNA levels despite both representing advanced disease. Our aim was to measure and compare plasma DNA levels in normal subjects, patients with localized esophageal cancer, patients with lymph node metastases, and patients with hematogenous spread to solid organs (systemic metastases). Methods: Plasma DNA was measured using PCR in 44 normal subjects, 25 patients with localized esophageal cancer (T1–3, N0, M0), 18 patients with lymph node metastases, and 7 patients with systemic metastases. Results: The 95th percentile of plasma DNA level in normal subjects was 19 ng/ml. The median plasma DNA levels were higher in all 3 groups of patients with esophageal cancer compared to control subjects. While there was no difference between the plasma DNA level in patients with localized esophageal cancer and those with lymph node metastases (median of 5 nodes involved, range: 1–31), patients with systemic metastases had a significantly higher level of plasma DNA compared to patients with lymph node metastases and those with localized esophageal cancer. Conclusion: Plasma DNA levels are elevated in patients with esophageal cancer, whether localized or associated with lymph node metastases. In patients with systemic metastases, a significant additional increase in the plasma DNA level occurs. This suggests that measuring the plasma DNA level is a useful molecular diagnostic tool for detection of disseminated esophageal cancer.

[Table: see text]

No significant financial relationships to disclose.
The use of CA15.3 in breast cancer: A single institution experience
Authors: Sheikh R. , Behbehani A. T. , Peader M. , McCaffrey J.
Published: March 2020

21017

Background: Breast cancer is a significant cause of morbidity and mortality worldwide. Recent advanced its treatment are promising. Gathering prognostic information may optimise treatment delivery. In addition to clinical parameters, the use of tumour markers may aid this process. CA 15.3, is a transmembrane glycoprotein.. Its clinical application varies from detecting disease recurrence in asymptomatic patients, assessing response in metastatic setting and monitoring the clinical course of the disease. Methods: A retrospective analysis was conducted evaluating medical record data of all the patients treated for breast cancer in our institution between 1999- 2005. CA15.3 was carried out using Roche 2010 (Elecsys system). Results: A total of 176 patients were identified. Table (1) Group A, one hundred patients remained disease free at follows up (58%). 95 patients had their CA15.3 within normal range, a diagnostic specificity of 95%. Group B, 61 patients developed metastatic/recurrent disease at follow up. 39 patients (64%) developed metastatic disease later. Group C, 15 patients had metastatic disease at diagnosis. We found that CA15.3 has a sensitivity value of 64% and a specificity of 95% in our institution.. This correlates well with ASCO review 67% and 92% respectively. In patients with no evidence of metastatic disease at diagnosis, a postive CA15.3 during follow up is strongly suggestive of disease recurrence. Giving a positive predictive value of 89%. In Two patients (5%) CA15.3 was the first predictor of recurrence. Radiology was the first indicator of recurrence in six cases (15%), while both radiological and serological correlation was noted in 31 patients (80%). Conclusions: We found CA15.3 a reliable marker in assessing response for therapy. In clinical practice, raised CA15.3 can be incorporated in decision making to change current chemotherapeutic regimen whenever there is a delay in obtaining prompt radiological evaluation.

[Table: see text]

No significant financial relationships to disclose.
Qualitative age interactions (or effect modification) suggest divergent pathways for early-onset and late-onset breast cancers
Authors: Anderson W. F. , Brinton L. A. , Chen B. , Devesa S. S.
Published: March 2020

21036

Background: Notwithstanding some recent declines, breast cancer incidence rates have risen for decades, though not equally for all age groups. We used the National Cancer Institute's SEER program to further explore the effect of aging upon breast cancer incidence. Materials and Methods: The SEER program collected data on n=494,543 in-situ + invasive female breast cancer cases, newly diagnosed during 1974–2003. Temporal trends by race, stage, and grade were stratified by age at diagnosis in decades: 20–29 to 80+ years. Results: We observed age interactions over time. For example, as the specification of grade improved from 1974–2003, temporal trends for high and low grade tumors varied with age. Among women ages <40 years, high grade lesions were more common than low grade tumors for all time periods. Among women ages 40+ years, high grade lesions were more common during the early years, and then rates crossed, after which low-grade tumors were more common than high grade lesions. Conclusion: Age at diagnosis was both a quantitative (non- crossover) and qualitative (crossover) effect modifier. The crossing of rates from high to low grade tumors among women ages 40+ years in the 1980s is consistent with more aggressive breast cancer screening, with mammography preferentially detecting low grade tumors among women targeted for screening, i.e., ages 40–80 years. Though once thought to be rare or artifactual, qualitative interactions or effect modification suggest etiologic heterogeneity in an otherwise homogeneous disease process. Indeed, if true, qualitative age interactions imply divergent pathways for early-onset and late-onset breast cancers.

No significant financial relationships to disclose.
Women with Her2 unamplified but chromosome 17 hyperploid metatstatic breast cancer (MBC) respond to traztuzumab
Authors: Brufsky A. , Chow S. , Kapoor A. , Bhargava R. , Surti U. , Rosenzweig M.
Published: March 2020

21051

Background: Guidelines for the interpretation of Her2 testing by FISH in determining therapy for Her2 positive metatstatic breast cancer generally suggest that only women with Her2 to chromosome 17 (CEP 17) amplification ratios of greater than 2.0 will benefit from traztuzumab. However, hyperploidy of chromosome 17 may lead to increased Her2 copy number despite a normal HER2/CEP 17 ratio, which may also predict response. We sought to examine hyperploid frequency in a well defined Her2 positive MBC population. We also sought to determine the time to progression (TTP) on first chemotherapy for MBC in such women, as well as their overall survival (OS) with MBC. Methods: A tissue mircoarray (TMA) with 3-fold redundancy was constructed using 0.6mm cores from primary or metatstatic paraffin embedded tumor from 124 cases which were Her2 2+ or 3+ by IHC, or amplified by FISH, on pathology report. Four micron thick TMA sections were used for HER2 IHC and HER2 FISH analysis. HER2/CEP 17 ratios of 2.0 or more was considered as amplification. If the tumor was 2+ or 3+ by IHC, greater than or equal to 3 signals for chromosome 17 were seen in a majority of cell nuclei, and the HER2/CEP17 ratio was less than 2.0, the tumor was considered hyperploid Her2 FISH negative. Results: Tissue blocks from 52 tumors delivered clearly interpretable amplification for Her2 by FISH. An additional 10 tumors (8%) were hyperploid, IHC positive (2+ or 3+), and FISH negative. Median survival (Kaplan-Meier) was 39 months (95% CI, 21–62) for women with hyperploid FISH negative tumors and 41 months (95% CI, 25–53) for women with FISH positive tumors (p=0.63, NS, Wilcoxon). Median time to progression (Kaplan-Meier) on first therapy for metastatic disease was 14 months (95% CI, 8–20) for hyperploid FISH negative tumors and 15 months (95% CI, 12–18) for women with FISH positive tumors (p=0.41, NS, Wilcoxon). Conclusions: In this analysis, women with hyperploid Her2 FISH negative IHC positive tumors had similar TTP and OS as women with Her2 FISH positive tumors. These women, although Her2 FISH negative, appeared to respond well to traztuzumab. These provocative results should be repeated on larger data sets.

No significant financial relationships to disclose.
A novel rapid genetic diagnosis for peritoneal recurrence in gastrointestinal cancer patients
Authors: Iinuma H. , Okinaga K. , Watanabe T. , Fukushima R. , Inaba T. , Mimura T. , Matsuda K. , Ohnaka S. , Hayashi T.
Published: March 2020

21052

Background: The prediction of peritoneal recurrence in gastrointestinal cancer patients is extremely important in order to prevent an unfavorable prognosis. The aim of our study was to evaluate the usefulness of a novel rapid RNA amplification system with transcription-reverse transcription concerted reaction (TRC) to detect isolated tumor cells in peritoneal washes of gastrointestinal cancer patients as an intra-operative genetic predictor of peritoneal recurrence. To clarify the characteristic qualities of TRC, we compared the results with those of one-step real-time RT-PCR. Methods: A total of 325 cytology-negative gastrointestinal cancer patients (164 gastric cancer, 161 colorectal cancer) were included. This study was approved by the institutional review board of our hospital and all patients provided written informed consent. Peritoneal washes of Douglas cavity were collected from patients. One-half of each wash was used for cytopathology and the other half was used for molecular diagnosis. Total RNA was extracted from cells which were separated from washes, and TRC and one-step real-time RT-PCR of multiple marker genes (CEA, CK20 mRNA) were performed using a TRCRapid-160 and LightCycler, respectively. Results: The rapidity and simplicity of the TRC is superior to that of one-step real-time RT-PCR. The detection time of marker genes by TRC was only 20 minutes as compared to 70 minutes of real-time RT-PCR. The sensitivity and reproducibility of the TRC were equal to those of real-time RT-PCR. Molecular detection of CEA and/or CK20 transcripts of the peritoneal washes by TRC showed a significant correlation to the depth of invasion, venous invasion, lymph node invasion, lymph node metastasis, peritoneal metastasis and stage. The peritoneal recurrence- free and overall survival rates of CEA and/or CK20 transcript-positive patients were significantly shorter than those of marker gene-negative patients. CEA and/or CK20 transcripts in peritoneal washes were independent prognostic factors of peritoneal recurrence-free survival and overall survival. Conclusion: TRC may be more useful than real-time RT-PCR due to its rapidity and simplicity for the intra-operative genetic diagnosis of peritoneal recurrence in patients with gastric and colorectal cancer.

No significant financial relationships to disclose.
Suppression of thymidine phosphorylase expression by promoter methylation
Authors: Blanquicett C. , Guarcello V. , Naguib F. , el Kouni M.
Published: March 2020

21100

Background: Thymidine phosphorylase (TP), an important enzyme in the pyrimidine salvage pathway, is also responsible for the activation of capecitabine (CAPE), a 5-FU prodrug. TP expression has been associated with response to CAPE. The regulatory mechanisms of TP expression in human tumor cells remain unclear. Since promoter methylation of CpG sites is a known mechanism of reversible silencing of gene expression, we investigated whether TP promoter methylation is involved in the regulation of TP expression. Methods: TP mRNA levels were determined in 5 cancer cells (SKBR-3, 786-O, HT-29, MDA-231, DLD-1) by Real- Time Quantitative PCR (RT-Q-PCR).The degree of methylation in these cells was identified by examining methylated CpG sites with restriction PCR and bisulfite sequencing. To analyze the TP promoter region, two fragments were PCR amplified from genomic DNA. Minimal promoter activity was determined by Luciferase reporter assays, and DNA-protein interactions were evaluated by Electrophoretic Mobility Shift Assays (EMSA). Results: SKBR-3 cells showed high TP expression, while DLD-1 cells did not express TP, as confirmed by examination of TP mRNA, protein, and enzyme activity. 786-O, HT29, and MDA-231 cells demonstrated intermediate TP expression. Methylation in the promoter, intron 1 and exon1 regions of the TP gene in SKBR-3 was lacking, while in DLD-1 cells, extensive promoter methylation was observed. Treatment of DLD-1 and SKBR-3 cells with the methylation-inhibitor, 5-aza-2-dC, resulted in a concentration-dependent increase in TP mRNA as well as protein levels in DLD-1 but not SKBR-3 cells. Trichostatin-A (TSA), a histone deacetylase inhibitor, improved the 5-aza-2dC induced TP reactivation. Gel shift assays demonstrated that methylation of the TP promoter significantly inhibited transcription factor binding. Supershift Analyses suggest that the Sp1 transcription factor has a role in the regulation of TP expression and to a lesser degree, so does Sp3. Conclusions: These results establish methylation of site-specific CpG in the TP promoter to be a putative mechanism of down-regulated TP expression in cancer cells. Insight into the TP regulatory mechanisms may have implications in CAPE therapy optimization and in modulating prognosis of cancer patients treated with CAPE.

No significant financial relationships to disclose.
Evaluation of clinical significance of basal-like subtype of breast cancer identified by immunohistochemistry
Authors: Cassol L. B. , Graudenz M. , Zelmanowicz A. , Cancela A. , Coral C. , Yser G. , Garicochea B.
Published: March 2020

21107

Background: At present time, prognostic evaluation of initial breast cancer is mostly based on patients’ clinical and tumoral histological features. Recently, molecular subtypes of invasive breast cancer were recognized through DNA microarray profiling studies. This new classification can potentially improve the prognostic evaluation but this technology is still not widely available. The possibility of identifying the molecular subtypes through simpler and cheaper methods is promising. The identification of basal-like breast cancer (BLBC) is particularly important because it has a poor outcome and fewer treatment options available. Additionally, Epidermal Growth Factor Receptor (EGFR) expression seems to be more frequent in this subtype. Methods: A retrospective cohort of 112 consecutive patients with pathologic stage I or II primary breast carcinomas, treated in the same institution between 1995 and 2000, was studied. Histological and clinical features as well as clinical outcome and survival were reviewed. Immunohistochemical analysis was carried out in representative blocks of tumors with antibodies against Estrogen Receptor (ER), Human Epidermal Growth Receptor - type 2 (HER2), CK5/6 and EGFR. The primary endpoint was to determine the prevalence of BLBC (ER and HER2-negative and CK 5/6 and/or EGFR-positive) in this population. Results: 13 of 112 tumors (11,6 %) were BLBC. Their mean age was 49 years; 77 % were stage II and 100 % were invasive ductal carcinomas. There was no prognostic difference between BLBC and the subtypes luminal (ER-positive and HER2-negative); HER2-overexpressing (HER2-positive) and undetermined (four markers negative) relating to disease-free and overall survival. This is probably related to limited number of patients in this study and good prognosis of initial-stage patients. 11 of 112 cases (10%) were positive for EGFR. EGFR-positive tumors tended to be ER- negative (23 % vs 5 %; p=0,01). Conclusions: Our results suggest that it is possible to identify BLBC by immunohistochemical analysis of ER, HER2, CK 5/6 and EGFR. Besides, EGFR expression seems to be more frequent in ER-negative tumors, which suggest EGFR-targeted drugs may benefit this population.

No significant financial relationships to disclose.
Employing a blood based gene expression signature to detect early stage breast cancer
Authors: Tobin D. , Lindahl T. , Hagen N. , Bårdsen K. , Jensen M. , Sharma P. , Lönneborg A. , Børresen-Dale A. , Aarøe2 J. , Sæbø S. , Skåne P.
Published: March 2020

21117

Background: Existing methods to detect breast cancer (BC) in asymptomatic patients have limitations, and there is a need to develop more accurate and convenient methods. We recently demonstrated the potential use of gene expression profiling in peripheral blood cells (PBC) for early detection of BC (1) and repeated this with a larger study using the Agilent platform with an accuracy of 75± 7%. Objective: 2 studies are presented that investigate: i) whether effective normalization of experimental conditions can improve diagnostic accuracy, ii) whether a blood based signature developed for BC can discriminate other forms of cancer, and iii) whether an expression signature developed using stage 0 patients can be used to predict BC in stage I disease, and vice versa. Material and Methods: Study I enrolled 60 females with BC and 60 healthy females. Study II enrolled 20 females with early stage BC (10 stage 0 and 10 stage I), 20 healthy females, and 8 females with colon cancer. Gene expression analysis was conducted using the ABI HGSM v2.0 with 32,878 oligo probes. Expression data were analyzed by PLSR for model building and results validated using cross-validation and test set validation. Results: Effective normalization of the data led to improved diagnostic performance. The signature developed using 20 BC and 20 non-BC samples classified 7/8 colon cancer patients as non-BC. The signature developed using stage 0 vs non-BC detected cancer in stage I patients, and the signature developed for stage 1 detected cancer in stage 0 patients. Conclusion: A blood-based gene expression signature can be developed for early stage breast cancer, which is specific and able to distinguish between other forms of malignancy such as colon cancer. The gene expression pattern is systemically affected in early stage BC patients in which there is typically no direct contact of blood cells with cancer cells. References: 1. Sharma P et al. (2005) Breast Cancer Res. 7 (5): R 634–44 2. Aaroe J et al (2006), poster no:125, 97th AACR Annual Meeting, Washington DC, USA Some RT-PCR analyses were performed by Marion Hirt IMGM Laboratories, Martinsried, Germany.

[Table: see text]
Breast cancer submicrometastasis detection in sentinel lymph node by molecular biology techniques: A new tumor staging method?
Authors: Perazzo F. , Denninghoff V V. , Avagnina A. , Paesani F. , Allende D. , García A. , Crimi G. , Abalo E. , Elsner B.
Published: March 2020

21120

Background: The purpose of this study was to analyze by molecular biology techniques (MBT) the presence of RNAm of mammaglobin (MAG) A and B in breast sentinel lymph nodes (SLN) by RT-PCR, and to correlate these findings with breast tumor characteristics. Methods: SLN from 51 patients with breast tumors smaller than or equal to 3 cm, with no palpable axillary lymphadenopathies were included. Hematoxylin-eosin (HE), immunohistochemistry study (IHC) and MBT were performed. Patients’ staging was assessed according to Saint Gallen's Consensus. Twenty-five patients had clinical follow-up. Results: HE showed metastasis in 4/51 cases, 5/51 were detected with IHC, and one of them negative for HE. MBT allowed the detection of 18/51 positive SN, which included the 5 above-mentioned cases. The other lymph nodes herein studied (33/51) showed no metastases with MBT. Patients’ mean age was 58 years, tumor's mean size was 0.96 cm. The average follow-up was 15 months (range: 1–29 months). The patient with a recurrence at 23 months of clinical follow-up was found to be the only one with HE (+), IHC (+), MAG-A (+) and MAG-B (+). Conclusions: SN study with HE fails to identify all SN with metastases. Immunohistochemistry and MBT increase metastasis detection. Multiplex RT-PCR technique for A and B MAG proves to be specific and sensitive. No direct relationship was found between the risk factors analyzed and the expression of MAG. Therefore, MAG could be used independently as a prognostic factor. The presence of hidden metastasis plays a significant role mainly in the overall survival rate of pre- and postmenopausal patients. This study will be useful to formulate hypotheses. Further research, including a larger population and a longer follow-up period, will be required to confirm these hypotheses. Should our findings be confirmed in the future, molecular biology determinations could modify patients staging and treatment.

No significant financial relationships to disclose.
Molecular analysis of hormone refractory prostate cancer biopsies supports the rationale of using mTOR inhibitors
Authors: Stoss O. , Zielinski D. , Czeloth K. , Middel P. , Henkel T. , Albers P.
Published: March 2020

21126

Background: The aim of our group is to identify molecular signatures in samples of hormone refractory prostate cancer (HRPC) patients (pts) that lead to novel rationales for medical treatment. We have previously shown that transurethral resections (TUR) of the prostate in HRPC pts are useful specimens for gene expression profiling using microarrays (ASCO 2006). Aim of this study was to prove the feasibility of gene expression profiling on prostate biopsies and to develop a standardised tissue handling protocol in order to facilitate multicenter research. Methods: Biopsy material and corresponding TUR chips or classical specimens from 8 pts with HRPC, 13 pts with localized PCA, 6 pts with benign prostatic hyperplasia (BPH) and 11 pts without cancer or BPH were investigated and compared. The tumor type and content was evaluated by a pathologist. Tissues were preserved in liquid nitrogen or RNAlater. Different tissue lysis and RNA purification methods were compared by the quantity (NanoDrop measurement) and quality (Bioanalyser, Agilent) of isolated RNA. Gene expression profiling occurred on Affymetrix HG-FOCUS arrays. Results: Most reliable gene expression results were obtained by biopsy lysis in Trizol using the QIAshredder. A total of more than 1 μg RNA was isolated from one biopsy. RNA quality fulfilled pre-defined criteria such as a 28S/18S rRNA ratio of > 0.8, an area under the curve of > 10% and a RNA integrity number > 6.5. A comparison of HRPC and PCA samples clearly confirmed previous results of a deregulation of protein biosynthesis (translation initiation and elongation factors, ribosome biogenesis) and PI3K signalling pathway components. Conclusions: Gene expression profiling supports the induction of the PI3K-AKT-mTOR pathway in HRPC. A standardised protocol for gene expression profiling from prostate biopsy samples applicable for translational research programs within multicenter clinical trials is now available. As a part of a clinical phase II trial that aims to investigate survival benefits on HRPC pts treated with docetaxel ± RAD001, a translational research program is now set up in parallel to identify biomarkers for response prediction using microarray gene expression analysis from prostate biopsies.

No significant financial relationships to disclose.
Avemar inhibits the growth of mouse and human xenograft mammary carcinomas comparable to endocrine treatments
Authors: Tejeda M. , Gaál D. , Szűcs I. , Telekes A.
Published: March 2020

21132

Background: An in vitro study demonstrated that Avemar increased the effect of Tamoxifen on MCF7 (ER+) mammary carcinoma cells. Methods: MXT (ER+) mouse mammary tumor tissue was transplanted s.c. into BDF1 mice. The tumor bearing animals were treated p.o. with Avemar. Then the most effective Avemar dose (3.0 g/kg), Tamoxifen (0.5 mg/kg s.c.), Examestane (10 mg/kg i.p.) and Anastrasol (5 mg/kg i.p.) monotherapies and their combinations with Avemar was compared. All treatments were given once daily, for 10 days, starting 7 days after the tumor transplantation. The same experimental schedule was repeated using T47/D (ER+) human breast carcinoma cell lines transplanted into C.B-17/Icr-scid/scid mouse. Finally, the growth of T47/D and MDA-MB-231 (ER-) xenografts treated by Avemar was compared. Tumor volume was measured up to 25 days after transplantation in MXT and 55 days in xenograft. Results: In MXT model all monotherapies and combinations led to retardation of tumor growth. Combination of Avemar with any of the endocrine treatment enhanced the efficacy compared to endocrine monotherapy. Out of the four monotherapies the best result was achieved by Avemar (50% inhibition). The combination of Avemar with Examestane increased the tumor growth inhibition to 60.4% compared to control. The other treatments did not exceed the effect of Avemar monotherapy. In xenograft model Avemar produced 50% tumor growth inhibition compared to control and was more effective than the other treatments Examestane (26%), Anastrasol (25%) or Tamoxifen (42%). Combined treatment with Avemar always improved efficacy within the range of 3–10%. Avemar showed similar efficacy when T47/D (49%) and MDA-MB-231 (52%) xenografts were compared. Conclusions: The tumor growth inhibitory effect of Avemar on ER positive MXT mouse breast carcinoma as well as in T47/D xenograft models are comparable (equal or better) to standard endocrine treatments. Avemar certainly did not reduce the effect of endocrine treatments. The antitumor activity of Avemar did not depend on the estrogen receptor status.

No significant financial relationships to disclose.
The effect of surgical resection on serum proteomic profiles in non-small cell lung cancer (NSCLC)
Authors: Alzetani A. , Ward D. G. , Rathinam S. , Starczynski J. , Rajesh P. B. , Martin A. , James N. D. , Johnson P. J.
Published: March 2020

21143

Background: Surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI) was used to detect characteristic serum proteomic profiles that discriminate between Non-small Cell Lung Cancer (NSCLC) and non-cancer controls. The changes in these profiles in response to curative resection were examined to determine if they returned to “normal” as would conventional tumor markers. Methods: Serum samples were collected from 70 patients and 75 controls. Further samples were obtained from 25 of these patients following resection with curative intent. SELDI analyses using CM10 & IMAC ProteinChip arrays were undertaken. The Wilcoxon rank test was used to detect differentially expressed peaks. Results: A preliminary analysis using CM10 on 39 patients, 38 controls, and 17 follow-ups showed 19 differentially expressed peaks (p<0.01) but no evidence of return to normal after treatment. The IMAC chip analysis, on all samples, revealed 40 discriminatory peaks (p<0.01). These data were used to classify patients with a specificity and sensitivity of more than 75%. Some of these cancer associated peaks returned to normal at follow-up. We have identified 10 of the discriminatory proteins. Conclusions: SELDI profiling has detected differentially expressed proteins in the serum of lung cancer patients. Successful treatment resulted in some, but not all, of the discriminatory peaks returning to non-cancer levels. It could be hypothesized there is a tumour specific profile which changes with treatment and a host specific profile that represents the patient's response to the presence of the disease or its inducing factors.

No significant financial relationships to disclose.
The effect of antisense oligodeoxynucleotides targeting Aurora A kinase on cell proliferation and chemosensitivity to paclitaxel in human lung cancer cell line A549
Authors: Meng R. , Wu G. , Yang K. Y. , Cheng J.
Published: March 2020

21147

Background: Aurora kinases representing a family of evolutionarily conserved mitotic serine/threonine kinases have been found elevated in lung andenocarcinoma cell line A549. It is suggested that the overexpression of Aurora A contributes to the carcinogenesis, chromosomal instability (CIN), and de-differentiation of lung cancers. To address its possibility as a therapeutic target for lung cancer, we employed the antisense oligodeoxynucleotide (ASODN) technique to inhibit Aurora A expression and investegate its effect on tumor growth and cell cycle of A549, as well as the chemosensitivity of paclitaxel. Methods: Aurora A ASODN was synthesized and transfected into A549 cells by lipofectAMINE 2000.Aurora A mRNA and protein expression were examined by reverse transcription -polymerase chain reaction (RT-PCR) and Western blot respectively.Cell cycle distribution was observed by flow cytometer.MTT assay was used to evaluate cell inhibition ratio before and after transfection. Results: The proliferation of the A549 cells was inhibited by Aurora A ASODN dose and time dependently. It was also observed that the IC50 of A549 cells after 48 hours’ treatment of ASODN was about 300nmol/L and under such circumstances, the Aurora A mRNA and protein expression significantly decreased (P<0.05), along with the induction of accumulation of cells in S phase and the G2-M transition. Furhermore, cell inhibition ratio of the combination of Aurora A ASODN and paclitaxel was higher significantly than paclitaxel(P<0.05) or Aurora A ASODN alone (P<0.05). Conclusions: Inhibition of Aurora A expression can results in the suppression of cell growth and chemosensitizing activity to paclitaxel in human lung cancer cell line A549.

No significant financial relationships to disclose.
Time to recurrence and survival in triple negative early-stage breast cancer
Authors: Gerson R. , Villalobos A. , Alban L. , Serrano A.
Published: March 2020

21151

Background: Breast cancer (BC) is the most common neoplasm among Mexican women. Clinical, tumoral and biologic factors have proven useful in predicting prognosis regarding recurrence and survival. Triple negative (TN) phenotype (ER, PR and HER2 negative) has been reported to be associated with more aggressive clinical behavior. Objective: To compare clinical, tumor, biologic characteristics of TN time to recurrence and survival to other phenotypes in early BC. Methods: Records of women with stage I - II BC evaluated from Jan. 2000 to June 2006 were reviewed. ER/PR+: > 10 fmol/pgr and HER2+, 3+ by immunohistochemistry or FISH > 2.2 were considered. Five groups were designed: 1) TN, 2) triple positive, 3) HER2-/ER/PR+, 4) HER2+/ER/PR-, 5) HER2-/ one hormonal receptor (HR) +. ANOVA, Chi-2 and Kruskal-Wallis tests were applied for the statistical analysis. Results: 110 patients were included (17, 14, 52, 11, 16 respectively). Median age (43, 49.5, 55, 53 51 yrs); clinical stage; tumor size, axillary lymph node status and angiogenesis score were similar in all groups, p > 0.05. Median Ki67 was higher in TN group (47.5, 20, 20, 42.5, 10, p< 0.000). Proportion of patients with conservative surgery was similar, p= 0.308. Fourteen recurrences were observed, 2 local and 12 systemic (3, 1, 3, 5, 2 in each group). Median time to recurrence (6, 54, 30, 20, 27 mos); there were 7 deaths due to tumor. Number of deaths was higher in TN and HER+/HR- (17.4, 7.1, 0, 18.1, 6.2%). Conclusions: TN phenotype represents 15% in this early BC population and was associated to higher Ki67. There are premature signs (age, number of recurrences and deaths) that suggest a poor prognosis for TN patients, similar to those with HER2+/ERPR- .

No significant financial relationships to disclose.
Cancer prevalence in kidney transplant recipients in two general hospitals from Peru
Authors: Beltran B. E. , Morales D. , Medina M. , Espejo J. , Castillo R. , Riva L. , Hurtado de Mendoza F. , Salinas E. , Carrasco A. , Malaga J.
Published: March 2020

21155

Background: Malignancy following kidney transplantation is an important medical problem during long-term follow-up. The accrual risk is approximately 100 times greater than the general population. We report some features of the cancers developed in our patient population Methods: We retrospectively reviewed records of 1050 kidney transplant recipients who received both unrelated or related allograft transplants from January 1972 to April 2006 and recorded the incidence of de novo malignancies that developed in this cohort. The study was carried out in two centers in Peru. The statistical method was descriptive and parametrical. Survival was calculated using the Kaplan-Meier method. Results: Forty-six cancer were diagnosed in 42 recipients (4.3%). Twenty six were men and 16 women, mean age was 46.0 years old (range:17–67). Malignancy was diagnosed between 2 to 240 months after transplantation. The tumors included Kaposi's sarcoma (KS) in ten patients, squamous cell carcinoma (SCC) in seven, basal cell carcinoma (BCC) in six, cervix cancer in four, colon and breast cancer in three and hepatocarcinoma in two. Also they were reported one case of small intestine cancer, osteosarcoma, pancreatic cancer, lung cancer, bladder cancer, schwanoma, melanoma, tongue cancer, postransplant lymphoproliferative disease, pelvis renal cancer and carcinomatosis from unknown primary. Thus, KS was the most common malignancy encountered in our series, with a prevalence of 0.95%, followed by SCC observed in 0.66% and BCC found in 0.57% of the patients. The average latency period between transplantation and development of malignancy was 25 months for KS, 72.0 months for SCC and 36.0 months for BCC. KS occurred earlier compared with the other cancers ( P < 0.05); We failed to demonstrate any correlation between age/sex and specific type of cancer. The 10 year - survival was 71%. Conclusions: The prevalence of cancer in our renal transplant recipients was 4.3%. KS and non melanoma skin cancer were the most frequent cancer. Low incidence of postransplant lymphoproliferative disease was found.

No significant financial relationships to disclose.
Outcome of patients with locally advanced breast cancer (LABC) followed at the University of Cincinnati (UC)
Authors: Komrokji R. S. , Nahleh Z. , Dhaliwal S. , Sivasubramaniam D.
Published: March 2020

21160

Background: LABC poses a difficult clinical challenge . The correlation of complete clinical (cCR) and pathological response rates (pCR) based on molecular tumor characteristics with outcome is of great clinical interest. Methods: We conducted a retrospective chart review on consecutive patients diagnosed with LABC who completed NC between 2001–2006 at UC. Pathological response was classified as pCR (no invasive tumor in breast and axillary lymph nodes), RDLN (disease in lymph nodes), RDB( disease in breast), and RDBLN (disease in both). Overall survival (OS)and event free survival (EFS) were calculated using Kaplan-Meier analysis. Result: We included 45 patients. Median age 51, 40% (n=18) white and 60% (n=27) African American, Stage IIB 9%, IIIA 29%, IIIB 51 % and IIIC 11%. 75 % invasive ductal, 9% invasive lobular and 16% inflammatory breast cancer (IBC). ER+/or PR+ in 47% (18% ER + / PR +, 27% ER +/PR -, 2% ER-/PR+), and 53% ER -/PR-. HER2 neu + ( IHC 3 + or FISH ratio > 2.2) was identified in 27% of patients. NC regimens included: doxorubicin or epirubicine plus taxane (paclitaxel or docetaxel) 80 %, anthracycline only 10%, single agent taxane 4%, and 6% other regimens (2 CMF, 1 capecitabine). One patient received NC with trastuzumab. Response to NC was as follows: Clinically, 55% (n=25) achieved cCR, 38% partial clinical response, 4% stable disease and 2% progressive disease. Pathpogically, pCR was achieved in 22% (n=10) of all patients, 7% pPRLN, 24% pPRB and 47% RDBLN . None of the patients with IBC had pCR. Among ER+ and or PR + tumors , 19% achieved pCR compared to pCR of 25% among ER-/PR-. Among HER2 neu +, 17% achieved pCR compared to 25% in HER2 neu -. Among all patients who achieved cCR, only 36% actually had pCR. For patients who did not achieve pCR, OS and EFS were 5.7 years and 19 months respectively compared to both not yet reached for those with pCR. Conclusion: LABC has poor prognosis overall using standard chemotherapy. Clinical response followingNC was not well predictive of pathological response. ER-/PR - tumors respond better to neoadjuvant chemotherapy compared to ER+/orPR+ tumors. Less than 20% of HER2 neu + tumors achieve pCR before trastuzumab's routine use. More research is urgently needed to optimize treatment strategies and improve outcome of LABC and IBC.

No significant financial relationships to disclose.
Multi-clinical laboratory validation of a gene expression-based tissue of origin test applied to poorly differentiated and undifferentiated cancers
Authors: Monzon F. A. , Dumur C. I. , Lyons-Weiler M. , Sciulli C. M. , Price M. , Buturovic L. , Becker S. , Rigl C. T. , Anderson G. G.
Published: March 2020

21161

Background: This multi-clinical laboratory validation assessed the accuracy, reproducibility and robustness of the Pathwork™ Tissue of Origin Test. We focused on tumor specimens that are poorly differentiated to undifferentiated (G3-G4; high grade) because this type of specimen can consume a disproportionate amount of physician time and diagnostic resources. A subset of this type of specimen ultimately will be categorized as cancer of unknown primary (CUP), which comprises 4–5% of all malignancies. The Test uses proprietary analytics and a companion genomic microarray (Pathchip™) to compare expression levels of poorly differentiated to undifferentiated specimens with 15 types of cancer. Test development involved over 2000 specimens from 14 labs, representing 15 cancers and sixty morphologies. Methods: The studies addressed operability limits, specimen stability, potential interferences and reproducibility, as well as validation in molecular diagnostics and commercial laboratories. In all, over 700 frozen tumor specimens and microarrays were analyzed. Results: Clinical validation data demonstrated that the percent agreement of the Tissue of Origin Test was 88% across all tissue types. Between-lab concordance was 95%. If the quantitative result (Similarity Score) exceeded the recommended threshold, the probability that the indicated tissue is present was 95% across all tissue types. If the Similarity Score was less than 5, the probability that the indicated tissue is absent was 98% across all tissues types. Conclusions: The Pathwork™ Tissue of Origin Test, which is under development, is accurate and highly reproducible across laboratories in this study. The test gave consistent results for different tissue handling and extraction methods and has the potential to be an effective aid in the diagnosis of cancer patients presenting with poorly differentiated and undifferentiated tumors.

No significant financial relationships to disclose.
Synergistic tumoricidal effect between celecoxib and gabexate mesilate on the human breast cancer cells
Authors: Suh Y. , Chun C. , Song B. , Oh S. , Jung S.
Published: March 2020

21179

Background: Selective cyclooxygenase 2 (COX2) inhibitors, including celecoxib, has shown its antitumor effects against various cancers including breast cancer. Gabexate mesilate (GM) can be found to have anti-cancer activities against tumors such as colon cancer. We tried to determine whether synergism can exist between GM and celecoxib against human breast cancer cells. Methods: MCF7/Her18 (estrogen receptor positive) and MDA-MB-436 (estrogen receptor negative) human breast cancer cells were used. Celecoxib and GM were added into the culture media at a dose of 30 and 50 μM for estrogen receptor (ER) (+) cells and 50 and 75 μM for ER (-) cells. Cellular proliferation assays wer performed and trypan blue exclusion method was adopted to count the viable cells after culture. Cell cycle analysis and fluorescein-assorted cell sortings were done to check the cell cycle changes after treatment. Immunoblotting using Akt, phosphorylated Akt (p- Akt), β-catenin, COX2 and VEGF was done to evaluate changes in expression of these proteins. Results: Combination treatment group showed significantly enhanced tumoricidal effect than either mono-treatment group on cellular proliferation study. Combined treatment yielded more G1 phase population and G2-M phase cells. (p<0.05) The level of Akt, p-Akt, VEGF, COX2 expression were decreased more significantly than either mono-treatment group. (p<0.05) Conclusions: We think that there could be synergistic effect between GM and celecoxib on the human breast cancer cells. Either drug has been used for many cases without significant problem, and can be tried for further ex vivo studies to determine synergistic effects between them. Possible antiangiogenentic actions after the combination should be evaluated thoroughly in other cell lines to get more preclinical data.

No significant financial relationships to disclose.
Correlation between expression of p53, EGFR, cell proliferation defined by Ki67, and survival in stage III/IV non-small cell lung cancer (NSCLC)
Authors: Malika G. B. , Bouzid K. , R Baba-Ahmed G. , Makhloufi T , Taright S , Amrane R , Hannoun D
Published: March 2020

21181

Background: The aim of the study was to assess the relation between expression of EGFR, p53, cell proliferation defined by the monoclonal antibody Ki67 and survival of patients with non-small cell lung cancer stage III and IV. Methods: 80 patients were included in this study (male 72 / female 8); the median follow up was 15 months. All tumor samples were formalin-fixed and paraffin-embedded. The expression of p53, EGFR and Ki 67 were assessed with the use of immunohistochemically (IHC). P53 was assessed in 66 cases, EGFR in 73 cases and cell proliferation defined by the monoclonal antibody Ki67 in 63 cases. Results: The expression of p53 was positive in 20 % of cases, EGFR was positive in 58,7 % of cases and cell proliferation in 40 % of cases. Survival was estimated from the date of first cycle of chemotherapy using median survival and the Kaplan-Meier survival analysis method. Conclusion: At this time of the study, there was no relation between expression of p53, EGFR, cell proliferation defined by ki67 and survival. Larger and longer follow-up studies may be needed to determine the prognostic role of expression of those factors in NSCLC.

[Table: see text]

No significant financial relationships to disclose.
No association between NQO1 polymorphism and breast cancer risk in Siberian population
Authors: Filipenko M. L. , Pechkovsky E. V. , Mishukova O. V. , Lazarev A. F. , Petrova V. D. , Selezneva I. A. , Sinkina T. V. , Dimitriadi J. N. , Zarubina N. A. , Terekhova S. A.
Published: March 2020

21185

Background: NQO1 is a two-electron reductase, which metabolizes a variety of xenobiotics. This FAD-binding protein forms homodimers and reduces quinones to hydroquinones. This protein's enzymatic activity prevents the one electron reduction of quinones that results in the production of radical species. Mutations in this gene have been associated with tardive dyskinesia (TD), an increased risk of hematotoxicity after exposure to benzene, and susceptibility to various forms of cancer. Genetic polymorphism of NQO1 is a C to T point mutation at base pair 609 of exon 6, which codes for a proline to serine substitution in NQO1 protein. This mutation results in a loss of NQO1 activity. Previously it was reported that wild-type NQO1 increased lung adenocarcinoma risk among male smokers in Taiwan. The association of the P187S polymorphism with breast cancer found in study of two independent populations (one from Tyrol, Austria, and the other from Prague, Czech Republic) (Menzel et al., 2004). Methods: The purpose of this study was to determine whether polymorphism in the NQO1 gene may influence breast cancer risk in Siberian population. The prevalent case-control design was used. The cases were 203 patients with breast cancer. Controls consisted of 182 noncancer outpatients. Genotyping for detecting of NQO1 gene polymorphism was performed using PCR amplification with the primer set of 5'- ACGCTAGCTCTGAACTGATTCTCT -3' and 5'- TTTTCTCCTCATCCTGTACCTCT –3’. The amplified PCR products were digested with HinfI and analyzed using electrophoresis on a 2.5% agarose gel. Results: Compared to subjects having C alleles (genotype CC), odds ratio (chi2=0.04, p=0.84309) were 1.116 (0.376–3.311) for subjects having genotype TT. Conclusions: These results suggest that polymorphic variation P187S of the NQO1 gene has no influence on breast cancer risk in Siberian women.

No significant financial relationships to disclose.