bluuebunny/crossref_metadata_2025_split huggingface dataset:
SEER study of breast cancer specific mortality (BCSM) in patients with lobular tumors treated based on recurrence score results.
Authors: Baehner Frederick L. , Shak Steven , Miller Dave P. , Petkov Valentina I. 
Published: September 2018

11568 Background: Linking the 21-gene assay RS result to the SEER Registries demonstrated very low 5-y BCSM with low RS and high 5-y BCSM with high RS across subgroups, such as nodal status, age, tumor size and grade (npj Breast Cancer 2016). Given the large sample size and interest in outcomes as a function of tumor characteristics, we characterized the relationship between RS results and BCSM in patients reported by SEER with lobular morphology. Methods: Patients with RS and lobular morphology based on the registry ICD-O-3 code 8520 were eligible if node negative (N0) or node positive up to 3 positive nodes (N+mic,1-3), HR+, HER2- negative, no prior malignancy, and diagnosed between Jan 2004 and Dec 2012. No information in SEER is available regarding lobulars, ie., trabecular, alveolar, solid and pleomorphic. 5-y BCSM was estimated using actuarial methods. Results: There were 6,075 eligible patients reported with lobular morphology (11% of cases). Median age was 59 years; 88%/12% were N0/N+; 31%/62%/7% grade 1/2/3; 61%/39% ≤2 cm/>2 cm. Median follow-up was 44 months. A minority (8%) had RS >25. Chemotherapy (CT) use and BCSM increased with increasing RS. In multivariable analysis in N0 disease, continuous RS result and tumor size predicted BCSM (p=0.003 and p=0.04, respectively), whereas age and tumor grade were non-significant. In multivariable analysis in N+ disease, continuous RS result alone predicted BCSM (p=0.002). Conclusions: In these analyses the prognosis of patients with lobular breast cancer treated based on RS results depends on both nodal status and the RS result. The 5-y BCSM for lobular breast cancer is excellent with RS of 25 or less, and increases for RS >25. [Table: see text]
Function and expression of checkpoint inhibitors and immune agonists on immune cells in monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM) and MM and tumor-specific T lymphocytes.
Authors: Bae Jooeun , Nguyen Brandon , Tai Yu-Tzu , Hideshima Teru , Chauhan Dharminder , Munshi Nikhil C. , Anderson Kenneth Carl 
Published: September 2018

11577 Background: Characterization of expression and function of immune regulatory molecules in tumor microenvironment will provide the framework for developing novel therapeutic strategies. Methods: We evaluated the expression and functional impact of various immuno-regulatory molecules, PD-1, PDL-1, PDL-2, LAG3, TIM3, OX40 and GITR, on the CD138+ tumor cells, myeloid derived suppressor cells (MDSC), and T cell subsets from patients with MGUS, SMM and active MM (newly diagnosed, relapsed, relapsed/refractory), and the myeloma-specific cytotoxic T lymphocytes (CTL) induced with XBP1/CD138/CS1 peptides. Results: PDL-1/PDL-2 was more highly expressed on CD138+ myeloma cells in active MM than SMM or MGUS. G-type MDSC (CD11b+CD33+HLA-DRlowCD15+). Treg cells (CD3+CD4+/CD25+FOXP3+) numbers were increased and expressed higher levels of PD1/PD-L1 in active MM than in MGUS, SMM or healthy donors. Among the checkpoint molecules (PD-1, PDL-1, PDL-2, LAG3, OX40, GITR) evaluated, PD-1 showed the highest expression on CD3+CD4+ and CD3+CD8+T cells in BMMC and PBMC from patients with active MM. Functionally, T cells from MM patients showed increased proliferation upon treatment with an individual immune agonist ( > 150%) or checkpoint inhibitor ( > 100%). Interestingly, each individual anti-checkpoint molecule induced proliferation of T cells expressing other checkpoint molecules. In addition, the blockade of PD1, LAG3 or TIM3 enhanced MM antigen-specific cytotoxicity, assessed by parameters including CD107a, granzyme B and IFN-g production, which was most prominent within the memory CTL subset of MM antigen-specific T cells. Conclusions: These results demonstrate an increased frequency of immune regulatory cells, which highly express checkpoint inhibitors in active MM. Direct stimulation with an immune agonist or blockade of a checkpoint inhibitor increased MM patients’ T cell proliferation and myeloma-specific CTL function, supporting development of combination immune regulatory therapies to improve patient outcome in MM.
Association of MLL2 mutation positive non-small cell lung cancer with prognosis.
Authors: Ardeshir-Larijani Fatemeh , Wildey Gary , Fu Pingfu , Bhateja Priyanka , Lipka Mary Beth , Dowlati Afshin 
Published: September 2018

11598 Background: Myeloid/lymphoid or mixed-lineage leukemia protein 2 (MLL2) is an epigenetic regulator expressed in many tissues. Although MLL2 mutations are associated with poor prognosis in different types of cancer, the clinical impact of this gene in lung cancer remains unclear. Here, we evaluated the clinical and genomic characteristics of MLL2 alteration in non-small cell lung cancer (NSCLC) and compared it to small cell lung cancer (SCLC) Methods: Between 2014 and 2016 tumor samples of 194 Stage III and IV NSCLC patients and 50 SCLC patients underwent targeted-exome sequencing. The association of MLL2 mutation with survival outcomes was measured using KaplanMeier methods (PFS, OS). Coxs proportional hazards regression model was performed for multivariate survival analyses with known clinical prognostic features. All tests were two-sided and p-values = 0.05 were considered statistically significant. Results: The MLL2 mutation rate was 17.5% (N=34) in NSCLC. Patients with mutant MLL2 had significantly lower overall survival (OS) (9.97 vs. 30.2 months, p < 0.0001) and progression-free survival (PFS) (8.46 vs. 24.1 month, p = 0.0007) compared to those with wild type MLL2. The median overall survival in the entire NSCLC cohort was 23.3 months (95% CI: 16.5  34.4). Interestingly, MLL2 mutation was significantly more common in females (p = 0.017). There was no significant association of MLL2 mutation status with age, smoking history, race or histology . Using a multivariate Cox regression model with adjustments based on tumor stage, smoking histology and chemotherapy, MLL2 mutation remained the most remarkable prognostic factor in NSCLC: OS Hazard Ratio 2.79, p = 0.0001 and PFS Hazard Ratio 1.99, p < 0.001. By comparison, the MLL2 mutation rate in SCLC was 24% (N=12) and showed no gender bias (p=0.874). There was no significant decrease in survival associated with MLL2 mutation in SCLC (OS p = 0.966, PFS p = 0.641). Conclusions: This study demonstrates that MLL2 mutation specifically impacts survival outcome only in NSCLC but not SCLC.
Impact of PIK3CA tumor mutation on the association of aspirin or NSAID use and time to breast cancer recurrence.
Authors: McCarthy Anne Marie , He Wei , Regan Susan , Chan Andrew T. , Moy Beverly , Iafrate A. John , Bardia Aditya , Armstrong Katrina 
Published: September 2018

1521 Background: Aspirin or NSAID (A/N) use post diagnosis is associated with lower risk of breast cancer recurrence and mortality in cohort studies. A potential mechanism is that A/Ns may suppress cell growth and induce apoptosis in tumors driven by phosphatidylinositol 3 kinase ( PIK3CA), the most common oncogene mutation in breast cancer. An interaction of A/Ns and PIK3CA mutation has been observed for colorectal cancer prognosis, but has not been studied in breast cancer. The objective was to assess time to breast cancer recurrence (TTR) with respect to A/N use and PIK3CAmutation. Methods: Patients with HR+/HER2- breast cancer treated at Massachusetts General Hospital in 2009-2014 who received tumor genotyping were included. PIK3CA mutations, including 8 common hotspot mutations, were assessed by a high-throughput tumor genotyping assay using DNA from formalin-fixed, paraffin-embedded tumor tissue. A/N use beginning 6 months post diagnosis through metastasis was extracted from electronic medical records using coded data and natural language processing. Patients with de novo metastatic disease or progressive disease within 6 months of primary diagnosis were excluded. TTR was estimated using Cox proportional hazards models. Results: Among breast cancer patients (N=212), 60 (28%) used A/Ns and 69 (33%) had PIK3CA mutation (see Table). After adjusting for age, stage, adjuvant endocrine therapy, radiation, and chemotherapy, A/N users had significantly longer TTR (HR=0.65 p=0.01). The association was similar for wild type (HR=0.58 p=0.01) and PIK3CA mutated tumors (HR=0.60 p=0.06), with no significant interaction of A/N use and PIK3CA (p=0.34). Conclusions: Among HR+ breast cancer patients, those who used A/Ns following primary diagnosis had longer TTR than non-users, regardless of tumor PIK3CA mutation status. The study provides a model for how tumor genomics could be integrated into secondary chemoprevention studies. [Table: see text]
Awareness of cervical cancer and screening among rural Nepalese women.
Authors: Shrestha Anju 
Published: September 2018

1553 Background: Cervical cancer is leading female cancer in Nepal. Despite the existence of effective screening using Pap smear, the uptake of screening is poor. Objectives of this study were to determine the baseline information about the knowledge of cervical cancer and explore attitude and practice of Pap smear screening among the women of rural community of Nepal. Methods: A cross sectional population based descriptive study of female attending free cervical cancer screening camp in different rural community of Nepal organized by Nepal cancer Support group and Nepal cancer Hospital, funded by Direct Relief was conducted from 1/06/2016 to 31/12/2016- using self- administered questionnaire to elicit information on demographic characteristics, knowledge, screening behaviors and determinants of cervical cancer. Results: A total of 2529 women participated in nine screening camp, out of which 55.95% (1416) were illiterate whereas only 4.95% (129) were graduate. Mean age of participates were 40.5±11.97 (17-83)yrs. 31.63% (800) of women married before age of 16 and 32.08% (811) women had their first childbirth before age of 18 years. Only 6.88% (174) women were working outside and rest were working in household work and farming. 76.24% (1928) women knew nothing about cervical cancer. Although 38.71% (979) women heard about Pap smear, only 10.36% (262) knew about eligibility of screening, 1.58% (40) knew about screening interval and 16.57% (419) know that Pap smear is used for detections of cancerous and precancerous lesions of cervix. However, knowledge of risk factors for cervical cancer was found in 5.9% (150). Of the female respondents, 78.09% (1975) did not feel susceptible to cervical cancer and 82.25% (2080) had never been screened before. The most common reason for not doing Pap test is they never heard about it (59.99%:1516). The other reason includes do not have any symptoms (17.79%:450); embarrassment (2.49%:62); do not know where to do (1.27%:32); fear of finding out cancer (0.51%:13) and never advised by doctor (0.4%:10). Conclusions: The study revealed very low cervical cancer knowledge and poor screening behavior among the women. This may be due to lack of awareness, education and low priority of women’s health issue.
The clinical impact of the Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) score on breast cancer patients survival.
Authors: Yamashita Nami , Inoue Yuka , Tanaka Kimihiro , Saeki Hiroshi , Oki Eiji , Tokunaga Eriko , Maehara Yoshihiko 
Published: September 2018

1560 Background: Recent reports show that the preoperative immunonutritional status correlate with the survival rate in cancer patients. The Prognostic Nutritional Index (PNI) and Controlling Nutritional Status (CONUT) score are used as screening tools for immunonutritional status and reported to be a predictor of postoperative recurrence in patients with various gastrointestinal cancers. However, the clinical importance of the PNI and CONUT in breast cancer has not been elucidated. The aim of this study is to investigate the clinical impact of preoperative PNI and CONUT on long-term survival of breast cancer patients. Methods: We retrospectively analyzed 653 consecutive stage I-III breast cancer patients who were treated from January 2002 to December 2013. The PNI score was calculated as 10 x serum albumin (g/dl) + 0.005 x total lymphocyte count (per mm3). The CONUT score is calculated from three parameters, serum albumin, cholesterol, and total lymphocytes count. The patients were divided into two groups according to the PNI and CONUT score. The uni- and multivariate Cox regression analyses were performed to evaluate the prognositic value of the PNI and CONUT in breast cancer. Results: The malnutritional status was observed in 170 (26%) and 131 (20%) patients as low-PNI and high-CONUT, respectively. The relapse-free survival (RFS) and overall survival (OS) rates were significantly lower in the low-PNI group (RFS: p < 0.0001, OS: p < 0.0001) and high-CONUT group (RFS: p = 0.0009, OS: p = 0.0018). In the multivariate analysis, low-PNI was independent prognostic factors for both RFS and OS (RFS: HR2.33, p = 0.032, OS: HR5.01, p = 0.0009). In the subset analysis, the low-PNI group showed poor prognosis especially in the postmenopausal, hormone receptor negative patients. The low-PNI also had poorer prognosis in post-recurrence survival. Conclusions: The preoperative PNI is a strong independent predictor of long-term survival among breast cancer patients.
Development and validation of a residual risk score to predict breast cancer risk in unaffected women negative for mutations on a multi-gene hereditary cancer panel.
Authors: Hughes Elisha , Judkins Thaddeus , Wagner Susanne , Wenstrup Richard J. , Lanchbury Jerry S. , Gutin Alexander 
Published: September 2018

1579 Background: Women who are unaffected with cancer but have a significant family history of breast cancer (BC) are frequently referred for hereditary cancer testing with multi-gene panels; however, < 10% test positive for clinically actionable mutations. Large-scale genotyping studies have identified common variants (primarily single-nucleotide polymorphisms) that individually confer modest BC risk, but together may explain the genetic susceptibility for BC in many women without monogenic mutations. Here, we describe the development and validation of a polygenic residual risk score in a large, consecutive cohort of women who tested negative for mutations in known BC susceptibility genes. Methods: This IRB-approved study includes women of European ancestry tested with a multi-gene hereditary cancer panel who were negative for mutations in 11 genes associated with BC ( BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, BARD1). Clinical information was collected from provider-completed test request forms. The dataset was divided into a training (July – November 2016) and validation cohort (November 2016 – April 2017). Multivariable logistic regression models were used to evaluate 94 common variants and develop candidate residual risk scores as predictors of personal BC history (invasive ductal carcinoma, IDC) in the training cohort. Independent variables included age, personal/family cancer history, and ancestry. An optimal subset of the 94 common variants and a residual risk score will be selected through cross-validation followed by independent validation. Results: The training cohort includes 11,838 women (median age 47 years), 18% of whom reported a personal history of IDC and 36% of whom reported BC in a first-degree relative. Results from validation of the residual risk score in an independent cohort of approximately 12,000 women will be completed at the time of presentation. Conclusions: The validation and clinical implementation of a residual risk score for women at risk for hereditary BC may offer significant potential for the management of high-risk, unaffected women who test negative for monogenic BC mutations.
Identification of single nucleotide polymorphism of PI3k-AKT-TOR pathway as a risk factor of central nervous system metastasis in metastatic breast cancer.
Authors: Bonneterre Jacques , Bertrand Nicolas , Tresch-Bruneel Emmanuelle , Dumont Aurelie , Preusser Matthias , Weller Michael , Revillion Francoise , Le Rhun Emilie 
Published: September 2018

2007 Background: Although new therapeutic options are available, an early diagnosis of central nervous system (CNS) metastasis may be needed to improve the prognosis. The PI3k-Akt-mTor pathway has been shown to be relevant in the development of CNS metastasis. Our aim was to identify risk-associated single nucleotide polymorphisms (SNP) of the PI3K Akt-mTOR pathway in the development of CNS metastasis in patients with metastatic breast cancer. Methods: We performed a secondary analysis in a subpopulation of patients from the GENEOM study (NCT00959556). In this previous study, blood samples were collected from 914 breast cancer patients treated by chemotherapy in the neoadjuvant, adjuvant or metastatic setting for genomic analysis. We identified CNS metastatic patients (both leptomeningeal and parenchymal) and non-CNS metastatic patients (no neurological symptoms or normal brain MRI before death or during 5-years metastatic period). Based on the literature, 88 SNPs of the PI3K-Akt-mTOR pathway were analyzed, including AKT1 (17 SNPs), AKT2 (4), FGFR1 (2), mTOR (7), PDK1 (4), PI3KR1 (11), PI3KCA (20), PTEN (17), RPS6KB1 (6). Results: Of the 342 patients with metastases in the GENEOM cohort, 100 patients with CNS metastasis (parenchymal lesions only, n = 51; leptomeningeal lesions only, n = 18; both, n = 31) and 107 patients without CNS metastasis were included. Negative hormonal status (p = 0.002) and presence of vascular emboli on breast cancer samples (p = 0.006) were associated with CNS metastasis. In univariate analysis, genotypes CC of AKT1 rs3803304, AA of AKT2 rs3730050, CC of AKT2 rs8100018, TT of PDK1 rs1168690, GG of PDK1 rs11904366 and GG of PI3KR1 rs251408 were associated with CNS metastasis at the p < 0.05 threshold. Only genotype TT of PI3KR1-rs706716 was statistically associated with CNS metastasis after Bonferroni correction (p = 0.0003, < 0.00085). Conclusions: PI3KR1-rs706716 is associated with CNS metastasis in metastatic breast cancer patients, in addition to negative hormonal status and presence of vascular emboli and could be combined in a composite score to predict the risk of and to detect early CNS metastasis in this population.
Results of the OPARATIC trial: A phase I dose escalation study of olaparib in combination with temozolomide (TMZ) in patients with relapsed glioblastoma (GBM).
Authors: Halford Sarah E. R. , Cruickshank Garth , Dunn Laurence , Erridge Sara , Godfrey Lisa , Herbert Christopher , Jefferies Sarah , Lopez Juanita Suzanne , McBain Catherine , Pittman Marc , Sleigh Rebecca , Watts Colin , Webster-Smith Mark F , Chalmers Anthony J. 
Published: September 2018

2022 Background: Olaparib, a small molecule inhibitor of poly (ADP-ribose) polymerase (PARP), may improve GBM outcomes by enhancing cytotoxic effects of ionising radiation and TMZ. Clinical development of PARP inhibitors has been restricted by exacerbation of hematological toxicity. We investigated tumor pharmacokinetics (PK) of olaparib and safety and tolerability of its combination with TMZ. Methods: Dose escalation explored different schedules of olaparib (tablet formulation) with 42 day cycles of daily low dose TMZ. A dose expansion cohort evaluated the maximum tolerated schedule. PK analysis was performed on tumor and blood samples from patients undergoing neurosurgical resection, who received 4 olaparib doses pre-operatively. Results: 48 patients were recruited (median age 51(18-68); 29 male, 19 female) of whom 27 underwent surgery and 35 received olaparib/TMZ and were evaluable. 13 evaluable patients received expansion dose schedule (median age 54(21-67); 9 male, 4 female). Olaparib was detected in 73 of 74 tumor core specimens from 27 patients; mean conc. 588nM (97-1374nM), and in 27 of 28 tumor margin specimens from 10 patients; mean conc. 500nM (97-1237nM). Margin: core ratios ranged from 0.2–3.9(mean 1.2); tumor: plasma ratios ranged from 0.01 to 0.9 (mean 0.25). Olaparib dosing on days 1-5 was hindered by myelosuppression. Expansion cohort dose was defined as TMZ 75 mg/m2daily plus olaparib 150 mg (OD) days 1-3 weekly. Of 13 evaluable patients receiving expansion dose-schedule, 9 completed cycle 1, 2 completed cycle 2 and 2 completed cycle 3. Currently 45% of the evaluable patients remain progression-free at 6 months, with 2 still on treatment (full data set May2017). Of 35 evaluable patients, 24 experienced AE Grade ≥3 (see Table). Conclusions: Olaparib penetrates both core and margins of recurrent GBM despite failing to penetrate the intact brain barrier in pre-clinical heathy rodent models. Combination with extended low dose TMZ is safe and well tolerated, yielding encouraging 6 month progression-free survival rates. Clinical trial information: NCT01390571. [Table: see text]
Comparison of 2-hydroxyglutarate (2HG) levels in tissue and serum of isocitrate dehydrogenase (IDH)-mutated (MUT) versus wild-type (WT) gliomas.
Authors: Sim Hao-Wen , Nejad Romina , Zhang Wenjiang , Mason Warren P. , Bernstein Mark , Aldape Ken , Zadeh Gelareh , Chen Eric Xueyu 
Published: September 2018

2037 Background: IDH mutations are common in low-grade gliomas and confer significantly improved prognosis. IDH catalyzes the oxidative decarboxylation of isocitrate to α-ketoglutarate, and subsequently to the oncometabolite 2HG. Mutant IDH leads to preferential accumulation of the R relative to the S enantiomer of 2HG. We analyzed the ratio of R to S enantiomers (rRS) in glioma tissues and matched serum samples, and correlated findings with IDH status, 1p19q codeletion status and survival. Methods: Fresh frozen glioma tissues and matched serum samples were obtained from the University of Toronto Brain Tumor Bank. IDH status was determined by immunohistochemistry and confirmed by 450K methylation profile or direct sequencing. 1p19q codeletion status was determined by loss-of-heterozygosity PCR analysis. R-2HG and S-2HG levels were quantified using HPLC tandem mass spectrometry coupled with a CHIROBIOTIC column. Results: Glioma tissues from 70 patients were analyzed – 52 with IDH MUT and 18 WT. 30 had matched serum samples. Using glioma tissues, rRS clearly distinguished MUT vs WT (median 574 vs 1.3, p < 1x10-9) with only three outliers. In contrast, rRS was not elevated in serum samples (median 1.5 vs 1.2, p = 0.13). Overall survival (OS) was significantly longer for MUT vs WT (median 178 vs 33 months, p < 1×10-7). Stratifying MUT by tissue rRS, median OS was 197, 178, 178 and 122 months for lowest to highest quartiles of rRS respectively. 1p19q codeletion status and tumor latency did not explain this trend, given rRS was similar in codeleted vs non-codeleted MUT, and similar in MUT operated < 3 vs ≥3 months from diagnosis. Progression-free survival results corresponded to OS. Conclusions: rRS from glioma tissues effectively differentiated MUT vs WT, whereas serum samples were unreliable. Unlike current methods, tissue rRS enables real-time determination of IDH status, and thus may guide clinical practice such as extent of surgical resection intraoperatively and upfront selection of adjuvant therapy. rRS potentially stratifies survival within MUT patients, providing detailed correlative information.