tbuckley/cabot-search huggingface dataset:
A human clinical trial using ultrasound and microbubbles to enhance gemcitabine treatment of inoperable pancreatic cancer
Authors: Georg Dimcevski, Spiros Kotopoulis, Tormod Bjånes, Dag Hoem, Jan Schjøtt, Bjørn Tore Gjertsen, Martin Biermann, Anders Molven, Halfdan Sorbye, Emmet McCormack, Michiel Postema, Odd Helge Gilja
Journal: Journal of Controlled Release (2016)

The primary aim of our study was to evaluate the safety and potential toxicity of gemcitabine combined with microbubbles under sonication in inoperable pancreatic cancer patients. The secondary aim was to evaluate a novel image-guided microbubble-based therapy, based on commercially available technology, towards improving chemotherapeutic efficacy, preserving patient performance status, and prolonging survival. Ten patients were enrolled and treated in this Phase I clinical trial. Gemcitabine was infused intravenously over 30 min. Subsequently, patients were treated using a commercial clinical ultrasound scanner for 31.5 min. SonoVue® was injected intravenously (0.5 ml followed by 5 ml saline every 3.5 min) during the ultrasound treatment with the aim of inducing sonoporation, thus enhancing therapeutic efficacy. The combined therapeutic regimen did not induce any additional toxicity or increased frequency of side effects when compared to gemcitabine chemotherapy alone (historical controls). Combination treated patients ( n = 10) tolerated an increased number of gemcitabine cycles compared with historical controls ( n = 63 patients; average of 8.3 ± 6.0 cycles, versus 13.8 ± 5.6 cycles, p = 0.008, unpaired t -test). In five patients, the maximum tumour diameter was decreased from the first to last treatment. The median survival in our patients ( n = 10) was also increased from 8.9 months to 17.6 months ( p = 0.011). It is possible to combine ultrasound, microbubbles, and chemotherapy in a clinical setting using commercially available equipment with no additional toxicities. This combined treatment may improve the clinical efficacy of gemcitabine, prolong the quality of life, and extend survival in patients with pancreatic ductal adenocarcinoma.
Genomic Heterogeneity and Exceptional Response to Dual Pathway Inhibition in Anaplastic Thyroid Cancer
Authors: William J. Gibson, Daniel T. Ruan, Vera A. Paulson, Justine A. Barletta, Glenn J. Hanna, Stefan Kraft, Antonio Calles, Matthew A. Nehs, Francis D. Moore, Amaro Taylor-Weiner, Jeremiah A. Wala, Travis I. Zack, Thomas C. Lee, Fiona M. Fennessy, Erik K. Alexander, Tom Thomas, Pasi A. Janne, Levi A. Garraway, Scott L. Carter, Rameen Beroukhim, Jochen H. Lorch, Eliezer M. Van Allen
Journal: Clinical Cancer Research (2016)

Purpose: Cancers may resist single-agent targeted therapies when the flux of cellular growth signals is shifted from one pathway to another. Blockade of multiple pathways may be necessary for effective inhibition of tumor growth. We document a case in which a patient with anaplastic thyroid carcinoma (ATC) failed to respond to either mTOR/PI3K or combined RAF/MEK inhibition but experienced a dramatic response when both drug regimens were combined.Experimental Design: Multi-region whole-exome sequencing of five diagnostic and four autopsy tumor biopsies was performed. Meta-analysis of DNA and RNA sequencing studies of ATC was performed.Results: Sequencing revealed truncal BRAF and PIK3CA mutations, which are known to activate the MAPK and PI3K/AKT pathways, respectively. Meta-analysis demonstrated 10.3% cooccurrence of MAPK and PI3K pathway alterations in ATC. These tumors display a separate transcriptional profile from other ATCs, consistent with a novel subgroup of ATC.Conclusions: BRAF and PIK3CA mutations define a distinct subset of ATC. Blockade of the MAPK and PI3K pathways appears necessary for tumor response in this subset of ATC. This identification of synergistic activity between targeted agents may inform clinical trial design in ATC. Clin Cancer Res; 23(9); 2367-73. ©2016 AACR.
Evaluation of AZD2171, an oral, highly potent and selective VEGFR signaling inhibitor, in renal cell carcinoma (RCC): Combined results from two phase I studies
Authors: C. van Herpen, J. Drevs, H. van Cruijsen, E. E. Voest, C. J. Punt, J. Robertson, O. Saunders, U. Zirrgiebel, C. Unger, G. Giaccone
Journal: Journal of Clinical Oncology (2007)

3560 Background: Antiangiogenic agents have recently demonstrated promising activity in patients with advanced RCC. AZD2171 is an oral, highly potent and selective inhibitor of VEGFR-1, -2 and -3 tyrosine kinases, and is currently in Phase II/III development in NSCLC and CRC. Safety and efficacy results are presented for patients with RCC who participated in two Phase I dose-escalation studies of AZD2171 in advanced solid tumors. Methods: Patients with advanced recurrent metastatic RCC received once-daily oral AZD2171, either as monotherapy (Drevs et al. Proc Am Soc Clin Oncol 2005: abst 3002; completed) or in combination with gefitinib (van Cruijsen et al. Proc Am Soc Clin Oncol 2006: abst 3017; ongoing). All patients had received prior interferon-a ± interleukin-2/ 5-FU or radiotherapy. Results: Twenty-one patients received AZD2171, 4 as monotherapy (20 mg, n=1; 60 mg, n=3) and 17 as combination therapy (AZD2171 20–45 mg with gefitinib 250 or 500 mg). The adverse event (AE) profile in RCC patients was similar to that reported previously for all patients in these studies; hypertension, dysphonia, nausea, vomiting, diarrhea and fatigue were the most common AEs. The most common CTC grade 3 AEs were hypertension (n=5) and diarrhea (n=4). Reductions in plasma levels of sVEGFR-2 were observed in RCC patients when AZD2171 was administered as a monotherapy or in combination with gefitinib; the reductions in the combination study were dose- and time-dependent (sustained). Nineteen patients were evaluable for efficacy (RECIST): 2/3 monotherapy patients experienced tumor regression, one of which was confirmed as a partial response (duration of response [DR] 87 days); in the combination study, 6/16 (38%) patients achieved a partial response (median DR 6 months; 3/6 ongoing at data cut off) and 7/16 (44%) patients had stable disease (4/7 had a confirmed 10–30% reduction in maximum tumor diameter). Conclusion: AZD2171, both as monotherapy and in combination with gefitinib, showed encouraging antitumor activity and a manageable toxicity profile in patients with advanced RCC who had failed prior therapy. A randomized Phase II investigation of AZD2171 monotherapy (45 mg/day) vs placebo in patients with advanced RCC is ongoing. [Table: see text]
GW26-e0266 Safety and effectiveness of Tadalafil on PAH from a post-marketing surveillance (Investigation on all patients in Japan, interim data)
Authors: Ping Xin, Masahiro Murakami, Yasuhiro Umeki, Masanori Taketsuna, Nobuyuki Kobayashi, Hiroyoshi Yamazaki
Journal: Journal of the American College of Cardiology (2015)
GW26-e0495 Impact of Myocardial Remodeling in a Rat Model of Heart Failure Transfected with Recombinant Adenovirus Vector-mediated Klotho Gene
Authors: Zheng Jia, Qian Liu, Lian Wang, Ziying Zhu, Jing Yang, Liping Zhang, Xiaohua Yang, Weiqiang Chen, Chunyan Sun, Ling Wei
Journal: Journal of the American College of Cardiology (2015)
Colorectal Cancer Screening Recommendations—Reply
Authors: Kirsten Bibbins-Domingo
Journal: JAMA (2016)

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Remission and tumor cell protection in PVG rats by subcutaneous injection of LTX-315 into an aggressive malignant rat mesenchymal tumor with stemness characteristics.
Authors: G. Kvalheim, M. Wang, S. Zinocker, K. Camilio, B. Rolstad, J. Vaage, O. Rekdal
Journal: Journal of Clinical Oncology (2010)

e21046 Background: LTX-315 (Oncopore) is a chemically designed cationic nonapeptide derived from a natural host defensive CAP, bovine lactoferricin (LfcinB) in development for local treatment of tumours. Earlier studies have demonstrated that treatment of A20 lymphomas and CT26WT carcinomas with LTX-315 in immunocompetent mice resulted in tumour regression. Re-challenge with tumor cells in the cured animals showed that a long- term protection was induced against the tumor. Methods: In the current experiments we have investigated if LTX-315 also can have the same effect on a novel established malignant rat mesenchymal tumor cell line with “stemness” properties. Following long term culturing of bone marrow derived rat mesenchymal cells we developed a rat transformed mesenchymal cell line (rTMSC). Previously we have shown that s.c. as well as i.v. and i.p. injection of rTMSC form immature sarcoma tumors both in nude rats as well as in PVG rats. The rTMSC has been stabled marked with a dual reporter gene GFP and Leuciferase and in the current study CCD camera was used for dynamic living imaging. 5×105 rTMSCs were subcutaneously inoculated into 20 PVG rats. After 7 days measurable tumors could be observed and 18 animals was treated with LTX-315. Results: In spite of repeated injection with the peptide 8 animals lost tumor control, while 9 animals within 38 days achieved complete tumor responses as assessed with CCD camera. Re-challenges of the tumor free animals with injection of 5×104 tRMSCs show no tumor growth while all control animals had a fast tumor formation. Conclusions: 50% of the treated animals have developed an impressive tumor protection of this aggressive mesenchymal tumor with “stemness” properties. Most likely more animals can be cured if the peptide injection procedure can be improved and further studies are underway. Altogether our results bear promises for LTX-315 in future cancer therapy. No significant financial relationships to disclose.
Case-Control Pilot Study of the Immune Modulating Effect of FEIBA® on Patients with Haemophilia a and Inhibitors
Authors: Ihosvany Fernandez Bello, María Teresa Álvarez Román, Victor Jiménez Yuste, Monica Martín Salces, Gemma Iruin, Santiago Bonanad, María Fernanda López Fernández, Carmen Altisent, Faustino García Candel, María Isabel Rivas Pollmar, Miguel Canales, Nora Butta
Journal: Blood (2015)
GW26-e4593 Childhood adiposity is associated with carotid atherosclerosis and left ventricular hypertrophy but not with arterial stiffness at adulthood: Beijing Blood Pressure Cohort Study
Authors: Yinkun Yan, Dongqing Hou, Yajun Liang, Xiaoyuan Zhao, Yuehua Hu, Junting Liu, Hong Cheng, Ping Yang, Xinying Shan, Jie Mi
Journal: Journal of the American College of Cardiology (2015)
Novel drug discovery by pharmacogenomic profiling of 36 colorectal cancer cell lines.
Authors: Peter Eide, Jarle Bruun, Anita Sveen, Astrid MurumÃƒÂ¤gi, John Mpindi, Mariliina Arjama, Olli Kallioniemi, Ragnhild A Lothe
Journal: Journal of Clinical Oncology (2016)

604 Background: Patients with advanced colorectal cancer (CRC) are commonly administered chemotherapy by 5-Fluorouracil in various combinations with leucovorin, oxaliplatin and irinotecan. Metastatic CRCs are additionally eligible for targeted anti-VEGF treatment and anti-EGFR therapy if the tumor is KRASwt. Unfortunately, the response rates are low and novel drugs are needed. Cell lines have successfully been employed to predict drug response and several studies have demonstrated that CRC cell lines recapitulate the genetic variation among primary CRCs. Methods: We performed a high-throughput drug screen (n= 461) of 36 CRC cell lines. A multiplexed assay assessed drug effects on cell viability and cytotoxicity from a five-fold concentration range. Sensitivities were measured by calculating a drug sensitivity score for each drug using a validated algorithm that estimates the relative inhibition by normalization against the top asymptote of the drug concentration curve. By integrating drug sensitivity data with in-house datasets on DNA copy number, gene expression and deep DNA sequencing, we aimed to validate genetically indicated drug sensitivities and identify novel drug sensitivities among subsets of CRCs. Results: Pharmacological relationships for molecular subgroups of CRC were revealed by clustering analyses, outlier analysis and t-tests of the drug sensitivity scores. We found robust correlations between BRAF-mutation status and response to BRAF-inhibitors, and lack of response to Fluorouracil and its prodrug Capecitabine for cell lines with microsatelite instability. These cell lines were sensitive to Topoisomerase I-inhibitors, such as Irinotecan, Valrubicin and Idarubicin. Cell lines with TP53wt were sensitive to the TP53-MDM2 interaction inhibitor Nutlin-3. We additionally identified a more potent novel TP53-MDM2 interaction inhibitor. Pharmacologic correlations for drug classes such as MEK-, EGFR-, Aurora A/B-, PI3K/AKT-, HSP90 and IGF1R-inhibitors were also found. Conclusions: A comprehensive drug screen of 36 CRC cell lines confirms pharmacogenomic relationships and reveals novel potentially relevant therapies for CRC.
PRIMA-1<sup>MET</sup> (APR-246): A novel targeted therapy for triple negative breast cancer?
Authors: Naoise C Synnott, Patricia M. McGowan, Aisling Pierce, Maeve Kiely, Norma O'Donovan, John Crown, Patrick A Kiely, Michael J. Duffy
Journal: Journal of Clinical Oncology (2015)

e12072 Background: Despite intensive efforts, a validated targeted therapy for triple-negative breast cancer (TNBC) remains elusive. One of the most frequent genetic alterations identified to date in TNBC is mutation in the p53 gene, which has been found in > 80% of these samples. The aim of this study was therefore to investigate mutant p53 as a potential target for the treatment of TNBC. Methods: The small compound PRIMA-1MET (APR-246), which has previously been shown to reactivate mutant p53 and convert it to a form with wild-type properties, was investigated in a panel of 23 breast cancer cell lines (TN = 11; non-TN = 12). Cytoxicity was determined using both the MTT assay and colony formation assay. Proliferation was measured using the real-time xCELLigence system, while induction of apoptosis was measured using flow cytometry. p53 protein levels were determined by Western blot and ELISA. Results: Using the MTT assay, IC50 values across the panel of breast cancer cells ranged from 0.9 to 31.1 µM, for PRIMA-1MET. Inhibition of cell growth varied from 3.1 to 96.6%, using concentration of inhibitor at 6.25 µM. PRIMA-1MET also reduced the ability of breast cancer cells to form colonies, in the 6 cell lines investigated, with IC50 values ranging from 0.69 to 6.4 μM. These findings were confirmed with the xCELLigence system. p53 mutated cell lines were significantly more sensitive to PRIMA-1MET than p53 WT cells (p = 0.0144, Student’s t-test). Response to PRIMA-1MET correlated strongly and significantly with p53 protein level (p = 0.0001, r = -0.7579, Spearman test). In addition to inhibiting cell proliferation, PRIMA-1MET also induced apoptosis in the p53 mutated cell lines MDA-MB-453 and MDA-MB-468 but not in the p53 WT cell line, MCF7. Combined treatment with PRIMA-1MET and either cisplatinum, carboplatinum or docetaxel significantly increased inhibition of cell growth (p = 0.028, p = 0.013, p = 0.0011, respectfully). Conclusions: Our preclinical results suggest that targeting mutant p53 with PRIMA-1MET (APR-246) is a potential new approach for treating p53-mutated breast cancers, including the subgroup with triple-negative disease. Acknowledgement: This work was funded by the BREAST-PREDICT (CCRC13GAL) programme of the Irish Cancer Society.
Predictors of Stem Cell Yield Via Apheresis in Patients Undergoing Stem Cell Mobilization,
Authors: Rima M Saliba, Alexandre Chiattone, Alejandro Majlis, Viviane C. Chiattone, Gabriela Rondon, Araci M. Sakashita, Nelson Hamerschlak, Jose Mauro Kutner, Elizabeth J Shpall, Paolo Anderlini, Issa Khouri, Muzaffar H Qazilbash, Uday Popat, Richard Champlin, Chitra M Hosing, Marcos De Lima
Journal: Blood (2011)
Selection of induction chemotherapy (CT) in esophageal and gastroesophageal junction cancer by positron emission tomography (PET)
Authors: A. Irigoyen, J. Delgado, A. Rodriguez, J. Ferron, R. Luque, P. Reche, E. Gonzalez, V. Conde, C. Rodriguez, J. Pleguezuelos
Journal: Journal of Clinical Oncology (2006)

14041 Background: Preoperative CT improves survival in esophageal cancer. 50% of patients (pts) do not respond to cisplatin+5-FU (C+F). The reduction of fluorodeoxyglucose uptake after 14 days (d) of CT predicts clinical response (rsp). Our objective was to measure the rsp (rsp) rate after CT adjusted according to PET rsp. Methods: Eligible pts were ≥ stage II esophageal cancer and able to tolerate CT. By adjusting CT according to PET rsp, we expected an increase of rsp rate by 25%. Taking into account a confidence level of 90%, an error β of 20% and a minimal error of 15% (even with such a high error rate the data will exceed the standard results), we calculated a sample size of 23 pts. All underwent esophagoscopy, computed tomography and PET scan prior to C (100mg/m 2 d1) +5-FU (1,000mg/m 2 d1–5). If PET rsp after first cycle (uptake decreased ≥ 35%), we continued up to third C+F cycle, then if endoscopy rsp: C+F + concurrent radiation only if stage II or III. If no endoscopy rsp, surgery only if stage II or III. On the other hand, if the pts had no rsp in PET after first C+F cycle they continued with 2 cycles of docetaxel (35mg/m 2 d 1 &amp; 8) and irinotecan (50mg/m 2 d 1 &amp; 8) (D+I) every 21 d and then if endoscopy rsp: radiation + docetaxel only if stage II or III. If no endoscopy rsp, surgery. Results: Since 2/04, 23 pts have been enrolled. Location: 2 cervical, 4 upper thoracic, 7 mid-thoracic, 10 GE junction. PET stage: 7 IIA, 6 IIB, 2 III, 2 IVA, 6 IVB. Up-staging with PET in 6 pts, down-staging in 4 pts. Histology: 10 Adenocarcinoma, 13 squamous carcinoma. Improved swallowing function: from a total of 12 PET responders, 9 had a clinical rsp after C+F, 3 did not. From 11 PET non-responders, 7 had a clinical rsp after D+I, 4 did not. Global clinical rsp = 16/23 (70%). Endoscopy rsp (frequent inaccuracy by overstaging): from a total of 12 PET responders, 6 had a clinical rsp after C+F, 6 did not. From 11 PET non-responders, 7 had a clinical rsp after D+I, 4 did not. Global clinical rsp = 13/23 (57%). Conclusion: Our results suggest that it is possible to significantly increase the percentage of pts who respond to induction CT adjusted according to PET in esophagogastric cancer before concurrent chemoradiotherapy or esophagectomy, or both. No significant financial relationships to disclose.
Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses
Authors: Kelly D Moynihan, Cary F Opel, Gregory L Szeto, Alice Tzeng, Eric F Zhu, Jesse M Engreitz, Robert T Williams, Kavya Rakhra, Michael H Zhang, Adrienne M Rothschilds, Sudha Kumari, Ryan L Kelly, Byron H Kwan, Wuhbet Abraham, Kevin Hu, Naveen K Mehta, Monique J Kauke, Heikyung Suh, Jennifer R Cochran, Douglas A Lauffenburger, K Dane Wittrup, Darrell J Irvine
Journal: Nature Medicine (2016)
A phase III, randomized, double-blind, multicenter trial comparing the investigational agent orteronel (TAK-700) plus prednisone (P) with placebo plus P in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or following docetaxel-based therapy.
Authors: Robert Dreicer, David B. Agus, Joaquim Bellmunt, Johann Sebastian De Bono, Daniel Peter Petrylak, Bindu Tejura, Yuanjun Shi, Karim Fizazi
Journal: Journal of Clinical Oncology (2012)

TPS4693 Background: The investigational agent orteronel is a selective inhibitor of 17,20-lyase, a key enzyme in the testosterone synthesis pathway. In a phase 1/2 study in men with mCRPC, orteronel reduced prostate-specific antigen (PSA) levels, and inhibited testosterone and DHEA-S consistent with potent 17,20-lyase inhibition (Agus D, et al. J Clin Oncol 2012;30:s5 abst 98). Docetaxel-based chemotherapy is an effective but noncurative therapy for mCRPC that has progressed on hormonal therapy; new therapeutic options are needed. Methods: This double-blind, multicenter study is assessing orteronel + P vs placebo + P in men with mCRPC (NCT01193257; C21005). Patients must have evidence of disease progression during or after receiving a total of ≥360 mg/m 2 docetaxel within a 6-mo period. Patients who are clearly intolerant to docetaxel or have progressive disease before receiving ≥360 mg/m 2 are also eligible if they have received at least 225 mg/m 2 of docetaxel within a 6-mo period and meet the other inclusion criteria. Other eligibility criteria include radiographically documented metastatic disease and baseline testosterone &lt;50 ng/dL following surgical or medical castration. Prior adrenal-targeted therapies are not permitted. Men may have opioid-requiring bone pain. The planned sample size is 1083; men will be randomized 2:1 to receive orteronel 400 mg twice daily (BID) plus P 5 mg BID or placebo plus P. The primary endpoint is overall survival; other endpoints are radiographic progression-free survival, PSA decrease of ≥50% at 12 wks, pain response at 12 wks, safety, time to PSA progression, objective response by RECIST, circulating tumor cell and endocrine marker changes, and patient-reported outcomes. After disease progression, men may continue to receive study drug. Tumor specimens will be analyzed for biomarkers that may predict orteronel antitumor activity, including the TMPRSS2:ERG fusion gene. The same regimens are being evaluated in a concurrent phase 3 study in chemotherapy-naïve men with mCRPC (NCT01193244).
Inaccurate data may lead to insufficient resources
Authors: A. C Burnett, P. Bland
Journal: BMJ (1995)

People are overusing sunbedsED1rOR,-David Shuttleworth drew attention to the question of whether sunbeds that emit ultra- violet A radiation cause skin cancer.'To determine the prevalence of use of sunbeds during 1994 the Department of Health commissioned the omnibus survey of the Office of Population Censuses and Surveys to interview British adults, who were randomly selected and stratified by socioeconomic variables.A balanced response rate of 76% was achieved, producing 2017 interviews.Of the 284 respondents aged 16-24, 68 (24%) had used a sunbed during the year, as had 106 (10%) of the 1056 respondents aged 25-54; the overall ratio of men to women who had used a sunbed was 7:1 1.A total of 184 people had used sunbeds.Half had used them at home (ratio of hired to privately owned equipment 1:2), and half had used commer- cial facilities, with about one fifth of the total use of sunbeds occurring on local authority premises.Information regarding use of sunbeds is available from, among others, the Health and Safety Executive (existing guidance is under revision),'