bluuebunny/crossref_metadata_2025_split huggingface dataset:
Estimation of expected survival time using gene expression profiling for tumor site origin.
Authors: Henner William David , Nystrom J. Scott , Hainsworth John D. , Varadhachary Gauri R. , Greco Frank A. , Amin Mahul , Walker Michael , Becker Shawn , Pillai Raji , Stein Sandy , Hornberger John C. 
Published: March 2020

10584 Background: Expected survival is an important factor in treatment selection and patient decision making. Gene expression profiling for tissue of origin (GEP TOO) can be used to classify metastatic and poorly-differentiated tumors according to the most likely primary site for difficult-to-diagnose tumors. The Pathwork Tissue of Origin Test, (Redwood City, CA) generates Similarity Scores (SS), one for each of the 15 tissues on the Tissue of Origin Test Panel and sum to 100. The highest SS has been validated as the most likely tissue of origin in a large validation study (Pillai et al. 2010). This abstract reports the relationship between the highest SS for a sample and patient survival. Methods: Two cohorts were analyzed in IRB-approved studies. Cohort 1 consisted of 45 patients with carcinoma of unknown primary treated empirically with therapy for carcinoma of unknown primary with known outcome data including survival. Cohort 2 consisted of 107 patients receiving the TOO test in routine clinical practice and included in a decision impact registry study. The relationship between the highest SS generated by the TOO test was examined using parametric (Gamma) and non-parametric (Cox Proportional Hazards) regression models with covariates of age, gender and median survival of the cancer type indicated. Logrank tests were performed to compare survival in patients with SS above or below 50 in each cohort. Results: The highest SS generated by the TOO Test was strongly and positively correlated with patient survival in both Cohort 1 (p = 0.0093, Cox PH) and in Cohort 2 (p=0.0045, Gamma). In Cohort 1, survival for patients with a SS < 50 was 5.9 mos and for patients with a SS ≥ 50 was 9.7 mos (p=0.03, logrank). In Cohort 2, survival for patients with a SS < 50 was 10.6 mos and 22.6 mos for patients with a SS ≥ 50 (p=0.0073, logrank). Conclusions: The Similarity Scores generated by GEP TOO Test have been validated as an aid to diagnosis for difficult-to-diagnose malignancies. Two independent studies of this GEP TOO Test demonstrated a strong positive relationship between the highest SS and survival. This has the potential to expand the clinical utility of this test beyond diagnosis to include prognosis. Further studies to examine this question are underway.
Novel malignant-mesothelioma-associated antigens (Gene-X and THBS-2) in the diagnosis of malignant pleural mesothelioma (MPM).
Authors: Tanaka Fumihiro , Shigematsu Yoshiki , Hanagiri Takeshi , Uramoto Hidetaka , So Tomoko , Yoneda Kazue , Takuwa Teruhisa , Hashimoto Masaki , Matsumoto Seiji , Okumura Yoshitomo , Kondo Nobuyuki , Hasegawa Seiki 
Published: March 2020

10585 Background: Malignant pleural mesothelioma (MPM) is a highly aggressive malignant tumor of the pleura associated with asbestos exposure, and its diagnosis is usually difficult at early stage. We identified novel mesothelioma-related antigens, Gene-X and thrombospondin-2 (THBS-2), recognized by tumor-infiltrating B cells (Cancer Sci 2009), but the clinical significance in the diagnosis of MPM remains unclear. Methods: A total of 120 patients, who presented with a suspicion of MPM and received pleural biopsy, were reviewed; 97 patients were finally diagnosed with MPM and 27 were with non-malignant diseases (NM). The antibody-titers against Gene-X and THBS-2 in the sera were measured by ELISA method. Results: The serum antibody-titer against THBS-2 was significantly higher in MPM patients than in NM (P<0.01), but there was no difference in the serum antibody-titer against Gene-X (Table). The receiver operating characteristic (ROC) curve analysis showed a significant diagnostic value of serum antibody-titer against THBS-2 with the area-under curve of 0.886 (95% CI, 0.797 - 0.975; P<0.001) in discrimination of MPM from NM diseases; the sensitivity and specificity, when the cut-off value was 0.08, were 72.2% and 95.5%, respectively. Conclusions: The serum antibody-titer against THBS-2 can be a useful non-invasive marker in the diagnosis of MPM. [Table: see text]
Multisite validation of a 92-gene molecular classifier: Diagnostic accuracy and clinical utility in metastatic cancer.
Authors: Schnabel Catherine A. , Kerr Sarah E , Sullivan Peggy S , Zhang Yi , Singh Veena , Carey Brittany , Erlander Mark G. , Highsmith W Edward , Dry Sarah M , Brachtel Elena F 
Published: March 2020

10588 Background: Accurate tumor classification is increasingly critical to individualized care as patient outcomes improve with use of targeted cancer therapies and predictive biomarkers. In metastatic cancers of uncertain or unknown origin, identification of a primary site remains equivocal in a significant number of cases. Gene expression signatures may improve accuracy and specificity of tumor classification, however, large-scale, blinded validation studies that demonstrate stable performance in metastatic and poorly differentiated cases are currently lacking. Methods: Seven hundred and ninety cases (51% female, 44% metastatic, 63% grade 2 and 3, 14% limited tissue specimens) representing 28 tumor types and 50 subtypes were processed and adjudicated between Mayo Clinic, UCLA and Massachusetts General Hospital. Blinded FFPE tumor sections were submitted and tested using a 92-gene RT-PCR assay (CancerTYPE ID, bioTheranostics Inc.). Molecular predictions were evaluated for concordance with the reference diagnosis; diagnostic accuracy between clinical subsets was compared. Results: The 92-gene assay demonstrated overall sensitivities of 87% for tumor classification and 82% for subtyping. Forty-seven (5.9%) cases were considered unclassifiable. Comparative analysis of performance between metastatic (n=329) and primary (n=414) tumors showed no statistically significant difference in accuracy (85% vs 88%, p=0.16). Similarly, no significant decreases in performance were observed across histological grades (p=0.58) and when comparing limited tissue to excisional biopsy specimens (p=0.16). Strong precision was demonstrated for accurate identification of a primary tumor in tissues biopsied from common metastatic sites, reported as positive predictive values of 100% for lung, brain and peritoneum, 92% for ovary and 80% for liver. Conclusions: Results from this multisite, blinded study validate the diagnostic accuracy of the 92-gene assay for classifying a diverse set of tumors, and support its clinical utility in the diagnosis of metastatic tumors to determine tissue of origin, and in the differential diagnosis of metastatic vs new primary disease.
Genomic profiling of non-small cell lung cancer (NSCLC) for personalized targeted therapy using CT-guided transthoracic needle biopsy (TTNB).
Authors: Gill Ritu R. , Heon Stephanie , Yeap Beow Yong , Butaney Mohit , Lindeman Neal Ian , Rabin Michael S. , Jackman David Michael , Janne Pasi Antero , Johnson Bruce E. ,   Dana-Farber Cancer Center
Published: March 2020

10592 Background: Genomic profiling for personalized targeted therapy is emerging for NSCLC. DFCI introduced systematic testing for mutations in BRAF, HER2, PIK3CA and ALK translocations in addition to EGFR and KRAS in July 2009 as part of a prospective study. We report the utility, efficacy and safety of CT guided TTNB in this cohort. Methods: Patients with stage IV or relapsed NSCLC seen at the DFCI were referred to BWH for CT guided TTNB of their tumors to identify driver mutations prior to starting therapy. Pathology specimens were dissected and analyzed by PCR-Sanger sequencing for mutations in selected exons of EGFR, KRAS, BRAF, PIK3CA and HER2. ALK rearrangements were detected with fluorescence in-situ hybridization (FISH). Testing was performed after the pathologist deemed that the tissue was adequate. Complications such as pneumothorax and hemorrhage were recorded. Admission rates were also recorded. Results: Between 7/1/2009 and 1/09/2011, 81 patients underwent TTNB. The median age was 63 years. 54 (67%) were female, 66 (88%) were former/current smokers and 58(72%) had stage IIIB/IV disease. 64(79%) patients had sufficient tissue on core biopsies for genomic profiling, 4 (6%) of the 64 patients failed analysis for ALK rearrangements due to less than 50 tumor cells on the hybridized slide. The number of samples obtained ranged from 1-5 (2 cm 18-20 (G)). Lesions biopsied ranged in size from 1.2–8.9 cm. Mutations were identified in 38/81 (46.9%) patients (EGFR: 18; KRAS: 17; ALK: 2; PIK3CA: 1). 23(28.3%) had pneumothoraces 15(<10%), 5 (10-30%) and 3(>30%). 6 (7%) patients needed chest tubes. 9 (11%) were admitted post procedure for observation (8 for (24hrs) and 1 (72hrs). 19(23%) (18 grade1; 1 grade 2) had intra-parenchymal hemorrhage. A higher rate of pneumothorax was observed with the 18 gauge needles (p =.05). 15 of 20 (75%) patients with EGFR, HER2, BRAF or ALK alterations were treated with molecularly targeted therapy based on their genetic alteration. Conclusions: CT guided TTNB is a feasible, safe and efficacious technique for genomic profiling for targeted therapy and enables the acquisition of sufficient tissue for gene mutation analyses.
A circulating epithelial cell type merging stem cell, EMT, and hypoxic stress markers in early and advanced breast cancer.
Authors: Habets Leo , Koerber Wolfgang , Frenken Bettina , El Ghali Ilham , Danaei Mahmoud , Kusche Manfred , Peisker Uwe , Kroll Torsten , Pachmann Katharina 
Published: March 2020

10600 Background: MAINTRAC as developed by our coworkers from Jena finds more CETC. They found CETC in 90% of high risk patients. Circulating cells in epithelial mesenchymal transition (EMT+) should be detectable in early disease. Methods: 2 colours (7AAD, EP-FITC) detected living and dead cells. Cells in EMT (EP-FITC, Vim-PE) were analysed in paralell. Complex marker expression urged us to introduce a three colour technique. 1. EPCAM-FITC, Vimentin-PE and DAPI , marking living or dead cells in EMT. 2. EP-FITC, Vim-PE and CD44 PB for stemness. ACA9 (hypoxia) and PARP-1 expression (genotox) were used too. Results: In the 2 colour phase we examined CEC in 110 patients with early disease and 44 patients with metastasis. Cells were detectable in both disease situations in 50 and 60% of patients, in a control population only in few patients low numbers were found. In non cancer situations e.g liver disease high numbers of EMT+cells were found.The results of 3 colour analysis are shown in the table. No clear differences between the classical risk groups are found, other subgroups are too small yet to be considered. Conclusions: Our findings show that in both disease situations cells merging EMT, stemcells ( EP+,Vim+.CD44+) and other markers are detectable. This cell type however is found also in non cancer conditions.We hypothesize that hypoxia is the common driver. Metastasis gives different patterns. Highly aggressive cancers show often none or few cells. In less agressive disease high cell numbers are found. We need to characterize the "benign" EMT phenomenon, as it could mingle with "real" CTC. Definitely liver is the source of these benign cells. Multi colour analysis will reveal the differences. Nevertheless monitoring of this special cell type could give new insights in the metastatic process in early and late disease. [Table: see text]
Exploratory study of histopathological and biomolecular characteristics of breast cancer in two different populations: African (Tanzania) and Caucasian (Italy).
Authors: Serra Patrizia , Bravaccini Sara , Masalu Nestory Andrew , Puccetti Maurizio , Rengucci Claudia , Tumedei Maria Maddalena , Serra Luigi , Zoli Wainer , Amadori Dino ,   on behalf of Associazione Vittorio Tison
Published: March 2020

10601 Background: There is little information available on the clinical and molecular epidemiology of breast cancer in Sub-Saharan African women. In Tanzania, breast cancer mortality is the second cause of death after cancer of the uterine cervix, with the majority of tumors diagnosed at a very advanced stage. We aimed to compare the distribution of histopathological and biomolecular characteristics (ER, PgR, Ki67, HER2, grading) of breast cancer in African (Tanzania) and Caucasian (Italy) patients. Methods: 142 women with invasive breast cancer, 71 from Tanzania and 71 from Italy, were considered. Histopathological classification and biomolecular determinations were performed at the Biosciences Laboratory of the Cancer Institute of Romagna (I.R.S.T., Meldola, Italy) as part of a joint Cancer Control Project between I.R.S.T and the Bugando Medical Center in Mwanza, Tanzania. All cases were evaluable for histopatological characterization, while biomolecular determination was possible in only 61 of the African patients. Hormone receptor status and Ki67 were determined by IHC; HER2 was evaluated by IHC for the African population and by FISH for the Italian one. Results: Whilst histopathological patterns were similar in the two populations, some biomolecular characteristics differed substantially. Of note, 64% of African breast cancer patients had ER negative tumors compared to only 17% of the Caucasian population. Important differences were observed in high Ki67 (>15%) values: 76% in Tanzanian women vs 58% in Italian breast cancer cases. HER2 positivity rates also differed in the two populations (25% in Tanzanian and 17% in Italian patients), as did the incidence of triple negative disease (13% and 7% in African and Caucasian populations, respectively). Conclusions: This preliminary study shows that breast cancer in African (Tanzanian) women is characterized by a high frequency of HER2 positive, ER negative, highly proliferating tumors. These biological patterns, together with very advanced stage at diagnosis, could be considered the main prognostic factors related to the high mortality rates for breast cancer in this African population.
pAKT expression in paraffin-embedded xenograft tumors after fixation delays and human breast cancer by optimized immunohistochemistry.
Authors: Yang Sherry X. , Nguyen Diana , Rubinstein Larry , Sherman Mark E , Swain Sandra M. , Tomaszewski Joseph E. , Doroshow James H. 
Published: March 2020

10603 Background: With progress in targeting PI3K/AKT pathway in the treatment of a wide range of cancers, it is getting more important than ever for optimization of detection method of AKT kinase, a central effector of the pathway, in archived tissues. Recently, we found that pAKT-S473 (pAKT) significantly predicts paclitaxel benefit in breast cancer (JCO 28: 2974, 2010), in which a good analytical and clinical performance of quantitative pAKT immunohistochemistry (IHC) was demonstrated. The current study evaluates pAKT stability in human breast cancer xenograft tumors after delays in fixation, and assesses a detection window following fixation delays with an established cutoff [staining index (SI) > 2]. Methods: Xenograft tumors with high (MDA-MB-468) and intermediate levels (MDA-MB-231) of pAKT were fixed or snapped frozen in 10% neutral-buffered formalin or liquid nitrogen after delays post-excision. pAKT staining was performed in xenograft tumors and 96 cases of human surgical breast tumors by our optimized and traditional IHCs, and Western blot. Results: The mean SIs were 133, 121, 112, 94, 84, and 66 using optimized, and in contrast were 51, 44, 29, 14, 12, and 6.4 on traditional method at 0, 15, 30, 60, 120 and 180 min (2.6-fold by comparing the optimized with the traditional at baseline) in MDA-MB-468 xenograft tumors. pAKT level was ½ by the optimized, similar to the level detected by Western blot, relative to 1/8 of the baseline by the traditional (10.6-fold) at 180 min. The logarithmic decline rate by the optimal was 3.1 times (95% CI, 2.4 - 3.7) less than that of the traditional (normal approximation; 2-sided P < 0.0001). pAKT expression was observed in 38.5% (37/96 ) of surgical breast tumors, comparable to 38% (606/1581) in a large cohort derived from the NSABP B-28 trial. There was little loss of pAKT in MDA-MB-231 xenograft tumors up to 180 min by IHC and Western blot. Conclusions: The optimized pAKT IHC significantly increases the sensitivity of detection with a large window for positivity. It is suitable for use in archived human specimens although it warrants further standardization and validation among research laboratories and perhaps diagnostic laboratories in the future.
Monitoring of plasma pro-GRP level during EGFR-TKI treatment.
Authors: Kawano Yuko , Horiike Atsushi , Tanimoto Azusa , Sakatani Toshio , Saito Ryota , Kaburaki Kyohei , Yanagitani Noriko , Kudo Keita , Ohyanagi Fumiyoshi , Hagiwara Sachiko , Horai Takeshi , Nishio Makoto 
Published: March 2020

10604 Background: Lung cancers harboring mutations in the epidermal growth factor receptor gene (EGFR) respond to EGFR tyrosine kinase inhibitors (EGFR-TKI), but drug resistance invariably emerges. The major acquired mechanisms of resistance are the EGFR T790M mutation or MET gene amplification. Transformation from NSCLC into small-cell lung cancer (SCLC) has been recently identified in acquired resistance to EGFR-TKI. However, it is difficult to predict the transformation during EGFR-TKI treatment because obtaining serial and sufficient specimens for biopsy is difficult. Pro-gastrin-releasing peptide (Pro-GRP) is a specific and sensitive tumor marker for SCLC. We evaluated the plasma Pro-GRP levels in EGFR-mutant NSCLCs and determined whether plasma Pro-GRP levels could predict SCLC transformation in resistance to EGFR-TKI. Methods: From July 2008 to December 2011, 49 patients with EGFR-mutant NSCLC who received EGFR-TKI treatment were enrolled. Plasma was obtained from these patients before EGFR-TKI treatment and when EGFR-TKI treatment failed. Pro-GRP and CEA levels were measured and compared before and after treatment. Results: Patient characteristics for 49 patients (15 men, 34 women) were as follows: median age, 62 years (41–81 years); histology, 46 adenocarcinomas (AD) and 3 non-AD tumors; and EGFR mutation type, 25 exon 19 deletions and 24 exon 21 L858R. All 49 patients had received EGFR-TKI treatment (45 with gefitinib and 4 with erlotinib); the response to EGFR-TKI treatment was PR in 39 patients, SD in 7, PD in 2, and NE in 1. Positive rate of ProGRP and CEA at pre-EGFR-TKI treatment was 2.0% and 57.2% and that at post-EGFR-TKI treatment was 6.1% and 69.4%, respectively. In 3 of 49 patients, the Pro-GRP levels had increased after treatment, but the CEA level did not increase. Objective responses to cytotoxic chemotherapy were noted in all 3 patients after EGFR-TKI treatment. Conclusions: Monitoring of plasma Pro-GRP during EGFR-TKI treatment may be useful for early detection of SCLC transformation in resistance to EGFR-TKI.
Study of the usefulness of angiotensin type 1 receptor (AGTR1) as a possible response predictor in patients with metastatic breast cancer (mBC) subjected to chemotherapy and treatment with bevacizumab (AVALUZ Study).
Authors: De la Haba- Rodriguez Juan , Salvador Bofill Javier , Codes Manuel , Ciruelos Eva M. , Jaen Ana , Galan Antonio , Gil Miquel , Serrano M. Jose , Baena Jose Manuel , Villanueva Silva Maria Jose , Gonzalez Encarnacion , Murias Adolfo , Miguel Ana , Garcia Helena , Bayo Juan L. , Sánchez-Rovira Pedro 
Published: March 2020

10608 Background: Angiotensin type 1 receptor (AGTR1) is a membrane receptor implicated in the regulation of arterial pressure. It has also been related to carcinogenesis and tumor spread, and participates in neoangiogenesis. AGTR1 is expressed in a number of neoplasms as BC. In a previous neoadjuvant study, a significant relationship was observed between AGTR1 expression and CR to a regimen of chemo and bevacizumab (B). To study and confirm the relationship between tumor expression of AGTR1 and response to a regimen of chemo and B in pts with mBC. Methods: AGTR1 expression was subjected to immunofluorescence (monoclonal AGTR1 sc1173 antibody, Santa Cruz Biotechnology, CA, USA Dilution 1:50) in 50 samples of mBC pts from the AVALUZ study treated with first line bevacizumab 10 mg/kg, paclitaxel 150 mg/m2 and gemcitabine 2000 mg/m2 d 1 and 15 c/28 d until PD, unacceptable toxicity or medical decision. Immunoreactivity was reported as negative (0), low positive (1+) and high positive (2+). RNA was extracted from paraffin blocks, using the QIAamp DNA FFPE Tissue Kit and Deparaffinization Solution (QIAGEN) and expression of AGTR1 candidate gene was quantified using reverse transcription-PCR (RT-PCR). Results: 60% of the samples expressed AGTR1 (26% weak and 34% intense) – expression being more frequent in HR + tumors (65% vs 45%). Among the 50 samples analyzed, measurable disease was present in 39 pts. Treatment activity was significantly greater in the tumors AGTR1 expression 2+ (p=0.009) (Table). With a median follow-up of 19.30 months, the progression-free interval was longer in the tumors with intense AGTR1 expression (17.7 vs 10.8 months, p=0.132). More consolidated PFS and OS will be presented. Conclusions: AGTR1 expression may be useful as a predictor of response to chemo and bevacizumab. Prospective studies are needed to confirm these findings. [Table: see text]
The lipid metabolome of clear cell renal cell carcinoma (CCRCC).
Authors: George Saby , Choi Kyoung-Soo , Pili Roberto , Kazim Abdul Latif 
Published: March 2020

10609 Background: The commonest type of kidney cancer is CCRCC. Treatment approaches mostly target aberrant vasculature. However, kidney cancer is also known to accumulate lipids and a detailed knowledge of the lipid species present in these tumors could lead to a better understanding of the underlying aberrant metabolic pathways and suggest possible treatment strategies. Lipidomics is an emerging field driven by rapid advances in mass spectrometry (MS), and is widely used to discover biomarkers. We attempt to identify the lipidomic profile of CCRCC using a liquid chromatography MS-based approach (LC-MS). Methods: We utilized 6 fresh frozen representative samples of CCRCC and matching non-tumor areas of kidney from nephrectomy samples. Lipids and other non-polar cellular constituents were extracted from both CCRCC and control tissues by methyl-t-butyl ether /methanol. LC-MS based lipid profiling was performed on a Waters Q-ToF Premier MS coupled with Ultra Performance LC. The peak detection and alignment across all chromatograms were performed using the XCMS software (v 1.14.1, Scripps Center for Metabolomics). Statistical comparisons of the intensities of aligned peaks were performed using the XCMS-built-in Welch's t-test. Results: The outcome of XCMS was converted to a table that contains fold change, p-value and mass to charge ratio (m/z) for each peak, its corresponding retention time, and the integrated peak intensities from all samples. 224 peaks out of 1419 differed between CCRCC and the control group, with p <0.05, calculated by XCMS. About an equal number of analytes increased or decreased in CCRCC compared with control samples. Preliminary attempts to identify the analytes included use of METLIN (Scripps Center for Metabolomics) and HMDB (Human metabolome database, Genome Alberta & Genome Canada) databases. Many of the hits identified phosphatidylcholines, phosphatidylethanolamines, triacylglycerols and diacylglycerols, as well as other lipid species. Conclusions: The lipid metabolomic profile varied significantly between CCRCC and control. Further studies are required to confirm the identities of the lipid species contributing to this variation by obtaining structural information using tandem MS (LC-MS/MS).