tbuckley/cabot-search huggingface dataset:
Genome-wide copy number analysis of cell-free DNA from patients with chemotherapy-resistant metastatic triple-negative breast cancer.
Authors: Daniel G. Stover, Heather Anne Parsons, Gavin Ha, Samuel Freeman, William Thomas Barry, Hao Guo, Greg Gydush, Sarah Reed, Justin Rhoades, Denisse Rotem, Melissa E Hughes, Ian E. Krop, Sara M. Tolaney, Nikhil Wagle, Gad Getz, Matthew Meyerson, J. Christopher Love, Eric P. Winer, Nancy U. Lin, Viktor Adalsteinsson
Journal: Journal of Clinical Oncology (2017)

1092 Background: Triple-negative breast cancer (TNBC) is a poor prognosis breast cancer subset characterized by relatively few mutations but extensive copy number alterations (CNAs). Cell-free DNA (cfDNA) offers the potential to overcome infrequent tumor biopsies in metastatic TNBC (mTNBC) and interrogate the genomics of chemotherapy resistance. Methods: 506 archival or fresh plasma samples were identified from 164 patients with mTNBC who had previously received chemotherapy. We performed low coverage sequencing to determine genome-wide copy number and estimate ‘tumor fraction’ of cfDNA (TFx). In patient samples with TFx &gt;10%, we identified regions that were significantly gained or lost using GISTIC2.0. We compared CNAs of mTNBCs with primary TNBCs from a publicly-available dataset, METABRIC (TNBC n=277). Results: We successfully obtained high quality, low coverage whole genome sequencing data for 478 (94.5%) plasma samples from 158 patients, with 1 to 14 samples per patient. Archival samples had significantly higher average cfDNA per mL plasma and TFx than fresh samples, potentially due to later average line of therapy. Average TFx of first blood draw was significantly higher in patients with liver metastases (TFx 28.3% vs. 14.4%, p=1.1e-7). 101/158 patients (63.9%) had at least one sample with TFx &gt;10%, our threshold for high confidence CNA calls. Most alterations significantly enriched in chemotherapy-resistant mTNBCs were chromosomal gains, including NOTCH2 and ERCC1. Median overall survival from time of first blood draw was 9 months, and TFx was highly correlated independent of metastatic line of therapy, age at metastatic diagnosis, BRCA status, and primary stage: adjusted hazard ratio between 4 th and 1 st quartiles = 4.29 (95% CI 1.66-11.1; p=0.0008). Conclusions: It is feasible to perform genome-level copy number analysis from cfDNA in both archival and fresh samples from patients with mTNBC. Copy number alterations enriched in mTNBC may have implications in the understanding of metastasis, therapeutic resistance, and novel therapeutic targets. ‘Tumor fraction’ of cfDNA is correlated with overall survival and may be an independent prognostic marker in mTNBC.
Study of the impact of Charlson comorbidity index on the efficacy of aromatase inhibitors in patients with hormone-receptor-positive postmenopausal breast cancer.
Authors: Mehmet Ali Nahit Sendur, Sercan Aksoy, Kamile Silay, Muhammed Bulent Akinci, Nuriye Özdemir, Ozan Yazici, Saliha Ozbek, Nurullah Zengin, Bulent Yalcin, Kadri Altundag
Journal: Journal of Clinical Oncology (2015)

e11565 Background: The risk of breast cancer (BC) increases with age, so BC patients often have comorbid diseases at the time of diagnosis. Owing to the better disease-free survival (DFS) rate and lower recurrences with aromatase inhibitors (AIs) compared to tamoxifen in early BC, AIs have been accepted as first line treatment in the adjuvant treatment of hormone receptor (HR)-positive postmenopausal BC. We determine Charlson comorbidity Index (CCI) to provide prognostic information about the efficacy of AIs independent of known factors. Methods: We retrospectively evaluated 961 HR-positive postmenopausal BC patients treated with adjuvant AIs from 2005 to 2015 in our clinic. Patient’s demographics, including survival data and tumor characteristics were obtained from medical charts. Patients with CCI score ranging between 0-2 were considered as Arm A (n = 465) patients with CCI score ≥ 3 were considered as Arm B (n = 496). Results: The median follow-up time for this analysis was 43 months. Median age in Arm A and B were 55 (31-69) and 65 (43-92), respectively (P < 0.001). In both arms, histology of the primary tumor, type of surgery and the incidence of lymphovascular invasion, perineural invasion, extracapsular extension, HER2 positivity, and histological grade were similar. Also, there were no apparent differences in baseline nodal status (P 0.51), tumor size (P = 0.79) and tumor stage (P = 0.53) between the two arms. In both arms, letrozol and anastrozole were used with similar ratio. Chemotherapeutic (CT) combinations were used in 64.9% and 40.1% of patients in Arm A and B, respectively (P < 0.001). 5-year DFS rate was 89.9% in Arm A, whereas it was 79.1% in Arm B (P = 0.003). 5-year OS rate was 95.0% and 84.1% in Arm A and Arm B, respectively (P < 0.001). After stratification of higher rate of CT combinations usage No effect of CT combinations on OS and DFS were found and CCI independently predict DFS and OS after adjustment of prognostic factors. Conclusions: In our study, higher CCI score significantly predict DFS and OS in HR-positive postmenopausal BC patients treated with AIs.
Abstract 042: Radiation-Associated Cardiovascular Risks for Future Deep-Space Missions
Authors: Xinhua Yan, Sharath P Sasi, Hannah Gee, Juyong Lee, Yongyao Yang, Jin Song, Joseph Carrozza, David A Goukassian
Journal: Circulation Research (2013)

During the future Moon and Mars missions astronauts will be exposed to space radiation (IR) for extended time. The effect of cosmic IR during and after space flights on cardiovascular (CV) system is unknown. Nine-month old C57BL/6N male mice were IR once with proton 50 cGy or 56Fe 15 cGy, both at 1 GeV/nucleon. We evaluated IR-induced biological responses - underlying molecular mechanisms, calcium handling, signal transduction and gene expression. Cardiac function was assessed by echocardiography and hemodynamic measurements. Left ventricular end diastolic pressure (LVEDP) was increased in 56Fe mice 1 and 3 months post-IR (p&lt;0.001). One month post-IR, compared to control, proton- and 56Fe-IR sarcolemmal Na+-Ca2+ exchanger (NCX) (p&lt;0.007) and sarco(endo)plasmic reticulum calcium-ATPase (SERCA2a, p&lt;0.02) were both increased more than 200% and p-p38 was decreased 400% (p&lt;0.05), suggesting activation of compensatory mechanisms in [Ca2+]i handling in these hearts. By 3 months, compared to control, proton- and 56Fe-IR hearts SERCA2a and p-Creb1 was decreased 200-500% (p&lt;0.02), suggesting reduced capacity in intracellular [Ca2+]i handling, suggesting that [Ca2+]i handling dysfunction combined with LVEDP increase in 56Fe-IR may be due to prolonged activation of compensatory mechanisms that lead to changes in SERCA2a and p-Creb1 levels. By 10 months, compared to control, LVESP was decreased in proton- and 56Fe-IR (p&lt;0.03), suggesting IR-associated decrease in contractile function. However, compared to age-matched controls (18 months), the LVEDP was increased (p&lt;0.05) and dP/dt Min was decreased (p&lt;0.02) in proton-IR but not 56Fe-IR mice. This data suggests that after 10 months proton- but not 56Fe-IR affects considerably contractile and relaxation functions during aging. Our longitudinal 1, 3 and 10 months studies reveal that a single full body low dose proton- and 56Fe-IR have long-lasting negative effect on heart homeostasis during aging. The divergent effects of low dose proton vs. 56Fe-IR on heart function during aging suggest significantly different biological mechanisms responsible for this ion-dependent dichotomy over 10 months post-IR and necessitate further studies into underlying molecular mechanisms.
Re: Ian D. Davis, Wanling Xie, Carmel Pezaro, et al. Efficacy of Second-line Targeted Therapy for Renal Cell Carcinoma According to Change from Baseline in International Metastatic Renal Cell Carcinoma Database Consortium Prognostic Category. Eur Urol 2017;71:970–8
Authors: Roberto Iacovelli, Walter Artibani, Giampaolo Tortora
Journal: European Urology (2016)
Association of PD-L1/CD8+TIL and expression of PD-L1, PTEN as predictive biomarkers for long-term follow-up in early breast cancer.
Authors: Uhi Toh, Mina Okabe, Nobutaka Iwakuma, Shuko Saku, Momoko Akashi, Etsuyo Ogo, Kyogo Itoh, Yoshito Akagi
Journal: Journal of Clinical Oncology (2017)

e12072 Background: The aim of this study was to investigate the correlation of immunologic factors including the expression of PD-1/PD-L1, PTEN, and the density of TILs, macrophages in the tumor area of breast cancer, using immunohistological staining and to evaluate the association between the immunologic factors and the clinical outcome for early breast cancer (EBC). Methods: A total of 97 EBC patients (pts) who underwent surgery from February 1995 to November 2005 were investigated.The postoperative adjuvant chemotherapies were routinely performed, adjuvant Tmab were not available in Japan within this period.The immunohistological staining was performed with the monoclonal antibodies for PD-1/PD-L1, PTEN, CD3, CD8, and CD163. Pathological analysis was performed to measure the expression area of each antibody, using images scanned by a CCD digital camera (Nikon), and the digitized data of the expression area (μm 2 ) were analyzed by ‘Win ROOF’ (version 5.7) software. The association between the immunologic factors and clinical outcome was statistically analyzed for over 10-years follow-up. Results: The density of CD3+TILs, CD8+TILs, CD163+ macrophages and non-expression of PTEN was significantly higher in triple negative breast cancer (TNBC). CD8+TIL density and PD-L1+/CD8+ expression were predictive factors for DFS and OS. Her2+ pts with PTEN expression and luminal/Her2- patients without PD-L1 expression had longer OS, compared to patients without PTEN expression (p=0.049) and with PD-L1 expression (p=0.036), respectively. Furthermore, the pts with PD-L1+/CD8+ expression had worse median PFS (p = 0.022) and median OS (p = 0.037), compared with pts without PD-L1+/CD8+ expression. Conclusions: Our results demonstrated that CD3+ TILs, CD8+ TILs, and CD163+ macrophages were shown to infiltrate the tumor area of EBC. In particular, TNBC had a higher rate of TIL infiltration within the tumor environment. PTEN expression and lack of PD-L1 expression were associated with favorable survival in Her2-positive and luminal/Her2-negative EBC patients, respectively. The PD-L1 expression combined with CD8+ density was significantly associated with an aggressive clinical outcome.
Abstract DPOC-007: PROGESTERONE/PR ERADICATES p53–DEFECTIVE CELLS IN THE FALLOPIAN TUBE EPITHELIUM BY INDUCTION OF NECROPTOSIS
Authors: Tang–Yuan Chu
Journal: Clinical Cancer Research (2017)

Abstract Cervical Cancer Prevention Center, Department of Research, Tzu Chi Medical Center, Hualien, Taiwan, Republic of China. Institute of Medical Sciences, Tzu Chi University, Taiwan, Republic of China. The fallopian tube (FT) fimbriae, which are regularly exposed to ovulatory carcinogens, have been identified as the origin of high–grade serous ovarian carcinoma (HGSOC), with loss of p53 determined to be a universal and the earliest step of carcinogenesis. In previous studies, we have identified ROS in ovarian follicle is highly mutagenic and toxic to the fallopian tube fimbria that bath in the ovulatory follicular fluid (FF) after ovulation. We also found that loss of p53 renders fimbrial epithelial cells less vulnerable to the ROS stress, and that hemoglobin in ovulated FF could rescue the ROS–stressed fimbrial epithelial cells from apoptosis. Given that both ovulation and retrograde menstruation, the two proven risk factors for HGSOC, are commonplace in menstrual cycles, and that occurrence of tubal p53 signature is frequent but HGSOC is rare, we hypothesize that luteal–phase progesterone (P4) is responsible for clearance of p53–defective epithelial lesions as a natural protection. Herein, we show that P4 and progesterone receptor (PR) induce necroptosis of tubal epithelial cells in p53–null mice and in immortalized p53–deficient human fimbria epithelial cells through the TNF–α/RIPK1/RIPK3/p–MLKL pathway. The clearance acts regularly in the luteal phase of the menstrual cycle, recovering shortly thereafter, and can be augmented with P4 supplementation. With the inhibition of PR, the oviduct epithelium of Trp53–null mice escapes the clearance and, upon repeated ovulation exposures, accumulates DNA double–strand breaks. Through the induction of necroptosis of p53–deficient epithelial cells, luteal phase P4 prevents the transformation of the FT epithelium after ovulation. This protection can be augmented with P4 supplementation. Citation Format: Tang–Yuan Chu, MD, PhD. PROGESTERONE/PR ERADICATES p53–DEFECTIVE CELLS IN THE FALLOPIAN TUBE EPITHELIUM BY INDUCTION OF NECROPTOSIS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr DPOC-007.
Factors affecting perceptions of clinical trials by cancer center patients.
Authors: Robert J. Korst, John R Rutledge, Neil Shah
Journal: Journal of Clinical Oncology (2013)

9583 Background: Patient misconceptions concerning clinical trials may be barriers to accrual. We hypothesized that patients’ perceptions regarding trials may be affected by the physician specialty being visited, and positively influenced by noncompulsory exposure to an educational videotape in the waiting area prior to physician interaction. Methods: Perceptions of all new patients at a suburban cancer center regarding clinical trials were assessed over 4.5 months using an 8-item questionnaire that allowed for quantitative assessment. A 13 minute educational videotape regarding the clinical trials process was created and displayed in patient waiting areas and all subsequent new patients were identically evaluated over the following 4.5 months. Responses were tabulated and the effect of physician specialty (medical oncology, radiation oncology, breast surgery, thoracic surgery, gynecologic surgery) and videotape exposure on the frequency of positive responses was evaluated. Results: 2201 questionnaires were collected during the total study period. Prior to videotape exposure, patients who visited breast surgery were more fearful of trials than those who visited gynecologic surgery (p=0.01) and thoracic surgery (p=0.03), and were also less likely to participate in a clinical trial (p=0.001 and p=0.02). Patients who visited medical oncology and radiation oncology were less likely to participate in clinical trials than those who visited gynecologic oncology (p=0.007 and p=0.03). Exposure to the videotape positively influenced breast surgery patients regarding their understanding of randomization (p=0.001), likelihood of receiving better care in a trial (p=0.04), and likelihood of participation in a trial (p=0.02). Gynecologic surgery patients understood the concept of a placebo better after videotape exposure (p=0.02). In no group of patients did exposure to the videotape have a negative effect on their perceptions of the clinical trials process. Conclusions: Cancer center patients have different perceptions of the clinical trials process depending on the type of specialist visited. These perceptions can be positively influenced in select patients by the noncompulsory exposure to an educational videotape.
New structures needed for the UK health service
Authors: Tessa Richards
Journal: BMJ (2000)

“Radical organisational change is needed if the UK National Health Service is to survive,” Sir Michael Peckham, director of public policy at the University of London told a conference on 21st century health care organised by the Economist last week.

One example of such change was to be the establishment later this year of a new, cross sectoral development forum in south London. The new forum will bring together teaching …
NCCN Guidelines Insights: Head and Neck Cancers, Version 2.2017
Authors: David Adelstein, Maura L. Gillison, David G. Pfister, Sharon Spencer, Douglas Adkins, David M. Brizel, Barbara Burtness, Paul M. Busse, Jimmy J. Caudell, Anthony J. Cmelak, A. Dimitrios Colevas, David W. Eisele, Moon Fenton, Robert L. Foote, Jill Gilbert, Robert I. Haddad, Wesley L. Hicks, Ying J. Hitchcock, Antonio Jimeno, Debra Leizman, William M. Lydiatt, Ellie Maghami, Loren K. Mell, Bharat B. Mittal, Harlan A. Pinto, John A. Ridge, James Rocco, Cristina P. Rodriguez, Jatin P. Shah, Randal S. Weber, Matthew Witek, Frank Worden, Sue S. Yom, Weining Zhen, Jennifer L. Burns, Susan D. Darlow
Journal: Journal of the National Comprehensive Cancer Network (2017)

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Head and Neck Cancers provide treatment recommendations for cancers of the lip, oral cavity, pharynx, larynx, ethmoid and maxillary sinuses, and salivary glands. Recommendations are also provided for occult primary of the head and neck (H&N), and separate algorithms have been developed by the panel for very advanced H&N cancers. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding the increase in human papillomavirus–associated oropharyngeal cancer and the availability of immunotherapy agents for treatment of patients with recurrent or metastatic H&N cancer.
Radiation plus concurrent nimotuzumab versus CDDP in locally advanced nasopharyngeal cancer: Results of a phase III randomised trial.
Authors: Lin Kong, Qin Lin, Chaosu Hu, Tingting Xu, Xiyi Liao, Chunying Shen, Jiade J. Lu
Journal: Journal of Clinical Oncology (2016)

6002 Background: Nimotuzumab, a novel humanized anti-EGFR monoclonal antibody, is one of the recommended concurrent regimen with radiotherapy (RT)for locally advanced nasopharyngeal cancer (LA-NPC)by the Chinese NCCN. However, concurrent nimotuzumab/RT has never been compared with CDDP/RT, which is often associated with severe acute toxicities. The aim of this trial is to compare the efficacy and safety of the two combinations in LA-NPC patients (pts). Methods: Pts with stage III-IVB NPC were randomized and received concurrent RT(70 Gy/35 fractions)plus CDDP (40mg/m2/week) or nimotuzumab (200 mg/week x 8 week) after docetaxel/CDDP/5FU (TPF) induction chemotherapy (ICT). The primary and secondary endpoints were Grade 3/4 acute toxicities occurred during or within 90 days after RT, overall survival (OS), progression-free survival (PFS). An interim analysis after 50% accrual of a total of 304 pts (to provide 80% of power to detect a 15% difference in the primary endpoint by 2-sided test, Type I error 5%) is required by the protocol. Results: Between 7/2012 and 11/2015, 155 pts were randomized and received RT plus nimotuzumab (82 pts) or CDDP (73 pts). All pts completed planned RT, but 97.3% vs. 40.2% completed planned nimotuzumab (8 cycles) or CDDP (5 cycles) (P<0.001), respectively. GI and hematological toxicities were significantly higher in the CDDP group; however, PFS and OS rates were similar in both groups with a median follow-up of 24 months (range 3-42 mo) (Table). Conclusions: Nimotuzumab produced similar PFS and OS as compared to CDDP with concurrent RT for LA-NPC, and it is highly improbable to observe significant differences in PFS and OS between the two groups if the study is continued. GI and hematological toxicities were significantly less in pts treated with nimotuzumab. As the differences in toxicity are significant, early stop rule will be applied. Clinical trial information: NCT02012062.Acute toxicities and outcomes of LA-NPC pts treated with nimotuzumab or CDDP plus RT. Nimotuzumab CDDP P Value Acute Toxicities GI (G3-4) 4.2% 33.7% <0.001 Hematologic (G2-G4) 9.7% 59.0% <0.001 Mucositis/Dermatitis (G3-4) 27.8% 41.0% 0.13 Outcomes (2/3-yr) PFS 82.7/79.8% 83.5/83.5% 0.69 OS 97.2/93.5% 94.8/94.8% 0.95
Decreased IGF1-R and EGFR expression by the thioredoxin inhibitor PX12 is mediated by SP-1 inhibition
Authors: Hubert Kasperczyk, Katia Laferla-Bruehl, Andrew Westhoff, Klaus-Michael Debatin, Simone Fulda
Journal: Cancer Research (2005)

2296  Thioredoxin-1 (Trx-1) is a 14 kD redox protein that is often over expressed in cancer cells. Trx-1, as part of the thioredoxin redox system, has been shown to reduce oxidized transcription factors resulting in restoration of transcription factor activity and increased gene expression. Recently, Trx-1 has been implemented in the redox regulation and activation of the transcription factor Specificity protein 1 (Sp-1). Sp-1 binds GC rich sequences in promoters and regulates a number of genes involved in cancer progression, including growth factor such as the type I insulin-like growth factor receptor (IGF1-R) and the epidermal growth factor receptor (EGFR). Both receptors have been shown to play an important role in cancer cell development and growth. Expression of these genes is correlated to increased cellular size and resistance to apoptosis. Here we demonstrate that treatment of HT29 colon cancer cells with either PX-12, a pharmacological inhibitor of Trx-1, or siRNA against TRX-1 deceases Sp-1:DNA binding as measured by EMSA. Real time RT PCR analysis indicates that inhibition of Trx-1, with 50 μM PX12 for 72 hours, results in a 2.3 fold decrease in IGF1-R expression and a 3.6 fold decrease in EGFR expression. Western blot analysis indicates that inhibition of TRX-1, with 50 μM PX12 for 48 hours, results in 2.1 fold decrease in IGF1R protein levels and a 1.5 fold decrease in EGFR protein levels. These studies show the importance of Trx-1 redox activation of transcription factors and offer a novel mechanism for PX12’s ability to inhibit cancer cell growth.
Oral chemotherapy or targeted therapy compliance: An observational multicenter French study in cancer patients.
Authors: Tatiana Ceban, Sophie Abadie-Lacourtoisie, Patrick Soulie, Philippe Maillart, You Heng Lam, Olivier Capitain, Catherine Devys, Hugues Pierre Bourgeois, Jean Philippe Metges, Anne-Lise Septans, Jessy Delaye, Virginie Berger, Remy Delva
Journal: Journal of Clinical Oncology (2014)

e11562 Background: the use of oral cancer chemotherapy (OCT) or targeted therapy (OTT) is in constant increase, because of new pharmacological presentations, patient convenience or in order to increase health cost effectiveness. In a self administered medication, patient’s compliance has to be considered. Nevertheless, little is known about OCT or OTT compliance. It appeared of interest to evaluate the compliance rate in France for such therapies. Methods: the primary objective was compliance assessed based on Medication Possession Ratio (MPR): number of doses taken divided by number of doses expected. At each cycle a pharmacist counted tablets taken and remaining ones. Tolerance and dose adaptation were assessed through patient’s diary and adverse events. QOL, treatment perception and understanding from patient’s side were secondary objectives. Ethic committee’s approval was obtained. Population: patients >18 years, OCT and/or OTT planned for cancer, willing to participate, able to manage oral treatment alone and to swallow. Results: 150 pts were included in one year; women 105 (70%), men 45; median age 64 years; breast 79 (52.7%), colon 30 (20%), kidney 13 (8,6%), others 28 (18,6%); chemotherapies 128 (85%): capecitabine 96 (64%), vinorelbin 12 (8%) cyclophosphamide 11 (7.3%), others 9 (6%); targeted therapies 22 (15%): sunitinib 8 (5.3%), everolimus 6 (4%), gefitinib 3 (2%), lapatinib 2 (1.3%), imatinib 2 (1.3%), sorafenib 1 (0.6%). Median MPR was 91%. The majority of patients (102, 90.3%) considered themselves as autonomous, and well informed about toxicities (101, 89.4%), but 108 (95.6%) didn’t stop treatment in case of major toxicity. Conclusions: this prospective study has shown an important compliance of 91%, but also the risk of over-treatment. So the question in oral cancer treatment would be not “is the treatment taken?”, but “is the treatment stopped before major toxicity?”, and that would be the main goal of a patient education program. Clinical trial information: 2009-A000932-55.