bluuebunny/crossref_metadata_2025_split huggingface dataset:
Members of the glutathione (GSH) and ABC-transporter families are associated with clinical outcomes in patients with diffuse large B-cell lymphoma (DLCL)
Authors: Andreadis C. , Gimotty P. A. , Wahl P. , Hammond R. , Houldsworth J. , Schuster S. J. , Rebbeck T. R. 
Published: March 2020

10035 Background: Chemotherapy only cures 60–70% of DLCL patients (pts). While genes in both the GSH and ABC-transporter families have been implicated in drug resistance in other malignancies, their role in DLCL remains controversial. Methods: This study includes 94 DLCL pts with tissue expression data obtained prior to anthracycline-based chemotherapy from 2 oligonucleotide microarray datasets (Affymetrix) with annotated clinical information. Patient-level expression was derived for 10 key genes utilizing probe set matching and levels were adjusted for a common probe set signal. Freedom-from-progression (FFP) was analyzed using an accelerated failure-time regression model, stratified by the international prognostic index (IPI). CART software was used to develop a classification tree for the 2-year disease-free rate. Results: Based on IPI, 48% of pts were low risk, 23% were low-intermediate (int) risk, 24% high-int risk, and 12% were high risk. After therapy, 30 pts (32%) had disease relapse or progression within 2 yrs and 58 pts (62%) were disease-free; 6 (6%) had shorter follow-up. Expression of multi-drug resistance 1 (MDR1; ABCB1) was favorably associated with FFP (β=1.89, p=0.004), with a 100-point change in the expression signal resulting in a near-doubling of the time to failure (time ratio (TR) = 2.2, 95%CI: 1.3–3.6). Expression of GSH S-transferase μ, classes 1/2/4 (GSTM124) was also favorably associated with FFP (β=0.14, p=0.001); a 1000-point signal change resulted in a near-doubling of the time to failure (TR=1.8, 1.3–2.4). Based on our tree, 2 risk groups were identified using IPI and 3 genes: ABCB1, GSTM124, and GSH cysteine ligase modifier (GCLM). Thus, 89% (78%-96%) pts in the low-risk group (N=56) were disease-free at 2 yrs vs. 25% (11%-43%) pts in the high-risk group (p<0.001). Conclusions: We observed a significant favorable association between expression of genes in the GSH and ABC-transporter families, and FFP in pts treated for DLCL. Moreover, we generated 2 risk groups based on the IPI and the expression of 3 key genes, which we plan to validate in an independent dataset. Our findings suggest an additional role for these genes that are classically associated with drug resistance. No significant financial relationships to disclose.
Screening for ATM sequence alterations in African-American women diagnosed with breast cancer
Authors: Hirsch A. E. , Atencio D. P. , Rosenstein B. S. 
Published: March 2020

10037 Background: Women who are heterozygous for mutations in the ATM gene, ATM carriers, are reported to have an increased risk of breast cancer compared with noncarriers of the mutation. There are few data on breast cancer susceptibility mutations in African-American women, particularly the non-BRCA mutations. We set out to determine whether there is evidence that ATM represents a breast cancer susceptibility gene in African-American women. Methods: One hundred thirty-two African-American women were screened for ATM sequence alterations. Thirty-seven (28%) were women with a histological diagnosis of breast cancer (cases) and 95 (72%) were age-matched women who were seen for a screening mammogram and had no evidence of cancer (controls). Genetic variants were identified using Denaturing High-Performance Liquid Chromatography (DHPLC). Results: Eighteen of 37 (49%) cases and 54/95 (57%) possessed at least one ATM variant (p =0.256). Missense variants were seen on 16/37 (43%) cases and 66/95 (69%) controls. In addition, 5/37 cases and 24/95 controls possessed multiple ATM sequence variants (p=0.107). The most common polymorphisms were: 378 T ->A, seen on 7/37 (19%) cases and 26/95 (27%) controls (p=0.219); 2685 A-> G, seen on 5/37 (11%) cases and 7/95 (6%) controls (p=0.217); and 1254 A-> G, seen on 2/37 (3%) cases and 9/95 (9%) controls (p=0.357). There were no significant differences in any of the single nucleotide polymorphisms (SNPs) detected between the cases and controls. Conclusions: We found no significant differences in the overall frequency of ATM variants between African-American women with breast cancer and an age-matched cohort of African-American women without breast cancer. ATM, therefore, does not appear to represent a breast cancer susceptibility gene in the African-American population. Many of the ATM variants that we found in high frequency were consistent with prior reports of common variants in patients of African ancestry. Comparing the difference in the frequency of ATM variants in the African-American population screened in this study with prior reports on non-African-American subjects will enable us to characterize the differential distribution of genetic alterations in various patient populations and lead to more optimally tailored cancer therapy. No significant financial relationships to disclose.
Utility of clinical markers to identify patients with high risk cervical dysplasia and cancer
Authors: Ueda S. , Carney M. , Killeen J. , Wakabayashi M. 
Published: March 2020

10055 Background: The natural history of cervical neoplasias appears unpredictable with 1/3 to 1/2 of CIN lesions regressing without intervention; therapeutic targeting aids in screening and selecting patients at risk and elucidating treatment response. This study aimed at determining if a pattern of tumor suppressor, oncogene, and growth factor expression (specifically HER-2/neu, progesterone and estrogen receptors (ER/PR), p53, and Ki67) exists in the progression of cervical cancer utilizing the widely applicable process of immunohistochemistry. Methods: Paraffin sections from 128 cervical biopsy, cone, and hysterectomy specimens collected from 1/00–12/04 were obtained from the surgical pathology repository at a tertiary care center with a primarily Asian and Polynesian patient population. Levels of expression in normal, low and high grade dysplasias, and invasive carcinomas were measured via automated immunohistochemical analysis. Results: 30% of samples came from patients who smoked. Ki-67 index rose with increasing dysplastic change (17–43%) but dropped with invasive carcinomas (<17%). HER-2/neu staining occurred at greater levels in high grade lesions and invasive carcinomas but average intensity measured <1, with >2.2 being of prognostic significance because of candidacy for Herceptin therapy by breast criteria. ER/PR expression generally remained low with a penchant for parabasal cells (2–14%), and p53 levels likewise appeared minimally affected (3–5%). Conclusions: While HPV infection immortalizes cervical cells via a p53/pRb pathway, the equivocal expression of wild-type p53 across pre-invasive and more aggressive lesions suggests the involvement of other environmental toxins and genetic mutations. PR and ER play only a minor role in the development of adenosquamous carcinomas, indicating a lack of hormonal control in cervical tumor growth and proliferation. Her-2/neu, however, participates in the late events of cervical malignancy but at such levels that clinical usefulness proves questionable. Although HER-2/neu perhaps holds limited prognostic value in cervical carcinogenesis, similar molecular pathways independent of HPV need to be investigated as adjuncts to the common Pap smear. No significant financial relationships to disclose.
A lung cancer genomic risk prediction model derived from paraffin-embedded tissue
Authors: Harpole D. H. , Joshi M. M. , Petersen R. P. , Conlon D. H. , Tanaka K. , Shimizu D. , Kuramochi H. , Williams M. , Danenberg P. V. , Danenberg K. 
Published: March 2020

10059 Background: We previously developed a validated fresh tissue-based genomic risk model in patients with early stage non-small cell lung cancer (NSCLC) using the Affymetrix U133 plus 2.0 Genechip. Limitations of this fresh tissue-based model include the need for immediate processing and limited availability; however, formalin-fixed, paraffin-embedded (FFPE) tissue is readily available and archived on every patient resected in North America. We investigated the ability of gene expression profiles generated on DNA microarrays using RNA isolated from FFPE NSCLC specimens to distinguish short-term and long-term survivors. Methods: Five to ten 5 um sections of FFPE tumor were collected from 61 NSCLC patients consisting of equal numbers of long- (+5-year) and short-term (<2 year cancer death) survivors. Fifty-five samples were microdissected (6 samples contained no tumor tissue) and RNA was extracted using a proprietary procedure of Response Genetics, Inc. For this feasibility study, Actin 300 < 30 cTs was chosen as a threshold for adequate RNA quantity for amplification to the GeneChip. Amplification and labeling of RNA were done using the Affymetrix two cycle amplification kit. The resulting cRNA was successfully hybridized to the U133 plus 2.0 GeneChip in 54/55 samples (98%). Data were analyzed using the SAM statistical software with Kaplan Meier survival analyses. Results: All analyses were performed using unsupervised hierarchical clustering and blinded duplicate samples had nearly identical gene expression profiles, indicating reproducibility. Adenocarcinoma segregated from squamous cell carcinoma with 98% accuracy (p=0.00004). A differentially expressed gene list between long and short survivors was determined. Distinct gene clusters were observed within each histological type segregating the tumors according to outcome. Kaplan Meier survival analysis stratifying on these clusters revealed significant differences in survival (cluster 1 and cluster 2 median survival>75 mos. vs. 30 mos., respectively; p<0.001). Conclusions: We have demonstrated the feasibility of creating a preliminary genomic risk prediction model using FFPE NSCLC tissue. Data will be presented on a larger training set (100+ patients) and a separate validation cohort of 100 patients. [Table: see text]
Competing risk events determining probability of cause-specific failure in nasopharyngeal carcinoma
Authors: Huang Y. , Zee B. , Lam M. , Teo P. 
Published: March 2020

10082 Background: The commonly employed Kaplan-Meier (KM) method is based on the assumption that different failure types (local-regional, distant, etc.) are independent. In reality, these failures occur at different stages in disease progression and are strongly correlated with each other. The assumption of independence of different failure types may violate certain assumptions in the modeling, and hence may affect the clinical interpretation and treatment selection. A better approach to estimate cause-specific failure probability is to calculate cumulative incidence rates by taking into account other events within a competing risk framework, in which the dependency of different failures are considered. Methods: The data was based on a large retrospective cohort study conducted at the Prince of Wales Hospital in Hong Kong, China, in 1996–97. 945 patients with nasopharyngeal carcinoma (NPC) had been treated with a standard protocol and been followed up regularly with a median follow-up period of 69 months (1–122 months). We calculated the cumulative incidence rates of local-regional failure and distant metastasis, and compared the result against KM method. In competing risk analysis, local regional failure, distant metastases and death were considered as competing events during the remaining lifetime of NPC patients from first presentation. Results: The probability of local-regional failure and distant metastasis was higher by KM method than by competing risk method. The result indicated that KM analysis overestimated event rate and the difference became larger in a longer follow-up period, when more competing events occurred. Conclusion: Kaplan-Meier analysis overestimates the probability of cause-specific failure. Competing risk analysis provides us a more accurate method in the determination of the pattern of failure. It provides better evidence to clinicians to enable them to predict the prognosis and select proper therapy. [Table: see text] No significant financial relationships to disclose.
Persistence of disseminated tumor cells (DTC) in bone marrow (BM) of breast cancer patients predicts increased risk for relapse—Results of pooled European data
Authors: Janni W. J. , Wiedswang G. , Fehm T. , Jueckstock J. , Borgen E. , Rack B. , Braun S. , Sommer H. , Pantel K. , Naume B. 
Published: March 2020

10083 Background: The prognostic significance of DTC in the BM of breast cancer patients at the time of primary diagnosis has recently been confirmed by a large pooled analysis. If the persistence of DTC after adjuvant therapy confers a similar risk for relapse, there might be an indication for secondary adjuvant treatment. Methods: We analyzed BM aspirates of 697 patients from academic breast cancer units in Oslo (n=356), Munich (n=228) and Tuebingen (n=113) during recurrence-free follow-up at a median interval of 32.4 months (standard deviation [std] 19.4 mon) after primary diagnosis of breast cancer pT1–4, pN0–3 pM0. Carcinoma cells were detected using a standardized immunoassay with the monoclonal antibodies A45-B/B3 (Munich, Tuebingen), or AE1 and AE3 (Oslo), directed against cytokeratin (CK). Patients were followed for a median of 54.2 months (std 24.5 mon) after primary diagnosis. Results: Persistent DTC in the BM were detected in 15.6% of the patients (n=109). The Kaplan-Meier estimate for mean distant relapse-free survival estimate was 155.6 mon (142.4 - 168.9 95%CI) in patients with negative and 102.3 mon (93.6 - 111.0, 95% CI, p< .0001, log rank test) in patients with positive BM status. Patients without evidence of persistent DTC had a significantly longer overall survival (164.4 [155.6 - 173.3]), than patients with positive BM status (101.7 mon [89.4 - 113.9], p< .0001). In multivariate Cox regression analysis, allowing for bone marrow status, tumor size, nodal status, histopathological grading and hormone receptor status, DTC was of higher independent prognostic significance for subsequent reduced breast cancer specific survival (RR 5.9, 2.8 - 12.8, 95% CI, p< .0001), than nodal status at time of primary diagnosis (RR 1.2, 1.0 - 1.3, 95% CI, p=.014). Conclusion: Evidence of persistent DTC in breast cancer patients indicates an increased risk for subsequent relapse, and may serve for monitoring in future clinical trials. Such trials might investigate the benefit of individualized secondary adjuvant treatment or extended adjuvant therapy of patients with DTC. No significant financial relationships to disclose.
Phase II breast cancer chemoprevention study with celecoxib in women at increased risk for breast cancer
Authors: Arun B. , Valero V. , Yin G. , Babiera G. , Murray J. L. , Browne D. , Gong Y. , Cook E. , Hortobagyi G. N. , Sneige N. 
Published: March 2020

1010 Background: Short-term chemoprevention trials offer a convenient model to screen chemopreventive agents and identify endpoint biomarkers. One of the potential agents is celecoxib (C), which has antiproliferative and apoptosis inducing properties. In this prospective study, our primary aim was to evaluate changes in proliferation induced by C in breast tissue of high risk women. Here, we report changes in estrogen receptor (ER) proliferation index. Methods: 42 eligible high risk women were enrolled into the study, underwent fine needle aspiration (FNA) and started celecoxib treatment at 400 mg BID. Median age: 51.9 years. Risk factors: Gail risk > 1.67% (n=13), lobular carcinoma insitu (n=13), atypical hyperplasia (n=11), previous history of breast cancer (n=5). For ER and Ki-67 testing, thin preparations slides were incubated with primary mouse monoclonal antibody 6F11 against the ER and clone MIB-1, respectively. Appropriate negative and positive controls were included. At least 100 epithelial cells were evaluated per slide. Immunoreactivity for each marker was scored as the percentage of positive nuclei. We assessed the difference in ER and Ki-67 levels before and after treatment using a Wilcoxon signed rank test. Results: The average pre-treatment ER expression in FNA samples was 35.9% and Ki-67 was 2.4%. 19 (45%) showed hyperplasia or atypical hyperplasia. 39 patients underwent also post-treatment FNAs. The pre-and post treatment ER expression in this group was 35.7% (range 0–100%) and 27.4% (range: 0–100%), respectively. The difference in ER levels was statistically significant (p = 0.04). Twenty-six patients had Ki-67 levels measured both before and after treatment. The median difference in Ki-67 levels was 0 (range 0- 5). This change was not statistically significant (p = 0.63). Conclusions: We have completed accrual to a prospective short-term chemoprevention trial with celecoxib. We have found a significant downregulation of ER expression with 6 months celecoxib. Since ER expression is a marker of proliferation, this finding confirms celecoxibs antiproliferative properties. Currently, we have not observed a change in Ki-67; this could be partly due to the small number of samples and the fact that Ki-67 is low in normal epithelium. [Table: see text]
Selective spatial up-regulation of intratumoral stromal aromatase in breast cancer patients: Evidence for imbalance of local estrogen metabolism
Authors: Singer C. F. , Fink-Retter A. , Gschwantler-Kaulich D. , Hudelist G. , Czerwenka K. , Kubista E. 
Published: March 2020

10105 Background: The suppression of local estrogens levels is of key importance in the treatment of ER positive breast cancer. Essentially all endocrine strategies act by either suppressing estrogen formation or by competitively inhibiting receptor binding in tumor cells. Nevertheless, little is still known about the local expression of aromatase and sultotransferase which are key modulators of intra-tumoral estrogen levels. Methods: We have performed immunohistochemostry to investigate the expression of aromatase and sulfotransferase in 42 samples obtained directly from malignant breast tumors, and compared it to biopsies obtained from uninvolved tissue in the vicinity of the invasion front, and to distant breast tissue. Results: We found that aromatase was equally detectable in both tumor epithelial and stroma, but was mostly epithelial in non-malignant tissues (p=0.00008, Fisher’s Exact Test). Also, aromatase protein expression was significantly more common in tumoral stroma when compared to peri-tumoral and distant breast stroma (p=0.00005, and p<0.00001, respectively). With the notable exception of cystosarcoma phylloides, sulfotransferase protein was only detectable in epithelial tissues, regardless of the location within the diseased breast. Epithelial sulfotransferase was, however, correlated with epithelial aromatase (r=0.35461, p=0.0009, Spearman’s Rho test) and with the epithelial ER status (r=0.29313, p=0.005). Conclusions: Taken together, we have demonstrated a differential aromatase and sulfotransferase protein expression pattern that is dependent of the spacial relation to a malignant breast tumor. Our results indicate a net increase in intra-tumoral active estrogen levels through increased stromal aromatization, while physiological local inactivation by sulfotransferase activity remains essentially unchanged. No significant financial relationships to disclose.
Cervical cytologic screening: Optimal management of atypical squamous cells of undetermined significance in young women
Authors: Gibb R. K. , Wright J. D. , Davila R. , Powell M. A. , Rader J. S. , Gao F. , Mutch D. G. 
Published: March 2020

1019 Background: HPV testing is a cost-effective strategy for the management of ASC-US cytology. However, young women have a high prevalence of transient HPV infections and low incidence high grade cervical lesions which may limit the utility of HPV testing in these women. We sought to determine the utility of HPV testing for young women with ASC-US. Methods: A review of all patients with ASC-US cytology between January, 2003 and December, 2004 was performed. Reflex HPV testing using the Hybrid Capture II system was performed on all samples. Age stratified rates of HPV positivity, rates of high grade dysplasia and sensitivity and specificity were estimated. Results: A total of 1290 women with ASC-US cytology were identified. The percentage of ASC-US samples that were HPV positive was highest in the young women and decreased with advancing age: < 25 yo (55%), 26–40 (36%), 41–50 (13%), > 50 yo (12%) (p<0.0001). Among HPV positive women with ASC-US, the identification of high grade lesions (HSIL, CIN2, CIN3, cancer) was lowest in the young women and increased with age: < 25 (12%), 26–40 (24%), 41–50 (19%), > 50 yo (24%) (p=0.05). A negative HPV test more reliably excluded high disease in the young women. No high grade lesions were detected in the HPV negative women ≤ 25 compared to 3.8% of those > 50 (p=0.04). The sensitivity for detection of high grade disease was higher in women < 25 compared to those > 50 (100% vs. 50%), while specificity was lower (14% vs. 44%). Conclusions: Given the high prevalence of HPV and low occurrence of high grade lesions in young women with ASC-US, an HPV based triage strategy will result in the referral of a large number of women for colposcopy and may limit its cost effectiveness. A program of repeat cytology may be more appropriate for the follow-up of young women with ASC-US. [Table: see text]
NSAIDs, osteoarthritis, and colorectal cancer risk: Can administrative data provide a window into the effectiveness of a cancer prevention?
Authors: Lamont E. B. , Dias L. E. 
Published: March 2020

1022 Background: Randomized trials show that non-steroidal anti-inflammatory drugs (NSAIDs) reduce the risk of pre-cancerous polyps and may reduce the risk of invasive colorectal cancer (CRC), but studies of effectiveness have not been reported. Given the ubiquity of NSAIDS, existing population-level data sources may be leveraged to provide a window into the effectiveness of NSAIDs in CRC prevention. Methods: With data from the National Center for Health Statistics’ National Ambulatory Medical Care Survey, we established the suitability of the diagnosis of osteoarthritis (OA) as an instrument or marker of NSAID therapy among the elderly. With data from the National Cancer Institute’s SEER-Medicare program, we then identified elderly Medicare beneficiaries diagnosed with CRC in 1995 and compared them to elderly Medicare beneficiaries without histories of CRC according to antecedent OA diagnoses in Medicare claims files. Using logistic regression, we estimated the odds of CRC diagnosis among elderly Medicare beneficiaries with histories of OA compared to those without. As a control analysis, we also estimated the odds of a breast cancer diagnosis among those elderly female Medicare beneficiaries with histories of OA compared to those without. Results: Within the SEER-Medicare data files, we identified 4,599 elderly patients with a SEER diagnosis of invasive CRC and 100,270 patients without a SEER diagnosis of invasive CRC. Individuals with a diagnosis of OA in Medicare claims in the prior three years had an 18% lower risk of being diagnosed with CRC than individuals whose claims did not reflect antecedent OA (OR 0.82, 95% CI: 0.77–0.88). No association between antecedent OA and subsequent breast cancer (OR 0.99, 95% CI: 0.92–1.05) was found. Conclusions: In this case-control study that treats certain ICD-9 codes within Medicare claims as instruments of NSAID use, we find that elderly Medicare beneficiaries with ICD-9 codes for OA have an18% lower odds of being diagnosed with invasive CRC. Further, the magnitude of the CRC odds reduction is similar to what would be expected from the excess NSAID use alone. No significant financial relationships to disclose.