bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nuclear factor-kB (NF-kB), p53, survivin, Ki-67, and Bcl-2 as prognostic factors in locally advanced rectal cancer patients receiving radiochemotherapy
Authors: Berardi R. , Mandolesi A. , Onofri A. , Maccaroni E. , Mantello G. , Bearzi I. , Scartozzi M. , Pierantoni C. , Marmorale C. , Cascinu S. 
Published: August 2020

e22062 Background: NF-kB, p53, Survivin, Ki-67 and Bcl-2 expressions have been demonstrated to be prognostic factors in solid tumors. The aim of our analysis was to investigate the importance of their expression, as prognostic factors in patients with locally advanced rectal cancer patients receiving receiving neoadjuvant radiochemotherapy Methods: We analyzed the expression of NF-kB, p53, Survivin, Ki-67 and Bcl-2 in patients with locally advanced rectal cancer who underwent neoadjuvant treatment (radiotherapy ± chemotherapy) at our Department Results: Seventy-four patients were eligible for our analysis. Median age at diagnosis was 66 years (range 36–85). Male/female ratio was 47/37; 37 patients (90%) were diagnosed with adenocarcinoma, whilst 4/41 (10%) with mucinous adenocarcinoma. All the patients received radiotherapy ± 5-fuorouracil/capecitabile-based chemotherapy. Median follow up was 28 months (range 6,7–56,6 months). At univariate and multivariate analysis of the above mentioned parameters, NF-kB, Ki67 and bcl-2 showed an impact on outcome.In particular, in NF-kB-strongly positive patients time to progression (TTP) and overall survival were significantly shorter (p=0,011 and p=0,018 respectively). Moreover a high expression of Ki-67 and a low expression of bcl-2 were associated with a better TTP Conclusions: Our results suggest that NF-kB, bcl-2 and Ki-67 could represent important parameters able to predict the outcome in patients receiving neoadjuvant treatment for rectal cancer. Further prospective studies are warranted in order to confirm the prognostic role of the above mentioned factors in this setting. This could be useful in order to select patients to receive adjuvant chemotherapy after neoadjuvant treatment and surgery for locally advanced rectal cancer, intensifying the adjuvant therapy in some groups of patients and obviating the use of the some drugs (i.e. those involving NF-kB in their mechanism of action) in selected patients No significant financial relationships to disclose.
Differential outcomes in patients treated with endocrine therapy for early or locally advanced breast cancer based on BRCA mutation status
Authors: Wesolowski R. , Shealy A. G. , Tao J. , Moore H. C. 
Published: August 2020

e22065 Background: Mutations in BRCA1 and BRCA2 genes lead to defects in DNA repair. Estrogen receptor modulates transcription of genes responsible for cell division, which depends on cell's ability to repair DNA for genomic integrity. Differential efficacy of endocrine therapy for breast cancer, therefore, may be possible depending on the tumor's BRCA mutation status. Methods: Through an IRB approved registry, breast cancer patients tested for BRCA1 and BRCA2 mutations and treated with endocrine therapy for hormone-receptor positive non-metastatic disease were identified. Primary and secondary endpoints were overall survival (OS) and progression-free survival (PFS) respectively. Fisher's exact test or Wilcoxon rank sum test were used to assess differences among subgroups with respect to their characteristics. Cox proportional hazard analysis was used to identify univariate and multivariate risk factors for OS and PFS. Results: Of 115 breast cancer patients tested for BRCA mutations, 63 met the inclusion criteria of whom 16 patients were BRCA 1 or 2 mutation positive and 47 were negative. In the BRCA(+) group, 14 patients (87.5%) had stage I-III disease at diagnosis. In the BRCA(-) group, 5 patients (10.6%) had stage 0 disease while 41 patients (87.2%) had stage I-III disease at diagnosis. Stage at diagnosis was unavailable for 2 BRCA(+) and 1 BRCA(-) patients. Both groups were similar with respect to Her-2 expression status, history of ovarian suppression, age of diagnosis, and age of menopause. Median age was 48 yo in BRCA(+) group, 42 yo in BRCA(-), (p=0.12). Median follow up was 76.1 mos in BRCA(+) and 62.9 mos in BRCA(-) group. OS was worse in BRCA(+) group (HR 7.38, 95% [CI] 1.49–36.4 p=0.014). After adjustment for stage and history of ovarian suppression, the difference remained significant (HR 16.6, 95% [CI] 1.95–142, p=0.010). There was no difference in PFS (HR 2.02, 95% [CI] 0.82–4.96, p=0.13). Conclusions: Patients with BRCA mutation, hormone-receptor positive hereditary breast cancer treated with endocrine therapy had inferior survival compared with similar patients who are BRCA mutation negative. Prospective studies to evaluate the differential effects of endocrine therapy in these populations are warranted. No significant financial relationships to disclose.
Molecular changes in epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC) biopsies at time of progression compared to initial biopsy
Authors: Speranza G. , Cohen V. , Agulnik J. S. , Chong G. , Meilleur F. , Brandao G. , Kasymjanova G. , Small D. , Miller W. H. 
Published: August 2020

e22066 Background: EGFR mutations predict sensitivity and clinical outcome to tyrosine kinase inhibitors (TKI) in NSCLC. The two most commonly described mutations are Exon 19 deletion and Exon 21 L858R missense mutations. Genetic alterations over time have been described in other tumour types, but studies assessing EGFR genotypic changes with lung cancer progression are lacking. We sought to compare EGFR mutational status from lung tumors at time of recurrence or progression with the primary tumor. Methods: Using the Jewish General Hospital lung cancer database, of all patients diagnosed with NSCLC since 1999, those with biopsies at two different points in time were identified. All tumour samples were genotyped for EGFR exons 19 and 21 mutations using denaturing high performance liquid chromatography (dHPLC). Results: 29 patients were identified. Data for 12 patients, whose time of recurrence or progression varied between 4 months and 6 years, are available at this time. Of 12 patients, one had EGFR exon 19 mutation at time of diagnosis. One patient who initially displayed no EGFR mutation was found to have an exon 19 deletion at time of recurrence. The one with exon 19 at time of initial diagnosis continued to express exon 19 in the second biopsy. Conclusions: To our knowledge, this is the only study assessing changes in molecular genotype using dHPLC between primary and recurrent or progressive lung cancer biopsy specimens. Although sample size is small, it is evident that changes in EGFR mutational status can occur. Further prospective studies are required to determine how commonly molecular changes occur. No significant financial relationships to disclose.
MicroRNA-based assay for differential diagnosis of mesothelioma
Authors: Benjamin H. , Lebanony D. , Tabak S. , Barabash N. , Gibori H. , Morgenstern S. , Meiri E. , Bentwich Z. , Rosenwald S. , Cohen D. 
Published: August 2020

e22079 Background: Malignant mesothelioma is an aggressive pleural neoplasm, strongly linked to environmental exposures such as asbestos. Mesothelioma can be difficult to differentiate from other tumors in the lung or pleura such as primary lung adenocarcinoma presenting with pleural effusion or metastatic adenocarcinoma from extrathoracic sites. We addressed the increasing need for accurate differential diagnosis of these tumors by developing a diagnostic assay based on expression levels of microRNAs, a family of small, non-coding RNAs whose tissue-specificity has proven applicability for identification of cancer tissue type and histology. Methods: We developed protocols for extraction of high-quality RNA that retain the microRNA fraction from FFPE tissue samples. Microarrays were used for initial profiling. qRT-PCR was used to validate results and to develop a diagnostic assay. Results: We identified microRNAs that are differentially expressed between mesothelioma, lung adenocarcinoma, and other confounding tumor types. A diagnostic assay (miRview™ meso) was developed, that utilizes qRT-PCR measurement of a small set of microRNAs to differentiate between mesothelioma and non-mesothelioma samples. After establishing this profile in more than 30 mesotheliomas and 200 samples of confounding tumors, the microRNA biomarkers were measured using a standardized protocol on a blinded test set. The assay had accuracy greater than 90% in differentiating mesothelioma from other confounding tumor types. More than ¾ of samples were classified with high confidence, and these samples were all correctly identified. Conclusions: MicroRNAs are emerging as effective cancer biomarkers. A robust and simple assay based on the expression level of a few microRNA biomarkers can accurately differentiate mesothelioma from other possible tumors in the lung and pleura. This assay provides an important new tool for diagnosing mesothelioma. [Table: see text]
Use of multidrug-resistance gene (MDR1) expression levels to predict outcome to adjuvant cisplatin/gemcitabine based chemotherapy in patients with with locally advanced urothelial cancer
Authors: Gauler T. , Hoffman A. C. , Wild P. , Leicht C. , Bertz S. , Danenberg K. D. , Stöhr R. , Stöckle M. , Eberhardt W. E. , Lehmann J. , Hartmann A. 
Published: August 2020

e22081 Background: The human MDR1 gene encodes an integral membrane protein, P glycoprotein (Pgp), whose function is the energy dependent export of substances from the inside of cells, and from membranes, to the outside. MDR1 mRNA levels have been shown to influence metabolism of cancer drugs. We tested whether MDR1 gene expression is associated with outcome in patients with locally advanced bladder cancer. Methods: 43 formalin fixed paraffin embedded (FFPE) tumor samples from patients with locally advanced and/or lymph node-positive bladder cancer undergoing treatment with cisplatin/gemcitabine were analyzed.FFPE tissues were dissected using laser-captured microdissection and analyzed for MDR1 expression using a quantitative real- time RT-PCR method. Gene expression values (relative mRNA levels) are expressed as ratios between the target gene and internal reference gene (beta-actin). Results: MDR1 was significantly correlated to overall survival. We included tumor stage (pT), lymph node status (pN) and the blood vessel invasion along with the measured gene expression in a stepwise multivariate Cox proportional hazards regression model. The overall model fit had a significance level of p=0.04 (<0.05). The relative risk for shorter survival in patients with High MDR1 expression was 1.9. Conclusions: These results suggest that MDR1 gene expression levels predict response and overall survival in patients with locally advanced urothelial cancer. MDR1 gene expression levels may allow the selection of patients who benefit likely from adjuvant cisplatin/gemcitabine based chemotherapy. Further studies are warranted to study this association. [Table: see text]
The role of HER3 on HER2-driven gallbladder carcinogenesis and possible HER2/HER3 targeting therapy by pertuzumab for gallbladder canrcinoma
Authors: Kawamoto T. , Ishige K. , Sugiyama H. , Onuki K. , Krishnamurthy S. , Thomas M. , Yamamoto M. , Shoda J. 
Published: August 2020

e22083 Background: ErbB2 has been known to be important for gallbladder carcinogenesis. Supporting this, the gene amplification of HER2 was found in ca. 20% of human gallbladder carcinoma (GBC) (Kawamoto, et al. Gastrointest Cancer Res 2007). Following these results, a Phase II study of trastuzumab for treatment of GBC (NSC 688097) is being conducted. Although the mechanism of HER2 activation is not well understood, the role of HER3 in HER2-driven tumorigenesis has been discussed and we have concluded that HER2/HER3 heterodimerization might be important for GBC cell proliferation (ASCOGI 2009, ab#155). In this study, we determined HER family expressions in human GBC and examined the effect of pertuzumab against human GBC cell lines. Methods: Tissues from 47 GBCs and 6 non-cancerous gallbladders were examined. All cases were screened for HER1, HER2, HER3 expressions by immunohistochemistry (IHC) and those HER family gene amplification by fluorescence in situ hybridization (FISH) were performed. 6 human GBC cell lines were also analyzed by Western blotting and FISH as well and their growth assays were investigated with heregulin stimulation to confirm the existence of HER2/HER3 heterodimerization. Then, GBC cells were cultured with heregulin and various doses of pertuzumab for 72 hours and CCK-8 assay was performed. Results: HER3, HER2 and HER1 overexpression by IHC was found in 34%, 32% and 19% of GBCs, respectively. Phosphorylated (p-) HER2 and p-HER1 were found in 23% and 11% of GBCs, respectively. FISH analysis was considered successful in the same serial sections. HER3, HER2 and HER1 FISH (+) was found in 26%, 19% and 4% of GBCs, respectively. Three of 6 GBC cell lines were recognized their growth curves with heregulin were increasing. These 3 cell lines showed good responses to the treatment with pertuzumab. Conclusions: More than 20% of GBC over-expressed either HER2 or HER3. These HER2 and HER3 may form heterodimer, which in turn results in the activation of HER2. The cell lines proliferating with the administration of heregulin showed good responses to the pertuzumab treatment. Therefore, HER2/HER3 heterodimerization may be an ideal biomarker for the treatment by pertuzumab and this agent may be a new therapeutic regimen for GBC. No significant financial relationships to disclose.
Immunohistochemical analysis of tumor regression grade for rectal cancer after neoadjuvant chemoradiotherapy
Authors: Moreno Garcia V. , Cejas P. , Feliu J. , De Castro J. , Belda-Iniesta C. , Barriuso J. , Larrauri J. , Gonzalez Baron M. , Casado E. 
Published: August 2020

e22089 Background: Tumor regression grade (TRG) as defined by Rodel et al. has been suggested as an independent prognostic factor for rectal carcinoma patients treated by preoperative chemoradiotherapy (CRT). However TRG 2 and 3 determination, semiquantitatively defined as more/less than 50% tumor regression, respectively, do not clearly correlate with prognosis. TRG 2 vs 3 discrimination is largely subjective hurdling prognostic analysis. The purpose of our study was to find an immunohistochemical pattern to better stratify these patients according to prognosis in term of disease free survival (DFS) and overall survival (OS). Methods: Immunohistochemistry of EGFR, VEGF, CD133, p53 and Ki67 was evaluated by tissue microarrays on surgical specimens from 88 patients. Preoperative chemotherapy was UFT-LV (30%) or oxaliplatin-based (70%) plus pelvic radiotherapy (50 Gy) followed by mesorectal excision. TRG was determined by the amount of viable tumor versus fibrosis, ranging from TRG 4 when no viable tumor cells were detected, to TRG 1 when regression was less than 25%. TRG 2 and 3 were defined as described above. Univariate analyses were performed according to the Kaplan-Meier method. Comparisons between curves were evaluated by the log-rank test. Cox regression was used for the multivariate analysis. Results: At a median follow-up of 39 months, the TRG was an independent predictor of DFS (p=0.05) and OS (p=0.001) but no differences were found between TRG 2 and 3 in terms of DFS (p=0.74) or OS (p=0.41). Our results show an immunohistochemical bad prognostic profile for tumors TRG 2 and 3 configured by double negativity of EGFR and CD133 expression (less than 5% of tumor cells membrane immunoreactivity for both antibodies). 3-year DFS and OS for these patients (vs. TRG 2 and 3 not-double negative) were 33 vs 65% (p=0.05) [HR=2.4 (95%CI, 0.9–6.1) p=0.06] and 77 vs 95% (p=0.06) [HR=4.1 (95%CI, 0.7–21.5) p=0.09]. Conclusions: The EGFR/CD133 double negative rectal tumors with TRG 2 or 3 after chemoradiotherapy show a higher risk of relapse or death. These results can help clinicians to determine better individual prognosis and are worth to confirm prospectively. No significant financial relationships to disclose.
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]