tbuckley/cabot-search huggingface dataset:
Politiques nationales de prévention de la résistance aux antibiotiques – la situation de 17 pays européens fin 2000
Authors: Hélène Therre
Journal: Eurosurveillance (2001)

Une enquete menee parmi les Pays Membres de l’Union Europeenne et la Norvege montre que seul deux d'entre eux ne disposaient pas, en decembre 2000, d’une surveillance nationale des microorganismes resistants aux antibiotiques. En Italie, en Irlande et en Ecosse, ces systemes ont ete mis en place tres recemment (respectivement 1998, 1999 et 1999). Par ailleurs, a l’exception de l’Irlande et de l’Ecosse, ils disposent tous d’un systeme national de surveillance de la consommation des antibiotiques, l’Autriche, l’Italie et le Luxembourg depuis l’annee 2000. Plusieurs de ces systemes ont donc ete mis en place apres la publication des recommandations de la conference europeenne  La Menace Microbienne  qui s’est tenue a Copenhague en septembre 1998. De plus, un certain nombre d’autres mesures ont ete prises depuis : campagne d’education du public en Angleterre et au Pays de Galles, Irlande ou France, mise en place de comites specifiquement charges de la surveillance de la consommation en Italie ou de la prevention de la resistance en Belgique ou en Irlande, publications de recommandations sur le bon usage des antibiotiques en Autriche et en Finlande, etc.
Forty-eight cases of leiomyosarcoma of bone in Japan: A multicenter study from the Japanese Musculoskeletal Oncology Group (JMOG).
Authors: Robert Nakayama, Tomoaki Mori, Makoto Endo, Hiroaki Hiraga, Masato Tomita, Naomasa Fukase, Eisuke Kobayashi, Akira Kawai, Takafumi Ueda, Hideo Morioka
Journal: Journal of Clinical Oncology (2016)

e22505 Background: Leiomyosarcoma of bone (LMSoB) is a rare malignant bone tumor. Its clinical outcome has not been deeply assessed in the literature. This multicenter retrospective study was conducted to investigate the diagnosis and the clinical outcome of primary LMSoB in Japan. Methods: Forty-eight patients (average age: 52 years [range 14-88 years]) with primary LMSoB who were treated at registered institutes in Japan between 1991 and 2014 were recruited. The median follow-up period was 44 months (range: 2-273). Results: The 5-year overall survival rates and disease-free survival rates were 78.3% and 44.9% respectively. Surgical treatment was performed in 42 patients (87.5%), and an adequate safe margin (R0 resection) was achieved in 31 patients (73.8%). Neoadjuvant chemotherapy was administered in 18 patients. The most common regimen (cisplatin-based chemotherapy) was administered in 15 patients (83.3%), but no patient achieved a good response in both radiological and histological evaluation. The presence of metastasis at the first visit and a lack of definitive surgery were significantly correlated with poor overall survival (p = 0.0036 and p = 0.0355, respectively), and the surgical margin was a significant prognostic factor for disease-free survival (p = 0.0005). Conclusions: The present study reveals the clinical outcomes and treatments in the largest case series ever reported for LMSoB. Surgical treatment with wide margins was the only treatment that proved to be effective, whereas adjuvant chemotherapy did not improve the overall survival. The results underscore the need to seek a novel chemotherapy regimen and alternative chemotherapy regimens that are effective for leiomyosarcoma arising from other tissues need to be tested for LMSoB.
Abstract 2215: Pembrolizumab and ipilimumab reduce human RKO colon carcinoma tumor growth in HLA matched CD34-NSG humanized mice
Authors: Marcio Lasaro, Jason M. Davis, Mark Ellison, Martin R. Graf, Vivek Mahajan, Aidan Synnott, Robert J. Mullin, Paula L. Miliani De Marval.
Journal: Cancer Research (2016)

Abstract Over the past decade there has been an increasing demand for preclinical models useful for evaluating the efficacy of checkpoint inhibition-based cancer immunotherapies. The recently developed humanized mouse models composed of various types of human immune cells has the potential to recapitulate the human anti-tumor response modulated by checkpoint inhibitors. Tumor cells may develop multiple mechanisms to evade immune surveillance, including PD-L1 upregulation which suppresses T-cell effector responses towards the tumor. In the present study, we evaluated the efficacy of the checkpoint inhibitors pembrolizumab (anti-PD-1) and ipilimumab (anti-CTLA-4) in the human RKO colon carcinoma xenograft model in CD34-NSG humanized mice. These mice were engrafted with human hematopoietic stem cells (HSC) that matched the HLA haplotype of the RKO cells (HLA-A*01). Flow cytometry analysis confirmed high level of expression of PD-L1 in RKO colon carcinoma cells. The results from this study revealed that pembrolizumab and ipilimumab monotherapies significantly inhibited tumor growth. Surprisingly, combination therapy did not provide additive or synergistic effects and resulted in the same level of efficacy as the individual regimens. In order to understand the impact of these therapies on distinct immune cell populations, we analyzed the distribution of CD4 and CD8 T lymphocytes, Treg cells, NK cells and B cells in peripheral blood, spleen and tumor samples from tumor bearing humanized mice, via flow cytometry. We found that these checkpoint inhibitors can enhance effector functions of CD4+ and CD8+ T cells associated with increased expression of IFN-Γ. A parallel study with these checkpoint inhibitors carried out with humanized mice engrafted with HSC of the same haplotype as the RKO cells but from a different donor resulted in identical anti-tumor efficacy. In summary, these studies validate the use of humanized mouse models to test the tumor response to immune-checkpoint based therapies as it shows significant anti-tumor growth as a result of pembrolizumab and ipilimumab monotherapies associated with activation of T lymphocytes. Citation Format: Marcio Lasaro, Jason M. Davis, Mark Ellison, Martin R. Graf, Vivek Mahajan, Aidan Synnott, Robert J. Mullin, Paula L. Miliani De Marval. Pembrolizumab and ipilimumab reduce human RKO colon carcinoma tumor growth in HLA matched CD34-NSG humanized mice. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2215.
Nomogram for individualized prediction of hepatocellular carcinoma occurrence in hepatitis C virus cirrhosis (ANRS CO12 CirVir)
Authors: Nathalie Ganne‐Carrié, Richard Layese, Valérie Bourcier, Carole Cagnot, Patrick Marcellin, Dominique Guyader, Stanislas Pol, Dominique Larrey, Victor de Lédinghen, Denis Ouzan, Fabien Zoulim, Dominique Roulot, Albert Tran, Jean‐Pierre Bronowicki, Jean‐Pierre Zarski, Ghassan Riachi, Paul Calès, Jean‐Marie Péron, Laurent Alric, Marc Bourlière, Philippe Mathurin, Jean‐Frédéric Blanc, Armand Abergel, Lawrence Serfaty, Ariane Mallat, Jean‐Didier Grangé, Pierre Attali, Yannick Bacq, Claire Wartelle, Thông Dao, Yves Benhamou, Christophe Pilette, Christine Silvain, Christos Christidis, Dominique Capron, Brigitte Bernard‐Chabert, David Zucman, Vincent Di Martino, Jean‐Claude Trinchet, Pierre Nahon, Françoise Roudot‐Thoraval
Journal: Hepatology (2016)

The aim of this work was to develop an individualized score for predicting hepatocellular carcinoma (HCC) in patients with hepatitis C (HCV)‐compensated cirrhosis. Among 1,323 patients with HCV cirrhosis enrolled in the French prospective ANRS CO12 CirVir cohort, 720 and 360 were randomly assigned to training and validation sets, respectively. Cox's multivariate model was used to predict HCC, after which a nomogram was computed to assess individualized risk. During follow‐up (median, 51.0 months), 103 and 39 patients developed HCC in the training and validation sets, respectively. Five variables were independently associated with occurrence of HCC: age &gt; 50 years (hazard ratio [HR], 1.94; 95% confidence interval [CI], 1.16; 3.25; P = 0.012); past excessive alcohol intake (HR, 1.55; 95% CI, 1.02; 2.36; P = 0.041); low platelet count (&lt;100 Giga/mm 3 : HR, 2.70; 95% CI, 1.62; 4.51; P &lt; 0.001; [100; 150] Giga/mm 3 : HR, 1.87; 95% CI, 1.10; 3.18; P = 0.021); gamma‐glutamyl transpeptidase above the upper limit of normal (HR, 1.96; 95% CI, 1.11; 3.47; P = 0.021); and absence of a sustained virological response during follow‐up (HR, 3.02; 95% CI, 1.67; 5.48; P &lt; 0.001). An 11‐point risk score was derived from the training cohort and validated in the validation set. Based on this score, the population was stratified into three groups, in which HCC development gradually increased, from 0% to 30.1% at 5 years for patients with the lowest (≤3) and highest (≥8) scores ( P &lt; 0.001). Using this score, a nomogram was built enabling individualized prediction of HCC occurrence at 1, 3, and 5 years. Conclusion : This HCC score can accurately predict HCC at an individual level in French patients with HCV cirrhosis. (H epatology 2016;64:1136‐1147)
Accumulating nanoparticles by EPR: A route of no return
Authors: Romeo Ngoune, Annette Peters, Dominik von Elverfeldt, Karl Winkler, Gerhard Pütz
Journal: Journal of Controlled Release (2016)

Nanoparticle-based drug delivery to ease anticancer therapy relies primarily on the enhanced permeability and retention effect (EPR). The leaky vascular structure in tumors allows extravasation of nanoparticles, often termed passive targeting. Long term retention of nanoparticles is attributed to the lack of lymphatic drainage, and unidirectional extravasation has been implied. Fluorescent liposomes with a plasma half-life of 29h were injected into tumor-bearing rats, and biodistribution in tumor, skin, paws and ears was monitored via in vivo fluorescence measurements. To calculate tissue accumulation, an algorithm was developed to subtract the blood signal from the total fluorescence recorded. Accumulation in tumor tissue was much higher than that in other tissues monitored, initially exhibiting very rapid accumulation followed by a long plateau phase with little change. Discontinuous plasmapheresis was established that was as effective as highly sophisticated clinical plasmapheresis. We observed no difference in the tumor tissue's accumulation when plasmapheresis was performed 22h after liposome injection. In contrast, plasmapheresis led to a significant inhibition of further accumulation in other tissues. When the liposomes' blood concentration was rapidly lowered, we detected no drop in tumor fluorescence. Thus extravasation via EPR is most likely a route of no return. These data support the emerging view of a more dynamic model of EPR, where gaps or entire vessels may open and close over time, or accumulated liposomes become entangled within the pores, hampering further accumulation.
Selective internal radiation therapy (SIRT) using Y90 resin microspheres as consolidation treatment for liver metastases from colorectal cancer (LCRC).
Authors: Ana Chopitea, Javier Rodriguez, Macarena Rodriguez, Mercedes Iñarrairaegui, Jose I Bilbao, Alberto Benito, Carlos Garzón, Fernando Rotellar, Fernando Pardo, Bruno Sangro
Journal: Journal of Clinical Oncology (2015)

e14662 Background: SIRT has proved valuable for the treatment of LCRC in combination with chemotherapy (CT) or as a rescue treatment but it has not been explored as a consolidation treatment. Methods: We have retrospectively analyzed all pts (2004-13) with CRC and liver-predominant disease that received SIRT as consolidation treatment (pts on partial response or stable disease) after 1st line CT (C1L) or 2nd to 4th line CT (CxL). Time to progression (TTP), time to liver progression (TTLP) and overall survival (OS) were calculated from the day of SIRT and usual tests were used for statistical analysis. Results: 64 pts were analyzed (C1L: 48.4%; CxL: 51.6%). 63% had a partial response (PR) to pre-SIRT CT and 33% had a small burden of extrahepatic disease. 86% and 13% of patients were exposed to oxaliplatin and irinotecan in 1st line, respectively, while 36% were exposed to Bevacizumab (Bev) (13% in 1st line). Median activity of Y90 administered was 1.2 GBq. Among 58 evaluable pts, PR and stable disease were observed in 28% and 43%, respectively. Liver resection was performed in 3 pts that responded to SIRT in the C1L group (9.3%). With a median follow-up of 11.1 mo (IQR 5.7-20.7), TTP was 4.1 mo (95%CI 3.2-4.9) and TTLP was 5.2 (95%CI 3.1-7.2). We found a significant difference in TTP between C1L and CxL (4.9 vs. 3.1 mo, p = 0.024) but not in TTLP (7.9 vs. 4.3; p = 0.21). PR to pre-SIRT CT was a predictive factor for TTP in multivariate analysis (HR: 0.5; p = 0.04) while absence of exposure to Bev was also a predictive factor for TTLP (HR: 0.33; p = 0.02). Median OS was 15.3 mo (C1L: 18.1 mo (95%CI 15-21.1); CxL: 7.4 mo (95%CI 3.2-11.6)). OS was significantly better in the CxL group than in 21 pts receiving SIRT as rescue therapy beyond 2nd line CT (7.5 vs. 4.5 mo). Prognostic factors for OS in multivariate analysis were a GGTP level before SIRT (HR: 1.005; p = 0.04), and exposure to Bev (HR: 2.92; p = 0.06). Conclusions: When used as consolidation treatment after first or further lines CT, SIRT may reduce the rate of liver progression and improve survival. Clinical trials in this setting are warranted and the negative effect of Bev on outcomes should be studied further.
British scientists seek guarantees for researchers bidding for EU funding
Authors: Adrian O’Dowd
Journal: BMJ (2016)

Leading scientists have called on the government to underwrite any funding that UK based researchers are currently applying for from the EU.

Venki Ramakrishnan, president of the Royal Society, has called for the UK government to ensure that EU research funding is guaranteed in case this financial support ends when Britain leaves the EU, following June’s referendum that voted for a “Brexit” from Europe.

During an interview with the BBC’s Newsnight programme screened on 26 July, he said, “I am worried that if we are perceived as an inward looking country that’s not welcoming to the outside world—and that is the impression that some people have got—then I think it’s bad.

“We’re in a global market for talent and we need to attract …
Efficacy and Safety of Eltrombopag in Persistent and Newly Diagnosed ITP
Authors: Tomás José González-López, Blanca Sánchez-González, Cristina Pascual, María Teresa Alvarez-Roman, Gloria Pérez-Rus, Fernando Fernández-Fuentes, Silvia Bernat, José Angel Hernández-Rivas, Montserrat Cortés, Marcio Andrade, Pavel Olivera, Isidro Jarque, Susana Pérez-Crespo, Marta Gómez-Nuñez, Angeles Fernández-Rodríguez, Violeta Martínez-Robles, Carmen Fernández-Miñano, Miguel Angel Fuertes-Palacio, Abelardo Bárez, Rosa Fisac, Carlos Aguilar, María Jesús Peñarrubia, Erik de Cabo, Eva Mingot, Raquel Ranedo-Zaldo, Esther Arrieta-Cerdán, Miguel A. Sanz, Javier García-Frade, José Ramón González-Porras
Journal: Blood (2015)
A phase 1/2 study of pomalidomide (POM), dexamethasone (DEX), and pegylated liposomal doxorubicin (PLD) for patients with relapsed/refractory multiple myeloma (RRMM).
Authors: James R. Berenson, Leonard M. Klein, Peter J. Rosen, Thomas B. S. Woliver, Shahrooz Eshaghian, Youram Nassir, Regina A. Swift, Robert A. Vescio
Journal: Journal of Clinical Oncology (2014)

e19586^ Background: The POM-DEX combination is an effective treatment for RRMM patients (pts), even those refractory to lenalidomide (LEN). We investigated the combination of POM-DEX-PLD using a modified dose and schedule (28-days) for RRMM pts. Methods: Phase 1 (Ph1) pts had progressive MM at study entry and received at least one prior regimen. Ph2 pts were refractory to LEN (progressive disease (PD) while receiving LEN or relapsed within 8 weeks of last dose). During Ph1, the maximum tolerated dose (MTD) of POM was established at 4 mg. POM was administered orally on days 1-21 of a 28-day cycle, while DEX (40 mg) and PLD (5 mg/m2) were infused on days 1, 4, 8, and 11. Ph2 enrollment began at 4mg; however, 58.8% pts developed ≥ Gr3 neutropenia, and the dose of POM was reduced to 3 mg for subsequently enrolled pts. Results: As of January 10th 2014, 39 pts were registered, 28 in Ph2. Pts had received a median of 5 prior treatments (range, 1-18). Thirty-six patients have discontinued treatment. Median number of cycles is 4 (range, 1-8) and median follow-up time is 5.2 months (range, 0.2-15.9). Ph2 pts have completed 3.5 cycles (range, 1-8) with a follow-up time of 4.0 months (range, 0.2-8.8). Overall response (ORR) and clinical benefit rates (CBR) were 35.3%and 50%, respectively (N=34). Nine pts (26.4%) showed stable disease (SD) while 8 (23.5%) pts exhibited PD. For LEN refractory pts (Ph2; N=25), ORR and CBR were 28% and 48%, respectively, with 6 pts (25%) showing SD and 7 pts (29.2%) showing PD.ORR and CBR for all pts receiving POM at 3 mg (N=15) were 33.3% and 53.3%, respectively. Common ≥ Gr3 adverse events were neutropenia (18 pts; 46.2%), lymphopenia (8 pts; 20.5%), hyponatremia (5 pts; 13%), anemia (2 pts; 5.1%), and thrombocytopenia (2 pts; 5.1%). One pt died of Gr5 sepsis. Conclusions: The POM-DEX-PLD combination administered in 28-day cycles shows efficacy for pts with progressive RRMM refractory to LEN. Clinical trial information: NCT01541332.
Sorafenib treatment efficacy and KRAS biomarker status in the Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial.
Authors: R. S. Herbst, G. R. Blumenschein, E. S. Kim, J. Lee, A. S. Tsao, C. M. Alden, S. Liu, D. J. Stewart, I. I. Wistuba, W. K. Hong
Journal: Journal of Clinical Oncology (2010)

7609 Background: BATTLE is a phase II study to prospectively use biomarkers (BM) to guide treatment selection in patients (PTS) with advanced non-small cell lung cancer (NSCLC). This report details a subset analysis of the 8-week disease control rate (DCR) of PTS treated with sorafenib (S) relative to their BM status. Methods: In this phase II, multi-arm study, PTS with pretreated NSCLC, ECOG PS 0-2, consented to fresh core needle biopsies to test, in a research lab, 11 biomarkers related to 4 molecular pathways in NSCLC (EGFR, KRAS, and BRAF gene mutation [PCR-based sequencing], EGFR and Cyclin D1 copy number [FISH], and 6 proteins via IHC [VEGF/R and RXR receptors/Cyclin D1]). PTS were randomized, based on eligibility and BM grouping, into 1 of 4 treatments (erlotinib [E], sorafenib, vandetinab and erlotinib plus bexarotene). PTS randomized to the S arm received S 400 mg orally twice daily until tumor progression or an unacceptable toxicity. Tumor evaluations were performed at baseline and every 8 weeks. The primary objective was to assess DCR. Results: 105 PTS were randomized to receive S: 82% Caucasian, 51% male, 68% adenocarcinoma, 13% squamous cell carcinoma, ECOG status was 0-1 in 89% of PTS. 31 PTS had dose reduction/discontinuation of S. The most common reasons were hand-foot syndrome (n = 6), hemoptysis (n = 5), fatigue, and rash (n = 2 each). DCR for PTS treated with S was 58% (57 in 98 pts with outcome). No responses were observed. In PTS with the presence of a KRAS mutation, DCR was 61% (11/18), in contrast to 31% (4/13) in KRAS-mutated PTS treated with regimens with E. In PTS with an EGFR mutation, DCR was significantly lower (23%, 3/13) when compared to those PTS without the mutation (64%, n = 43/67) (p = 0.012). PTS with EGFR high-polysomy had a lower DC than those who did not (27%, 3/11; 62%, 42/68) (p = 0.048). Conclusions: DCR was improved in PTS treated with S who had KRAS mutations when compared to those who had EGFR mutations or copy number gain. This result suggests that PTS who have KRAS mutations may derive benefit from treatment with S, while those who have EGFR mutation/copy number gain may do worse. Supported by DoD grant W81XWH-6-1-0303. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Align 2 Action, Inc, AstraZeneca, Bayer, Bridger Capital, LLC, Gascon Associates, Genentech, Liquidia Technologies, Medacorp, Nectar Therapeutics, OSI, Trinity Partners, LLC AstraZeneca, Bayer, Genentech, OSI
Regorafenib dose optimization study (ReDOS): A phase II randomized study of lower starting dose regorafenib compared to standard dose regorafenib in patients with refractory metastatic colorectal cancer (mCRC).
Authors: Tanios S. Bekaii-Saab, Fang-Shu Ou, Kristen Keon Ciombor, Mohamed I. Farhat, Jeffrey J. Kirshner, James A. Knost, Daniel M. Anderson, Gamini S. Soori, Patrick McKay Boland, Donald B. Wender, Rodwige J. Desnoyers, Daniel J. Sargent, Axel Grothey
Journal: Journal of Clinical Oncology (2016)

TPS3630 Background: Regorafenib is an oral multikinase inhibitor that blocks several protein kinases involved in angiogenesis and oncogenesis. It was recently shown to provide a survival benefit in refractory metastatic colorectal cancer. Despite the observed benefits, toxicities such as palmar-plantar erythrodysesthesia syndrome (PPES- which occurs early in the first 1-2 weeks) and fatigue have limited its use. Multiple practices across the US adopted various dosing or interval scheduling despite the absence of supportive data. Methods: ReDOS (NCT02368886) is an Academic and Community Cancer Research United (ACCRU) network-led randomized phase II study of lower dose regorafenib compared to standard dose regorafenib in patients with refractory mCRC. Patients are randomized 1:1 to receive an escalating dose (Arm A: 80 mg daily Week 1, 120 mg daily Week 2,160 mg daily week 3 then 1 week off followed by Cycle 2) vs. standard dose (Arm B: 160 mg daily for 21 days/then 1 week off). Within each treatment arm, patients are further randomized to receive either pre-emptive or reactive Clobetasol for prevention/treatment of PPES (sub-arms A1, A2, B1 and B2). Eligibility criteria include histologically confirmed mCRC, ECOG ≤ 1, acceptable organ function, and patients must have failed all standard regimens including appropriate biologics. The primary endpoint is the 8 week planned continuation rate defined as the proportion of patients in each arm who complete 2 cycles of treatment and who intend to initiate cycle 3 if no progression is noted. Assuming an 8-week planned continuation rate of 75% in the control group (B), and desiring an improvement to 90% in the experimental group (A), a one-sided test with alpha = 0.20 and power of 80% will require a sample size of 110 patients enrolled to both regorafenib arms (A and B) with 28 patients randomized to treatment sub-arm (A1, A2, B1, B2). An additional 10 patients will be enrolled to account for dropout, cancellations, ineligibles, etc, to give a total sample size of 120 patients. The total study duration is expected to be approximately 2 years. Clinical trial information: NCT02368886.