tbuckley/cabot-search huggingface dataset:
Combined mTOR and AKT inhibition in renal cell carcinoma (RCC).
Authors: W. S. Holland, P. C. Mack, C. G. Tepper, D. R. Gandara, P. Lara
Journal: Journal of Clinical Oncology (2010)

e15041 Background: RCC is characterized by VHL abnormalities and upregulation of hypoxia inducible factor (HIF). Inhibition of mTOR, a regulator of HIF, is an established therapy for advanced RCC. mTOR inhibition results in compensatory activation of AKT, a promoter of cell survival and proliferation. Perifosine is an orally bioavailable alkylphospholipid with AKT inhibitory properties. We sought to determine whether the addition of perifosine to an mTOR inhibitor (rapamycin) would synergistically inhibit RCC in preclinical models. Methods: Four clear cell RCC cell lines were studied: 786-O, A498 (VHL mutant), CAKI-1 (VHL wt), and 769-P (VHL methylated). Dose curves of single-agent and combination perifosine + rapamycin were by MTT assay, evaluated by median-effect analysis. Status of phospho-AKT (S473) and HIF-2alpha was by Western blot. Total RNA was isolated from 786-O cells subjected to single-agent and combination treatments. Quantitative real-time PCR (qRT-PCR) was used to examine VEGF mRNA levels and genome-wide expression profiling was performed with Affymetrix HG-U133 Plus 2.0 arrays. Results: CAKI-1, 769-P, and 786-O were sensitive to single-agent perifosine with 50% inhibitory concentrations ranging from 5-10 uM, while A498 was largely insensitive. Perifosine blocked phosphorylation of AKT induced by rapamycin and inhibited HIF-2alpha expression at 72 hrs following treatment in the 786-O and CAKI-1 cell lines. However, combined treatment resulted in subadditive growth inhibition. Rapamycin reduced VEGF expression in all cell lines; however, perifosine markedly induced VEGF expression at 24 hrs in 786-O and CAKI-1, overriding this effect from rapamycin. GeneChip analysis and subsequent pathway modeling revealed an inhibition of the IL-8 pathway by these two agents, concomitant with a 5-fold upregulation of the KLF2 (Kruppel-like factor 2) gene, recently shown to be a suppressor of HIF1alpha. Conclusions: Perifosine is active in select RCC lines and can abrogate the induction of AKT phosphorylation mediated by mTOR inhibition. Combined mTOR and AKT inhibition resulted in the modulation of relevant angiogenesis-related pathways, providing a basis for future clinical investigations. (Egan Family Fund and Landgraf Foundation) No significant financial relationships to disclose.
Intraoperative radiotherapy (IORT) during repeated breast-conserving surgery (BCS) in the previously irradiated breast.
Authors: E. Blank, G. Welzel, A. Keller, M. Suetterlin, U. Kraus-Tiefenbacher, F. K. Wenz
Journal: Journal of Clinical Oncology (2010)

e11008 Background: Breast cancer recurrences in the previously irradiated breast lead to mastectomy. An option to avoid mastectomy and offer BCS to patients with recurrent breast cancer is intraoperative radiotherapy. Methods: Between 04/02 and 11/09, 22 patients (median age 65.9 yrs, range, 42.8-86.9) received IORT during BCS to treat in- breast tumor recurrence (IBTR) after previous radiation after a median of 154 ± 54 months (range, 34-219). Fourteen patients had ductal-invasive carcinoma, 4 lobular-invasive, 1 mucinous-invasive, 1 adenoid-cystic carcinoma (T1/2 in 19/1 patients, N0/1/x in 13/2/5, M0/1 in 18/2, G1/2/3 in 4/14/2, R0/x in 16/4 and L0/1/x in 15/2/3). Median tumor size was 11 mm (1-21). IORT was given with 50 kV X-rays and a single dose of 14.7-20.0 Gy (Intrabeam-System; Carl Zeiss Surgical, Oberkochen, Germany), median applicator size was 4.0 cm (2.0-5.0) and median radiation time 26.8 min (12.29-49.5). One patient had too short follow-up (F/U) and one patient had mastectomy after 2 months, for which reason 20 patients (17 breast recurrence, 3 Hodgkin's disease) were analyzed. Toxicity was assessed according to a modified LENT-SOMA scale. Results: At a median F/U of 37 months (12-91), 4 patients died (54 [lung cancer], 52 [old age], 37 [metastases], and 36 months [metastases] after IORT), 1 patient underwent mastectomy due to local relapse and contralateral secondary cancer 38 months after IORT. In total, there were 2 local relapses, 4 patients with metastases (2 before IORT, 19 and 33 months after IORT). Higher-grade fibrosis was seen in 9 cases, with a peak after 18 months. One patient developed teleangiectases, retraction and fibrosis °II. Seven patients had retraction, 57% of them in combination with fibrosis. Only 2 patients had pain, 1 hyperpigmentation, and 1 breast edema. Conclusions: IORT is feasible for treatment of in-breast tumour recurrence in previously irradiated breasts and offers an alternative to mastectomy with acceptable toxicity and good local control. No significant financial relationships to disclose.
Abstract P081: Increased Hepatic Fat Is Associated With A More Atherogenic Lipoprotein Profile In Adolescents
Authors: Ran Jin, Ngoc-Anh Le, James Otvos, Miriam B Vos
Journal: Circulation (2014)

Introduction: Nonalcoholic fatty liver disease (NAFLD) has emerged as the most common liver disease in pediatrics, and it has been estimated to affect more than one third of obese adolescents in the United States. In adolescents with NAFLD, traditional markers of increased cardiovascular risk are commonly reported including elevated triglycerides and reduced HDL-cholesterol levels. Despite the fact that lipoproteins are critically involved in atherogenesis and cardiovascular disease, the independent impact of NAFLD on size and particle concentration of major lipoproteins remains less well described and studies in pediatric population are particularly scarce. Hypothesis: In the current study, we assessed the hypothesis that in adolescents, high hepatic fat would have a strong association with an atherogenic pattern of lipoprotein particle size and concentration. Methods: Hispanic-American overweight and obese adolescents (n=50) were recruited from pediatric clinics at Emory Children’s Center and from nearby community centers through flyers and presentations at community events. We evaluated their hepatic fat content by magnetic resonance spectroscopy and measured lipoprotein particles by nuclear magnetic resonance (Liposcience, Raleigh, NC). Results: Using the 5% hepatic fat to stratify subjects with low (n=13) and high hepatic fat (n=37), adolescents with high hepatic fat have undesirable lipoprotein subclass profiles, including larger VLDL particle size (51.2 ± 1.36 vs. 44.8 ± 1.31 nm, p=0.010), more large VLDL particle numbers (5.75 ± 0.93 vs. 1.32 ± 0.18 nmol/L, p&lt;0.001), and fewer large HDL particles (4.15 ± 0.33 vs. 5.69 ± 0.67 μmol/L, p=0.033). Strong correlations were found between hepatic fat and the number of large VLDL particles (r=0.521, p&lt;0.001), VLDL particle size (r=0.439, p=0.002), and small, dense LDL particle numbers (r=0.291, p=0.040). Conclusions: The amount of hepatic fat is closely related to the presence of large VLDL particle and small dense LDL, two important predictors of CVD. This suggests that hepatic fat and the associated dyslipidemia have interrelated mechanisms. Further studies with histologic assessment of NAFLD (liver biopsies) will be needed to confirm our findings and to explore causation.
Role of cyclooxygenase-2 (COX-2) expression in tumor progression and survival in the squamous cell carcinoma of the head and neck (HNSCC)
Authors: M. S. Choe, M. Tighiouart, A. Rogatko, S. Muller, H. J. Shin, M. Francisco, V. A. Papadimitrakopoulou, F. R. Khuri, W. K. Hong, Z. Chen, D. M. Shin
Journal: Journal of Clinical Oncology (2005)

5508 Background: COX-2 has been implicated in carcinogenesis of human tumors and a promising target for cancer prevention and therapy. The role of COX-2 in HNSCC tumorigenesis still remains to be clarified. Methods: A total of 64 patients (pts) with premalignant lesions or HNSCC and 10 normal epithelia (normal control) of the head and neck from non-smokers without tumor were included. Among 64 pts, 39 with HNSCC were treated with an induction chemotherapy protocol and all tumor tissues were obtained before treatment. The remaining 25 pts with premalignant lesions were treated on a chemoprevention trial. The tissue was obtained either before or after treatment. All squamous epithelial tissues from pts samples were histologically classified as normal (‘normal in field’) (25), low grade dysplasia (LD; mild dysplasia) (14), high grade dysplasia (HD; moderate to severe dysplasia) (29) or carcinoma in situ (CIS) (14). COX-2 expression was evaluated by immunohistochemistry on paraffin-embedded tissue and scored using weight index (W.I.). COX-2 expression in squamous epithelia was scored layer by layer; basal/parabasal (B/PB), lower spinous (LS), upper spinous/granular (US/GR). COX-2 expression of HNSCC was analyzed by Low (W.I. <0.856) and High (W.I.≥0.856) and its correlation with clinical data was assessed in 34 pts. Results: COX-2 expression of B/PB and LS was significantly increased during tumor progression (p <0.05), while COX-2 in HNSCC was significantly decreased (p<0.05) (Table), suggesting that COX-2 may contribute to early tumor progression. COX-2 expression in HNSCC showed a poor prognostic marker (median survival, 218 wks in the COX-2 High group vs. not reached in the Low group with median follow-up of 228wks). Conclusions: COX-2 may be involved in early tumor progression of HNSCC and its expression in HNSCC appears to be associated with poor prognosis. (Supported in part by NCI U01CA101244 to D.M.S.). No significant financial relationships to disclose.
PWE-131 Bone mineral density: a poor predictor of fracture risk in cirrhosis?
Authors: L Chinnappan, F Yousuf, A Begum, P Richardson, I Patanwala
Journal: Gut (2015)

<h3>Introduction</h3> Metabolic bone disease is a recognised complication of cirrhosis and results in an increased incidence of fractures which incur significant morbidity in these patients. Dual energy x-ray absorptiometry (dexa) scans are recommended on a 2-yearly basis to screen for osteoporosis based on T scores along with calcium and vitamin D supplementation in patients with cirrhosis or severe cholestasis. Treatment with bisphosphonates is recommended to reduce the risk of fracture in those who are found to be osteoporotic. <h3>Aim</h3> The aim of this study was to assess the role of bone mineral density measurements in stratifying fracture risk in patients with cirrhosis. <h3>Method</h3> Cirrhotic patients who had undergone a DEXA scan between 2009 and 2013 were identified. Demographic data, liver disease stage (MELD and Chil Pugh Score), T scores as obtained at DEXA scan and fracture occurrence were recorded. Multivariate analyses was carried out using variables that were found to be statistically significant on Univariate analysis. <h3>Results</h3> 79 cirrhotic patients with a mean age of 58(±10) yrs, 45% of whom were female were identified for the study and followed up for a median of 33 months (IQR 17–51). The aetiology of liver disease was alcohol (49%), autoimmune liver disease (AIH/PBC) (19%), NASH (15%), HCV (8%) and others (19%). Median MELD and CP Score for the cohort was 10 and 6 respectively. Normal mineral bone density, osteopenia and osteoporosis were found in 27%, 58% and 15% patients respectively. Fractures occurred in 24% (95% CI 15–35) of the entire cohort and in 19%, 24% and 33% of patients with normal BMD, osteopaenia and osteoporosis. Aetiology (including alcohol) was not associated fracture risk (p = 0.846). On univariate analysis only MELD and Child Pugh Score were associated with fractures (see Table 1below). There was no statistical difference in the T Score in patients with or without fractures. On multivariate analysis only Child Pugh score was independently associated with fracture risk (p = 0.024). <h3>Conclusion</h3> Fractures occur in a significant proportion of patients with cirrhosis. DEXA scans to assess bone mineral density may not be sufficient in predicting the risk of fracture in this cohort. The severity of liver disease as defined by the Child Pugh score may be better at identifying patients at a higher risk in whom preventative strategies should be focused. <h3>Disclosure of interest</h3> None Declared. <h3>Reference</h3> J D Collier, M Ninkovic, J E Compston. Guidelines on the management of osteoporosis associated with chronic liver disease. Gut. 2002;50:suppl 1 i1-i9 doi:10.1136/gut.50.suppl_1.i1
Genetic susceptibility to prostate cancer in residents of the west Siberian region.
Authors: N. A. Oskina, D. Ganov, V. D. Petrova, A. F. Lazarev, G. Lifshits, M. L. Filipenko, U. A. Boyarskih, None Boyarskikh
Journal: Journal of Clinical Oncology (2010)

e12036 Background: Prostate cancer (PC) is becoming one of the most common cancers in males all over the World including Russia. PC incidence rates increased by 60% per year from 2002 to 2007 in Russia. Screening for prostate cancer aims to advance the time of diagnosis (lead time) and detect cancers that would not have been found without screening. We examined the residents of the West Siberian region in order to clear out the impact of a single nucleotide polymorphisms (SNPs) in the c-MYC gene (rs6983267), in the CASP8 gene (rs3834129) and CYP1B1 gene (rs1056836) in the risk of sporadic PC. Methods: The group consisted of 285 Caucasian men with sporadic PC (mean aged 69 years). Control group consisted of 198 Caucasian men (mean aged 62 years) without a history of cancer. The group was selected from patients of the Altai Affiliated Department of N. N. Blokhin Cancer Research Center and Altai Regional Oncological Center. Genotyping was carried out by real-time PCR using competitive TaqMan probes. Results: The incidence of polymorphic loci in control DNA samples and in samples from patients with sporadic PC corresponded to the Hardy-Weinberg distribution in both groups. No significant associations of rs6983267 and rs3834129 polymorphic loci and PC development were detected (OR = 1.27; p = 0.230 and OR = 1.0; p = 0.87, respectively). CYP1B1 is involved in the activation of many procarcinogens and the hydroxylation of testosterone. Conclusions: In our study rs1056836 G-allele of CYP1B1 gene was significantly associated with decreased risk for PC (OR = 0.713; C.I.= [0.547-0.930]; p = 0.012) among men of the West Siberian Region. Further studies with a larger sample size are needed to confirm our results. No significant financial relationships to disclose.
Three-Year Follow-Up of a Randomized Phase II Trial on Refinement of Early-Stage NSCLC Adjuvant Chemotherapy with Cisplatin and Pemetrexed versus Cisplatin and Vinorelbine (the TREAT Study)
Authors: Michael Kreuter, Johan Vansteenkiste, Jürgen R. Fischer, Wilfried E. Eberhardt, Heike Zabeck, Jens Kollmeier, Monika Serke, Norbert Frickhofen, Martin Reck, Walburga Engel-Riedel, Silke Neumann, Michiel Thomeer, Christian Schumann, Paul De Leyn, Thomas Graeter, Georgios Stamatis, Frank Griesinger, Michael Thomas
Journal: Journal of Thoracic Oncology (2016)
BMP9 as a potential biomarker for dalantercept efficacy against ALK1-mediated angiogensis in head and neck cancer.
Authors: Scott Pearsall, Nicolas Solban, Kenneth M. Attie, Matthew L. Sherman, Ravi Kumar
Journal: Journal of Clinical Oncology (2012)

30 Background: Activin receptor-like kinase 1 (ALK1) is a type 1 receptor in the TGF-β superfamily. The ALK1 pathway plays a role in vascular development and pathological angiogenesis. Mutations affecting this pathway result in hereditary hemorrhagic telangiectasia, a disease characterized by failed vascular development and arteriovenous malformations. Therefore, disruption of this pathway in adults may help in conditions with pathological angiogenesis. Bone morphogenetic protein 9 (BMP9) is a ligand that binds with high affinity to ALK1 and stimulates endothelial cell sprouting during vessel maturation. BMP9 is upregulated in the RIP1-Tag2 murine model of vascular invasive carcinoma; treatment with a murine version of dalantercept (RAP-041) can inhibit tumor growth. Methods: Dalantercept (ACE-041) is a soluble receptor protein comprising the extracellular domain of ALK1 linked to an IgG1 Fc region, which functions as a ligand trap to inhibit endogenous BMP9 signaling. Results: In a phase I study of dalantercept in advanced solid tumors, three patients with squamous cell carcinoma of the head and neck (SCCHN) were enrolled. One SCCHN patient received 10 cycles (30 weeks) at 0.4 mg/kg and had a partial response (32.5% decrease in target lesion size). A second SCCHN patient received 11 cycles (33 weeks) at 1.6 mg/kg and had a 28.9% decrease in lesion size. A third SCCHN patient had progressive disease after 1 cycle at 0.8 mg/kg. Dalantercept was generally well-tolerated. Common AEs included fatigue, peripheral edema, nausea, anemia, headache, anorexia, and dyspnea. Analysis of archived tumor samples from SCCHN patients demonstrated that 25% had high BMP9 expression and 44% had medium levels of expression. Conclusions: A phase II study to evaluate the efficacy, safety and pharmacodynamics (PD) of dalantercept in SCCHN is ongoing. The primary objective is ORR. Secondary objectives include PFS, OS, safety, tolerability and pharmacokinetics. Exploratory analyses in this study will examine BMP9 expression in archived and fresh tumor biopsies as well as serum levels of BMP9 and other markers; association of biomarkers with response to therapy will be examined as potential companion diagnostics.
Abstract 15097: Altered TGFβ Signalling Effector Molecules Contribute to Bicuspid Aortic Valve-associated Thoracic Aortopathy
Authors: Candice L Dilworth, Francesca Sadnick, Sari Padang, Yaxin Lu, Elizabeth N Robertson, Sanaz Maleki, Murat Kekic, Shisan Bao, Craig McLachlan, Richmond W Jeremy, Brett D Hambly
Journal: Circulation (2014)

Upregulated TGFβ signalling plays a key role in mediating congenital thoracic aortic aneurysms (TAA), and has been implicated in bicuspid aortic valve-associated TAA (BAV-TAA). TGFβ is normally stored within the extra-cellular matrix via sequestration proteins bound to the microfibrillar protein, fibrillin. TGFβ is released in response to changes in these sequestration proteins, allowing TGFβ to exert its signalling effects. We hypothesised that in BAV-TAA the upregulation of TGFβ signalling will pathologically alter effector molecule expression, causing matrix degradation and altered TGFβ sequestration. Immunohistochemistry was used to quantify protein expression in aortic tissue from 8 human BAV-TAA and 6 normal controls. In BAV-TAA, TGFβ expression was elevated in all layers (2.5:1; p&lt;0.05), particularly in the adventitia (3.4:1; p&lt;0.001). Microfibril-associated glycoprotein-1 (MAGP-1), which promotes TGFβ release, was elevated (2:1; p&lt;0.03), while latent TGFβ binding protein-1 (LTBP-1), which promotes TGFβ sequestration, was decreased (0.3:1; p=0.03). Matrix metalloproteinase-2 (MMP-2) and MMP-9 expression was elevated (2.6:1; p&lt;0.005, 1.5:1; p&lt;0.05, respectively), and MMP-3 expression was decreased (0.5:1; p&lt;0.05). Fibrillin-1 expression was not altered. The observed changes in TGFβ sequestration proteins will increase unbound TGFβ, leading to upregulation of downstream signalling. The elevated levels of MMP-2 and MMP-9 mediate pathological matrix remodelling, leading to aortic dilatation. The paradoxical decrease in MMP-3 may represent a compensatory mechanism that attempts to reduce overall pathological MMP activity, in order to limit damage to the aortic wall. In conclusion, in BAV-TAA excessive TGFβ signalling is potentiated by reduced TGFβ sequestration, causing extra-cellular matrix degradation by MMPs. This supports the rationale for the use of angiotensin II receptor blockers in BAV-TAA.
Abstract 15390: Diverse Functional Effects of GWAs CAD Risk Genes in Mice: CardioGENE KO-Project
Authors: Zouhair Aherrahrou, Thorsten Kessler, Jennifer Freyer, Moritz P Rumpf, Redouane Aherrahrou, Jaafar Al-Hasani, Kjestine Schmidt, Evanthia Mergia, Natalia Alenina, Michael Bader, Cor de Wit, Heribert Schunkert, Jeanette Erdmann
Journal: Circulation (2012)

Coronary artery disease (CAD) is a complex disease. Recently, more than 35 genomic loci have been shown to be associated with CAD on a genome-wide significance level. Up to now, only genes related ...
Usage of biosimilar filgrastim: A subanalysis of the next study.
Authors: Frederic Maloisel, Stephane Leprêtre, Didier Kamioner, Christian Berthou, Helene Albrand
Journal: Journal of Clinical Oncology (2014)

216 Background: Febrile neutropenia (FN), a major risk factor for morbidity/mortality, is associated with dose delays and/or reductions in potentially cytotoxic chemotherapy (CT) regimens. European recommend prophylactic use of granulocyte-colony stimulating factor (G-CSF) when using a CT regimen associated with a &gt;20% risk of FN or in less intensive CT regimens if certain risk factors (eg &gt;65 years, advanced disease) are present. Biosimilar filgrastim (Nivestim , Hospira Inc.) is a G-CSF licensed for the treatment of neutropenia and FN induced by myelosuppressive CT. As the NEXT (Nivestim safety profile in patients [pts] treated with cytotoxic CT in real-life clinical practice) study was conducted in France, the real-life usage of biosimilar filgrastim is compared with that recommended by current European guidelines. Methods: NEXT was a prospective, non-interventional, longitudinal, multicentre study conducted in France. Pts were undergoing CT for malignancies and receiving biosimilar filgrastim as prophylaxis or as curative treatment. This subanalysis included only pts receiving prophylactic biosimilar filgrastim. Individual FN risk factors were analysed. Results: Overall, 2102 pts were analysed in the study and 2065 pts received prophylactic biosimilar filgrastim. Of these, 19.4% received CT associated with a high risk of developing FN (intermediate risk 55.6%; low risk 25.0%). Of the pts receiving CT regimens associated with an intermediate or low risk of FN, 95.4% and 96.5%, respectively, had ≥1 risk factor for FN (Table). Of all pts analysed, 2.4% developed FN, 11.2% developed an infection and 2.4% were hospitalised for FN and/or infection after the first CT cycle. Median delay between the last CT dose and start of treatment was 2 days; mean ± SD duration of treatment was 6.0 ± 3.8 days. Conclusions: The majority of pts received prophylactic biosimilar filgrastim according to European guidelines (ie either had &gt;20% risk of FN or had ≥1 FN risk factor). Clinical trial information: NCT01574235. [Table: see text]