tbuckley/cabot-search huggingface dataset:
P16 Prospective risk of osteoporotic fracture in patients with advanced COPD: Abstract P16 Table 1
Authors: A Gupta, NJ Greening, RA Evans, N Toms, A Samuels, MC Steiner
Journal: Thorax (2015)

<h3>Introduction</h3> COPD is associated with an increased prevalence of osteoporosis with shared risk factors including smoking, low BMI and reduced mobility. However, the risk of future fractures is not routinely considered in the management of COPD. We aimed to quantify future fracture likelihood and identify factors associated with an increased probability of osteoporotic fractures in patients with advanced COPD. <h3>Methods</h3> Patients with advanced COPD were prospectively recruited and underwent a ‘comprehensive respiratory assessment’ as previously described.<sup>1</sup> The 10 year probability of developing either a major osteoporotic fracture or hip fracture was calculated using the fracture risk assessment tool (FRAX®)<sup>2</sup> using routinely collected data including age, gender, weight, height, smoking history, alcohol use, presence of inflammatory arthritis, corticosteroid use, but with the omission of family history and prior history of fractures. High risk was considered to be a ≥20% probability of a major osteoporotic fracture and ≥5% probability of a hip fracture. <h3>Results</h3> 181 patients were included: mean (SD) age of 65 (9) years, MRC score 4 (IQR 0), BMI 25.4 (6.9) kg/m<sup>2</sup>, 42% female and 25% current smokers. The mean (SD) 10-year probability for a major osteoporotic fracture was 9.1 (5.1)% and for a hip fracture was 3.5 (3.6)%. 43 (24)% of patients were considered to be high probability of a future fracture. 25 (14%) patients were prescribed a bisphosphonate and 17 (9%) maintenance daily oral prednisolone. Only 4 (24%) patients on oral steroids had a high probability for a future osteoporotic fracture. The cohort was divided into quartiles based on FRAX® score for future major osteoporotic fractures. There were significant differences between groups in exercise capacity, quadriceps strength, exacerbations, body composition and a trend to home oxygen use (Table 1). <h3>Conclusion</h3> A quarter of patients with advanced COPD had a high probability of a future major osteoporotic fracture despite our calculations being an underestimate. An increased likelihood of fracture was associated with a number of potentially modifiable measures including exacerbation frequency, reduced physical performance and reduced skeletal muscle bulk. <h3>References</h3> 1 Steiner MC. <i>Thorax</i> 2015;<b>70</b>(8):805–808 2 Kanis JA. <i>Lancet</i> 2002;<b>359</b>:1929–36
KRAS mutation status and clinical outcome of preoperative chemoradiation (CRT) with or without cetuximab in locally advanced rectal cancer (LARC): A pooled analysis of two phase II trials.
Authors: S. Kim, E. Shim, H. Yeo, Y. Hong, D. Kim, T. Kim, J. Kim, S. Im, K. Jung, H. Chang
Journal: Journal of Clinical Oncology (2010)

3650 Background: Cetuximab-containing chemotherapy is known to be active for KRAS wild type (KRAS- wt) metastatic colorectal cancer, but it is not clear that patients (pts) with KRAS-wt LARC also benefit from cetuximab-based preoperative CRT compared to CRT without cetuximab. Methods: We studied EGFR, KRAS, BRAF and PI3KCA mutation status in 82 LARC pts who were enrolled to IRIX trial (preoperative CRT with irinotecan and capecitabine; n=44) or ERBIRIX trial (preoperative CRT with irinotecan and capecitabine plus cetuximab; n=38). Both trials were similarly designed except administration of cetuximab; radiotherapy (RT) was given to a dose of 50.4 Gy/28 fractions with irinotecan 40 mg/m2 weekly and capecitabine 1,650 mg/m2/day for 5 days a week. In ERBIRIX trial, cetuximab was given with a loading dose of 400 mg/m2 on 1 week before RT, and then 250 mg/m2 weekly. Tumor regression grade (TRG), pathologic stage (ypStage) and disease-free survival (DFS) were correlated with biomarker profiles. Results: Baseline characteristics such as age, sex, performance status (PS) and clinical stage before CRT were balanced between the two trial cohorts. KRAS mutation in codon 12, 13 and 61 was noted in 15 pts (34%) in IRIX cohort and 5 pts (13%) in ERBIRIX cohort (p=0.028). Among 62 KRAS-wt pts, major pathologic response rate (TRG 3-4), DFS and ypStage did not differ significantly between the two cohorts within 62 KRAS-wt pts. (Table) Initial CEA level ≤ 5.0 ng/ml (p=0.015) and ECOG PS 0 (p=0.021) were associated with TRG 3-4. After adjustment for initial CEA level, PS and KRAS mutation status, addition of cetuximab was not associated with TRG (p=0.069). No mutations were detected in BRAF exon 11/15, PI3KCA exon 9/20, and EGFR exon 18-24 in all 82 pts. Conclusions: In pts with KRAS-wt LARC, addition of cetuximab to CRT with irinotecan plus capecitabine did not improve clinical outcome in terms of TRG, ypStage and DFS compared to CRT without cetuximab. IRIX: KRAS-wt (n=29) ERBIRIX: KRAS-wt (n=33) P value TRG 3-4 15 (52%) 10 (30%) 0.086 ypStage 0–I 15 (56%) 15 (45%) 0.436 3yr DFS 82.8% 84.6% 0.730 No significant financial relationships to disclose.
Endoscopic ultrasound-guided needle-based confocal laser endomicroscopy in solid pancreatic masses
Authors: Marc Giovannini, Fabrice Caillol, Geneviève Monges, Flora Poizat, Anne-Isabelle Lemaistre, Bertrand Pujol, Damien Lucidarme, Laurent Palazzo, Bertrand Napoléon
Journal: Endoscopy (2016)

<b>Background and study aims:</b> The differential diagnosis of solid pancreatic masses by endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is currently suboptimal in centers that are not equipped with rapid on-site evaluation. Needle-based confocal laser endomicroscopy (nCLE) enables real-time in vivo microscopic imaging during endoscopy. This study aimed to describe nCLE interpretation criteria for the characterization of pancreatic masses, with histopathological correlation, and to perform the first validation of these criteria. <b>Patients and methods:</b> A total of 40 patients were evaluated by EUS-FNA combined with nCLE for the diagnosis of pancreatic masses. Final diagnosis was based on EUS-FNA histology and follow-up at 1 year. Five unblinded examiners defined nCLE criteria for adenocarcinoma, chronic pancreatitis, and neuroendocrine tumor (NET) using a set of video sequences from 14 patients with confirmed pathology (Step 1). These criteria were retrospectively validated by four independent, blinded examiners using sequences from 32 patients (Step 2). <b>Results:</b> nCLE criteria were described for adenocarcinoma (dark cell aggregates, irregular vessels with leakages of fluorescein), chronic pancreatitis (residual regular glandular pancreatic structures), and NET (black cell aggregates surrounded by vessels and fibrotic areas). These criteria correlated with the histological features of the corresponding lesions. In the validation review, a conclusive nCLE result was obtained in 75 % of cases (96 % correct). Statistical evaluation provided promising results, with high specificity, and negative and positive predictive values for all types of pancreatic masses. <b>Conclusion:</b> Considering the low negative predictive value of EUS-FNA, nCLE could help to rule out malignancy after a previous inconclusive EUS-FNA. Larger studies are required to confirm these findings and to establish the role of nCLE in the diagnosis of pancreatic masses. Trial registration: ClinicalTrials.gov (NCT01563133).
Abstract 411: 1,25(OH)2D3 deficiency accelerates colon cancer progression via microenvironmental regulation
Authors: Xiaoqin Yuan, Yun Liu, Lulu Chen, Dengshun Miao
Journal: Cancer Research (2015)

Abstract Epidemiologic studies have revealed that low serum vitamin D levels are associated with an increased risk of colon cancer and inflammatory diseases such as inflammatory bowel disease (IBD) while underlying biological mechanisms remain largely unknown. It is also well established that tumor microenvironment plays an essential role in tumor progression. In this study, we sought to determine whether 1,25(OH)2D3 deficiency has a direct impact on colon cancer by using 25-hydroxyvitamin D 1-hydroxylase knockout [1α(OH)ase−/−] mice that had been fed with a rescue diet (high calcium, phosphate and lactose) from weaning. We injected CT26.WT cells (a murine colon cancer cell line) into 1α(OH)ase−/- and wild-type (WT) mice repectively and found that 1,25(OH)2D3 deficiency accelerated the growth of xenografted colon tumors. In the AOM/DSS model, heterozygous 1α(OH)ase+/− mice increased the multiplicity and size of colon tumors. Compared to WT mice, 1α(OH)ase−/− mice exhibited an increase of DNA damage, cellular senescence and the production of senescence-associated inflammatory cytokines in their colon stromal cells. These results suggest that 1,25(OH)2D3 deficiency may have a direct effect on colon cancer development, at least in part, by influencing tumor microenvironment. Note: This abstract was not presented at the meeting. Citation Format: Xiaoqin Yuan, Yun Liu, Lulu Chen, Dengshun Miao. 1,25(OH)2D3 deficiency accelerates colon cancer progression via microenvironmental regulation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 411. doi:10.1158/1538-7445.AM2015-411
Not All High-Dose Opioid Users Are Addicts
Authors: Ronald Hirsch
Journal: JAMA Internal Medicine (2016)

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Perilipin Staining Distinguishes Between Steatosis and Nonalcoholic Steatohepatitis in Adults and Children
Authors: Rotonya M. Carr, Ravindra Dhir, Kalyankar Mahadev, Megan Comerford, Naga P. Chalasani, Rexford S. Ahima
Journal: Clinical Gastroenterology and Hepatology (2016)
The Role of Genetic Testing in the Selection of Therapy for Breast Cancer
Authors: Polly Niravath, Burcu Cakar, Matthew Ellis
Journal: JAMA Oncology (2016)

The application of next-generation sequencing (NGS) genomic testing for somatic mutations in breast oncology has been slower than anticipated due to issues with clinical applicability and natural heterogeneity of breast cancer. This review summarizes the state of the field and considers approaches for more effective implementation.While there is an emerging role for germline genetic testing potentially predicting sensitivity to platinum salts and PARP inhibitors, the data regarding somatic mutation for prediction of drug sensitivity remains controversial. Currently, there are no guidelines or regulatory approvals for genomic somatic tumor mutation testing to direct therapy. However, some small populations show promise, such as those with ERBB2/HER2 mutation who may represent the first population to have a positive drug somatic mutation match. Similarly, those with ESR1 mutation may be the first to emerge for a negative association with the efficacy of aromatase-inhibitor treatment. One of the barriers to progress is the necessary focus on metastatic disease, which is often challenging, expensive, and risky to biopsy. In addition, because of the clonal heterogeneity of advanced disease, a single sample may not contain all the genomic information necessary for treatment. Thus, circulating tumor DNA analysis is perhaps one of the most practical and promising approaches.Circulating tumor DNA analysis, once sensitive and broad enough, will accelerate progress in the quest to make NGS technologies relevant to breast cancer treatment. A broad and coordinated coalition to systematically connect somatic mutations to clinical and pharmacologic data will be critical for progress. We recommend instituting an open source encyclopedia, which would serve as a reference for NGS sequencing report interpretation and would be available to all clinicians to help direct therapy.
A Phase I Study of Topotecan, Carboplatin and the PARP Inhibitor Veliparib in Acute Leukemias, Aggressive Myeloproliferative Neoplasms, and Chronic Myelomonocytic Leukemia
Authors: Keith W. Pratz, Michelle A. Rudek, Ivana Gojo, Mark R. Litzow, Michael A. McDevitt, Jiuping Ji, Larry M. Karnitz, James G. Herman, Robert J. Kinders, B. Douglas Smith, Steven D. Gore, Hetty E. Carraway, Margaret M. Showel, Douglas E. Gladstone, Mark J. Levis, Hua-Ling Tsai, Gary Rosner, Alice Chen, Scott H. Kaufmann, Judith E. Karp
Journal: Clinical Cancer Research (2016)

Abstract Purpose: The PARP inhibitor veliparib delays DNA repair and potentiates cytotoxicity of multiple classes of chemotherapy drugs, including topoisomerase I inhibitors and platinating agents. This study evaluated veliparib incorporation into leukemia induction therapy using a previously described topotecan/carboplatin backbone. Experimental Design: Employing a 3+3 trial design, we administered escalating doses of veliparib combined with topotecan + carboplatin in relapsed or refractory acute leukemias, aggressive myeloproliferative neoplasms (MPN), and chronic myelomonocytic leukemia (CMML). Results: A total of 99 patients received veliparib 10–100 mg orally twice daily on days 1–8, 1–14, or 1–21 along with continuous infusion topotecan 1.0–1.2 mg/m2/d + carboplatin 120–150 mg/m2/d on days 3–7. The MTD was veliparib 80 mg twice daily for up to 21 days with topotecan 1.2 mg/m2/d + carboplatin 150 mg/m2/d. Mucositis was dose limiting and correlated with high veliparib concentrations. The response rate was 33% overall (33/99: 14 CR, 11 CRi, 8 PR) but was 64% (14/22) for patients with antecedent or associated aggressive MPNs or CMML. Leukemias with baseline DNA repair defects, as evidenced by impaired DNA damage–induced FANCD2 monoubiquitination, had improved survival [HR = 0.56 (95% confidence interval, 0.27–0.92)]. A single 80-mg dose of veliparib, as well as veliparib in combination with topotecan + carboplatin, induced DNA damage as manifested by histone H2AX phosphorylation in CD34+ leukemia cells, with greater phosphorylation in cells from responders. Conclusions: The veliparib/topotecan/carboplatin combination warrants further investigation, particularly in patients with aggressive MPNs, CMML, and MPN- or CMML-related acute leukemias. Clin Cancer Res; 23(4); 899–907. ©2016 AACR.
Klotho response to treatment with growth hormone and the role of IGF-I as a mediator
Authors: Tami Rubinek, Shiri Shahmoon, Ayelet Shabtay-Orbach, Michal Ben Ami, Yael Levy-Shraga, Kineret Mazor-Aronovitch, Yonatan Yeshayahu, Ram Doolman, Rina Hemi, Hannah Kanety, Ido Wolf, Dalit Modan-Moses
Journal: Metabolism (2016)
Cholesterol and Coronary Heart Disease Risk in Elderly Patients
Authors: David L. Katz
Journal: JAMA (1995)

<h3>To the Editor.</h3> —The lack of association between cholesterol and mortality in very elderly subjects reported by Dr Krumholz and colleagues<sup>1</sup>justifies circumspection in the management of hyperlipidemia in this group. However, the mean age of subjects within cholesterol tertiles was not disclosed. Even if age were comparable across tertiles, the extreme influence of age on mortality might require a larger sample or longer follow-up to detect outcome differences attributable to cholesterol. Information on prior screening of subjects was not provided. These subjects must fall, prima facie, into one of the following three groups: (1) those not previously screened for cholesterol, (2) those previously found to have low or normal cholesterol, or (3) those previously found to have elevated cholesterol. Subjects not screened prior to old age may not represent the general public and may simply be resistant to hypercholesterolemia, albeit over an unspecified period of time. Subjects previously
Possible role for chemokine receptor CCR7 mRNA expression in lymph node metastasis in head and neck squamous cell carcinoma
Authors: C. M. Campofiorito, F. R. R. Mangone, F. S. Pasini, S. Maistro, I. Snitcovsky, F. Walder, C. N. Lehn, M. B. Carvalho, M. Brentani, M. H. H. Federico
Journal: Journal of Clinical Oncology (2004)

9677 Background: Chemokine receptor-ligand interactions may play a role in the spread of Head and Neck Squamous Cell Carcinomas to regional lymph nodes. Methods: In this work, we have analyzed the mRNA expression of chemokine receptors (CXCR1–5, CCR7 and CX3CR1), by Ribonuclease Protection Assay (Riboquant RPA system, Pharmingen), in fragments of primary tumor (T), normal adjacent mucosa (M) of 39 patients (pts) with operable HNSCC. These data and of 10 grossly compromised lymph nodes (LN) were correlated with clinical-pathological parameters. Results: Primary tumors, when compared to normal adjacent matched mucosa (n=37), showed higher CXCR4 mRNA expression (T: 0.216 ± 0.116 vs 0.139 ± 0.128:M, p=0.003, t-test paired). Considering all sites, we did not find differences between pN0 (n=16) vs pN+ (n=22) primary tumors. Compromised lymph nodes LN (n=10), as compared to matched primary tumors, expressed higher CCR7 mRNA densitometric values: (LN:0.054 ± 0.064 vs 0.007 ± 0.008:T, p = 0.044). Conclusions: Chemokine receptor CXCR4 mRNA expression was significantly higher in tumors, as compared to normal adjacent mucosa. In addition, chemokine receptor CCR7, presented higher mRNA expression in compromised LN as compared to matched primary tumors. We conclude that these receptors are, respectively, candidate markers of neoplastic transformation and spread to lymph nodes in HNSCC. Further studies are warranted in this area to confirm these results. No significant financial relationships to disclose.
Drug-Driven Synthetic Lethality: Bypassing Tumor Cell Genetics with a Combination of AsiDNA and PARP Inhibitors
Authors: Wael Jdey, Sylvain Thierry, Christophe Russo, Flavien Devun, Muthana Al Abo, Patricia Noguiez-Hellin, Jian-Sheng Sun, Emmanuel Barillot, Andrei Zinovyev, Inna Kuperstein, Yves Pommier, Marie Dutreix
Journal: Clinical Cancer Research (2016)

Purpose: Cancer treatments using tumor defects in DNA repair pathways have shown promising results but are restricted to small subpopulations of patients. The most advanced drugs in this field are PARP inhibitors (PARPi), which trigger synthetic lethality in tumors with homologous recombination (HR) deficiency. Using AsiDNA, an inhibitor of HR and nonhomologous end joining, together with PARPi should allow bypassing the genetic restriction for PARPi efficacy.Experimental Design: We characterized the DNA repair inhibition activity of PARPi (olaparib) and AsiDNA by monitoring repair foci formation and DNA damage. We analyzed the cell survival to standalone and combined treatments of 21 tumor cells and three nontumor cells. In 12 breast cancer (BC) cell lines, correlation with sensitivity to each drug and transcriptome were statistically analyzed to identify resistance pathways.Results: Molecular analyses demonstrate that olaparib and AsiDNA respectively prevent recruitment of XRCC1 and RAD51/53BP1 repair enzymes to damage sites. Combination of both drugs increases the accumulation of unrepaired damage resulting in an increase of cell death in all tumor cells. In contrast, nontumor cells do not show an increase of DNA damage nor lethality. Analysis of multilevel omics data from BC cells highlighted different DNA repair and cell-cycle molecular profiles associated with resistance to AsiDNA or olaparib, rationalizing combined treatment. Treatment synergy was also confirmed with six other PARPi in development.Conclusions: Our results highlight the therapeutic interest of combining AsiDNA and PARPi to recapitulate synthetic lethality in all tumors independently of their HR status. Clin Cancer Res; 23(4); 1001-11. ©2016 AACR.
Cytotoxic Properties of a DEPTOR-mTOR Inhibitor in Multiple Myeloma Cells
Authors: Yijiang Shi, Tracy R. Daniels-Wells, Patrick Frost, Jihye Lee, Richard S. Finn, Carolyne Bardeleben, Manuel L. Penichet, Michael E. Jung, Joseph Gera, Alan Lichtenstein
Journal: Cancer Research (2016)

Abstract DEPTOR is a 48 kDa protein that binds to mTOR and inhibits this kinase in TORC1 and TORC2 complexes. Overexpression of DEPTOR specifically occurs in a model of multiple myeloma. Its silencing in multiple myeloma cells is sufficient to induce cytotoxicity, suggesting that DEPTOR is a potential therapeutic target. mTORC1 paralysis protects multiple myeloma cells against DEPTOR silencing, implicating mTORC1 in the critical role of DEPTOR in multiple myeloma cell viability. Building on this foundation, we interrogated a small-molecule library for compounds that prevent DEPTOR binding to mTOR in a yeast-two-hybrid assay. One compound was identified that also prevented DEPTOR–mTOR binding in human myeloma cells, with subsequent activation of mTORC1 and mTORC2. In a surface plasmon resonance (SPR) assay, the compound bound to recombinant DEPTOR but not to mTOR. The drug also prevented binding of recombinant DEPTOR to mTOR in the SPR assay. Remarkably, although activating TORC1 and TORC2, the compound induced apoptosis and cell-cycle arrest in multiple myeloma cell lines and prevented outgrowth of human multiple myeloma cells in immunodeficient mice. In vitro cytotoxicity against multiple myeloma cell lines was directly correlated with DEPTOR protein expression and was mediated, in part, by the activation of TORC1 and induction of p21 expression. Additional cytotoxicity was seen against primary multiple myeloma cells, whereas normal hematopoietic colony formation was unaffected. These results further support DEPTOR as a viable therapeutic target in multiple myeloma and suggest an effective strategy of preventing binding of DEPTOR to mTOR. Cancer Res; 76(19); 5822–31. ©2016 AACR.