bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diabetes in elderly patients with breast cancer in the United States: An analysis of data from the Surveillance, Epidemiology, and End Results (SEER)–Medicare linked database
Authors: O'Malley C. D. , Danese M. , Lindquist K. , Griffiths R. , Gleeson M. , Einhorn T. , Wyszynski D. 
Published: August 2020

11050 Background: Despite increases in both breast cancer and diabetes, little is known about their co-occurrence. With evidence that cancer and diabetes can reflect related processes such as obesity, understanding the prevalence of diabetes in patients with breast cancer is critical. Methods: Using the SEER-Medicare linked database, 52,977 women newly diagnosed with breast cancer at ages 66+ years during 1998–2002 were identified, and a random sample of Medicare beneficiaries without cancer, matched (1:1) on sex and residence county were selected as a comparison cohort. The occurrence of diabetes was defined as ≥1 hospital or ≥2 physician service claims, and the date of cancer diagnosis served as the index date for the breast cancer patient and her matched cancer-free individual. For both cohorts, diabetes prevalence was measured for the ≥12 months prior to the index date, and incidence was estimated for non-diabetic patients during three time periods after the index date (3 months, 12 months, and overall), with follow-up through 2005. Prevalence and incidence rates (per 1,000 person-years) and their 95% confidence intervals (CI) are standardized to the age and race distribution of the breast cancer group. Results: Rates were higher in breast cancer patients for all time periods, particularly shortly after diagnosis. This pattern of heightened risk immediately following cancer diagnosis held when rates were stratified by age, stage, and race/ethnicity.For both cohorts, diabetes incidence was typically two times greater in Blacks and Hispanics compared to Whites. Conclusions: Older women with breast cancer are at increased risk for diabetes, suggesting that there may be shared biologic pathways such as insulin, INSR, IGF-1, and IGF-1R. [Table: see text] [Table: see text]
Implementation of genomic predictors of chemotherapy response for guiding preoperative therapy in a prospective breast cancer trial
Authors: Marcom P. K. , Datto M. B. , Barry W. T. , Geradts J. , Foster T. L. , Dressman H. K. , Olson J. , Potti A. , Ginsburg G. , Nevins J. R. 
Published: August 2020

11057 Background: Personalized approaches to breast cancer therapy depend on genomic assays. While assays based on fixed tissues offer greater convenience, the spectrum of biology interrogated is limited. Full-transcriptome assays using microarrays are more challenging, but have the advantage of providing multiple prognostic and predictive signatures in one assay. We have created a clinical infrastructure with the objective of obtaining full genome expression data on breast cancer samples as a clinical assay for use in a prospective trial. Methods: “Performance of Genomic Expression Profiles to Direct the Use of Preoperative Chemotherapy for Early Stage Breast Cancer” is a prospective trial validating genomic signatures for predicting response to doxorubicin (A) or docetaxel (T) treatment in HER2 negative cancers. Fresh-frozen cores are reviewed by the study pathologist for tumor content. RNA is then extracted and probe generated to hybrize to an Affymetrix U133Plus2.0 microarray. Microarray data quality is determined using summary metrics for U133Plus2.0 arrays and principal component analysis (PCA) plots. The data is then used for predicting A or T sensitivity. Results: Thirteen cancers have been analyzed in the context of the above trial. Histologic type was lobular for 1, and predominantly ductal for 12 (10 ER positive, 3 ER negative). Median tumor size was 3.4 cm (range, 1.8–5.7). Microarray analysis was successful on 11 tumors (84%), providing data of sufficient quality to make predictions of A and T sensitivity. One sample hybridization failed QC as detected by PCA analysis, and one sample had insufficient RNA. The median “tissue to array data” time and “study consent to initiation of treatment” time were 5 days (range, 3–8) and 14 days (range, 11–36), respectively. Conclusions: Our initial experience shows that full-genome expression analysis on frozen tumor using an Affymetrix platform is feasible as a clinical assay for breast cancer. The resulting data is being used in a prospective marker validation protocol for predicting chemosensitivity. The data can also be analyzed for a variety of other potential prognostic and predictive signatures for guiding therapy. No significant financial relationships to disclose.
Sensitivity of 6-[F-18]fluoro-L-dihydroxyphenylalanine positron emission tomography for localizing tumors causing catecholamine excess
Authors: Fiebrich H. , Brouwers A. H. , Kerstens M. N. , Pijl M. E. , Kema I. P. , de Jong J. R. , van der Wal J. E. , Sluiter W. J. , de Vries E. G. , Links T. P. 
Published: August 2020

11064 Background: Positron emission tomography (PET) using the catecholamine precursor 6-[F-18]fluoro-L-dihydroxyphenylalanine (18F-DOPA) has emerged as promising technique to localize tumors with catecholamine excess. This study investigated the sensitivity of 18F-DOPA PET, compared to 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy and computer tomography (CT)/ magnetic resonance imaging (MRI) in patients with catecholamine excess. Methods: In a single center prospective study 18F-DOPA PET was compared to 123I-MIBG and CT/MRI in patients with catecholamine excess. The performance of each imaging modality was analyzed for individual patients and individual lesions. 18F-DOPA PET, 123I-MIBG, and CT/MRI were compared using a composite reference standard derived from all available imaging, clinical and histological information. Sensitivities were calculated and discordance between imaging techniques was compared. 18F-DOPA PET uptake was measured to determine whole body metabolic burden. Correlations between 18F-DOPA PET imaging and biochemical data were evaluated. Results: 48 patients were included. The tumor localization was found in 45 patients, 43 with 18F-DOPA PET, 31 with 123I-MIBG and 32 with CT/MRI, resulting with surgery in final diagnosis of pheochromocytoma in 40, adrenal hyperplasia in 2, paraganglioma in 2, ganglioneuroma in 1 and 3 unknown (as yet no lesion detected). Per patient based analysis showed sensitivities for 18F-DOPA PET, 123I-MIBG and CT/MRI of 90, 65 and 67% (P<.01 18F-DOPA PET vs 123I-MIBG, P<.01 18F-DOPA PET vs CT/MRI, P=1.0 123I-MIBG vs CT/MRI). Corresponding sensitivities in the lesion based analysis were 73, 48 and 44%, respectively (P<.001 for both 18F-DOPA PET vs 123I-MIBG and vs CT/MRI, P=.51 123I-MIBG vs CT/MRI). The 8F-DOPA PET+CT/MRI combination was superior to 123I-MIBG+CT/MRI (93 vs 76%, P<.001) Whole body metabolic burden measured with 18F-DOPA PET correlated with plasma free normetanephrine (r=.82) and 24h urinary total normetanephrine (r=.84) and metanephrine (r=.57). Conclusions: The sensitivity of 18F-DOPA PET to localize tumors with catecholamine excess is superior to either 123I-MIBG scintigraphy or CT/MRI. No significant financial relationships to disclose.
Significance of serum colony-stimulating factor-1 as a breast cancer marker
Authors: Aharinejad S. , Thomas A. , Singer C. , Kubista E. , Paulus P. , Miksovsky A. , Abraham D. 
Published: August 2020

11071 Background: A specific and sensitive biomarker that indicates the presence of breast cancer is highly desirable, yet available markers are of limited value. Colony-stimulating factor-1 (CSF-1) is involved in mammary gland development and mediates breast cancer progression. Earlier work indicated correlation of serum CSF-1 with breast cancer staging, and a recent report suggests that CSF-1 is a potential breast cancer marker, however the data reported so far await validation. Methods: In a prospective study in 799 women with no history of malignant disease undergoing surgery, serum CSF-1 levels were measured by a commercially available ELISA. In this cohort, 312 patients had breast cancer and 487 age-matched women had benign tumors. The tumor size, nodal and metastasis status, histological tumor type, hormone and human epidermal growth factor receptor 2 (HER2) and menopausal status were evaluated. Mean CSF-1 serum concentrations were compared between the patient groups by non-parametric Wilcoxon two-sample and Kruskal-Wallis test. The area under the receiver operating characteristic curve was calculated by logistic regression. Results: Mean serum CSF-1 concentrations were significantly higher in all patients with malignant tumors (502±429 pg/mL) as compared to those with benign tumors (382±344 pg/mL) (p<0.0001, Wilcoxon). Increased CSF-1 concentrations were significantly related to malignant versus non-malignant disease in logistic regression and receiver operating characteristic analysis (p<0.0001, AUC=0.6). Increased CSF-1 levels in patients with malignant tumors were associated with postmenopausal (p=0.0038) but not premenopausal (p=0.94) status (Wilcoxon). Serum CSF-1 concentrations did not correlate significantly with tumor size, nodal and metastasis status, hormone receptor and HER2 status of patients (Kruskal-Wallis). Conclusions: Our data suggest that serum CSF-1 could serve as a breast cancer marker in postmenopausal women. While its serum levels are not related to breast cancer stage at diagnosis, they might be useful for breast cancer screening in postmenopausal women. No significant financial relationships to disclose.
Predicting risk of developing invasive breast cancer in the African American female population
Authors: Wheeler A. J. , Zhang A. Y. , Drohan B. , Lawrence C. , Roche C. , Kopans D. B. , Moore R. H. , Smith B. L. , Sharko J. , Kevin H. S. 
Published: August 2020

11080 Background: African Americans (AA) have a lower incidence of breast cancer with a poorer prognosis than Caucasians. It is unclear whether AA women have fewer known risk factors for breast cancer or that risk factors have a lesser effect in AA. We evaluated the accuracy of the race-based modification Gail Model in predicting the risk of developing invasive breast cancer in the AA population. Methods: With IRB approval, we performed a retrospective analysis of data obtained from women (n=15,973) ages 40–79 presenting to our Breast Center(5/2003 to 7/2005) for a screening mammogram. The five-year probability of breast cancer for AA (n=702) versus Caucasians (n=15,721) was calculated for each individual using 3 methods: 1) the race specific Gail model, 2) the Gail model ignoring race (AA using the Caucasian model), and 3) age and race matched SEER projection using DevCan (v6.1.1) software. Results: There was no significant difference between the 5-year probability of breast cancer for Caucasians as calculated by the Gail model vs. the SEER prediction (p=NS), suggesting our population was representative of the larger study population from which SEER data was derived. As compared to SEER prediction, the modified Gail model underestimated the breast cancer risk for all age groups of AA (p<0.0001). When the Gail Model without the race-based modification was applied to the AA population, the projected risk was not significantly different from the SEER prediction (p=0.1049). Conclusions: This study suggests that the race-based modification of the Gail Model underestimate the risk of breast cancer in AA women. When the model is applied to AA women without incorporating the modification for race, the Gail model accurately reflects SEER 5-year projections of risk of invasive cancer in AA women. Differences in risk factor distribution among race, rather than a differential effect of those factors on risk, may have a substantial role in explaining the lower incidence in AA women as compared to Caucasian women over 40. [Table: see text] No significant financial relationships to disclose.
A functional procedure using fresh samples to select patients with acute myeloid leukemia prior to treatment with the novel targeted cytotoxic agent F14512
Authors: Barret J. , Dumontet C. , Annereau J. , Brel V. , Breillout F. , Guminski Y. , Imbert T. , Guilbaud N. , Bailly C. 
Published: August 2020

11087 Background: The Polyamine Transport System (PTS) is an energy-dependent machinery generally hyper-active in cancer cells with a high demand for polyamines. This system can be viewed as a suitable molecular gate to deliver selectively polyamine-based molecules into cancer cells. We exploited this strategy to target to PTS-positive cancer cells, F14512 , a novel polyamine-epipodophyllotoxin conjugate, that exhibits significant anti-tumor activity and has been selected for further clinical development. This study was undertaken to investigate the potential of N-methyl-spermine-NBD, a proprietary fluorescent polyamine conjugate, designed to select patients with PTS-positive leukemic cells. Methods: The uptake of this probe was first measured by flow cytometry in a panel of human leukemia cell lines. The procedure was then adapted and optimized to measure N-methyl-spermine-NBD fluorescence in blood samples from healthy donors. After the selection of the optimal CD gating, median value of fluorescence of our probe was measured by flow cytometry in lymphocytes and blastes of each patient. Results: Data showed that high level of fluorescence was detected in F14512 -sensitive cancer cell lines whereas leukemia cells responding poorly to F14512 generally exhibited very low levels of PTS. We then demonstrated that human leukocytes incorporate N-methyl-spermine-NBD in a time, concentration and temperature dependent manner, confirming the active transport of polyamines in these cells. The incorporation in lymphocytes was found low and with a weak inter-individual variation. A panel of 50 fresh human acute myeloid leukemia samples showed a larger inter-individual variation and, interestingly, incorporation of the fluorescent probe was generally higher in leukemia blasts than in lymphocytes. Median values of fluorescence intensity were similar in blood and bone marrow samples, suggesting that these two sources might be used for this analysis. Conclusions: The data show that the PTS can easily be evaluated in fresh AML blasts and provides a simple means to identify patients for future enrollment in clinical trials with F14512. [Table: see text]
Model-based prediction of defective DNA mismatch repair using clinicopathological variables in stage II and III colon cancers
Authors: French A. J. , Sinicrope F. , Foster N. R. , Thibodeau S. N. , Sargent D. J. , O'Connell M. J. 
Published: August 2020

11093 Background: Defective DNA mismatch repair (MMR) results in microsatellite instability (MSI) and is detected in approximately 15% of sporadic colon cancers. MMR status has been shown to provide prognostic and predictive information in primary colon cancers. We sought to develop a model to predict MMR deficiency using clinically available data, and thereby facilitate patient selection for MMR or MSI testing. Methods: TNM stage II and III colon carcinomas (n= 982) were studied from six 5- fluorouracil-based adjuvant therapy trials conducted by the North Central Cancer Treatment Group. MMR status in tumors had been analyzed by MSI (using mono- and dinucleotide markers) or by immunohistochemistry for MMR proteins (hMLH1 and hMSH2). Logistic regression and a recursive partitioning and amalgamation (RPA) analysis was used to identify important predictive factors of MMR status. Factors explored included age, gender, histologic grade, tumor site, stage, lymph node metastases, and T-stage. Results: Defective MMR was found in147 (15%) cancers. Tumor site was the most important predictor of MMR status followed by histologic grade. Distal tumors had a low likelihood of defective MMR (3% rate overall; 13/468), whereas proximal tumors had a greater likelihood of defective MMR (26%; 130/506). For patients with proximal tumors, the addition of histologic grade and gender increased the prediction of defective MMR ( Table ). Using tumor site, histologic grade, and gender, the logistic regression model showed excellent discrimination (c- statistic = 0.81). Conclusions: Tumor site is an important predictor of defective MMR that is rare in distal and increased in proximal tumors. The combination of proximal site, poor differentiation, and female gender resulted in a 51% likelihood of defective MMR. Therefore, this model can facilitate the selection of sporadic colon cancers for MMR or MSI testing to enable its use in clinical decision-making. [Table: see text] No significant financial relationships to disclose.
Translational disequilibrium as an interference marker to study miRNA and methylation silencing of APRIN, a stem cell regulator in breast cancer microchimerism
Authors: Geck P. , Denes V. , Pilichowska M. , Makarovskiy A. , Carpinito G. A. 
Published: August 2020

11109 Background: Gene silencing is universally observed in cancer and involves promoter DNA methylation. We found that a cohesin-related stem cell regulator, APRIN (Pds5B) was silenced in breast cancer clinical samples. Surprisingly, in 40% of these samples DNA methylation was not involved. Furthermore, in some breast cancer cell lines the APRIN protein was silenced without transcript downregulation or promoter methylation. This “translational disequilibrium” has been frequently reported with other proteins, but without mechanistic explanations. Recent results with RNA interference indicate that gene repression through microRNAs (typically mismatched) is mostly translational without transcript degradation. We propose, therefore, that the puzzling translational disequilibrium phenomenon is a new form of epigenetic silencing by miRNA mechanisms. We aim (i) to verify miRNA epigenetics of APRIN silencing in breast cancer cell lines; (ii) to study clinical breast cancer samples for methylation vs. miRNAs mechanisms in APRIN translational disequilibrium; and (iii) to investigate if miRNA silencing of APRIN affects a fetal embryonic stem cell pool in breast cancer (microchimerism). Methods: (i) We used miRNA mimics and miRNA inhibitors in breast cancer cell lines to verify specific miRNA involvement in APRIN silencing. (ii) We used immunohistochemistry with bisulfite converted DNA for methylation and microdissected RNA for microRNA interference studies from 56 clinical breast cancer samples. (iii) We used Y-chromosome markers on microdissected DNA for fetal microchimerism studies. Results: (i) We found that in breast cancer cell lines with APRIN translational disequilibrium a set of microRNAs correlate with APRIN silencing. (ii) We found miRNA related mechanisms in about 35 percent of breast cancer samples where APRIN was silenced and (iii) APRIN may specifically affect stem cells of fetal origin in the mother's mammary gland and contribute to cancer. Conclusions: The novel miRNA-based mechanism maybe a new epigenetic factor of gene silencing in cancer. We experimentally confirmed a set of APRIN specific miRNAs and established preliminary correlations with fetal microchimerism in breast cancer. No significant financial relationships to disclose.
Association of increase in thymidine uptake relative to tumor cell proliferation in indolent NHLs and DNA repair
Authors: Juweid M. E. , Buck A. K. , Ponto L. L. , Mottaghy F. M. , Syrbu S. , Moller P. , Vose J. M. 
Published: August 2020

11116 Background: Uptake of radiolabeled thymidine (tdR) or its analogs is frequently used to assess tumor cell proliferation as well as tumor DNA repair synthesis after inhibition of tumor cell proliferation with certain drugs. We determined whether the relationship between thymidine (td) uptake and tumor cell proliferation may be different between indolent and aggressive NHLs. Methods: Twenty-four patients with histologically confirmed aggressive (n=16; all DLC) or indolent NHLs (n=8; 7 FL gr I-II, 1 MZL) underwent pretherapy imaging with the td analog 18F-fluorothymidine (FLT) and biopsy to determine the proliferative cell fraction by the Ki-67 index. Tumoral FLT uptake was determined by the maximum standardized uptake values (SUVmax) and correlated with the Ki-67 index. The FLT-SUV to Ki-67 ratio was also compared between indolent and aggressive NHLs. Results: Disproportional increase in FLT-SUVmax relative to tumor cell proliferation was found in indolent NHLs: median %Ki-67 was 5% in indolent vs. 80% in aggressive NHL whereas median FLT-SUVmax was 3.6 vs. 9.4, respectively. The disproportional increase in FLT-SUV in indolent NHLs could not be explained by nonspecific FLT uptake in tumor extracellular space estimated to account for <0.2 SUV unit. Difference in the ratio of FLT-SUVmax to Ki-67 index between indolent and aggressive NHLs was highly significant (1.21 ± 0.77 vs. 0.18± 0.20; P=0.006). These data are in line with a previous study using tdR where the ratios of median tdR (in cpm) to median %-Ki-67 or %-S phase cells in indolent were ∼1.5x those in aggressive NHLs which was associated with relatively increased expression of DNA repair proteins (PCNA) in indolent NHLs (Holte et. al. Acta Oncologica, 1999) Conclusions: Disproportional increase in td uptake relative to %proliferating tumor cells in indolent NHLs likely reflects enhanced DNA repair in quiescent cells or, less likely, constitutively increased Tk1 expression. Studies are underway to determine expression of proteins that, unlike Ki-67, are associated with both DNA repair and replication (e.g., RFA, PCNA). If enhanced DNA repair is confirmed in indolent NHLs this could have major implications with respect to understanding their natural course and treatment options. No significant financial relationships to disclose.