bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular markers to differentiate between pancreatic cancer and normal pancreas/chronic pancreatitis: Gene expression profiling study
Authors: Jarzab M. , Olakowski M. , Oczko-Wojciechowska M. , Kowalska M. , Fujarewicz K. , Chmielik E. , Lange D. , Świerniak A. , Jarz'ab B. , Lampe P. 
Published: March 2020

21150 Background: The aim of the study was to analyze the gene expression profile of pancreatic cancer by multivariate methods of class prediction. Methods: The snap-frozen or RNA-later preserved samples of 18 pancreatic adenocarcinomas, 9 chronic pancreatitis cases and 6 specimens collected from microscopically unchanged pancreas (N/CP) were analyzed by HG-U133 Plus 2.0 oligonucleotide microarrays (Affymetrix). The obtained dataset was pre-processed using GC-RMA method, gene selection was carried out both by class comparison methods (Welch test with Benjamini-Hochberg correction, False Discovery Rate FDR<5%) and by our own algorithms of class prediction, based on Support Vector Machines technique (Recurrent Feature Replacement and Bootstrap-Based Feature Ranking). Real- time quantitative PCR (Q-PCR) was carried out on Applied Biosystems 7900 HT machine, with Universal Probe Library (Roche) fluorescent probes and normalization by three reference genes index (geNorm, Vandesompele et al.). Results: We compared gene expression profiles between pancreatic cancer samples and N/CP specimens. 23850 probesets significantly differentiated between these three classes (FDR<5%). No ideal discrimination between cancer and N/CP samples was possible by any of single markers. We selected the optimal multi- gene classifier by Support Vector Machines, using Bootstrap-Based Feature Ranking method. The smallest classifier resulting in 100% accuracy consisted of three genes, 45 genes were included in more than half of the diagnostic genesets obtained during bootstrapping process. 14 genes were selected for Q-PCR validation, again none of them ideally discriminated between cancer and normal specimens, with the area under the receiver-operating-characteristic curve ranging from 0.82–0.93. Three-gene combinations allowed for proper classification of all samples. Conclusions: The multi-gene classifier, derived both by microarray technique and Q-PCR analysis, is properly discriminating between pancreatic cancer and chronic pancreatitis/normal pancreas. At least three genes must be included in the classifier to obtain satisfying accuracy. MO and MJ equally contributed to the study. No significant financial relationships to disclose.
Epitope mapping of epidermal growth factor receptor (EGFR) in lung cancer using immunohistochemistry: Fine tuning the protocols
Authors: TIMAR J. , Derecskei K. , Dome B. , Moldvay J. 
Published: March 2020

21162 Background: Until now, immunohistochemistry was not able to become a reliable diagnostic approach for EGFR targeted therapies. The golden standard of the determination of EGFR protein expression in paraffin embedded cancer tissues is the EGFRpharmDXtm kit. Methods: Here we show data based on analysis of 110 lung adenocarcinomas, that the recommended protocol may not be optimal for ideal performance of the immunodetection, since microwave retrieval, extended primary antibody-incubation time and replacement of the developer reagent converted four EGFR-negative tumor into EGFR protein positive out of eight lung adenocarcinoma cases. Protocol modification improved the performance of another widely used EGFR-kit, Ventana's CONFIRM, where replacement of the protease antigen retrieval with microwave cooking converted several EGFR-negative tumors to strongly positive. Meanwhile both EGFR-kits detect EGFR expression (juxtamembrane domain) but do not provide information on the expression of epitopes critical from the point of view of targeted therapy. Results: We have developed two protocols, which can detect the ligand-binding (AB-10, BioMarkers) and C-terminal (AB- 335, Biogenex) cytoplasmic domains of the EGFR protein in paraffin embedded lung cancer tissues. We have shown, based on the analysis of more than 110 lung adenocarcinoma tissues, that the ligand binding domain of EGFR is rarely expressed while the C-terminal domain is ubiquitously expressed in EGFR-PharmDX and CONFIRM-positive cancers. The biological activity of EGFR can be characterized either by autophosphorylation of the receptor or by detection of divers phosphorylated downstream signaling components. We have found that unlike p1086 (detected by a Zymed antibody), the p1173 site of EGFR (identified by a rabbit monoclonal of Epitomics) can be detected 27/110 paraffin embedded lung adenocarcinomas. Conclusions: Using the tested antibody panel we can reliably determine the EGFR protein expression in paraffin embedded (lung)cancer tissues. This work was supported by Ministry of Education (NKFP1a-0024–05). No significant financial relationships to disclose.
The alternation of estrogen receptor (ER) and progesterone receptor (PgR) expression in primary breast cancer patients treated with neoadjuvant chemotherapy (NAC)
Authors: Kitagawa D. 
Published: March 2020

21165 Background: Currently, neoadjuvant chemotherapy (NAC) for the operable primary breast cancer has become standard treatment strategy. Primary treatment could affect the status of Estrogen receptor (ER) and Progesterone receptor (PgR) expressions in the tumor, and might have impact on the choice of adjuvant hormone therapy. Methods: We evaluated consecutive 165 primary breast cancer cases those treated with 4 cycles of FEC (500–100–500 mg/m2, q3wks) followed by 4 cycles docetaxel (75 mg/m2, q3wks) as their neoadjuvant treatment in our institution from January 2000 to February 2006. Except for the bilateral breast cancer cases and patients achieved pCR, 107 pairs of core needle biopsy before treatment and tumor block after surgery were evaluated by immunohistochemistry (IHC) for receptor status and analyzed by Allred scoring. Score 4 or more was designated as positive. Results: Median age of patients was 51 (23–71) years old. Hormone receptor (HR) phenotypes before treatment were following; ER+/PgR+:62(57.9%), +/ -:23(21.5%), -/ +:2(1.9%), -/ -:20(18.7%). As the HR status, 94.4 % of patients did not show any alternation for their HR evaluation. Only 4.7% of patients experienced changes from HR+ to HR-, and HR- to HR+ were extremely rare (0.9%). Although ER positivity was not changed in most of cases (95.1%), conversion from PgR + to - were observed in 35.5% of ER+/PgR+ cases. Particularly, the rate of negative conversion of PgR were found more frequently in patients with age under 50 (51.7% in <50y.o. vs. 22.6% in =50 y.o., p=0.03). Whereas, in older patients, negative conversion of PgR correlated to favorable pathological response. Conclusions: In most of patients, neoadjuvant chemotherapy did not affect the evaluation of HR status. Alternation of PgR expression seems to reflect the chemotherapy induced amenorrhea in younger patients. In the older patients, negative conversion of PgR may have some impact on pathological response. No significant financial relationships to disclose.
A novel case of Silver Russell Syndrome (SRS) and male breast cancer
Authors: Hamm C. M. , Jagiello L. 
Published: March 2020

21178 Introduction: Silver Russell Syndome (SRS) is a heterogeneous disorder of asymmetric growth retardation and typical dysmorphic features often associated with maternal disomy 7 and chromosome 17q23–24. The BRCA1 gene is found on 17q21. The relationship between SRS and breast cancer has not been described to date. Case Presentation: We report a case of a 37 year old male diagnosed with metastatic breast cancer involving the liver and bone. Patient presented with a left proximal hip fracture related to metastatic bone disease. Biopsy of the right breast lesion revealed a moderately differentiated adenocarcinoma consistent with breast primary. Abdominal ultrasound and full body bone scan revealed extensive liver and bone metastases. There was no significant family history of cancer, specifically breast nor ovarian cancer. Discussion: The BRCA2 gene is known to be responsible for DNA repair. The SRS cases associated with chromosome 17q24–25 abnormalities are known to be associated with growth hormone deletions. Further investigations into this relationship are warranted. No significant financial relationships to disclose.
Identification of a new cancer/testis antigen from small cell lung cancer
Authors: Lee M. , Kim K. 
Published: March 2020

21182 Background: Serological analysis of recombinant cDNA expression libraires has led to identification of tumor antigens, which are considered promising candidates for early detection and immunotherapy. They are recognized by the immune system of cancer patients including small cell lung cancer (SCLC) patients. Methods: SEREX method was used to screen normal testis and NCI-H889 cell line cDNA library with serum obtained from a SCLC patient who has survived over 50 months. Also SADA test was done to SCLC patients and normal serum. Results: Immunoscreening of libraries with the selected serum led to the isolation of 58 (SCLC-1 through SCLC-58) and 18 (SCLCT-1 and SCLCT-18) independent antigens from NCI-H889 and testis respectively. Of these SCLCT-1 mRNA was expressed strongly only in normal testis. According to the SADA test, SCLCT-1 was only found in SCLC patients’ sera (34%). Conclusions: On the basis of its immunogenecity in SCLC patients’ sera, and its restricted mRNA expression profile, SCLCT-1 can be considered a novel CT antigen. No significant financial relationships to disclose.
Prospective study on prognostic significance of DNA ploidy and Ki-67 expression in colorectal cancer
Authors: Saggia C. , Santagostino A. , Forti G. , Biaggi G. , Angeli G. , Dacorsi M. , Cerrato D. , Loi G. , Porcile G. , Alabiso O. 
Published: March 2020

21184 Background: The prognostic value of flow cytometry DNA ploidy and Ki-67 expression in colorectal carcinomas has not been defined yet. The study tries to correlate tumoral DNA ploidy and proliferative activity (Ki-67) with therapy response, Overall Survival (OS), Disesase Specific Survival (DSS) and Disease Free Survival (DFS). Methods: From 01/09/02 to 30/06/05, 3 samples of cancer tissue and 1 sample of normal mucosa has been collected from all operating pieces of colorectal cancer. These samples were frosen and later disgregated, treated and coloured with Propidium Iodide. DNA ploidy was evaluated by FACSCalibur cytofluorimetry. Normal mucosa tissue was our internal control. Ki-67 was evaluated by immuno-histochemistry in all tumoral samples. All the patients were cured with chemo- and/or radiotherapy in our divisions. Results: 67 patients (M/F 35/32); median age was 70; staging: 19% I, 33% II, 30% III, 18% IV. We found aneuploidy in 65,7% of carcinoma and Ki-67 median expression was 55%. DNA tumoral heterogeneity was present in 27% of patients. DNA aneuploidy correlates with advanced disease stage at diagnosis (p<0,01), with high number of metastatic lymphnodes (p<0,005) and with serological markers positivity (p<0,04). After surgery and chemotherapy 35% of the patients with aneuploid carcinoma and high proliferative activity (Ki-67>55%) do not show evident disease versus 100% of patients with DNA diploidy and lower Ki-67. Tumoral aneuploidy correlates in a significative way with lower OS (48% vs 89% of diploid patients), lower DSS (tumor death happened just in patients with aneuploid DNA in every disease stages), with lower DFS (18% vs 86% of diploid patients). Univariated analysis stated that aneuploidy determinates an Odd Ratio=5,7 to develop disease progression (p=0,033). At the moment Ki-67 expression with 55% cut-off does not seem to correlate with OS, DSS and DFS. Conclusions: Preliminar results (the study is still in progress) seem to suggest that cytofluorimetric DNA-ploidy has a prognostic and predictive significance in colo-rectal carcinomas. Ki-67 expression (immuno-histochemistry) has an uncertain significance. The small number of patients and the short follow-up do not allow us to reach any definitive conclusions, but the study is worth to go on. No significant financial relationships to disclose.
Reproductive risk factors of breast cancer in elderly population. A single centre study
Authors: Torregrosa D. , Gironés R. , López P. , Díaz Beveridge R. , Maestu I. 
Published: March 2020

21187 Background: Relationship between reproductive variables and cancer risk has been yet established. Protective effect of late age at menarche (≥ 11) and high parity (≥ 4) and the increased risk of nulliparous women, older age at first birth (AFB) (≥ 28) and older age at menopause (≥ 52) seems to act differently in pre vs. postmenopausal elderly women. The aim of this study was to describe recognized reproductive risk factors for breast cancer in a selected population of a single centre. Methods: A cross- sectional study of women diagnosed ≥ 70 years. We selected women with removed early breast cancer and on follow-up. No disease recurrences were allowed. Between January 2005 to June 2006. Described reproductive risk factors for breast cancer were collected. Tumour characteristics also. Results: 91 patients were recruited. Mean age at time of diagnosis: 76 (70–92); mean age at study 80 (71- 95). Reproductive factors: late age at menarche (12; 9–16; percentile 75: 14) and late age at menopause: 48 (29–56); 75% ≥ 52 years old were common. Nulliparous women were similar at described in other series (10%); parity 2 (0–9); percentile 75: 3;late AFB: 26 (19–40); percentile 75: 29 years. No one had taken hormonal treatment. Only 16% had familiar history of breast cancer and 9% personal history. Almost all (84%) had positive tumours for the oestrogen receptor and 76% for progesterone receptor. 91% had ductal histology and 54% had II stage. Conclusions: Discussion: unexpected associations between classical reproductive risk factors and breast cancer on elderly patients have been described in other series. It seems that late age at menarche and late age at menopause is common in elderly breast cancer population, as in our serie. Nulliparous elderly continue to have risk but seems that the protective effect of parity dissipated in these population. Older age at first birth (≥28) is consistently associated with increased breast cancer risk. Conclusion: our study is based on a high selected population and clearly has a selection bias. Our results cannot be generalized to other populations but describes our patients. The results therefore should be internally valid. And it seems to coincide with other studies. No significant financial relationships to disclose.
Genetic variants in human carbonyl reductase 3 (CBR3) and their influence on doxorubicin pharmacokinetics in Asian breast cancer patients
Authors: Fan L. , Guo J. Y. , Wong C. I. , Lim R. , Yap H. L. , Khoo Y. M. , Iau P. , Goh B. C. , Lee H. S. , Lee S. C. 
Published: March 2020

2505 Background: Human carbonyl reductase 3 (CBR3) is one of the main metabolizing enzymes to extensively reduce doxorubicin to its major active metabolite, doxorubicinol in normal and tumor tissues. Recently, the CBR3 958G>A (V244M) genetic variant has been described to alter function in vitro. We postulate that CBR3 genetic variants could contribute to the inter-individual variability of doxorubicin pharmacokinetics in breast cancer patients. Methods: We studied 101 female breast cancer patients (66 Chinese, 26 Malay, 7 Indian and 2 of other ethnic origins) who were treated with doxorubicin at 75mg/m2 every 3 weeks. Comprehensive sequencing of the 3 exons of CBR3, including the splice-site junctions was performed. Plasma concentrations of doxorubicin and doxorubicinol were analyzed during the first doxorubicin cycle. Results: Five CBR3 coding region variants (239G>A, 483C>T, 507C>T, 598G>A and 958G>A) were detected, of which 239G>A, 598G>A and 958G>A were non-synonymous. 598G>A was novel, and was found in 1 Malay patient who was heterozygous. The genotype distributions of 239G>A and 958G>A were 36%/30%/34%, and 40%/36%/24% respectively for GG/AG/AA. The 239GG variant was associated with significantly higher AUC of doxorubicinol and AUC ratio of doxorubicinol to doxorubicin than the AG and AA variants (AUC of doxorubicinol 2.18±1.37ug/ml*h (GG) vs 2.04±2.11ug/ml*h (AG), p=0.05, and 1.55±0.61ug/ml*h (AA), p=0.004; AUC ratio of doxorubicinol to doxorubicin 1.90±1.29 (GG) vs 1.72±1.34 (AG), p=0.025, and 1.45±0.67 (AA), p=0.006). Patients with the 958AA variant had significantly higher AUC of doxorubicinol than those with the 958GG variant (2.29±1.60ug/ml*h vs 1.56±0.60ug/ml*h, p=0.009). The 239GG variant was more common in our population than in Caucasians (36% vs 20%. p=0.027), while the 958AA variant was more common than reported in Caucasians (24% vs 8%, p=0.014) and Japanese (24% vs 7%, p=0.016). Conclusions: CBR3 genetic variants may influence the pharmacokinetics of doxorubicin and its major metabolite doxorubicinol. Inter-ethnic differences in frequencies of CBR3 genetic variants exist and may account for differences in pharmacokinetics and pharmacodynamics of doxorubicin between different populations. No significant financial relationships to disclose.
Final results of a phase I clinical trial of the bioreductive drug RH1
Authors: Danson S. , Johnson P. , Ward T. , Dawson M. , Denneny O. , Watson A. , Jowle D. , Sharpe P. , Dive C. , Ranson M. 
Published: March 2020

2514 Background: RH1 (2,5-diaziridinyl-3-[hydroxymethyl]-6-methyl-1,4-benoquinone) is a novel bioreductive drug which is activated by the two electron reductase, DT-diaphorase (DTD) (NAD(P)H:quinone oxidoreductase). DTD is over-expressed in many tumors relative to normal tissue, especially lung, breast and colorectal tumors, so it is hoped that RH1 is selectively activated in such tumours with minimal normal tissue toxicity. Methods: Under the auspices of the CR-UK Drug Development Office, a dose escalation phase I trial of RH1 was performed at two centres. The primary objective was to establish the maximum tolerated dose (MTD) of RH1 given as a 10–30 minute infusion for 5 days every 3 weeks. Toxicity was assessed according to NCI CTC V2.0 criteria. Secondary objectives were to determine RH1 pharmacokinetics (PK), DNA cross-linking in peripheral blood lymphocytes and tumour cells, DTD activity in tumour, NQO1 polymorphism status and document any anti-tumour activity. Results: Eighteen patients of WHO performance status 0–1 with advanced refractory solid malignancies were enrolled. 14 patients were male and eight patients had colorectal adenocarcinoma. The MTD was 1,430 mcg/m2/day and the dose-limiting toxicity (DLT) was bone marrow suppression. DLT occurred in both patients treated at 1,905 mcg/m2/day: one developed grade 3 thrombocytopenia with haemorrhage and grade 3 anaemia; the other died from neutropenic sepsis. Other clinically significant drug-related toxicities included moderate phlebitis and fatigue. Plasma PK analysis on days 1 and 5 in cycle 1 showed rapid plasma clearance of RH1 (t1/2=12.3 mins) with AUC increasing proportionately with dose. The comet-X assay showed increases in DNA inter-stand cross-linking in peripheral blood lymphocytes treated at 200 mcg/m2/day or above. These cross-links were detectable within one hour of commencement of dosing and reached a maximum of 30%. DNA cross-linking after RH1 was seen in tumour samples, even with low levels of DTD. One patient was homozygous for the NQO1 polymorphism. No objective tumour responses were recorded. Conclusions: The MTD of 1,430 mcg/m2/day is the dose recommended for phase II clinical trials. Tested doses were associated with DNA cross-linking in both peripheral blood lymphocytes and tumour cells. No significant financial relationships to disclose.
A phase I study of MGCD0103 given as a twice weekly oral dose in patients with advanced leukemias or myelodysplastic syndromes (MDS)
Authors: Lancet J. E. , Nichols G. , Assouline S. , Ward M. , Burton M. , Mintz M. , Rousseau C. , Kalita A. , Brabant P. J. , Odenike O. 
Published: March 2020

2516 Background: Small molecule inhibitors of histone deacetylase (HDAC) have emerged as novel anticancer agents. MGCD0103 is an oral isotype selective small molecule inhibitor of HDAC. Methods: Eligible patients had relapsed/refractory (RR) AML or MDS (or newly diagnosed disease in patients >60 yrs, ineligible for induction chemotherapy); RR ALL; RR CML. MGCD0103 was administered 2x/weekly for 3 weeks, with no recovery period between cycles. Patients with stable disease or better were eligible to continue therapy indefinitely. Results: Patients have been treated at 4 dose levels: 40, 53, 66 and 83 mg/m2/day, including 19 enrolled patients with the following demographics: M:F = 15:4, median age (range) = 75 (52–83), ECOG 0:1:2 = 5:12:2, diagnosis of RR MDS= 7, RR AML or RR ALL=8: untreated AML or MDS = 4. Cytogenetics (n=12): Diploid = 3, Complex = 4, Del 7 = 3, Del 12 = 1, Del Y = 1. Nineteen patients are evaluable for safety. A total of 38 cycles have been administered with a median of 2 per patient (range, 1–6); 13 patients have completed =2 cycles. One patient experienced grade 3 fatigue at 53 mg/m2 and 2 patients had grade 3 weakness/fatigue at 83 mg/m2 (exceeded the Maximum Tolerated Dose [MTD]) Non-dose-limiting toxicities included lower grade fatigue, diarrhea, and nausea. Plasma PK in 14 patients revealed t 1/2 of 7–12 hr, tmax 0.6- 1 hr, and a dose proportional average Cmax of 155 ng/mL at 40 mg/m2 and 225 ng/mL at 53 mg/m2. Significant inhibition of whole cell total HDAC activity within PBMC was observed in a majority of patients, at all dosing levels. Four patients have experienced stable disease. Conclusions: MGCD0103 has been well-tolerated in patients with advanced leukemias or MDS. MTD has been reached, and the recommended phase II 2x/week dose is being confirmed. At all dose levels, significant HDAC inhibition was observed. [Table: see text]