tbuckley/cabot-search huggingface dataset:
Outcomes of neoadjuvant dual HER2 targeted therapy in HER2 amplified breast cancer in clinical practice: a single institutional experience.
Authors: Archana Chidambaram, Nischala Ammannagari, William E. Brady, Thaer Khoury, Tracey L. O'Connor, Ellis Glenn Levine, Jessica S. Young, Shicha Kumar, Helen M. Cappuccino, Kilian Elizabeth Salerno, Mateusz Opyrchal
Journal: Journal of Clinical Oncology (2016)

e12096 Background: Pathologic complete response (pCR- ypT0/isN0) could predict long-term outcomes in breast cancer. This study seeks to ascertain pCR reproducibility with neoadjuvant dual Her2 blockade in actual clinical practice compared to that seen in the landmark studies- NeoSphere (39%) & TRYPHAENA (58%). Methods: Sixty consecutive patients with newly diagnosed HER2 amplified invasive breast cancer seen at our institute between 1/1/2013 and 7/30/2015 (around the time dual Her2 therapy was approved) were reviewed. Of these, 25 patients treated with neoadjuvant dual Her2 blockade were deemed evaluable. Demographic, tumor & treatment characteristics, initial clinical- & final pathologic stages and treatment related toxicities were assessed. Results: Treatment regimens mainly included docetaxel, carboplatin, trastuzumab and pertuzumab [TCHP: 14 (50%)]; adriamycin, cyclophosphamide, docetaxel/paclitaxel, trastuzumab and pertuzumab [ACTHP: 7 (25%)] and 5-FU, epirubicin, cyclophosphamide, docetaxel, trastuzumab and pertuzumab [FEC-THP 3 (11%)]. Median age was 51 years (range 28-70 y) and 76% were Caucasian. One patient had stage I-, 16 had Stage II- and 8 patients had Stage III disease. Hormone receptor positivity was seen in 13 patients (52%). Ten patients were grade 2 by Nottingham criteria, and 13 were grade 3. pCR in breast and lymph node was seen in 11 (44%, 95% CI: 27%-63%) and in breast alone was seen in 12 patients (48%, 95% CI: 30%-67%). pCR rate was higher (67%) in ER negative than in ER positive patients (23%). Toxicities necessitating therapeutic adjustments occurred in 8 patients (32%), 7 of whom received TCHP, and included diarrhea (63%), neuropathy (25%), and fatigue (13%). One patient had progressive disease during treatment with TCHP and proceeded to surgery. Conclusions: Neoadjuvant dual HER2 blockade yielded pCR rates of 44% with most responders being ER negative. These results are lower than in the TRYPHAENA study which had similar chemotherapy regimens, across all sub-groups. Although small, this retrospective series suggests that patients enrolled in clinical trials may have higher pCR rates than a representative population of clinic patients.
Comparison of genomic and gene expression profile between cancer and healthy samples.
Authors: Ioannis Papasotiriou, Dimitrios Ntanovasilis, Panagiotis Apostolou
Journal: Journal of Clinical Oncology (2017)

e13001 Background: A variety of chromosomal aberrations underlie developmental abnormalities and cancer. Use of techniques such as microarrays provides an opportunity to perform gene expression analysis. A recent approach is the use of array based comparative genomic hybridization (aCGH) to detect genomic abnormalities in human tumors. The aim of this study is to compare genomic and gene expression profile between cancer patients and healthy individuals. Methods: DNA and RNA were isolated from peripheral blood mononuclear cells from 9 patients, with different types of cancer and 4 normal donors. aCGH (Agilent-60K) and gene expression microarrays (Microarrays Inc.-whole genome platform) were performed using commercial reference samples. Data were analyzed with Array-Pro analyzer and Cytogenomics software. Results: The aCGH data demonstrated the majority of gains and amplifications were observed in cancer samples, while the deletions and losses were higher in normal individuals. Among aberrations, common genes in both types of samples were detected. These genes included ACAD8, ACP1, B3GAT1, IDI1, IDI2, IGSF9B, IRX1, IRX2, JAM3, MYT1L, NTM, OPCML, PXDN, THYN1, TPO. However, there were abnormalities that included genes, which appeared only in cancer samples, like cadherins ( CDH11, CDH8 and CDH5) and EPHA5, while genes such as ACOX1, PTPRN2, TYMS and genes of zinc-finger proteins were observed only in normal samples. No statistical significant difference in gene expression, between cancer and normal samples, was observed. On the contrary, overexpression was observed in genes that were not detected in aCGH. Conclusions: Whereas it is acceptable that great achievements have been carried out in cancer field, the mechanism of tumorigenesis is not clear understood. The present study demonstrated that even though genomic aberrations exist, these are not always representative at gene expression level. However, the combination of both techniques could be used for more accurate and reliable data. This requires study in more samples including different cancer types so to be used at clinical level.
Prospective detection of chemoradiation resistance in patients with locally advanced esophageal adenocarcinoma.
Authors: Paolo Cotzia, Adam C. Berger, Daniel Rosen, Weiwei Shan, Jennifer Veaco, Natalie Lassen, Clare Johnson, Kristen M. Oelschlager, Derek Maetzold, Sunil S. Badve, John F Stone, Juan Palazzo, Robert W. Cook, Kenneth Kessler, Romil Saxena
Journal: Journal of Clinical Oncology (2015)

e15011 Background: Approximately 25% of patients with locoregional esophageal adenocarcinoma (EC) are resistant (marked by minimal tumor regression; TRG 3) to preoperative chemoradiation, including 5FU-based and CROSS regimens. We have previously validated an immunohistochemistry (IHC) test that accurately identifies patients as responders (TRG 0-2) or non-responders (TRG 3) to neoadjuvant CTRT. The current study was designed to identify gene expression profile (GEP) signatures able to predict response to preoperative treatment. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor tissue from 24 diagnostic biopsies (14 responders, 10 non-responders) was collected. RNA was isolated, and RT-PCR performed to assess the expression of 96 candidate genes chosen from in silicoanalysis. Genetic signatures incorporating genes with significant expression differences in pathologically determined responders versus non-responders were identified, and linear and non-linear predictive modeling methods were used to assess the accuracy of the signatures for predicting treatment response. Cross validation was performed to attain corrected accuracy values. Results: Ten-, 18-, and 24-gene signatures were identified with significantly different gene expression levels in responders compared to nonresponders (p < 0.05). Functional groups represented by the signatures included DNA damage repair, extracellular matrix remodeling, and 5FU metabolism. Partial Least Squares (PLS) prediction of treatment response was compared to pathologic TRG determined by blinded pathologic reading, and resulted in an area under the curve (AUC) of 0.99 and overall accuracy of 100% for the 24-gene signature. Corrected AUC of 0.99 and accuracy of 95% resulted from five-fold cross validation with 20 iterations. Heatmap analysis of the 24-gene signature separated the EC cases into two distinct clusters, the first with 93% responders and the second with 90% non-responders. Conclusions: The current study identifies novel gene signatures able to accurately predict EC patient response to preoperative treatment. The GEP may allow nonresponders to avoid unnecessary toxicities associated with chemoradiation therapy.
Abstract 131: C-kit+ Cells Generated From Failed Heart Do Not Improve Failed Heart Function
Authors: Liudmila Zakharova, Hikmet Nural, James R Nimlos, Snjezana Popovic, Lorraine Feehery, Mohamed A Gaballa
Journal: Circulation Research (2013)

A pilot clinical study using autologous c-Kit+ cells showed improvement in cardiac functions in congestive heart failure (CHF), however, it is unclear if c-Kit+ cells isolated from CHF hearts are equally as potent as cells from controls. To test the potency of CHF c-Kit+ cells, myocardial infarction (MI) was created by permanent ligation of the left anterior descending coronary artery. Six weeks after MI, animals with left ventricle end-diastolic pressure (LVEDP) ≥20 mmHg and scar size ≥30% of left ventricle (LV) were designated as CHF rats. We found that CHF atrial explants generated less c-Kit+ cells compared to shams (15.7% vs. 11% sham vs. CHF). CHF c-Kit+ cells exhibited elevated levels of epicardial to mesenchymal transition markers, including Snail (2.5 fold) and Pai1 (3 fold), while the expression level of epithelial marker, E-cadherin was 3 fold lower in CHF c-Kit+ cells. Moreover, CHF c-Kit+ cells exhibited reduced gene expressions of pluripotency markers; 2.1 fold decrease in Nanog and 4.5 fold decrease in Sox 2 compared to sham cells. To evaluate the potency of the c-Kit+ cells, 1 x 10 6 cells isolated from CHFs or shams were delivered to 3 weeks post-MI CHF hearts. Cells were pre-labeled with GFP to enable their tracing in vivo and delivered to the infarcted myocardium via left coronary vein by a retrograde coronary sinus cell infusion (RCI). RCI delivery resulted in a cell distribution of LV (30%), right atrium (30%) and right ventricle (20%), while only 10% of cells were found in a left atrium. Three weeks after cells delivery, rats transplanted with sham c-Kit+ cells showed improved LVEDP (29.4 ± 6 vs. 11.7 ± 3.5 mmHg, CHF vs. CHF+ sham c-Kit+ cells) and a rise in peak rate of pressure (dPdt max) (3988 ± 520 vs. 5333 ± 597 mmHg/s). In contrast, no functional improvement was detected in rats transplanted with CHF c-Kit+ cells. Histological analysis demonstrated that transplanted c-Kit+/GFP+ cells were mostly incorporated into blood vessels and co-localized with endothelial marker vWf, and α-smooth muscle actin. Our results showed that left coronary vein is an efficient route for c-Kit+ cell delivery and that c-Kit+ cells isolated from CHF rats are less potent when transplanted in chronic heart failure rat model compared to those isolated from control.
Comparative outcomes in glioblastoma based on age and MGMT analysis: The Cleveland Clinic experience.
Authors: Suryanarayan Mohapatra, April Choi, Kelly Braun, Erin Sennett Murphy, Samuel T. Chao, John H. Suh, Glen Stevens, David M. Peereboom, Xuefei Jia, Manmeet Singh Ahluwalia
Journal: Journal of Clinical Oncology (2017)

e13514 Background: Half of glioblastoma (GBM) patients are &gt; 65 years old (yo). We report our experience with GBM patients treated at a tertiary care center and compared outcomes in the two age groups. Methods: Half of glioblastoma (GBM) patients are &gt; 65 years old (yo). We report our experience with GBM patients treated at a tertiary care center and compared outcomes in the two age groups. Results: 1165 patients were included in the final analysis. 598 patients were &lt; 65 yo, and 567 were &gt; 65 yo. Patients who received chemotherapy + radiation (chemoRT) had a lower risk of death compared to patients who received RT only (p &lt; 0.001). Although the benefit of chemoRT seems more pronounced in patients ≥ 65 years of age [HR 0.45 (95% CI 0.36, 0.57) vs 0.61 in patients &lt; 65 yo (0.48, 0.80), (p = 0.04)], the difference in effects is not significant (p = 0.07). For both MGMT-unmethylated and MGMT-methylated patients, although chemoRT had a better OS/PFS than RT only, the impact was similar in both age groups. Patients who underwent GTR or STR had a better OS/PFS than biopsy only (all p &lt; 0.0001). The impact of extent of resection was not different in two age groups (all p ≥ 0.09). Patients diagnosed during 2006 – 2008 and 2009 - present had a better OS/PFS (p = 0.01 and 0.003) than those who were diagnosed during 2000-2005. The impact of diagnosis date on PFS was not different in age groups. In OS outcomes, patient diagnosed during 2009 - present had a better OS than those who were diagnosed before 2005, and the impact is more prominent for patient who were younger than 65 years (p = 0.010). Conclusions: Aggressive treatment with chemo-radiation is associated with better outcomes in both young and older GBM patients. MGMT status did not have any impact on outcomes between the two groups although MGMT status was available for only a subset of patients. [Table: see text]
Isocartormin, a novel quinochalcone C -glycoside from Carthamus tinctorius
Authors: Feng Li, Zhisheng He, Yang Ye
Journal: Acta Pharmaceutica Sinica B (2017)

A new semi-quinonechalcone C-glycoside isocartormin along with cartormin and safflomin C were isolated from the water extract of Carthamus tinctorius L. The structure of isocartormin was determined by extensive analysis of HR-MS, 1D- and 2D NMR data, and by comparison with those of cartormin reported previously by our group. Isocartormin was identified as a diastereoisomer of cartormin with a reverse configuration at C-18.
Assessment of concentrations of abemaciclib and its major active metabolites in plasma, CSF, and brain tumor tissue in patients with brain metastases secondary to hormone receptor positive (HR+) breast cancer.
Authors: Solmaz Sahebjam, Emilie Le Rhun, Palaniappan Kulanthaivel, Patricia Kellie Turner, Suzanne Klise, Haofei Tiffany Wang, Sara M. Tolaney
Journal: Journal of Clinical Oncology (2016)

526 Background: Abemaciclib, an oral drug administered twice daily on a continuous schedule, is an inhibitor of both cyclin-dependent kinases (CDKs) 4 and 6. A Phase 1 study of abemaciclib showed evidence of single-agent activity in a cohort of patients with heavily pre-treated HR+ metastatic breast cancer (MBC). These findings, coupled with preclinical data demonstrating that abemaciclib crosses the blood-brain barrier, have led to investigation of abemaciclib in the current trial which includes patients with brain metastases secondary to HR+ MBC. Methods: Study JPBO (NCT02308020) is an open-label, Phase 2 trial evaluating the safety and efficacy of doses of abemaciclib up to 200 mg administered orally every 12 hours on Days 1 to 21 of a 21-day cycle in patients with brain metastases secondary to HR+ MBC, NSCLC, or melanoma. An exploratory objective of this study is to assess approximately 8 patients with brain metastases secondary to HR+ MBC, NSCLC, or melanoma for whom surgical resection is clinically indicated, and who agree to provide post-treatment (5 to 14 days after initiating abemaciclib) brain tumor tissue, with the goal of determining concentrations of abemaciclib and its metabolites in plasma, CSF, and brain metastases. These patients may resume treatment with abemaciclib post-operatively. Results: To date, a total of 3 patients (all with HR+, HER2- MBC) have provided post-treatment brain tumor tissue for analysis. All 3 patients were treated for > 5 days with abemaciclib prior to tumor resection; thus, it is anticipated that abemaciclib was at steady state at the time of surgical resection. Measurable levels of abemaciclib and active metabolites were detected in brain tumor tissue for all 3 patients. Unbound concentrations of abemaciclib in the plasma and tumor tissue were comparable and generally consistent with the CSF concentration for each of the patients. Conclusions: These early data suggest that abemaciclib penetrates human breast cancer brain metastases. Further data, related to safety and efficacy, from this ongoing study are necessary to determine the clinical relevance of these findings. Clinical trial information: NCT02308020.
Apparent diffusion coefficient (ADC) decrease to predict longer survival in glioblastoma patients treated by dendritic cell immunotherapy plus standard of care.
Authors: Marica Eoli, Valeria Cuccarini, Domenico Aquino, Elena Anghileri, Maura Servida, Carla Schettino, Serena Pellegatta, Maria Grazie Bruzzone, Gaetano Finocchiaro
Journal: Journal of Clinical Oncology (2017)

2065 Background: The MRI follow –up of patients affected by glioblastoma (GBM) and treated with immunotherapy may be difficult, as immune responses may mimic tumor progression. To explore the potential contribution of quantitative MRI to the identification of patients with clinical benefit benefit, we used advanced MRI to study GBM patients treated with dendritic cell (DC) immunotherapy added to standard treatment (surgery, radiotherapy with concomitant temozolomide (TMZ) followed by adjuvant TMZ; DENDR1 trial, EUDRACT N° 2008-005035-15). Methods: A retrospective analysis was performed on longitudinal MRIs obtained soon after radiotherapy, within two days before the first vaccination (basal MRI) and every two months, in 22 patients enrolled in DENDR1. The following parameters were collected: tumor volume of contrast–enhanced lesions, mean rCBV, maximal rCBV, mean ADC, minimal ADC, ADC skewness. Receiver Operating Characteristic (ROC) curves were used to determine optimal sensitivity and specificity in differentiating patients as responder or not responder. Association with PFS (as per RANO criteria) and OS was analyzed using log-rank test and Cox regression. Results: Ten patients with PFS &gt; 12 months were defined as responders Their basal mean ADC was significantly higher than in non responders (1.34 ± 0.17 vs 1.14 ± 0.34, p = 0.03). After four DC vaccinations mean ADC significantly decreased in responders only from 1.34 ± 0.17 to 1.23 ±0.23 (p = 0.028); the decrease persisted during immunotherapy. A basal mean ADC value ≥ 1.07 and a decrease in mean ADC value ≥ 0.13 were significant predictors of longer PFS (15.4 vs 9 m p = 0.0006; 17.2 vs 10.2 p = 0.04) and OS (29 vs 12.5 mo p = 0.002; 33 vs 19.9 p = 0.04 No significant correlations between the other parameters and the outcome were observed. Conclusions: Association with prolonged survival may suggest that in DENDR1responders decreased ADC is partly contributed by immune cells infiltrating the tumor.
Impact of smoking on acute skin toxicity due to radiation therapy in breast cancer: A retrospective review from a single institution.
Authors: Raymond Elsoueidi, Eyob Adane, Ram Narayan
Journal: Journal of Clinical Oncology (2014)

e12019 Background: Cigarette smoking enhances reactions of normal tissues such as the oral mucosa, larynx and lungs to radiation exposure. The effect of smoking on the severity of acute skin reactions to radiation therapy in breast cancer is controversial mainly due to the small number of smokers in previous studies. Appalachian Regional Healthcare (ARH) Cancer Center serves a large population of smokers in Southeastern Kentucky. This retrospective study was conducted to examine the relationship between smoking and acute skin toxicity due to radiation therapy in breast cancer. Methods: We retrospectively reviewed the data of breast cancer patients who received adjuvant radiation therapy at the Appalachian Regional Healthcare Cancer Center between 2008 and 2012. Age, smoking history and body mass index were evaluated as potential predictors of skin toxicity. Differences in the occurrence of grade 3 and above acute skin reactions among smokers, non-smokers and ex-smokers were compared by Fisher's exact test. Results: Among the total of 98 patients with breast cancer who received adjuvant radiation therapy during the study period 61% were smokers, 27% were non-smokers and 12% were ex-smokers. Their median age was 62 years (Inter-Quartile Range 52-67). All patients received the same dose of radiation (6040 gray each) for a total of 33 days. Smokers (n=60) received a total of 1980 days of radiation and had 112 days of treatment interruption due to grade 3 skin toxicity defined as skin desquamation. Non-smokers (n=26) and ex-smokers (n=12) received a total of 1254 days of radiation and had 77 days of treatment interruption due to grade 3 skin toxicity. The occurrence of grade 3 and above skin toxicity among smokers was not statistically different from that of non-smokers or ex-smokers (p=0.6). Conclusions: Basedon these resultscigarette smoking did not increase acute skin toxicity in patients with breast cancer who received radiation therapy. However this study is limited because it is a retrospective review from a single institution and further studies are needed to clarify this issue.
Background and H2O2-induced micronuclei in peripheral blood lymphocytes as a risk factor for pancreatic cancer
Authors: Ping Chang, Manal Hassan, James L. Abbruzzese, Douglas B. Evans, Robert A. Wolff, Renato Lenzi, Peter W. Pisters, Ajay Nooka, Donghui Li
Journal: Cancer Research (2004)

1974   Accelerator mass spectrometry (AMS) is currently the most sensitive method for trace DNA adduct detection. AMS measures an isotope ratio, commonly  14 C: 13 C, rather than radioactive decay, to determine the concentration of labelled compound in a sample. At present, analysis of DNA adducts in humans by AMS entails the administration of  14 C-labelled compounds prior to adduct detection. We are developing a  14 C-postlabelling technique, involving incorporation of radiolabel into DNA adducts after isolation, enabling detection of the very low levels of adducts formed in humans by AMS, without the need to administer a  14 C-labelled compound. O 6 -MedG is a strongly mutagenic lesion formed by a variety of alkylating agents and although the repair enzyme ATase is present in human tissues, cellular concentrations can be low. For these reasons, O 6 -MedG was chosen as the DNA adduct for which to develop a  14 C-postlabelling procedure. Initially methods were developed for the derivatisation of 2′-deoxyguanosine (dG) and O 6 -methyl deoxyguanosine (O 6 -MedG) with unlabelled acetic anhydride, resulting in tri-acetylated products, which were isolated and verified by HPLC and mass spectrometry. Reactions were carried out with increasingly lower concentrations of O 6 -MedG and detected by HPLC with UV detection and LC-MS, to establish that the reaction was viable at increasingly lower adduct levels, resulting in detection limits of 1 nmole and 10 fmoles respectively. O 6 -MedG was acetylated with  14 C-acetic anhydride by adapting the established methods. In contrast to previous results, separating the reaction products by HPLC revealed that the major reaction product was  14 C-di acetyl O 6 -MedG. This labelled standard was used to determine the limit of detection by liquid scintillation counting as 745 fmoles of adduct.  14 C-Di acetyl O 6 -MedG was injected onto the HPLC system and one-minute fractions were collected. The fractions corresponding to the labelled adduct were analysed by AMS to produce a calibration line which confirmed a linear relationship between the actual amount of adduct and that measured by AMS over the concentration range examined. The theoretical limit of detection was found to be 128 attomoles. In order to validate and demonstrate the application of this assay in the detection of adducts, DNA was methylated with  3 H-methyl nitrosourea. The DNA was digested and separated by HPLC to isolate  3 H-O 6 -MedG, which was then subjected to the postlabelling procedure to ensure that the adduct can be isolated pure from other methyl adducts and is not degraded during any stage. In summary, a  14 C-postlabelling assay has been successfully developed for the detection of low levels of O 6 -MedG and based on the sensitivity achieved, could be applied to the quantitation of adducts in human samples.
Two invasive mosquito species, Aedes albopictus and Aedes japonicus japonicus, trapped in south-west Germany, July to August 2011
Authors: D Werner, M Kronefeld, F Schaffner, H Kampen
Journal: Eurosurveillance (2012)

Adult females of two invasive species, Aedes albopictus and Aedes japonicus japonicus, were collected for the first time in July and August 2011 in Germany. Previously, only immature stages of these species had been found in the country. Repeated detection of these species reveals the Upper Rhine Valley in south-west Germany to be a particularly sensitive region for the introduction and establishment of exotic mosquito species that needs careful observation.
Hyperinsulinemia during oral glucose tolerance test is associated with increased neointimal tissue proliferation after coronary stent implantation in nondiabetic patients
Authors: Tsutomu Takagi, Kiyoshi Yoshida, Takashi Akasaka, Shuichiro Kaji, Takahiro Kawamoto, Yasuhiro Honda, Atsushi Yamamuro, Takeshi Hozumi, Shigefumi Morioka
Journal: Journal of the American College of Cardiology (2000)