tbuckley/cabot-search huggingface dataset:
Use of serial <sup>18</sup>F-Fluorothymidine (FLT) PET and Ki-67 to predict response to aromatase inhibitors (AI) in women with ER+ breast cancer.
Authors: Toni Kay Roberts, Lanell Peterson, Brenda Kurland, Alena Novakova, Andrew Shields, Robert K Doot, Erin K Schubert, Vijayakrishna K. Gadi, Jennifer M. Specht, Julie Gralow, Janet F. Eary, Mark Muzi, Jeanne Link, Kenneth A. Krohn, David A. Mankoff, Hannah M. Linden
Journal: Journal of Clinical Oncology (2016)

e12039 Background: 18F-Fluorothymidine (FLT) PET non-invasively estimates cellular proliferation. In estrogen receptor positive (ER+) tumors, a low proliferative index (Ki-67) as little as two weeks after start of endocrine therapy predicts response. Determining which tumors will respond to endocrine therapy alone is desirable for treatment planning and can be accomplished in a brief pre-operative window. We tested associations between parametric analysis of dynamic FLT PET and Ki-67 at baseline and following two weeks of AI therapy to determine if early assessment FLT PET correlates with Ki-67 response in tumors in women with early stage ER+ invasive breast cancer. Methods: Women with ER+ HER2– operable tumors began AI monotherapy prior to definitive surgery. Dynamic FLT PET scans were performed before AI therapy, and 1-7 days before surgery. FLT SUVmax was determined from 30-60m SUV images. Dynamic FLT uptake was assessed using a 2-tissue compartment model to estimate flux (Ki). Ki-67 was measured in baseline core biopsy and in post AI therapy surgical specimens. Results: Twenty-six patients completed FLT imaging and surgery, average age 58 years (range 28-74). Nineteen tumors (73%) were ductal and 7 (27%) lobular carcinomas, the majority histologic grade ≥ 2 (n = 19). Baseline FLT SUVmax ranged from 1.1-7.7 (mean 3.0), and post run-in SUVmax (6-64 days later) ranged from 0.8-3.8 (mean 1.9). Baseline Ki-67 ranged from 4-54%, mean 26%; surgical Ki-67 post AI therapy ranged from 0-41% mean 8%; with six samples above 10%. Oncotype Dx was measured in 15 (58%) of the patient with an average of 15.5 (range 2-30). FLT SUVmax declined in all but one lesion with an average decline of 27% (range -77%-7%). FLT metabolic flux (Ki) declined in 73% of the lesions. Ki-67 declined in all lesions with an average of 68% (range -5% to -100%). Conclusions: Women with ER+ early stage breast cancer showed both imaging and tissue response to endocrine therapy. FLT-PET is a promising tool to assess cellular proliferation and response to therapy.
Immune profiling of oral pre-malignant lesions (OPLs): An Erlotinib Prevention of Oral Cancer (EPOC) study biobank analysis.
Authors: William Nassib William, Naohiro Uraoka, S. Andrew Peng, J. Jack Lee, Adel K. El-Naggar, Edwin Roger Parra Cuentas, Jaime Rodriguez-Canales, Ann M. Gillenwater, Heather Y. Lin, Ignacio Ivan Wistuba, Jeffrey Myers, Kathryn A. Gold, Patrick Hwu, John Heymach, Vassiliki Papadimitrakopoulou, Scott Michael Lippman
Journal: Journal of Clinical Oncology (2017)

1545 Background: We previously demonstrated that high-risk loss of heterozygosity (LOH) profiles (i.e., 3p14/9p21 LOH) and EGFR gene copy number gain (CNG) in OPLs were associated with inferior oral cancer-free survival (OCFS) in patients enrolled in the randomized EPOC trial. Herein, we performed comprehensive immune profiling of OPLs and correlated the findings with molecular features and outcomes, using the prospectively collected and clinically annotated EPOC biobank. Methods: We evaluated OPL specimens by multiplex immunofluorescence using the Opal 7-color fIHC Kit and the Vectra multispectral microscope / inForm Cell Analysis software. Markers included AE1/AE3 pancytokeratins, PD-L1 (clone E1L3N), CD3, CD8, and CD68. Wilcoxon rank-sum and Fisher’s exact tests were used to assess the associations between binary markers and continuous and categorical variables, respectively. Cox model was used to investigate associations of markers with OCFS. Results: The cohort included 188 OPL patients with hyperkeratosis/hyperplasia (18%), mild/moderate (44%), or severe dysplasia (5%); 65% had high-risk LOH profiles. The 5-year OCFS was 72.3% (median follow-up of 50 months). PD-L1 expression in &gt; 1% of epithelial cells occurred in 28% of OPLs. Intraepithelial CD3+, CD3+/CD8+, CD68+, and CD68+/PD-L1+ cells were detected in 100%, 88%, 88%, and 54% of the samples, respectively. OPLs with high-risk LOH profiles had increased epithelial PD-L1 expression (P = 0.007), intraepithelial CD68+/PD-L1+ cells (P = 0.002), and a trend towards more CD3+/CD8+ cells in the stroma (P = 0.06) but not in the epithelium (P = 0.97), compared with low-risk LOH OPLs. Increased epithelial PD-L1 expression was associated with inferior OCFS on univariate (P = 0.023), and multivariate analysis including LOH status and EGFR CNG as co-variates (P = 0.018). Conclusions: High-risk OPLs defined by LOH profiles had increased PD-L1 expression in epithelial cells and intraepithelial macrophages, as well as stromal CD3+/CD8+ immune infiltration. Higher PD-L1 expression was associated with increased oral cancer risk. The findings may support evaluation of (PD-1-targeted) immunoprevention strategies in high-risk OPLs.
Correlation of high p95HER2:HER2 ratio with poor outcome in two phase II clinical trials of trastuzumab-treated HER2-positive metastatic breast cancer.
Authors: Saranya Chumsri, Jeff Sperinde, Heshan Liu, Joseph Gligorov, Jean-Philippe Spano, Alvaro Moreno-Aspitia, Sarah A. McLaughlin, John William Winslow, Christos J. Petropoulos, Ahmed Chenna, Michael Patrick Bates, Jodi Marie Weidler, Yolanda Lie, Weidong Huang, Edith A. Perez
Journal: Journal of Clinical Oncology (2016)

603 Background: p95HER2 (p95) is a truncated form of HER2 receptor that had been shown to confer resistance to trastuzumab (T) in vitro. However, conflicting clinical results were observed between p95 and outcome in patients treated with T based therapy to date. Given that p95 level often correlates with high HER2 expression level which confers better outcome, we sought to evaluate the correlation between quantitative levels of HER2, p95, and p95:HER2 ratio in NCCTG N0337 (Phase II study of vinorelbine, capecitabine and T) and NCCTG 98-32-52 (Phase II study of weekly versus every-three-week paclitaxel, carboplatin and T). Methods: A total of 91 formalin-fixed, paraffin-embedded patient samples from N0337 and 98-32-52 were analyzed. The HERmark(R) Breast Cancer Assay (Monogram Biosciences, South San Francisco) was used to measure HER2 expression level. p95 expression was measured using the VeraTag(R) technology (Monogram Biosciences) with an antibody specific for the active Met611 carboxy-terminal fragment of HER2, commonly known as p95HER2. To increase power, cohorts from N0337 and 98-32-52 were combined for analysis. Median follow up was 60 months (range 4-106 months). Results: Increasing HER2 level showed a trend with improved progression-free survival (PFS) (HR = 0.68/log; p = 0.061) and overall survival (OS) (HR = 0.63/log; p = 0.055) when stratified by hormone receptor status and cohort. The correlation of p95 level with PFS or OS was not significant. However, in a multivariate model containing continuous HER2 and continuous p95, increasing HER2 was associated with longer OS (HR = 0.34/log; p = 0.002) and increasing p95 was associated with shorter OS (HR = 4.90/log; p = 0.014). The correlation with PFS was directionally similar, but only HER2 was significant. More importantly, the ratio of p95 to HER2 was significantly correlated with shorter PFS (HR = 1.80/log; p = 0.041) and OS (HR = 2.6/log; p = 0.003). Conclusions: High p95HER2:HER2 ratio identified metastatic breast cancer patients with reduced benefit from trastuzumab-based treatments. Further clinical study of the p95:HER2 ratio as a potential predictive biomarker for HER2 targeted therapy is warranted.
Minimal Residual Disease Assessment of Remission after Induction Therapy Is Superior to Morphologic Assessment for Risk Stratification in Childhood Acute Lymphoblastic Leukemia: A Report from the Children's Oncology Group (COG)
Authors: Sumit Gupta, Meenakshi Devidas, Si Chen, Cindy Wang, Mignon L. Loh, Elizabeth Raetz, Patrick Brown, Andrew J. Carroll, Nyla A. Heerema, Julie M. Gastier-Foster, Kimberly P. Dunsmore, Eric Larsen, Kelly Maloney, Leonard A. Mattano, Stuart Winter, Naomi Winick, William L. Carroll, Stephen Hunger, Michael J. Borowitz, Brent L. Wood
Journal: Blood (2016)
General household survey provides valuable data
Authors: J. Charlton, K. Dunnell
Journal: BMJ (1995)

respondents were home owners and 6 1 % car owners, was recruitment principally from the upper social class?Furthermore, it would have been beneficial if the authors had described the sociodemographic characteristics of the non- respondents, thereby allowing comparison with those ofthe respondents.Secondly, respondents were asked whether particular services would currently be of some help, great help, or no help.to them personally.It was therefore no surprise that the "healthy" group gave higher rankings to health promotion activities than to symptomatic treatments compared with the "unhealthy group."III individuals may be best placed to put a utility value on their own state of health.Sick people, however, would not be able to give "informed" opinions about health states that they have not experienced, and their judgment may be consciously or subconsciously biased.It would have been more useful for prioritisation purposes to have invited respondents to be more altruistic, by asking them to value primary care services for society as a whole.This would be similar to Rawls's "original position," when subjects are asked to make judgments from behind a "veil of ignorance."I Thirdly, it was disappointing that Hopton and Dlugolecka dealt very superficially with ethical issues such as equality and equity and then only at the end of their paper.Equity is similar to Aristotle's concept of justice, whereby equals are treated equally and unequals unequally, in propor-3 tion to their relevant differences.While the respondents in this study are different in terms of health state, there may be other factors of moral worth that we wish to consider.In any case, Hopton and Dlugolecka do not indicate how the views of unhealthy people may be given more weight.We would prefer to appeal to the ethical principle of equal consideration of interests.Since we are all potential users of health care, we should all have a right to participate in decisions on prioritisation, even if this is biased towards conditions that we would be least likely to experience rather than actual experience of a reduction in quality of life associated with different health states.
Abstract 39: CD47 Regulates Aberrant Ca2+ Channel Current in Cardiac Myocytes
Authors: Maryam Sharifi-Sanjani, Beth Gabris, Qiao Li, Guy Salama, Jeffrey S Isenberg
Journal: Circulation Research (2015)

Background: Left ventricular (LV) heart failure (HF) affects over 5 million Americans with 50% of HF patients dying within 5 years of diagnosis. Therapeutics, while only relieving symptoms and have multiple side effects, have not completely resolved this process. HF is associated with cardiac myocyte cytosolic Ca2+ overload due to impaired sarcoplasmic reticulum (SR) and/or membrane Ca2+ handling. We recently found that a widely expressed cell surface receptor CD47 and its high affinity ligand, thrombospondin-1 (TSP1), are expressed on cardiac myocytes. We further showed that activated CD47 increases isolated neonatal cardiac myocyte cytosolic Ca2+ levels in part through SR Ca2+ channels. We postulated that TSP1-CD47 signaling may in part play a role in LV HF secondary to dysregulation of Ca2+, though the specific Ca2+ dynamics through which TSP1-CD47 signaling controls cardiac Ca2+ remains to be determined. Methods: Isolated hearts from mutated mice lacking CD47 (CD47-/-) and wild type (WT) mice with and without 4 weeks of transverse aortic constriction (TAC) were studied in ex vivo perfused heart Langendorff using dual optical mapping of Cai transients and action potential or voltage measurements. Isolated cardiac myocyte experiments were performed using whole cell voltage-clamp analysis. Results: In TAC-stressed WT murine hearts studied in the Landendorff system, tetracaine (an inhibitor of SR ryanodine receptor2) blunted arrhythmia induced by electrical stimulation. Isoproterenol-induced Ca2+ transient irregularities in hearts from WT mice were ameliorated in CD47-/- mice. Further, hearts from WT mice treated with peptide 7N3, a TSP1 mimetic, showed induced Ca2+ transient irregularities and elicited early after depolarization which was also attenuated with K2O1 (ryanodine receptor2 stabilizer) treatment. Voltage-clamp studies of isolated adult mouse cardiac myocytes showed that 7N3 peptide increased the L-type Ca2+ channel current (ICa,L) whereas the scrambled control peptide did not alter ICa,L. Conclusion: These data demonstrate that CD47 activation may be a trigger for aberrant myocyte Ca2+ handling typically associated with HF. Targeting of TSP1-CD47 signaling may open a new therapeutic avenue to be further studied in HF.
Expression of Blood Coagulation Factor Xiiia in Lymphoblasts Predicts Favorable Outcome in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia
Authors: Csongor Kiss, Bettina Kárai, Zsuzsanna Hevessy, Eszter Szánthó, László Csáthy, Anikó Ujfalusi, Katalin Gyurina, István Szegedi, János Kappelmayer
Journal: Blood (2016)
Do spontaneous apoptosis and COX 2 expression predict response of rectal cancer to neoadjuvant radiochemotherapy?
Authors: FM Smith, E Kay, EF Gaffney, P Crotty, RB Stephens, MJ Kennedy, JV Reynolds
Journal: Endoscopy (2005)

Aims: Rectal cancer is increasingly treated by neoadjuvant chemoradiotherapy followed by surgery. A molecular understanding of predictors of response or resistance to neoadjuvant therapy is important and this study evaluated COX-2 expression and apoptosis.
Targeting the Achilles' shield of triple-negative breast carcinoma by androgen blockade.
Authors: Mohamed Abazeed, Brian Yard
Journal: Journal of Clinical Oncology (2016)

e12562 Background: Triple-negative breast cancers (TNBC) account for 15-20% of breast carcinomas and are defined by their lack of ER/PR expression, along with the absence of HER2 overexpression or gene amplification. The lack of recognized targets coupled with its aggressive biology makes this subset of breast cancer a subject of intensive effort for new molecular target identification. Several phase III clinical trials have shown a clear benefit in overall survival with androgen-deprivation therapy for prostate cancer patients with intermediate- and high-risk disease. In preclinical data, a subset of AR positive, TNBC are dependent on androgen receptor signaling for growth although the degree of dependency is substantially less than that observed in prostate cancer. The differential requirements for androgen signaling between prostate cancers and breast cancers that express AR remain poorly understood. Methods: We developed new technology that makes possible the profiling of cancer cell line response to targeted and cytotoxic therapies in high-throughput capacity. We used this technology to study the radiosensitivity of 28 breast cancer cell lines annotated by the Cancer Cell Line Encyclopedia (CCLE) project. Gene Set Enrichment Analysis (GSEA) was performed to correlate radiosensitivity with gene expression features of the assayed cell lines. We validated our results using cellular based assays and orthotopic mouse xenografts. Results: We demonstrate that: 1) androgens protect breast cancer cells from ionizing radiation by minimizing DNA damage and enhancing repair; 2) androgen blockade significantly sensitizes breast cancer cells that express AR to DNA damage both in vitro and in vivo, despite a modest effect on growth in cell lines and orthotopic cell line xenografts; and 3) the response of breast cancer cell lines to androgen blockade is heterogeneous, with resistance to anti-androgen therapy mediated in part by intracrine steroid synthesis. Conclusions: Our results establish multiple lines of evidence that androgen signaling confers therapeutic resistance and is a targetable event that can be exploited for therapeutic benefit in TNBC.
Abstract 12951: Predictors of Incident Heart Failure in Patients with Stable Coronary Heart Disease
Authors: Andrea Driscoll, Elizabeth Barnes, Stefan Blankenberg, Malcolm West, Harvey White, David Colquhoun, John Simes
Journal: Circulation (2013)

Background: Coronary heart disease (CHD) is a major cause of heart failure (HF). Availability of risk prediction models for HF in CHD patients that include both clinical parameters and biomarkers i...
Magnitude of invasive breast cancer (BC) risk associated with mutations detected by multiple-gene germline sequencing in 95,561 women.
Authors: Michael J. Hall, Elisha Hughes, Elizabeth Handorf, Alexander Gutin, Brian Allen, Anne-Renee Hartman, Allison W. Kurian
Journal: Journal of Clinical Oncology (2016)

1512 Background: Using a multiple-gene sequencing panel to assess hereditary BC risk increases the detection rate of clinically significant mutations. However, the magnitude of BC risk with mutations across these newly-tested genes is not clearly defined. Methods: We studied 95,561 women tested clinically for hereditary cancer risk with a 25-gene panel (see Table), including 13 genes associated with hereditary BC: BRCA1/2,TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, BARD1, BRIP1, and RAD51C. Patients who had single- or founder-site testing, or prior BRCA1/2testing, were excluded. Multivariable regression analysis was used to examine the association between pathogenic/suspected pathogenic mutations and personal BC history (Hx) (dependent variable). Independent variables were age, personal/family cancer Hx, and ancestry. Odds ratios (OR) with 95% confidence intervals (CI) excluding 1.0 were considered significant. Results: Mutations were detected in 6,775/95,561 (7%) patients; 5,760 (85%) were in BC-associated genes, including 3,007 (52%) in BRCA1/2. A significant association with personal BC Hx was found for 8 genes. Conclusions: Among nearly 100,000 women tested clinically for hereditary cancer risk, multiple-gene sequencing identified a wide spectrum of BC-associated mutations: approximately half in BRCA1/2 and half in other genes. Gene-specific estimates ranged from two (ATM, CHEK2, BARD1) to six (BRCA1, PTEN) times increased BC risk. These results inform the estimation of BC risk for mutation carriers of diverse high-risk genes. Gene OR (95% CI) for BC BRCA1 5.91 (5.25-6.67) PTEN 5.83 (2.43-14.0) TP53 5.37 (2.78-10.4) PALB2 3.39 (2.79-4.12) BRCA2 3.31 (2.95-3.71) CHEK2 1.99 (1.70-2.33) BARD1 1.92 (1.36-2.72) ATM 1.74 (1.46-2.07) STK11 4.41 (0.66-29.6) RAD51C 1.43 (0.97-2.12) CDH1 1.34 (0.66-2.68) NBN 1.30 (0.92-1.84) BRIP1 1.24 (0.93-1.66) SMAD4 3.68 (0.47-28.9) RAD51D 1.37 (0.76-2.49) MSH6 1.29 (0.93-1.79) BRIP1 1.24 (0.93-1.66) P16 1.22 (0.71-2.09) MLH1 1.06 (0.60-1.86) MSH2 1.01 (0.64-1.60) PMS2 0.89 (0.66-1.22) APC 0.68 (0.33-1.39) BMPR1A 0.66 (0.08-5.58) MYH 0.55 (0.22-1.38) CDK4 * P14ARF * *Could not be estimated.
Measles still spreads in Europe: who is responsible for the failure to vaccinate?
Authors: P L Lopalco, R Martin
Journal: Eurosurveillance (2010)

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TLR9-Mediated Conditioning of Liver Environment Is Essential for Successful Intrahepatic Immunotherapy and Effective Memory Recall
Authors: Marcin Cebula, Mathias Riehn, Upneet Hillebrand, Ramona F. Kratzer, Florian Kreppel, Georgia Koutsoumpli, Toos Daemen, Hansjörg Hauser, Dagmar Wirth
Journal: Molecular Therapy (2017)

Immune defense against hepatotropic viruses such as hepatitis B (HBV) and hepatitis C (HCV) poses a major challenge for therapeutic approaches. Intrahepatic cytotoxic CD8 T cells that are crucial for an immune response against these viruses often become exhausted resulting in chronic infection. We elucidated the T cell response upon therapeutic vaccination in inducible transgenic mouse models in which variable percentages of antigen-expressing hepatocytes can be adjusted, providing mosaic antigen distribution and reflecting the varying viral antigen loads observed in patients. Vaccination-induced endogenous CD8 T cells could eliminate low antigen loads in liver but were functionally impaired if confronted with elevated antigen loads. Strikingly, only by conditioning the liver environment with TLR9 ligand prior and early after peripheral vaccination, successful immunization against high intrahepatic antigen density with its elimination was achieved. Moreover, TLR9 immunomodulation was also indispensable for functional memory recall after high frequency antigen challenge. Together, the results indicate that TLR9-mediated conditioning of liver environment during therapeutic vaccination or antigen reoccurrence is crucial for an efficacious intrahepatic T cell response. Immune defense against hepatotropic viruses such as hepatitis B (HBV) and hepatitis C (HCV) poses a major challenge for therapeutic approaches. Intrahepatic cytotoxic CD8 T cells that are crucial for an immune response against these viruses often become exhausted resulting in chronic infection. We elucidated the T cell response upon therapeutic vaccination in inducible transgenic mouse models in which variable percentages of antigen-expressing hepatocytes can be adjusted, providing mosaic antigen distribution and reflecting the varying viral antigen loads observed in patients. Vaccination-induced endogenous CD8 T cells could eliminate low antigen loads in liver but were functionally impaired if confronted with elevated antigen loads. Strikingly, only by conditioning the liver environment with TLR9 ligand prior and early after peripheral vaccination, successful immunization against high intrahepatic antigen density with its elimination was achieved. Moreover, TLR9 immunomodulation was also indispensable for functional memory recall after high frequency antigen challenge. Together, the results indicate that TLR9-mediated conditioning of liver environment during therapeutic vaccination or antigen reoccurrence is crucial for an efficacious intrahepatic T cell response.