bluuebunny/crossref_metadata_2025 huggingface dataset:
Tissue expression of osteopontin (OPN) and mesothelin (MES) in malignant pleural mesothelioma (MPM). An immunohistochemical study of 70 consecutive cases
Authors: Betta P. , Libener R. , Orecchia S. , Salvio M. , Arnolfo E. , Bottero G. , Botta M. , Piccolini E. , Pavesi M.
Published: August 2020

e22102

Background: There is still no single test that can reliably identify malignant mesothelial cells. Recently soluble MES and OPN have been proposed as novel serum markers for MPM but a definitive consensus on their use in routine is still lacking. This study aims at 1. analysing the essential pathological features of a series of consecutive MPMs from a single institution and 2. assessing the tumour tissue expression of OPN and MES and speculating about the potential biological role of these molecules in MPM. Methods: All MPMs diagnosed between 1999 and 2008 were retrieved from the archives of the Pathology Unit of Alessandria Hospital. All the diagnoses had been made on the basis of conventional light microscopy features supplemented by a mucin stain (periodic acid-Schiff with and without diastase treatment) and a panel of immunostains (carcinoembryonic antigen, CD15/LeuM1, BerEP4, calretinin and cytokeratin 5). Immunostaining for OPN (polyclonal antibody) and MES (monoclonal antibody, clone 5B2) was performed using the labelled streptavidin-biotin method, and the staining intensity and extent were assessed. Results: The study group consisted of 50 males and 20 females with a mean age at diagnosis of 78.4 years (range 47–92). Histopathology was epithelial, mixed, and sarcomatous in 52, 12, and 6 patients respectively. OPN positivity (percentage of positive tumour cells >10%) was observed in 67 MPMs (96%) mostly in a granular cytoplasmic pattern and with an intensity ranging from weak (25%) to moderate (31%) and strong (44%). MES positivity (percentage of positive tumour cells >10%) was recorded in 60 MPMs (86%), of which 36% exhibited a weak, 36% a moderate and 28% a strong immunostaining in a membrane pattern. MES was positive in 100% of epithelial MPMs, in 67% of mixed and in 0% of sarcomatous. Positivity was restricted to the epithelial component in mixed MPMs. Conclusions: The high expression of OPN in MPM, irrespective of the histotype, seems to point to a role of this molecule as a marker of malignant transformation of mesothelial cells, while the restriction of positive staining for MES to the epithelial phenotype supports a role of MES as a marker of epithelial differentiation in MPM.

No significant financial relationships to disclose.
The effect of TAE226 on the non-small cell lung cancer including Japanese origin lung cancer
Authors: Otani H. , Jida M. , Takaoka M. , Kubo T. , Hayashi T. , Yamamoto H. , Kiura K. , Naomoto Y. , Toyooka S.
Published: August 2020

e22103

Background: Mutations in the epidermal growth factor receptor (EGFR) gene is the predictive factor for sensitivity of EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer. Focal adhesion kinase (FAK) that is the downstream molecule of EGFR has been reported to be highly expressed in NSCLC suggesting novel therapeutic target of NSCLC. TAE226, dual inhibitor for FAK and insulin like growth factor-I receptor (IGF-IR), have been developed as anticancer reagent. In this study, we examined the effect of TAE226 on NSCLC from the view point of EGFR mutation status. Methods: We used NSCLC cell lines consisting of 4 EGFR mutant cell lines (PC9, H3255, HCC827, H1975) and 3 EGFR wild type cell lines (H1819, H1299, A549). We also used PC9 derived resistant cell line (RPC9). Antiproliferative effect of TAE226 on NSCLC cell lines was examined with MTS assay. The status of EGFR related molecules including its downstream signal pathway was investigated by western blotting analysis. The effect of TAE226 on xenograft mouse models was also examined. Results: TAE226 was effective on NSCLC cell lines with EGFR mutation including T790M mutation, compared to those with EGFR wild type. The value of IC50 (μmol/L) for PC-9, H3255, HCC827, H1975, RPC-9 and H1819, H1299, A549 was 0.16, 0.12, 0.086, 0.17, 0.31 and 4.7, 2.8, 1.4, respectively. Western blotting assay showed that TAE226 preferentially inhibited phosphor-EGFR and its downstream signaling mediators. We could confirm the anticancer effect of TAE226 on EGFR mutant cells was confirmed in xenograft mouse models. Conclusions: We indicated that TAE226 showed antitumor effect on EGFR mutant cell lines even T790M mutant cells. Further study is necessary to understand the mechanism of TAE226 effect on EGFR mutant cell lines. Our results suggest that TAE226 will be expected as the novel strategy for NSCLC.

No significant financial relationships to disclose.
Risk of acute renal failure among breast cancer patients and chemotherapy treatment of breast cancer patients with a history of renal insufficiency in a commercially-insured population in the United States
Authors: Langeberg W. J. , O'Malley C. D. , Critchlow C. W. , Fryzek J. P.
Published: August 2020

e22104

Background: Risk of acute renal failure (ARF) among breast cancer (BC) patients may increase with nephrotoxic chemotherapy and other exposures, but this risk is not well characterized. Furthermore, among patients who present with renal insufficiencies (RI) at cancer diagnosis, subsequent treatment patterns are not well described. Methods: We performed a retrospective cohort study using a large national commercial claims database. The cohort included all women diagnosed with BC from 2000 to 2007 who were 18–64 years at diagnosis with no history of cancer (n=13,296). We defined a diagnosis of BC as at least one inpatient or two outpatient claims more than 30 days apart with an ICD-9 code of 174. Among patients with no history of RI (n=13,150), we calculated the cumulative incidence (CI) of ARF_the proportion with at least one inpatient or two outpatient claims with an ICD-9 code of 584 or 586 in the first year following cancer diagnosis. Treatment for BC patients with a history of RI (n=146) was also assessed. Results: Among BC patients with no history of RI, 0.3% were diagnosed with ARF within a year after cancer diagnosis. The CI of ARF was higher in patients with metastases: 0.7% for any metastasis, 2.3% for bone metastasis, and 0.1% for no metastasis. The CI of ARF among patients undergoing radiation or mastectomy was similar to the overall rate (0.3%) but was higher in patients receiving nephrotoxic chemotherapy (1.0%) or intravenous bisphosphonates (IV BPs) (2.1%). The CI of ARF was higher in patients with congestive heart failure (1.4%), diabetes (0.9%), and/or hypertension (0.8%) at cancer diagnosis compared to patients without these comorbidities (0.2%). Among BC patients with a history of RI, 7.5% were administered nephrotoxic chemotherapy, 30.1% received potentially nephrotoxic chemotherapy, and 1.4% were given IV BPs. Conclusions: Breast cancer patients who present with comorbidities, develop metastases, or are given nephrotoxic chemotherapy or IV bisphosphonates are at higher risk of acute renal failure in the first year after breast cancer diagnosis. More research is warranted on the treatment of breast cancer patients with a history of renal insufficiency.

[Table: see text]
Human Mena (hMena), estrogen receptor-β (ER-β), and epidermal growth factor receptor (EGFR) expression as prognostic factors in node-negative non-small-cell lung cancer (NSCLC)
Authors: Bria E. , Mottolese M. , Sperduti I. , Visca P. , Antoniani B. , Facciolo F. , Terzoli E. , Cognetti F. , Nisticò P. , Milella M.
Published: August 2020

e22105

Background: hMena is a cytoskeleton regulatory protein involved in adhesion and cell motility, particularly in response to EGFR activation. In addition, a possible correlation between ER-β and EGFR expression has been recently suggested in NSCLC. We therefore investigated the potential relationship and prognostic value of hMena, ER-β, and EGFR expression in node-negative NSCLC patients (pts) who underwent surgery at our institution. Methods: hMena, ER-β (isoforms 1, 2), and EGFR expression, analyzed on Tissue Micro Array, were correlated to disease-free, cancer-specific, and overall survival (DFS/CSS/OS) using a Cox model including sex, stage, age, grading, histology, number of resected nodes (RN). Logistic and generalized linear models were used to evaluate predictors of significant Cox-model variables. Receiver Operative Curve (ROC) analysis identified optimal cutoff values. Internal cross-validation (100 simulations with 80% of the dataset) was accomplished. Results: 248 pts were gathered (median follow-up 26 months, range 1–75; male/female 71/29%; adeno/other 43/57%; grading G1–2/G3 45/55%; Stage I/II 82/8%; RN ≤10/>10 34/66%). Multivariate analysis, highlighting the prognostic role of RN and hMena, is shown in the table . ER-β/2 and EGFR strongly predicted hMena overexpression (p=0.009, p=0.01); indeed, when hMena was removed from the multivariate model, both factors were independent predictors of DFS/CSS. Cross-validation analysis confirmed the prognostic role of hMena with a replication rate of 43/66% for DFS/CSS. Conclusions: hMena expression is prognostic in early NSCLC undergoing curative surgery. ER-β/2 and EGFR strongly correlate with hMena status and their prognostic role deserves further investigation.

[Table: see text]

No significant financial relationships to disclose.
Circulating tumor cells (CTCs) and endothelial cells (CECs) in the diagnosis of malignant pleural mesothelioma (MPM): A single institutional prospective study
Authors: Yoneda K. , Tanaka F. , Hashimoto M. , Takuwa T. , Matsumoto S. , Okumura Y. , Kondo N. , Hasegawa S. , Tsujimura T. , Fukuoka K. , Nakano T.
Published: August 2020

e22107

Background: Circulating tumor cell (CTC), a surrogate of distant metastasis, and circulating endothelia cell (CEC), a surrogate of angiogenesis, are potentially useful in the diagnosis of malignant tumors. Following a promising result of our preliminary study showing the diagnostic value of CTC/CEC in malignant pleural mesothelioma (MPM)(Tanaka F, et al. ASCO 2008), we conducted a prospective study. Methods: Patients (pts), who presented at our institute with suspicion or diagnosis of MPM, were eligible in the study. CTCs and CECs in peripheral blood (7.5mL and 4.0mL, respectively) were captured and quantitatively evaluated with the “CellSearch” system without knowledge of clinical characteristics of patients. Results: A total of 92 pts were enrolled into the study, and the final diagnosis was MPM in 68, other malignant tumors in 7, and non-malignant diseases in 17 pts ( Table ). CTC was positive (CTC-count, 1 or more per 7.5mL of the peripheral blood) in 35%(24/68) of MPM pts (range of CTC-count, 0–27 cells/7.5 mL). Among non-malignant pts, 3 pts (18%) showed a positive-CTC, but no patient showed 2 or more CTCs in 7.5mL of the peripheral blood. The mean CEC-count (/4.0mL) was significantly higher in MPM pts than in non-malignant pts (105.1 versus 40.2; p=0.047). When the cut-off value of CEC-count for the diagnosis of MPM was defined as 50(cells/4.0mL), the sensitivity, specificity, positive predictive value, and negative predictive value for the diagnosis of malignant diseases were 66%, 70%, 93%, and 26%, respectively. There was no correlation between CTC-positivity and clinical stage of MPM pts, but was a trend of increase in the mean CEC-count along with tumor progression (mean CEC-count for stage I, II, III, and IV pts: 63.0, 82.4, 95.6, and 116.7, respectively). Conclusions: CTC and CEC are useful clinical markers in the diagnosis of MPM.

[Table: see text]

No significant financial relationships to disclose.
Effect of caffeine treatment on low-dose γ- irradiation-induced chromatid-type aberrations in human leukemia cells and human normal fibroblast cells in culture
Authors: Jha M. N. , Bedford J. S. , Jha S. , Prasad K.
Published: August 2020

e22113

Background: It is estimated that low dose radiation can increase the risk of cancer as well as mutations. However, the interaction of low dose radiation with caffeine has not been adequately investigated. We investigated the effects of caffeine on low dose- gamma-radiation-induced chromosomal damage in human T leukemia cells (Jurket T-cells) and two normal human fibroblast cell lines (AG1522 and GM 2149). Method: Jurkat cells were maintained in RPMI 1640 medium and fibroblast in alpha-minimal essential medium (MEM) All cells were incubated at 37o C in a humidified atmosphere of 5% CO2 in air. Cells from the exponential phase were treated with 1 mg/ml caffeine ( control cells received same amount of solvent) and irradiated with low doses (3, 5, 10, 20 and 40 cGy,), using a 137 Cs-gamma radiation source. Colcemid at a concentration of 0.1 μg/ml was added to every flask. Cells were fixed in methanol: acetic acid solution and stained with Giemsa. 100 irradiated and un-irradiated metaphase- like cells were scored for chromatid-type aberrations. Results: Low dose gamma-radiation increased the levels of chromatid breaks(dose dependent) in both normal and cancer cells; however, cancer cells appeared to be more sensitive than the normal cells. Caffeine treatment markedly increased chromatid aberrations in Jurkat T-cells at all radiation doses but not in normal cells. Previously, we reported that caffeine eliminates gamma-ray-induced G2 delay in other human tumor cells but not normal cells (Jha, et.al., Radiat. Res. 157, 26–31, 2002). Conclusions: The mechanisms that may underlie this differential effect of caffeine in cancer and normal cells are unknown, but if one result of a G2 delay is to allow more time for chromosome breakage rejoining processes to occur, then elimination of this delay by caffeine in tumor cells but not normal cells might account for the difference. To the extent these observations are generally true for tumor vs normal cells, the differential sensitization could have an impact in improving the efficacy of radiation therapy.

No significant financial relationships to disclose.
Evaluation of plectin-1 immunohistochemical staining in human non-small cell lung cancer
Authors: Harris T. J. , Jones D. R. , Brenin C. M. , Kelly K. A. , George K. , Moskaluk C. A.
Published: August 2020

e22118

Background: Plectin-1 (PLEC1), a known scaffolding protein, impacts signaling pathways and has been found to be up-regulated and redistributed to the cell membrane in tumor cells. The redistribution of PLEC1 has shown promise as a novel molecular imaging biomarker in experimental systems. The purpose of this study was to examine the variation of PLEC1 staining in human non-small cell lung cancer (NSCLC). Methods: 142 NSCLC samples from 2001–2003 were obtained from pathology archives and placed into tissue microarray (TMA) format. TMA sections were stained with anti-PLEC1 antibody. A total PLEC1 immunohistochemical (IHC) staining score was obtained by multiplying the intensity of PLEC1 staining, scored 0 through 3, by the percent of tumor cells showing membrane staining, scored 1 for <25%, 2 for 25%-75% and 3 for >75%. The samples were then grouped into low (0–2), intermediate (3–5) or high (6- 9) membrane expression and analyzed for clinical correlations to tumor type and pathological staging. Results: A total of 125 samples were successfully stained for PLEC1. In all NSCLC subgroups, there was variability of PLEC1 staining. Approximately 50% of cases showed intermediate to high staining. There was a trend of lower PLEC1 staining as the tumor stage advanced (p=0.1). There appeared to be no significant variations of PLEC1 staining when compared to gender of the patients. Conclusions: These findings are the first to show that a significant number of human NSCLC exhibit strong expression of PLEC1 in the cell membrane. As this biomarker is being developed for molecular imaging modalities in other tumor types, it may have potential to be of use in the non-invasive detection of disease or therapeutic efficacy monitoring in NSCLC.

[Table: see text]

No significant financial relationships to disclose.
MYCN gene amplification and DNA ploidy in peripheral neuroblastic tumors
Authors: Abdalla D. M. , Hamza M. A. , Kandil A. E. , Younes L. K. , Sorrour A. F.
Published: August 2020

e22123

Background: Neuroblastoma is a neuroblastic tumor of the primordial crest cells which are precursors of the sympathetic nervous system and is the most common extracranial solid tumor of childhood comprising between 8 and 10% of all childhood cancers. Neuroblastoma is characterized by a diverse clinical and biological behavior The spectrum of clinical behavior suggests that genetic, biological and morphological features may be useful markers to stratify children with this disease for the most appropriate management Fluorescence in situ hybridization (FISH) is considered the best approach for detection of MYCN amplification because it can detect small copy number gains and copy number heterogeneity among tumor cells. Also, it can determine the source of amplified MYCN signal, whether extrachromosomal double minutes, expanded intrachromosomal region or chromosome 2 aneuploidy. Methods: 30 cases of peripheral neuroblastic tumors were analysed for MYCN oncogene copy number and DNA ploidy using FISH. The 30 cases were divided into: 25 cases of neuroblastoma, 2 cases of ganglioneuroblastoma intermixed, and 3 cases of ganglioneuroma. Results: MYCN oncogene was amplified in 8 out of 30 cases (27.5%). 3 cases showed double minutes, 3 cases showed homogenously staining regions and 2 cases showed both forms of amplification. As regard DNA ploidy, 18 cases were diploid and 12 cases were hyperdiploid. MYCN oncogene amplification was significantly correlated with unfavorable histology, advanced tumor stage increased recurrence and poor survival. Also ploidy was associated with increased recurrence and reduced survival. And so, MYCN oncogene amplification and DNA ploidy were poor prognostic markers and it is recommended that assessment of these factors should be routine in the management of any case of neuroblastoma. Conclusions: 1) MYCN gene amplificahion and DNA plidy are poor prognostic markers 2) They should be measured in every case of peripheral neuroblastic tumors. 3) FISH should be used in the detechion of MYCN oncogene amplification and DNA ploidy

No significant financial relationships to disclose.
Evaluation on the IGF-IR Inhibitor CP-751,871, alone and in combination with paclitaxel in lung and colon cell lines
Authors: Garcia-Carbonero R. , Agullo-Ortuño M. T. , Lopez-Rios F. , Diaz-Garcia C. V. , Cortijo A. , Cortes-Funes H. , Paz- Ares L.
Published: August 2020

e22125

Background: Signaling through the insulin-like growth factor 1 receptor (IGF-IR) has been implicated in the resistance to a number of clinically relevant anti-cancer agents. The aim of this study was to assess the direct anti-tumour effects of CP-751,871, alone and in combination with paclitaxel in lung and colon cancer cell lines. Methods: Four lung and four colon cancer cell line where treated with the IGF-IR inhibitor CP-751,871 and/or Paclitaxel in simultaneous or sequential treatments. Response to treatments was evaluated by WST-1 cell survival assays. Flow cytometric analysis was used to estimate the effect on the cell cycle and apoptosis. IGF-IR mRNA expression was determined by quantitative real-time PCR and relative gene expression values were calculated by the ΔΔCt method. Results: No correlation between basal IGF-IR mRNA expression and CP-751,871 response was observed in cell lines tested. Flow cytometric analysis demonstrated that CP-751,871 enhanced cell cycle arrest at the G1/G0 checkpoint with minimal effects on apoptosis. Combined simultaneous and, more strongly, sequential treatment with CP- 751,871 and Paclitaxel showed improved response in cell growth inhibition on HCC78, H1299, Colo205 and HT29 cell lines, and was statistically superior to Paclitaxel alone (p< 0.001) and CP-751,871 alone (p< 0.001). In H460, LS180 and DLD-1 cell lines, concomitant, but no sequential treatment resulted in antagonistic interactions. Conclusions: CP-751,871 showed a modest anti-tumour activity, predominantly cytostatic, against lung and colon cancer cell lines, that is not related to the mRNA expression. CP-751,871 tends to enhance the effects of paclitaxel in vitro, depending on sequence of administration and on the model system used.

No significant financial relationships to disclose.
ERCC1, VEGF along with clinical variants impact the outcome of advanced non-small cell lung cancer (NSCLC) patients
Authors: Abdel Karim N. F. , Bui H. X. , Patil N. , Pathrose P. , Rao M. , Mostafa A. , Mehta A. , Anderson M.
Published: August 2020

e22129

Background: ERCC1 is a useful marker of resistance to cisplatin and its analogues. Longer survival was noted in patients with ERCC1 negative expression when treated with platinum. VEGF and its receptor-KDR previously indicated poor prognosis with high tumor cell expression. Methods: From 1998–2008, a retrospective study included 32 patients with advanced NSCLC, where clinical variants as well as the levels of expression of VEGF and VEGFR using rabbit monoclonal Ab (VEGF: A-20, 1:100, SCBT; VEGFR: 55B11, 1:250, cell signaling) and immunohistochemistry for ERCC1 (Mouse monoclonal ab-8F1, Thermo Scientific, 1:200) were measured and co-related to the overall survival of those patients using Cox proportional hazards model. Results: Of the 32 patients, six received non-platinum and twenty six received platinum based regimens either first line or later. Eight patients were females (25%), three were African Americans (9%) and the median age was 62.5 (42–84). Females had a significantly higher overall survival; median survival of 30 months compared to 10.6 months for males (p=0.00089). There was no significant correlation between age and survival (p=0.2). Well differentiated NSCLC of any subtype showed better survival (p=0.04). VEGF low expression correlated with better overall survival (p=0.021). Among the 26 patients who received platinum based regimens, 11 (42%) were ERCC1 negative, 10 had strongly positive ERCC1 expression (39%) and 5 patients had weakly positive ERCC1 expression (19%). ERCC1 negativity was strongly associated with longer survival (p=0.0019) in patients treated with platinum based regimens, where patients treated with the first line platinum had better survival (p=0.034). VEGFR low expression was associated with longer survival in the same group of patients (p=0.013). Caucasians had better overall survival in comparison to African Americans (p=0.007). Higher White blood cell counts and platelet counts were associated with lower survival (p=0.0019 and 0.065 respectively). Conclusion: ERCC1 negativitiy with the first line platinum therapy, VEGF low expression, females, Caucasians as well as the absence of elevation of White blood cells and platelet counts correlate with improved overall survival in advanced NSCLC.

No significant financial relationships to disclose.
Targeting ctla-4 directly on melanoma cells: A possible novel perspective in the immunotherapy of cutaneous melanoma
Authors: Queirolo P. , Laurent S. , Boitano M. , Carrega P. , Saverino D. , Alviano F. , Caielli A. , Camoriano M. , Ferlazzo G. , Pistillo M. P.
Published: August 2020

e22138

Background: CTLA-4 (CD152) is an omodimeric membrane glycoprotein which behaves as the major negative regulator of T cell-mediated immune response. CTLA-4 inhibitory function in T cells mainly occurs upon engagement with the B7 ligands expressed on antigen presenting cells, resulting in inhibition of cytokine production and T cell proliferation. CTLA-4 expression has also been documented in established human melanoma cell lines and primary melanoma tumours. The aim of this study was to investigate the expression and functional role of CTLA-4 in primary melanoma cultures derived from biopsies of metastatic melanoma patients. Methods: Seven primary cultures were derived from melanoma samples by mechanical tissue dissociation, enzymatic digestion and filtration of single cell suspensions. Flow cytometry (FACS) with an anti-melanoma (MCSP) mAb was used to assess the growth of melanoma cells. CTLA-4 expression analysis was performed by FACS and real-time PCR. Cytokine secretion and apoptotic cells were evaluated by Elisa and Annexin V/PI staining after treatment with an agonistic anti-CTLA-4 mAb (3D5). The angiogenic property of melanoma culture supernatants was evaluated on mesenchimal stromal cells (msc) isolated from human thoracic aortas. All the study was approved by our Institutional Ethics Committee and patients gave written informed consent. Results: Constitutive CTLA-4 expression was found on all melanoma cultures with variable intensity at both the protein and transcript levels. CTLA-4 expressed by these cells is functional as its ligation, with an anti-CTLA-4 agonistic mAb, is able to induce inhibition of cell proliferation, due to apoptosis induction, and of IL-8, TNF-alpha and VEGF cytokine secretion. Moreover, CTLA-4 ligation down-modulates the ability of melanoma culture supernatants to induce angiogenic differentiation of msc as detected by the acquisition of their endothelial phenotype. Conclusions: Given the physiologic inhibitory function of CTLA-4, our results suggest its possible role in the functional biology of melanoma and open up the possibility of an anti-melanoma immunotherapy based on targeting CTLA-4 directly on tumour cells as this might allow inhibition of tumour cell growth and angiogenesis.

No significant financial relationships to disclose.
The outcome of patients with triple negative breast cancer: Evidence for a favorable ethnic subgroup? The Turkish Oncology Group experience
Authors: Eralp Y. , Basaran G. , Dogan M. , Dincol D. , Demirci S. , Icli F. , Onur H. , Saip P. , Topuz E. , Haydaroglu A.
Published: August 2020

e22158

Background: Triple negative breast cancer (TNBC) is generally considered as a poorer prognostic subgroup, with a propensity for earlier relapse and visceral involvement. The aim of this study is to evaluate the outcome of non-metastatic TNBC patients in a National registry setting and identify clinical and pathologic variables associated with survival. Methods: From a retrospective registry cohort of 296 TNBC patients treated and followed between 1993–2007, we identified 248 patients with early stage disease, with follow-up of at least 12 months. The prognostic impact of several clinical variables were evaluated by the Kaplan-Meier and Cox multivariate anayses. Results: Median age was 48. The majority of the patient group had invasive ductal carcinoma (n:204, 82.3%). Distribution by stage was as follows: stage 1: 49 (19.8%), st 2: 125 (50.4%), st 3: 69 (27.8%). Excluding 11 patients, all had received adjuvant chemotherapy. 5 year overall survival (OS) and disease-free survival (DFS) rates were 84±2.7 % and 69±3.3%, respectively. Median survival after initial recurrence was 20 months. Sites of relapse were as follows: lung: 26 (36.1%), liver:8 (11.1%), brain: 8 (11.1%), bone: 14 (19.4%), skin/lymphatic: 7 (9.7%). Univariate analysis revealed locally advanced disease (p:0.0001), larger tumor size (p:0.004), nodal positivity (p<0.00001), and extent of nodal involvement as significant factors for DFS; whereas, locally advanced disease (p:0.0099) and extent of nodal involvement (p:0.018) were identified as prognostic factors with an impact on OS. Multivariate analysis revealed locally advanced disease (HR: 3.3, p:0.02, 95% CI: 0.14–0.64) and extent of nodal involvement (HR:4.3, p:0.033, 95% CI: 0.059–0.88) as significant independent prognostic factors for DFS and OS, respectively. Conclusions: The outcome of patients with TNBC in this National registry cohort is comparable to other subsets with similar prognostic features and do not support the generally accepted notion that TNBC entails poor prognosis. It may be speculated that there may be inherent ethnic differences leading to distinctive tumor behaviour. Further translational research is required to identify molecular prognostic groups within the TN subset.

No significant financial relationships to disclose.
Cytoplasmic expression of HuR and cyclooxygenase-2 expression in colon cancer
Authors: Song J. , Choi S. , Lee J. , Lim S.
Published: August 2020

e22161

Background: HuR, human family embryonic-lethal abnormal vision-like protein, can bind to mRNAs and stabilizes them in the cytoplasm, resulting in more efficient translation. HuR is predominantly present in the nucleus and shuttles between the nucleus and cytoplasm. The mRNA of cyclooxygenase-2 (Cox-2) is stabilized by HuR in several cancers, including breast, stomach, lung and brain. Methods: We investigated the expression and its cellular location of HuR, and Cox-2 expression in 79 colorectal cancer patients with immunohistochemistry, and evaluated the biological implications in colorectal carcinoma. Results: Nuclear HuR expression was observed in 59 (74.7%) and cytoplasmic HuR expression was seen in 25 (31.6%). Cox-2 immunoreactivity was noted in 42 (53%). The expression of cytoplasmic HuR was significantly associated with Cox-2 expression (p=0.004). And cytoplasmic expression of HuR showed correlation with lymphatic invasion (p=0.025) and lymph node metastasis (p=0.027). Nuclear HuR showed no correlation with Cox-2 expression or other clinicopathological parameters examined. Conclusions: These results suggest that cytoplasmic translocation of HuR is associated with Cox-2 expression in some colorectal carcinoma.

No significant financial relationships to disclose.
Regenerating gene 1α (REG 1α) expression and new treatment strategies in early non-small cell lung cancer
Authors: Tojo T. , Tojo T. , Naito H. , Kimura M. , Takasawa S. , Dohi Y. , Nagata Y. , Taniguchi S.
Published: August 2020

e22178

Background: Regenerating gene (REG) I was originally isolated as an endogenous growth factor from pancreatic islet β cells. REG Iα protein is suggested to be involved in carcinogenesis in various gastroenterologic tissues. In the present study, to elucidate roles for REG Iα in non-small cell lung cancer (NSCLC), we investigated REG Iα expression in NSCLCs, focusing especially on its relationship with prognosis. Methods: We enrolled 70 NSCLCs (adenocarcinoma (AC)(n=48) and squamous cell carcinoma (SCC)(n=22)) who received surgery at Nara Medical University Hospital. Total RNA was extracted from each tumor tissue and corresponding normal lung tissue (NL)(n=70), cDNA was then reverse-transcribed from total RNA, and quantitative real-time reverse transcriptase-polymerase chain reaction was then carried out. The expression level of REG Iα in each sample was normalized with respect to that of β-actin, and the cutoff level was set at average+3SD expression of the 70 NLs. We also examined the relationship between REG 1α expression in the tumor tissue and the prognosis. Results: Six (12.5%) of the 48 ACs and 5 (22.7%) of the 22 SCCs were positive for REG Iα gene, and which is higher than that of NLs (2 of 70: 2.9%). After median follow-up of 26.2 months, 12 patients died due to disease progression. The survival rate among the REG 1α positive patients was significantly worse than among the REG 1α negative patients in ACs (P<0.05), and not significantly but worse in SCCs (P=0.07). In case of stage I, none of REG 1α negative patient died in both ACs and SCCs compared with 4 patients died of positive patients (AC:2, SCC:2), and also the survival rate among the REG 1α positive patients was significantly worse than among the negative patients in ACs (P<0.01) and SCCs (P<0.05). Disease free survival of REG 1α positive patients was also worse than negative patients in ACs (P<0.05) and SCCs (P=0.16). Conclusions: REG Iα expression in NSCLCs may be the risk factor for poor prognosis, and we anticipate that it will enable us to provide more appropriate and individualized treatment to patients of early NSCLC.

No significant financial relationships to disclose.
APC allele-specific expression in carriers of Ashkenazi Jewish mutation I1307K
Authors: Capella G. , Castellsague E. , Rennert G. , Gruber S.
Published: August 2020

e22181

Background: I1307K is a missense APC variant with incomplete penetrance that has been found in 6% of Jewish Ashkenazi population and confers a two-fold increased risk to develop multiple adenomas and colorectal tumours. It is believed that it creates a hypermutable region within the gene that leads to an accumulation of mutations. It remains unknown whether the presence of this mutation modifies APC expression. Our goal was to study whether allele-specific expression (ASE) of I1307K is present at the germline and tumoral level. Methods: Paired germline/carcinoma RNA and DNA was studied from eleven I1307K carriers. To analyze changes in the mutant/wt allelic ratio we used single nucleotide primer extension (SNuPE) for the I1307K and the rs2229992 APCcoding SNP. Fourteen controls were also analyzed. Results: No germline allele specific expression was found in I1307K carriers (range=0.954–1.173). Significant ASE was observed in 8 of the 10 carcinomas analyzed. In 4 cases the I1307K allele was overexpressed (range=2.51–9.51) and in 4 cases was underexpressed (range=0.09–0.28). Tumor ASE correlated with the DNA mutant/wt allelic dose. Conclusions: I1307K variant is not associated with allelic specific expression at the germline level. I1307K overexpression is not selected for during tumor progression.

No significant financial relationships to disclose.
KI67 in breast cancer: Correlation between proliferation cellular and other prognostic factors
Authors: Gerson R. , Alban L. , Martínez A. , Villalobos A. , Serrano A.
Published: August 2020

e22184

Background: Breast cancer (BC) is the most common tumor in Mexican women between 35 to 50 years old. KI67 is a nuclear antigen considered as a proliferation marker with potential prognostic significance in BC survival. Objective: To determine the correlation between KI67 and prognostic factors in BC patients (pts). Methods: Of 340 consecutive BC pts seen from January 2000 to September 2008, pts with invasive BC that have a complete IHC assay determination were analyzed (estrogen receptor [ER], progesterone receptor [PR], HER2, p53, KI67). KI67 was determined by monoclonal antibody MIB-1. Patients ´s clinical characteristics and tumor immunohistochemical factors were registered. Patients were divided into 4 groups according to KI67 levels: 1) KI67 < 5%, 2) 6 to 20%, 3) 21 to 50% and 4) > 51%. Descriptive statistical methods and X2, ANOVA tests were used. Results: 154 pts analyzed, mean age 53.5 ± 12 yrs, range 28 -83, median KI67: 25, (0 - 95%). Group 1: 22 pts (14.3%), Group 2: 52 (33.8%); group 3: 49 (31.8%), group 4: 31 pts (20.1%). Median KI67 by group: 5, 15, 30 70%. Among pts with KI67 > 51% we observed: higher proportion of advanced stages (III-IV) [27.3%, 7.7%, 25.6%, 38.7% (p= 0.027)], positive lymph nodes (59%, 25%, 42.8% 70.9%, [p=0.003]), ER negative (27.3%, 5.8%, 28.4%, 51.7% [p= 0.000]), PR negative (36.4%, 26.9%, 22.5%, 61.3%; [p= 0.003]); P53 +ve (9.1%, 71.1%, 73.4%, 77.4%; [p= 0.028]), angiogenesis [> 15 vessels × field] (31.8%, 21.1%, 24.5%, 54.5%; [p=0.006])), triple negative phenotype (4.5%; 3.8%, 10.2%, 41.9%; [p=0.000]). We do not observe correlation among KI67 status age, tumor size and HER2 (p > 0.05). Conclusions: High cellular proliferation through KI 67 (> 51%) was related to poor prognostic factors in BC.

No significant financial relationships to disclose.
Breast cancer in young women less than 30 years from southern India: Study on clinical profile and outcome
Authors: Rejiv R. , Biswajit D. , Neelesh R. , Sridevi V. , Sagar T. G. , Shanta V.
Published: August 2020

e22196

Background: Breast cancer in young patients have an aggressive behaviour with poorer outcome. The patients are in their reproductive age group and are concerned with fertility issues,pregnancy and lactation. The literature pertaining to patients less than 30 years is limited. Methods: 213 Patients under the age of 30 years with breast cancer were studied for Demographics, clinical presentations, pathological profiles, treatment and survival. The case records were retrospectively analyzed between Jan 1993 - Dec 2003 at Cancer Institute (WIA) Chennai. Results: The mean age of the study population was 28 years and ranged between 17 to 30 years. Early menarche, defined as less than 12 years (17.5 %), Nulliparity (21.1%), first child birth less than 18 years (26.8%) were the major risk factors noted. Family history of breast and ovarian cases were seen in 6.6% of the patients. The Stage distribution included Stage I (1.4%), Stage II (31%), Stage III (49.6) and Stage IV (11%) and unclassifiable (7%). Node positive tumours constituted 158 patients (74.1%). Hormone receptor studies were negative in 62% of the patients. Modified radical mastectomy was performed in 164 (77%) of the patients. Non infiltratring ductal carcinoma histopathology was noted in 13.6%. Surgical and radiocastration was performed in 35.2% and 17% of the cases respectively. Of 201 (94.3%) patients who received chemotherapy anthracycline based chemotherapy was delivered in 30.3%. Recurrence pattern included local, local and distant and distant recuurences in 8.5%, 23.5% and 2.3% respectively. The 5 year over all survival for the evaluable patients was 53.2%. Conclusions: Very young Indian patients less than 30 years constitute a unique subset of breast cancer patients with majority being hormone receptor negative and locally advanced stage at presentation. The over all outcome is inferior compared to older patients with breast cancer. More aggressive adjuvant treatment may help in improving survival.

No significant financial relationships to disclose.
Comparison of three methods to detect mutations in the PI3K oncogene in FFPE cancer samples
Authors: Rodgers J. , Murray C. , Leaves N.
Published: August 2020

e22212

Background: PI3Kinase is an important target for new oncology therapies, since it is central to several cell signalling pathways associated with proliferation and survival. Many pharmaceutical companies have PI3K inhibitors in their drug development pipelines all of which are in early phase trials. Activating mutations in exons 9 and 20 of the PI3KCA oncogene have been observed in a number of important cancer types including: gastrointestinal, breast, liver, lung and genito-urinary cancers. The presence of such mutations may prove useful as companion diagnostic biomarkers for prediction of response to therapy. Methods: Source BioScience (Nottingham, UK) tested three different methods for the detection of PI3K mutations in archival tumour samples, in their CPA and GLP accredited laboratories. Eighty formalin-fixed paraffin-embedded (‘FFPE') samples from histologically confirmed breast cancer samples were tested by the new DxS P13K Mutation Test Kit using real-time PCR, by pyrosequencing (Qiagen), and by conventional bidirectional capillary sequencing. Tumour content was evaluated by pathology review. Results: The results of the comparison showed that the DxS test using rtPCR technology was easy to perform, convenient and robust. The DxS test had a high degree of sensitivity provided there was more than 20% tumour content in the test sample as determined by histology and pathology review. Conclusions: In conclusion, the DxS test is a valuable tool for detecting PI3K mutations in FFPE samples from breast cancer patients.

No significant financial relationships to disclose.
Potential diagnostic markers in bronchial fluid of small cell lung cancer (SCLC)
Authors: Carrera Revilla S. , Muñoz A. , Zalacain R. , López-Vivanco G. , Uribarri M. , Simón L. , Calvo B. , Jangi M. , Rubio I. , Ruiz de Lobera A.
Published: August 2020

e22221

Background: Lung cancer is a major cause of mortality worldwide and overall survival rate has not improved significantly over the past 20 years. An early diagnosis could improve prognosis and survival among these patients. The aim of this study was to identify protein markers obtained from bronchial fluids of SCLC patients which may differ from non-pathological bronchoscopy samples. Methods: We have included 43 patients with SCLC diagnosed using bronchoscope and 49 consecutive patients with non pathological bronchoscopy. Bronquial fluid was obtained from each patient and potential protein markers were studied. After being centrifuged, supernatant proteins were analysed using bidimensional electrophoresis with poliacrilamid gel stained with silver nitrate. Gel was scanned and analysed with Progenesis PG6220 program, which measures intensity of each spot. Resultant intensities in each group of patients (SCLC/non pathological bronchoscopy) were compared using T-Student method. We selected as potential markers those spots with a p value of less than 0.05. We calculated “fold change” of each spot as the ratio between mean intensity in SCLC bronchoscopy samples and non pathological bronchoscopy samples. Results: Optimal bidimensional gels of each sample were obtained. Among 300 comparable spots, 10 of them were expressed with a different intensity in both groups of patients; 6 of these potential markers were over expressed in SCLC samples, whereas 4 of them were underexpressed. The “fold change” of these 10 spots ranges from 1.5 to 8.67. Conclusions: Different protein markers can be detected in bronchial fluid obtained from SCLC samples. Significant differences in expression of these biomarkers were detected between SCLC patients and non pathological bronchoscopy patients. The development of an early diagnostic test using these proteins must be validated in future studies.

No significant financial relationships to disclose.
Expression of steroids and HER2-neu receptors in breast tumors associated with BRCA1 gene mutations
Authors: Zarubina N. A. , Petrova V. D. , Sinkina T. V. , Terekhova S. A. , Lazarev A. F. , Boyarskikh U. A. , Pechkovsky E. V. , Mishukova O. V. , Filipenko M. L.
Published: August 2020

e22223

Background: Hereditary breast carcinomas that are attributable to BRCA1 mutations have their own morphological and immunohistochemical characteristics. This study was aimed to analyze the level of expression of steroids (estrogen and progesterone) and HER2-neu receptors in BRCA1 associated breast cancer. Methods: DNA patterns from 264 patients with hereditary breast cancers (breast cancer diagnosed at the age under 40; bilateral breast cancer; combination of breast and ovarian cancers; 2 and more breast cancers in blood relatives). All the patients were residents of the Altai Territory. BRCA1 gene mutations were registered in 34 patients (12.9%): 5382insC gene mutation - in 28 patients; 300A/C - in 2 patients; 4153del - in 3 patients; 185del - in 1 patient. The frequency of the BRCA1 5382insC allele mutation was 7.3; 300A/C - 0.52; 4153del - 0.26; 185del - 0.83. Immunohistochemical characteristics of BRCA1-associated breast tumors tissue from these patients were investigated. Results: 32 BRCA1-associated breast carcinomas were estrogen receptor- negative; 1 - week positive (H-score 50–100); 1 - moderate positive (H- score 100–200). 33 BRCA1-associated breast carcinomas were progesterone receptor- negative; 1 - positive (H-score 200 and more). HER2-negative were 31 BRCA1-associated breast carcinomas; 2 were week positive (HER2-neu +); 1 - was moderate positive (HER2-neu ++). Conclusion: BRCA1-associated beast carcinomas have been found to be more frequently estrogen receptor-, progesterone receptor-, and HER2- negative. These data show that hereditary breast cancer associated with BRCA1 gene mutations poses poor prognosis.

No significant financial relationships to disclose.
Risk and endocrine responsiveness (ER) categories in operated breast cancer (BC) patients (pts) from Tucuman, Argentina
Authors: Holgado S. , Elias de Vacaflor A. , Sanchez Segura M. , Viñuales A. , Audi V. , Raul A. , Vigo G. , Pedruzzi R. , Zarba J. J.
Published: August 2020

e22224

Background: BC is the most common malignancy and the 1st cause of death by cancer in women in Tucuman, Argentina.The expression of hormone receptors and Her 2 neu in tumor tissue with other microscopic variables have shown to be indicators of prognosis and is also useful in therapeutic decisions.The molecular basis for treatment selection is actually the best way for a treatment “target” identification.The objective of this trial was to determine the patients profile in the population with BC under program (all pts studied under methodologic norms of a BC Detection Program) from Tucumán Argentina, defined by risk categories (high, intermediate or low) and endocrine response (high, incomplete or no response)according St Gallen 2007. Methods: The population included in the study were 246 pts with BC from public and private institutions in the province of Tucumán.HE routine biopsies were used for the assessment of histological type and subtype, tumor grade (according to Elston et al. and Nottinghan breast cancer grading method), axillary nodes status, tumor size, and the IHC staining for estrogen, progesterone receptors and Her2 neu.The results were studied grouping and evaluating the data for risk and endocrine responsiveness.The statistic applied was the exploratory analysis.IHC methods were validated with external and internal controls, in 7 cases Her2 was determined also by Fish. Results: 217/246 pts completed all parameters and were classified on risk categories: high (60 patients- 27,6%-); intermediate (156 patients-71,9%-) and low (1 patient-0,5%).No significant differences were found between the ages of groups with different levels of risk.The ER of the pts(n:242/246) showed highly endocrine responsive in 109/242 (45%), incompletely endocrine responsive in 49/242 (20,2%), endocrine no responsive 84/242 (34,7%). and association between endocrine levels of response and age range and tumor size (p <0001 chi-square test and p<0,017). Conclusions: These results are comparable with international data and allows us to know the patients profiles in our population under BC program.

No significant financial relationships to disclose.