tbuckley/cabot-search huggingface dataset:
What drives overtreatment? Surgeon and radiation oncologist views on omission of adjuvant radiotherapy for elderly women with early stage breast cancer.
Authors: Dean Alden Shumway, Kent A. Griffith, Michael S. Sabel, Rochelle Jones, Sarah T. Hawley, Jacqueline Sara Jeruss, Reshma Jagsi
Journal: Journal of Clinical Oncology (2017)

562 Background: Although trials have shown no survival advantage and only a modest improvement in local control from adjuvant radiotherapy after lumpectomy in older women with stage I, ER+ breast cancer, radiotherapy is commonly administered, raising concerns about overtreatment. Therefore, we sought to evaluate physician attitudes, knowledge, communication, and recommendations in this scenario. Methods: We mailed a survey to a national sample of 713 radiation oncologists and 879 surgeons between June to October 2015. Of these, 913 responded (57%). We assessed physicians’ attitudes, knowledge of pertinent risk information, and responses to clinical scenarios. Results: In patients age &gt; = 70 with stage I, ER+ breast cancer treated with lumpectomy and endocrine therapy, omission of radiotherapy was felt to be unreasonable by 40% of surgeons and 20% of radiation oncologists (p &lt; 0.001). Many surgeons (29%) and radiation oncologists (10%) erroneously associated radiotherapy in older women with improvement in survival. Similarly, 32% of surgeons and 19% of radiation oncologists tended to substantially overestimate the risk of locoregional recurrence in older women with omission of RT. In a scenario with an 81-year-old with multiple comorbidities, 31% of surgeons and 35% of radiation oncologists would still recommend radiotherapy. On multivariable analysis, erroneous attribution of a survival benefit to radiotherapy (OR 6.2; 95% CI 3.9-9.8) and overestimation of remaining life expectancy (OR 6.5; CI 4.2-9.9) were strongly associated with the opinion that radiotherapy omission is unreasonable. Conclusions: Many radiation oncologists and surgeons continue to consider omission of radiotherapy as substandard therapy. A sizeable proportion of surgeons overestimate radiotherapy’s benefits and consider omission of radiotherapy to be an unreasonable departure from the standard of care, suggesting that surgeon involvement in decisions about radiotherapy omission may be a key factor in reducing overuse of aggressive care in this setting.
The efficacy of targeted next-generation sequencing for detection of clinically actionable mutations in cancer.
Authors: Yu-Ye Wen, Erica Fang, Yanchun Li, Condie Edwin Carmack, Marilyn M. Li
Journal: Journal of Clinical Oncology (2012)

10598 Background: The emergence of next-generation sequencing (NGS) technologies has significantly accelerated the identification of cancer-causing mutations and the development of personalized cancer care. However, the clinical application of these technologies to detect cancer gene mutations has been extremely limited due to the long turn around time, the high cost, and large amount of input DNA required by existing NGS-based tests. Methods: We have assessed the performance of a novel NGS technology that merges multiplex PCR with ion semiconductor sequencing (AmpliSeq, Life Technologies, Inc.) in our clinical diagnostic laboratory. The test interrogates 739 common mutations in 46 cancer genes including many clinically actionable mutations concurrently. First, we studied 12 tumor samples including 4 archived FFPE, 4 blood/bone marrow, and 4 cell line samples with known mutations to evaluate the sensitivity and specificity of the test. We then studied 34 de-identified, archived FFPE tumor samples of unknown genotype to further evaluate the efficacy of the test. Results: We successfully identified all known mutations previously detected by Pyposequencing or Sanger sequencing technologies. Multiple serial dilution studies showed that the test could detect mutations at frequencies as low as 5% with 99% confidence. For the samples of unknown genotype, we detected 23 COSMIC mutations in 16 samples including HRAS, BRAF, MET, TP53 mutations in lung cancer, KRAS, PIK3CA, TP53, APC, BRAF, ERBB2 mutations in colon cancer, TP53 and KRAS mutations in breast cancer, and KIT and PDGFRA mutations in GIST. Analysis of the variant call data showed that a minimum of 100X coverage is required in order to detect mutations at 10% frequency or above; a minimum 300K final library reads are necessary in order to minimize/eliminate amplicon dropout. Conclusions: The targeted NGS test can effectively detect cancer gene mutation with input DNA as low as a few nanograms, turn around time can be as short as two days, and can significantly lower cost compared to traditional Sanger sequencing. Our experience demonstrates that this technology holds great potential for clinical use, including diagnostic and therapeutic applications.
Abstract 12540: Epigenetic Modulation of Macrophage Polarization Toward a Proinflammatory Phenotype Increases the Susceptibility to Insulin Resistance in Adult Offspring of High-fat Diet Fed-dams
Authors: Naotoshi Wada, Hiroyuki Yamada, Shinichiro Motoyama, Kensuke Terada, Keita Yamamoto, Makoto Saburi, Masakazu Kikai, Noriyuki Wakana, Satoaki Matoba
Journal: Circulation (2016)

Background: Maternal high-fat diet (HFD) has been shown to promote the development of metabolic disorders such as obesity and insulin resistance in adult offspring; however, its underlying mechanisms remains undefined. Method and Result: Eight-week-old female wild-type mice were fed a HFD or normal diet (ND) one week prior to mating, and received either HFD or ND during gestation and lactation. Offspring of both groups were fed a ND after weaning and then fed a HFD from 8 to 20 weeks of age. After 4 weeks of HFD feeding, insulin tolerance test in male offspring of HFD-fed dams (O-HFD) showed a significantly impaired insulin sensitivity compared with those of ND-fed dams (O-ND), which was more prominent after 8 weeks of HFD feeding. In contrast, glucose tolerance did not differ between the 2 groups after 4 and 8 weeks of HFD feeding. The weight of epididymal white pads and adipocyte size were comparable between the 2 groups. Although the fraction of macrophages (F4/80 + CD11b + ) in epididymal white pads assessed by flow cytometry did not differ between the 2 groups, the ratio of M1/M2 macrophages (M1:CD11c + CD206 - , M2:CD11c - CD206 + ) was markedly increased in O-HFD compared with O-ND (18.3 vs. 1.6, O-HFD vs. O-ND; P &lt; 0.05). We examined the effect of maternal HFD on the bone marrow (BM) monocytosis and macrophage polarization in adult offspring before HFD feeding. The fraction of BM pro-monocyte (CD11b high Ly-6G low ) did not differ between the 2 groups; however, BM-derived macrophages (BMDMs) in O-HFD showed a higher expression levels of M1 marker genes after stimulation of IFN-γ, concomitant with the lower expression levels of M2 marker genes after stimulation of IL-4. Further, BMDMs in O-HFD showed a 2.9-fold increase in the mRNA expression levels of histone deacetylase 3 ( HDAC3 ) after stimulation of IL-4 ( P &lt; 0.05), whereas its expression was decreased by 64 % in O-ND ( P &lt; 0.05). Conclusion: Our findings demonstrated for the first time that BMDMs in adult offspring of HFD-fed dams are likely to be polarized toward a proinflammatory phenotype, thereby contributing to the increased susceptibility to insulin resistance. Modulation of epigenetic-mediated macrophage polarization could be a potential therapeutic target for preventing metabolic disorders.
Abstract 352: MicroRNAs Play A Crucial Role In The Induction Of Endothelial-to-Mesenchymal Transition-Mediated Cardiac Fibrosis.
Authors: Varun Nagpal, Mesut Eren, Marissa A Michaels, Douglas E Vaughan
Journal: Circulation Research (2013)

Introduction: Fibroblast-like cells derived from aberrant activation of endothelial-to-mesenchymal transition (EndMT) are an important contributor to cardiac fibrosis. TGF-beta signaling plays a pivotal role in the induction of EndMT and cardiac fibrosis. Our recent studies have shown that specific miRNAs are differentially regulated during TGF-beta-induced EndMT and blocking TGF-beta-receptor I (TbetaR1) kinase inhibits TGF-beta-induced EndMT. Hypothesis: We hypothesize that miRNAs that promote EndMT will potentially exacerbate cardiac fibrosis, and knockdown of these miRNAs will attenuate EndMT-mediated cardiac fibrosis. Results and Methods: We investigated the levels of miRNAs and profibrotic markers in the failing human myocardium compared to healthy human heart tissue. Our results indicate that miRNAs upregulated during EndMT were significantly elevated in the failing human myocardium. In addition, failing human myocardium exhibited significant upregulation of profibrotic markers including alpha-SMA, Col1 and PAI-1. Next, primary cultures of mouse cardiac endothelial cells treated with TGF-beta or SB431542 (TbetaR1 kinase inhibitor) were evaluated for EndMT markers using bright field microscopy, fluorescence microscopy, western blot analysis and qRT PCR. We observed that blocking TbetaR1 kinase by SB431542 inhibits specific miRNAs which were upregulated during TGF-beta-induced EndMT. In addition, in silico analysis revealed that these miRNAs target key TGF-beta effectors, which was further confirmed by western blot analysis. Furthermore, overexpression of specific miRNAs using mimics resulted in the induction of EndMT. Next, miRNA mimics in combination with TGF-beta substantially potentiated TGF-beta-induced EndMT. Finally, knockdown of these miRNAs using inhibitors or Cy3-tagged antagomiRs significantly attenuated TGF-beta-induced cardiac EndMT. Conclusions: Our results indicate that TbetaR1 kinase-induced expression of miRNAs is involved in cardiac EndMT. Thus, miRNAs may promote profibrotic signaling in EndMT-derived fibroblast-like cells, which may contribute to fibrogenesis in the human heart.
Two rare presentations and treatments of Ewing's sarcoma: A need for a standard treatment approach.
Authors: Kanyalakshmi Ayyanar, Nitya Narayan, Karen Moeller, William Gump, Thomas Moriarty, Craig I. Silverman, Vinod Balasa, Salvatore J. Bertolone
Journal: Journal of Clinical Oncology (2013)

e21000 Background: We describe two Caucasian boys with rare presentations of non-metastatic Ewings sarcoma (ES) with atypical primary sites. One was extradural but FISH negative for 22q11.2. Another was intradural but extramedullary, and FISH positive. Literature search showed few publications which describe such cases, and there is currently no standard of care. Methods: MG, an 11 year old male, presented with a frontal skull mass, with an intracranial epidural extension of about 5 mm. Biopsy confirmed ES. MG was treated with Vincristine, Doxorubicin, and Cyclophosphamide, alternating with Ifosfamide and Etoposide every 2 weeks, for 6 weeks. He underwent tumor excision for local control with good response. Chemotherapy continued, completing 14 cycles total. He is in remission 15 months after completion. AH, a 13 year old male, presented with lower back pain and paraesthesias of feet. MRI revealed an intradural, extra-medullary L1-L3 mass. Intra-operatively, all visible tumor peeled off readily, except for the L2 nerve root. The tumor was FISH positive for EWSR1. He was treated with the same regimen as MG for 6 cycles. Local control was done with radiation. He then continued chemotherapy, completing a total of 14 cycles. MRI scans 3 months later revealed enhancing intradural lesions along the spinal cord (involving C5, T5 and T8) and two lesions along the cerebellum. He was started on cyclophosphamide and topotecan and has completed 8 cycles without disease progression. Results: MG was diagnosed based solely on histo-pathological diagnosis. While MG’s lesion was extra-osseus in nature, more unusual presentations demonstrate the importance of molecular diagnostic techniques. AH was diagnosed based on chromosomal analysis. Progression is presumably from microscopic residual disease in intradural space that invaded CSF. He is presently on salvage chemotherapy. Nine months after relapse, disease is stable, with plans to minimize disease and consolidate. Conclusions: Intradural tumors tend to progress rapidly, maybe more so than extradural tumors. Future suggestions include developing a standard approach that will improve both treatment of Ewing’s sarcoma and prognostic outcomes for rare initial presentations.
Nonlesional atopic dermatitis skin shares similar T‐cell clones with lesional tissues
Authors: P. M. Brunner, R. O. Emerson, C. Tipton, S. Garcet, S. Khattri, I. Coats, J. G. Krueger, E. Guttman‐Yassky
Journal: Allergy (2017)

Atopic dermatitis (AD) is characterized by robust immune activation. Various T-cell subsets, including Th2/Th22 cells, are increased in lesional and nonlesional skin. However, there is conflicting literature on the diversity of the T-cell receptor (TCR) repertoire in lesional AD, and its relation to nonlesional skin remains unclear.We performed high-throughput deep sequencing of the β-TCR repertoire in 29 lesional and 19 nonlesional AD biopsies, compared to six healthy control and six cutaneous T-cell lymphoma (CTCL) samples from previously published cohorts.While greater T-cell infiltrates were observed in lesional vs nonlesional AD, TCR repertoire diversity was similar in lesional and nonlesional tissues, and absolute numbers of unique T-cell clones correlated with respective T-cell counts. Most (87%) top expanded lesional T-cell clones were shared with nonlesional tissues, and they were largely maintained after 16 weeks of successful treatment with topical triamcinolone. Nevertheless, both lesional and nonlesional AD showed a highly polyclonal TCR pattern, without evidence of oligoclonal expansion, or a preferred usage of certain V-β genes in AD skin. Size of the overall T-cell infiltrate, but not the level of clonality, correlated with mRNA levels of key inflammatory mediators (e.g., IL-13, CCL17, IL23p19, CXCL10).While AD harbors a highly polyclonal T-cell receptor repertoire, and despite the lack of information on TCR antigen specificity, the sharing of top abundant clones between lesional and nonlesional skin, and their persistence after months of therapy, points to the continuous presence of potentially pathogenic skin resident memory T cells well beyond clinically inflamed lesions.
Functional neuroimaging of high-risk 6-month-old infants predicts a diagnosis of autism at 24 months of age
Authors: Robert W. Emerson, Chloe Adams, Tomoyuki Nishino, Heather Cody Hazlett, Jason J. Wolff, Lonnie Zwaigenbaum, John N. Constantino, Mark D. Shen, Meghan R. Swanson, Jed T. Elison, Sridhar Kandala, Annette M. Estes, Kelly N. Botteron, Louis Collins, Stephen R. Dager, Alan C. Evans, Guido Gerig, Hongbin Gu, Robert C. McKinstry, Sarah Paterson, Robert T. Schultz, Martin Styner, Bradley L. Schlaggar, John R. Pruett, Joseph Piven
Journal: Science Translational Medicine (2017)

Functional brain imaging of 6-month-old infants with a high familial risk for autism predicts a diagnosis of autism at 24 months of age.
IGH/MYC Translocation in Burkitt Lymphoma Is Associated with BRCA2 Deficiency and Synthetic Lethality By PARP1 Inhibitors
Authors: Silvia Maifrede, Kayla Martin, Paulina Podszywalow-Bartnicka, Sullivan Katherine, Samantha Langer, Reza Nejati, Yashodhara Dasgupta, Daniel Gritsyuk, Margaret Nieborowska-Skorska, Lena Lupey, Katarzyna Piwocka, Mariusz A Wasik, Italo Tempera, Tomasz Skorski
Journal: Blood (2016)
ELABELA and an ELABELA Fragment Protect against AKI
Authors: Hong Chen, Lin Wang, Wenjun Wang, Cheng Cheng, Yu Zhang, Yu Zhou, Congyi Wang, Xiaoping Miao, Jiao Wang, Chao Wang, Jianshuang Li, Ling Zheng, Kun Huang
Journal: Journal of the American Society of Nephrology (2017)

Renal ischemia-reperfusion (I/R) injury is the most common cause of AKI, which associates with high mortality and has no effective therapy. ELABELA (ELA) is a newly identified 32-residue hormone peptide highly expressed in adult kidney. To investigate whether ELA has protective effects on renal I/R injury, we administered the mature peptide (ELA32) or the 11-residue furin-cleaved fragment (ELA11) to hypoxia-reperfusion (H/R)-injured or adriamycin-treated renal tubular cells in vitro ELA32 and ELA11 significantly inhibited the elevation of the DNA damage response, apoptosis, and inflammation in H/R-injured renal tubular cells and suppressed adriamycin-induced DNA damage response. Similarly, overexpression of ELA32 or ELA11 significantly inhibited H/R-induced cell death, DNA damage response, and inflammation. Notably, treatment of mice with ELA32 or ELA11 but not an ELA11 mutant with a cysteine to alanine substitution at the N terminus (AE11C) inhibited I/R injury-induced renal fibrosis, inflammation, apoptosis, and the DNA damage response and markedly reduced the renal tubular lesions and renal dysfunction. Together, our results suggest that ELA32 and ELA11 may be therapeutic candidates for treating AKI.
Cellular response of a novel PLK inhibitor in breast cancer cells
Authors: Zhi Hu, Wen-lin Kuo, Debopriya Das, Safiyyah Ziyad, Shenda Gu, Nicholas Wang, Heidi Feiler, Jeffrey Jackson, Sylvie Laquerre, Richard Wooster, Barbara Weber, Joe Gray
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

2397 

Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase with several important functions throughout the G2→M phase of the cell cycle. Previous data has shown PLK1 to be highly expressed in malignant cells and its expression portends poor prognosis in various human cancer. Therefore, Plk1 is a potential oncology drug target, and several small molecules including GSK461364 are being developed to target PLK1 and are in clinical trials. We describe here analyses of molecular responses to GSK461364. With this background, we measured responses to GSK461364 in a panel of 50 breast cell lines. GSK461364 inhibited cell growth with a GI50 range between 0.1nM to 8 µM. GSK461364 also induced cell apoptosis, and inhibited cell proliferation and G2/M arrest by high content imaging. Subtype analysis of responses to the breast cancer cell lines showed GSK461364 to be more cytotoxic in lines representing clinically aggressive basal B breast cancers sub-type than in luminal sub-type cell lines or nontransformed human mammary epithelial cultures. Predictive biomarkers of response to GSK461364 treatment were discovered by supervising genomic and mRNA expression signatures of cell lines with the GI50 profile of GSK461364. While further validation of these candidate biomarkers is needed, such predictors could be used to enrich patient populations for potential responders prior to initiating therapy in the clinic and to define tailored therapeutics for individual patients. (Supported by funds from NIH/NCI U54 CA112970, ASCO and GlaxoSmithKline)
Medical oncologist’s commitment in the end of life (EoL) care of cancer patients: The caregiver's perspective.
Authors: Romeo Bascioni, Francesca Giorgi, Barbara Esperide, Farnoosh Basirat, Maria Rosaria Borriello, Manuela Brugni, Sonia Scriboni, Francesca Rastelli, Remo Appignanesi, Giovanna Picciotti, Giorgio De Signoribus, Lucio Giustini
Journal: Journal of Clinical Oncology (2012)

9098 Background: Optimizing the impact of EoL care on cancer patients (pts) and their caregivers should be a primary goal of an oncology unit. In this study we evaluated satisfaction of family caregivers when the medical oncology team assisted pts until death. Methods: Two oncology units were reorganized to ensure continuity of care; oncologists trained in palliative care medicine assisted pts until EoL. The model assumes that the medical oncologist (MO) is the physician in charge throughout the entire disease trajectory. Relatives of pts assisted at home or at an inpatient hospice underwent a semistructured phone interview conducted by a psychologist or a social worker &gt; 1 month after pts' death. Satisfaction was evaluated for symptoms control, communication, psychological support, overall quality of care and continuity of therapeutic relationship with the MO. A final open-ended question was included for any additional comment. Satisfaction was measured using a five-point Likert scale ranging from very dissatisfied to very satisfied and converted to a 0-to-100 scale. Results: Relatives of 65 pts were contacted, 55 accepted the interview (27 spouses, 22 sons, 5 in-laws, 1 parent); 50/55 were the leader caregiver. Patients were followed at home (41) or at an inpatient hospice (14), for 1-24 wks. Satisfaction mean scores were: symptoms control 76/100, communication 85, psychological support 82 and overall quality of care 87; a specific question on the relevance of the MO in EoL care produced a score of 87, with no negative or neutral responses recorded for this item. Of note, a common perception among caregivers was the appreciation of the MO's commitment during EoL in addition to the technical quality of the intervention. The overall satisfaction score was higher than in our previous study in which a continuity of care model was not formally adopted, with a score improvement from 55 to 87/100. Conclusions: A care pathway where the MO is involved in EoL management of cancer pts improved satisfaction of caregivers.When a longstanding and trusting relationship has been established, the pts-MO connection should not be lost to prevent feelings of abandonment.
Surrogate properties of survival endpoints in metastatic soft-tissue sarcoma: A meta-analysis.
Authors: Marion Savina, Saskia Litière, Nicolas Penel, Virginie Rondeau, Tomasz Burzykowski, Maud Toulmonde, Antoine Italiano, Simone Mathoulin-Pélissier, Carine A. Bellera
Journal: Journal of Clinical Oncology (2015)

10547 Background: Alternative endpoints to overall survival (OS) such as progresion-free survival (PFS), time-to-progression (TTP) or time-to-treatment failure (TTF) are increasingly used to assess treatment efficacy in randomized controlled trials (RCT) to reduce inclusions and trials’ duration. Their properties in terms of surrogate markers need to be assessed to ensure that they can adequately replace OS. Methods: We conducted a literature review to summarize by cancer type studies evaluating surrogate endpoints for OS. In the absence of data for soft-tissue sarcoma (STS), we assessed surrogate properties for OS of PFS, TTP and TTF in advanced STS. We relied on a meta-analytical framework to estimate individual-level association (association between the candidate surrogate endpoint and OS) and trial-level association (association between the treatment effects on the candidate surrogate and on OS). Statistical methods included weighted linear regression (WLR) and the two-stage method introduced by Burzykowski et al., which relies on the joint modeling of 2 survival endpoints with a copula function and a regression model. Results: Individual data of 2020 patients from 10 European RCTs were analyzed. We censored OS at 2 years and PFS, TTP and TTF at 1 year. Regardless of the method, the highest individual-level association was observed for PFS (R² = 0.62 IC95% [0.27; 0.76]; Kendall's tau = 0.43 IC95% [0.40; 0.46]). Even if WLR suggested that PFS had the highest trial-level association, it was not significant for any of the two methods (WLR: R² = 0.44 IC95% [0.00; 0.69]; two-stage model: R² = 0.01 IC95% [-0.46; 0.48]). Conclusions: Out of the 3 endpoints, PFS had the best surrogate properties. Associations with OS were however moderate and cannot validate PFS as a surrogate for OS. This could be partly explained by a lack of precision due to our small sample size in terms of patients and trials. STS are rare tumors ( < 2% of all cancers) which explains the low number of available trials with usually smaller sample sizes compared to other cancers. We are however collecting additional trials to improve these estimations and complementary analyses are ongoing to validate our regression models on external data.