US Intergroup Trial of Response-Adapted Therapy for Stage III to IV Hodgkin Lymphoma Using Early Interim Fluorodeoxyglucose–Positron Emission Tomography Imaging: Southwest Oncology Group S0816

PubMed Central

Li, Hongli; Schöder, Heiko; Straus, David J.; Moskowitz, Craig H.; LeBlanc, Michael; Rimsza, Lisa M.; Bartlett, Nancy L.; Evens, Andrew M.; Mittra, Erik S.; LaCasce, Ann S.; Sweetenham, John W.; Barr, Paul M.; Fanale, Michelle A.; Knopp, Michael V.; Noy, Ariela; Hsi, Eric D.; Cook, James R.; Lechowicz, Mary Jo; Gascoyne, Randy D.; Leonard, John P.; Kahl, Brad S.; Cheson, Bruce D.; Fisher, Richard I.; Friedberg, Jonathan W.

2016-01-01

Purpose Four US National Clinical Trials Network components (Southwest Oncology Group, Cancer and Leukemia Group B/Alliance, Eastern Cooperative Oncology Group, and the AIDS Malignancy Consortium) conducted a phase II Intergroup clinical trial that used early interim fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to determine the utility of response-adapted therapy for stage III to IV classic Hodgkin lymphoma. Patients and Methods The Southwest Oncology Group S0816 (Fludeoxyglucose F 18-PET/CT Imaging and Combination Chemotherapy With or Without Additional Chemotherapy and G-CSF in Treating Patients With Stage III or Stage IV Hodgkin Lymphoma) trial enrolled 358 HIV-negative patients between July 1, 2009, and December 2, 2012. A PET scan was performed after two initial cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and was labeled PET2. PET2-negative patients (Deauville score 1 to 3) received an additional four cycles of ABVD, whereas PET2-positive patients (Deauville score 4 to 5) were switched to escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) for six cycles. Among 336 eligible and evaluable patients, the median age was 32 years (range, 18 to 60 years), with 52% stage III, 48% stage IV, 49% International Prognostic Score 0 to 2, and 51% score 3 to 7. Results Three hundred thirty-six of the enrolled patients were evaluable. Central review of the interim PET2 scan was performed in 331 evaluable patients, with 271 (82%) PET2-negative and 60 (18%) PET2-positive. Of 60 eligible PET2-positive patients, 49 switched to eBEACOPP as planned and 11 declined. With a median follow-up of 39.7 months, the Kaplan-Meier estimate for 2-year overall survival was 98% (95% CI, 95% to 99%), and the 2-year estimate for progression-free survival (PFS) was 79% (95% CI, 74% to 83%). The 2-year estimate for PFS in the subset of patients who were PET2-positive after two cycles of ABVD was 64% (95% CI, 50% to 75%). Both nonhematologic and hematologic toxicities were greater in the eBEACOPP arm than in the continued ABVD arm. Conclusion Response-adapted therapy based on interim PET imaging after two cycles of ABVD seems promising with a 2-year PFS of 64% for PET2-positive patients, which is much higher than the expected 2-year PFS of 15% to 30%. PMID:27069074

Volcaniclastic stratigraphy of Gede volcano in West Java

NASA Astrophysics Data System (ADS)

Belousov, A.; Belousova, M.; Zaennudin, A.; Prambada, O.

2012-12-01

Gede volcano (2958 m a.s.l.) and the adjacent Pangrango volcano (3019 m a.s.l.) form large (base diameter 35 km) volcanic massif 60 km south of Jakarta. While Pangrango has no recorded eruptions, Gede is one of the most active volcanoes in Indonesia: eruptions were reported 26 times starting from 1747 (Petroeschevsky 1943; van Bemmelen 1949). Historic eruptions were mildly explosive (Vulcanian) with at least one lava flow. Modern activity of the volcano includes persistent solfataric activity in the summit crater and periodic seismic swarms - in 1990, 1991, 1992, 1995, 1996, 1997, 2000, 2010, and 2012 (CVGHM). Lands around the Gede-Pangrango massif are densely populated with villages up to 1500-2000 m a.s.l. Higher, the volcano is covered by rain forest of the Gede-Pangrango Natural Park, which is visited every day by numerous tourists who camp in the summit area. We report the results of the detailed reinvestigation of volcaniclastic stratigraphy of Gede volcano. This work has allowed us to obtain 24 new radiocarbon dates for the area. As a result the timing and character of activity of Gede in Holocene has been revealed. The edifice of Gede volcano consists of main stratocone (Gumuruh) with 1.8 km-wide summit caldera; intra-caldera lava cone (Gede proper) with a 900 m wide summit crater, having 2 breaches toward N-NE; and intra-crater infill (lava dome/flow capped with 3 small craters surrounded by pyroclastic aprons). The Gumuruh edifice, composed mostly of lava flows, comprises more than 90% of the total volume of the volcano. Deep weathering of rocks and thick (2-4 m) red laterite soil covering Gumuruh indicates its very old age. Attempts to get 14C dates in 4 different locations of Gumuruh (including a large debris avalanche deposit on its SE foot) provided ages older than 45,000 years - beyond the limit for 14C dating. Outside the summit caldera, notable volumes of fresh, 14C datable volcaniclastic deposits were found only in the NNE sector of the volcano where they form a fan below the breached summit crater. The fan is composed of pyroclastic flows (PFs) and lahars of Holocene age that were deposited in 4 major stages: ~ 10 000 BP - voluminous PF of black scoria; ~ 4000 BP - two PFs of mingled grey/black scoria; ~ 1200 BP - multiple voluminous PFs strongly enriched by accidental material; ~ 1000 BP - a small scale debris avalanche (breaching of the crater wall) followed by small scale PFs of black scoria. The intra-crater lava dome/flow was erupted in 1840 (Petroeschevsky, 1943). Three small craters on the top of the lava dome were formed by multiple post-1840 small-scale phreatomagmatic eruptions. Ejected pyroclasts are lithic hydrothermally altered material containing a few breadcrust bombs. The Holocene eruptive history of Gede indicates that the volcano can produce moderately strong (VEI 3-4) explosive eruptions and send PFs and lahars onto the NE foot of the volcano.

Aerodynamic and Acoustic Effects of Abrupt Frequency Changes in Excised Larynges

ERIC Educational Resources Information Center

Alipour, Fariborz; Finnegan, Eileen M.; Scherer, Ronald C.

2009-01-01

Purpose: To determine the aerodynamic and acoustic effects due to a sudden change from chest to falsetto register or vice versa. It was hypothesized that the continuous change in subglottal pressure and flow rate alone (pressure-flow sweep [PFS]) can trigger a mode change in the canine larynx. Method: Ten canine larynges were each mounted over a…

Switch Box For Controlling Flows Of Four Gases

NASA Technical Reports Server (NTRS)

Wishard, James R.; Lamb, James L.

1995-01-01

Switch box designed for use in simultaneously controlling flows of as many as four out of total of six available gases into semiconductor-processing chamber. Contains switches, relays, logic circuitry, display devices, and other circuitry for connecting each of as many as four gas controllers to any one of as many as six available mass-flow controllers. Front panel of switch box apprises technician of statuses of flows of various gases.

Spark gap switch with spiral gas flow

DOEpatents

Brucker, John P.

1989-01-01

A spark gap switch having a contaminate removal system using an injected gas. An annular plate concentric with an electrode of the switch defines flow paths for the injected gas which form a strong spiral flow of the gas in the housing which is effective to remove contaminates from the switch surfaces. The gas along with the contaminates is exhausted from the housing through one of the ends of the switch.

A High Pressure Flowing Oil Switch For Gigawatt, Repetitive Applications

DTIC Science & Technology

2005-06-01

for testing the high pressure switch concept under repetitive pulse conditions is a 4.8 Ω, 70 ns water pulse forming line (PFL). The water PFL is...Cox Instruments. A pair of Hedland variable area flow sensors monitored relative flow rates in the two oil lines that fed the high pressure switch . High... pressure switch was tested under both single shot and repetitive conditions over a range of pressures, flow rates and temperatures. The primary

Comprehensive theory of the Deans' switch as a variable flow splitter: fluid mechanics, mass balance, and system behavior.

PubMed

Boeker, Peter; Leppert, Jan; Mysliwietz, Bodo; Lammers, Peter Schulze

2013-10-01

The Deans' switch is an effluent switching device based on controlling flows of carrier gas instead of mechanical valves in the analytical flow path. This technique offers high inertness and a wear-free operation. Recently new monolithic microfluidic devices have become available. In these devices the whole flow system is integrated into a small metal device with low thermal mass and leak-tight connections. In contrast to a mechanical valve-based system, a flow-controlled system is more difficult to calculate. Usually the Deans' switch is used to switch one inlet to one of two outlets, by means of two auxiliary flows. However, the Deans' switch can also be used to deliver the GC effluent with a specific split ratio to both outlets. The calculation of the split ratio of the inlet flow to the two outlets is challenging because of the asymmetries of the flow resistances. This is especially the case, if one of the outlets is a vacuum device, such as a mass spectrometer, and the other an atmospheric detector, e.g. a flame ionization detector (FID) or an olfactory (sniffing) port. The capillary flows in gas chromatography are calculated with the Hagen-Poiseuille equation of the laminar, isothermal and compressible flow in circular tubes. The flow resistances in the new microfluidic devices have to be calculated with the corresponding equation for rectangular cross-section microchannels. The Hagen-Poiseuille equation underestimates the flow to a vacuum outlet. A corrected equation originating from the theory of rarefied flows is presented. The calculation of pressures and flows of a Deans' switch based chromatographic system is done by the solution of mass balances. A specific challenge is the consideration of the antidiffusion resistor between the two auxiliary gas lines of the Deans' switch. A full solution for the calculation of the Deans' switch including this restrictor is presented. Results from validation measurements are in good accordance with the developed theories. A spreadsheet-based flow calculator is part of the Supporting Information.

Nitrate sinks in perennial vegetation filter strips in the toeslopes of agricultural watersheds

USDA-ARS?s Scientific Manuscript database

Integration of perennial filter strips (PFS) into the toeslope of agricultural watersheds may decrease downstream NO3 losses, especially if subsurface flow interacts with the rooting zone of the perennial vegetation. However, the long-term effectiveness of NO3 removal depends on the relative importa...

On/off switching of capillary vessel flow controls mitochondrial and glycolysis pathways for energy production.

PubMed

Abo, Toru; Watanabe, Mayumi; Tomiyama, Chikako; Kanda, Yasuhiro

2014-07-01

Capillary vessel flow in the base of the fingernail can be observed by microscopy. This flow is switched off under some conditions, such as coldness, surprise, and anger and is switched on again under other conditions, such as warming, relaxation, and mild exercise. In other words, capillary vessels perform two functions: switching flow on and off. It is speculated that the switch-off function is necessary to direct energy production to the glycolysis pathway, while the switch-on function is necessary for the mitochondrial pathway. This is because glycolysis takes place under anaerobic conditions, while oxidative phosphorylation in the mitochondria proceeds under aerobic conditions in the body. To switch off circulation, the negative electric charges on the surface of erythrocytes and the capillary wall may be decreased by stimulation of the sympathetic nerves and secretion of steroid hormones. Negative charge usually acts as repulsive force between erythrocytes and between erythrocytes and the capillary wall. By decreasing the negative charge, erythrocytes can aggregate and also adhere to the capillary wall. These behaviors may be related to the capillary flow switch-off function. Here, it is emphasized that the capillary vessels possess not only a switch-on function but also a switch-off function for circulation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Surrogacy of progression free survival for overall survival in metastatic breast cancer studies: Meta-analyses of published studies.

PubMed

Kundu, Madan G; Acharyya, Suddhasatta

2017-02-01

PFS is often used as a surrogate endpoint for OS in metastatic breast cancer studies. We have evaluated the association of treatment effect on PFS with significant HR OS (and how this association is affected by other factors) in published prospective metastatic breast cancer studies. A systematic literature search in PubMed identified prospective metastatic breast cancer studies. Treatment effects on PFS were determined using hazard ratio (HR PFS ), increase in median PFS (ΔMED PFS ) and % increase in median PFS (%ΔMED PFS ). Diagnostic accuracy of PFS measures (HR PFS , ΔMED PFS and %ΔMED PFS ) in predicting significant HR OS was assessed using receiver operating characteristic (ROC) curves and classification tree approach (CART). Seventy-four cases (i.e., treatment to control comparisons) from 65 individual publications were identified for the analyses. Of these, 16 cases reported significant treatment effect on HR OS at 5% level of significance. Median number of deaths reported in these cases were 153. Area under the ROC curve (AUC) for diagnostic measures as HR PFS , ΔMED PFS and %ΔMED PFS were 0.69, 0.70 and 0.75, respectively. Classification tree results identified %ΔMED PFS and number of deaths as diagnostic measure for significant HR OS . Only 7.9% (3/39) cases with ΔMED PFS shorter than 48.27% reported significant HR OS . There were 7 cases with ΔMED PFS of 48.27% or more and number of deaths reported as 227 or more - of these 5 cases reported significant HR OS . %ΔMED PFS was found to be a better diagnostic measure for predicting significant HR OS . Our analysis results also suggest that consideration of total number of deaths may further improve its diagnostic performance. Based on our study results, the studies with 50% improvement in median PFS are more likely to produce significant HR OS if the total number of OS events at the time of analysis is 227 or more. Copyright © 2016 Elsevier Inc. All rights reserved.

Predicting changes in flow category in patients with severe aortic stenosis and preserved left ventricular ejection fraction on medical therapy.

PubMed

Ngiam, Jinghao Nicholas; Kuntjoro, Ivandito; Tan, Benjamin Y Q; Sim, Hui-Wen; Kong, William K F; Yeo, Tiong-Cheng; Poh, Kian-Keong

2017-11-01

Controversy surrounds the prognosis and management of patients with paradoxical low-flow severe aortic stenosis (AS) with preserved left ventricular ejection fraction (LVEF). It was not certain if patients in a particular flow category remained in the same category as disease progressed. We investigated whether there were switches in categories and if so, their predictors. Consecutive subjects (n = 203) with isolated severe AS and paired echocardiography (>180 days apart) were studied. They were divided into 4 groups, based on their flow categories and if they progressed on subsequent echocardiography to switch or remain in the same flow category. Univariate analyses of clinical and echocardiographic parameters identified predictors of these changes in flow category. One hundred eighteen were normal flow (SVI ≥ 35 mL/m 2 ), while 85 were low flow on index echocardiography. In the patients with normal flow, 33% switched to low flow. This was associated with higher valvuloarterial impedance (Zva, P < .001) and lower systemic arterial compliance (SAC, P < .001) compared to index echocardiography, and predicted by higher initial Zva (optimized cutoff >4.77 mm Hg/mL/m 2 , AUC = 0.81 [95% CI:0.75-0.87, P < .001]). In patients with low flow, 25% switched to normal flow, which was associated with lower Zva and higher SAC and the switch was predicted by a higher initial mean transaortic pressure gradient. A significant number of patients switched flow categories in severe AS with preserved LVEF on subsequent echocardiography. Changes in flow were reflected by respective changes in Zva and SAC. Identifying echocardiographic predictors of a switch in category may guide prognostication and management of such patients. © 2017, Wiley Periodicals, Inc.

Saccharomyces cerevisiae-Secreted Fusion Proteins Pfs25 and Pfs28 Elicit Potent Plasmodium falciparum Transmission-Blocking Antibodies in Mice

PubMed Central

Gozar, Mary Margaret G.; Price, Virginia L.; Kaslow, David C.

1998-01-01

Transmission-blocking vaccines based on sexual-stage surface antigens of Plasmodium falciparum may assist in the control of this lethal form of human malaria. Two vaccine candidates, Pfs25 and Pfs28, were produced as single recombinant fusion proteins. The 39-kDa chimeric proteins, having a C-terminal His6 tag, were secreted by Saccharomyces cerevisiae, using the prepro-α-factor leader sequence. Pfs25-28 fusion proteins were significantly more potent than either Pfs25 or Pfs28 alone in eliciting antibodies in mice that blocked oocyst development in Anopheles freeborni mosquitoes: complete inhibition of oocyst development in the mosquito midgut was achieved with fewer vaccinations, at a lower dose, and for a longer duration than with either Pfs25 or Pfs28 alone. Increased antigen-specific immunoglobulin G titers and highly significant lymphoproliferative stimulation by Pfs28-containing antigens suggest the presence of an immunodominant helper T-cell epitope in the Pfs28 portion of the fusion proteins. This epitope may be responsible for the enhanced humoral response to both Pfs25 and Pfs28 antigens. Protein production of the fusion protein was improved 12-fold by converting Pfs28 codons to yeast-preferred codons (TBV28), using a modified ADH2 promoter and incorporating a (Glu-Ala)2 repeat after the Kex2 cleavage site. PMID:9423839

Non-volatile, solid state bistable electrical switch

NASA Technical Reports Server (NTRS)

Williams, Roger M. (Inventor)

1994-01-01

A bistable switching element is made of a material whose electrical resistance reversibly decreases in response to intercalation by positive ions. Flow of positive ions between the bistable switching element and a positive ion source is controlled by means of an electrical potential applied across a thermal switching element. The material of the thermal switching element generates heat in response to electrical current flow therethrough, which in turn causes the material to undergo a thermal phase transition from a high electrical resistance state to a low electrical resistance state as the temperature increases above a predetermined value. Application of the electrical potential in one direction renders the thermal switching element conductive to pass electron current out of the ion source. This causes positive ions to flow from the source into the bistable switching element and intercalate the same to produce a non-volatile, low resistance logic state. Application of the electrical potential in the opposite direction causes reverse current flow which de-intercalates the bistable logic switching element and produces a high resistance logic state.

Endotypes of pollen-food syndrome in children with seasonal allergic rhinoconjunctivitis: a molecular classification.

PubMed

Mastrorilli, C; Tripodi, S; Caffarelli, C; Perna, S; Di Rienzo-Businco, A; Sfika, I; Asero, R; Dondi, A; Bianchi, A; Povesi Dascola, C; Ricci, G; Cipriani, F; Maiello, N; Miraglia Del Giudice, M; Frediani, T; Frediani, S; Macrì, F; Pistoletti, C; Dello Iacono, I; Patria, M F; Varin, E; Peroni, D; Comberiati, P; Chini, L; Moschese, V; Lucarelli, S; Bernardini, R; Pingitore, G; Pelosi, U; Olcese, R; Moretti, M; Cirisano, A; Faggian, D; Travaglini, A; Plebani, M; Verga, M C; Calvani, M; Giordani, P; Matricardi, P M

2016-08-01

Pollen-food syndrome (PFS) is heterogeneous with regard to triggers, severity, natural history, comorbidities, and response to treatment. Our study aimed to classify different endotypes of PFS based on IgE sensitization to panallergens. We examined 1271 Italian children (age 4-18 years) with seasonal allergic rhinoconjunctivitis (SAR). Foods triggering PFS were acquired by questionnaire. Skin prick tests were performed with commercial pollen extracts. IgE to panallergens Phl p 12 (profilin), Bet v 1 (PR-10), and Pru p 3 (nsLTP) were tested by ImmunoCAP FEIA. An unsupervised hierarchical agglomerative clustering method was applied within PFS population. PFS was observed in 300/1271 children (24%). Cluster analysis identified five PFS endotypes linked to panallergen IgE sensitization: (i) cosensitization to ≥2 panallergens ('multi-panallergen PFS'); (ii-iv) sensitization to either profilin, or nsLTP, or PR-10 ('mono-panallergen PFS'); (v) no sensitization to panallergens ('no-panallergen PFS'). These endotypes showed peculiar characteristics: (i) 'multi-panallergen PFS': severe disease with frequent allergic comorbidities and multiple offending foods; (ii) 'profilin PFS': oral allergy syndrome (OAS) triggered by Cucurbitaceae; (iii) 'LTP PFS': living in Southern Italy, OAS triggered by hazelnut and peanut; (iv) 'PR-10 PFS': OAS triggered by Rosaceae; and (v) 'no-panallergen PFS': mild disease and OAS triggered by kiwifruit. In a Mediterranean country characterized by multiple pollen exposures, PFS is a complex and frequent complication of childhood SAR, with five distinct endotypes marked by peculiar profiles of IgE sensitization to panallergens. Prospective studies in cohorts of patients with PFS are now required to test whether this novel classification may be useful for diagnostic and therapeutic purposes in the clinical practice. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

High pressure flow-rate switch

NASA Technical Reports Server (NTRS)

Gale, G. P.

1970-01-01

Flow-rate switch adjusts easily over a wide switching range and operates uniformly over many cycles. It adapts easily to control of various fluids and has the possibility of introducing multi-point switching. Novel design features include the tapered spool, balanced porting, capillary-bypass lubrication, and capillary-restriction damping.

High-speed pulsed mixing in a short distance with high-frequency switching of pumping from three inlets

NASA Astrophysics Data System (ADS)

Sugano, K.; Nakata, A.; Tsuchiya, T.; Tabata, O.

2015-08-01

In this study, we propose a mixing method using alternate pulsed flows from three inlets with flow direction control. In conventional pulsed mixing, a residual flow near the sidewalls inhibits the rapid mixing of two solutions at high switching frequency. In this study, we addressed this issue in order to perform rapid mixing in a short distance with a low Reynolds number. We fabricated a microfluidic mixing device consisting of a cross-shaped mixing channel with three inlet microchannels and three valveless micropumps. In conventional T-shaped or Y-shaped mixing channels, a residual flow is observed because of the incomplete switching of solutions. The three inlet configuration enabled us to split the residual flow at a switching frequency of pumping of up to 200 Hz, thus resulting in rapid mixing. Furthermore, by controlling the flow direction at the confluent area using the reverse flow of the micropump, the mixing speed was dramatically increased because of the complete switching of the two solutions. As a result, we achieved the mixing time of 3.6 ms and the mixing length of 20.7 µm, which were necessary to achieve a 90% mixing ratio at a high micropump switching frequency of 400 Hz and reverse flow ratio of 1/4.

Immunogenicity and malaria transmission reducing potency of Pfs48/45 and Pfs25 encoded by DNA vaccines administered by intramuscular electroporation.

PubMed

Datta, Dibyadyuti; Bansal, Geetha P; Gerloff, Dietlind L; Ellefsen, Barry; Hannaman, Drew; Kumar, Nirbhay

2017-01-05

Pfs48/45 and Pfs25 are leading candidates for the development of Plasmodium falciparum transmission blocking vaccines (TBV). Expression of Pfs48/45 in the erythrocytic sexual stages and presentation to the immune system during infection in the human host also makes it ideal for natural boosting. However, it has been challenging to produce a fully folded, functionally active Pfs48/45, using various protein expression platforms. In this study, we demonstrate that full-length Pfs48/45 encoded by DNA plasmids is able to induce significant transmission reducing immune responses. DNA plasmids encoding Pfs48/45 based on native (WT), codon optimized (SYN), or codon optimized and mutated (MUT1 and MUT2), to prevent any asparagine (N)-linked glycosylation were compared with or without intramuscular electroporation (EP). EP significantly enhanced antibody titers and transmission blocking activity elicited by immunization with SYN Pfs48/45 DNA vaccine. Mosquito membrane feeding assays also revealed improved functional immunogenicity of SYN Pfs48/45 (N-glycosylation sites intact) as compared to MUT1 or MUT2 Pfs48/45 DNA plasmids (all N-glycosylation sites mutated). Boosting with recombinant Pfs48/45 protein after immunization with each of the different DNA vaccines resulted in significant boosting of antibody response and improved transmission reducing capabilities of all four DNA vaccines. Finally, immunization with a combination of DNA plasmids (SYN Pfs48/45 and SYN Pfs25) also provides support for the possibility of combining antigens targeting different life cycle stages in the parasite during transmission through mosquitoes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dynamic switching enables efficient bacterial colonization in flow.

PubMed

Kannan, Anerudh; Yang, Zhenbin; Kim, Minyoung Kevin; Stone, Howard A; Siryaporn, Albert

2018-05-22

Bacteria colonize environments that contain networks of moving fluids, including digestive pathways, blood vasculature in animals, and the xylem and phloem networks in plants. In these flow networks, bacteria form distinct biofilm structures that have an important role in pathogenesis. The physical mechanisms that determine the spatial organization of bacteria in flow are not understood. Here, we show that the bacterium P. aeruginosa colonizes flow networks using a cyclical process that consists of surface attachment, upstream movement, detachment, movement with the bulk flow, and surface reattachment. This process, which we have termed dynamic switching, distributes bacterial subpopulations upstream and downstream in flow through two phases: movement on surfaces and cellular movement via the bulk. The model equations that describe dynamic switching are identical to those that describe dynamic instability, a process that enables microtubules in eukaryotic cells to search space efficiently to capture chromosomes. Our results show that dynamic switching enables bacteria to explore flow networks efficiently, which maximizes dispersal and colonization and establishes the organizational structure of biofilms. A number of eukaryotic and mammalian cells also exhibit movement in two phases in flow, which suggests that dynamic switching is a modality that enables efficient dispersal for a broad range of cell types.

A pooled analysis of sequential therapies with sorafenib and sunitinib in metastatic renal cell carcinoma.

PubMed

Stenner, Frank; Chastonay, Rahel; Liewen, Heike; Haile, Sarah R; Cathomas, Richard; Rothermundt, Christian; Siciliano, Raffaele D; Stoll, Susanna; Knuth, Alexander; Buchler, Tomas; Porta, Camillo; Renner, Christoph; Samaras, Panagiotis

2012-01-01

To evaluate the optimal sequence for the receptor tyrosine kinase inhibitors (rTKIs) sorafenib and sunitinib in metastatic renal cell cancer. We performed a retrospective analysis of patients who had received sequential therapy with both rTKIs and integrated these results into a pooled analysis of available data from other publications. Differences in median progression-free survival (PFS) for first- (PFS1) and second-line treatment (PFS2), and for the combined PFS (PFS1 plus PFS2) were examined using weighted linear regression. In the pooled analysis encompassing 853 patients, the median combined PFS for first-line sunitinib and 2nd-line sorafenib (SuSo) was 12.1 months compared with 15.4 months for the reverse sequence (SoSu; 95% CI for difference 1.45-5.12, p = 0.0013). Regarding first-line treatment, no significant difference in PFS1 was noted regardless of which drug was initially used (0.62 months average increase on sorafenib, 95% CI for difference -1.01 to 2.26, p = 0.43). In second-line treatment, sunitinib showed a significantly longer PFS2 than sorafenib (average increase 2.66 months, 95% CI 1.02-4.3, p = 0.003). The SoSu sequence translates into a longer combined PFS compared to the SuSo sequence. Predominantly the superiority of sunitinib regarding PFS2 contributed to the longer combined PFS in sequential use. Copyright © 2012 S. Karger AG, Basel.

Sediment removal by prairie filter strips in row-cropped ephemeral watersheds

Treesearch

Matthew J. Helmers; Xiaobo Zhou; Heidi Asbjornsen; Randy Kolka; Mark D. Tomer; Richard M. Cruse

2012-01-01

Twelve small watersheds in central Iowa were used to evaluate the eff ectiveness of prairie filter strips (PFS) in trapping sediment from agricultural runoff. Four treatments with PFS of different size and location (100% rowcrop, 10% PFS of total watershed area at footslope, 10% PFS at footslope and in contour strips, 20% PFS at footslope and in contour strips)...

Evolution of Randomized Trials in Advanced/Metastatic Soft Tissue Sarcoma: End Point Selection, Surrogacy, and Quality of Reporting.

PubMed

Zer, Alona; Prince, Rebecca M; Amir, Eitan; Abdul Razak, Albiruni

2016-05-01

Randomized controlled trials (RCTs) in soft tissue sarcoma (STS) have used varying end points. The surrogacy of intermediate end points, such as progression-free survival (PFS), response rate (RR), and 3-month and 6-month PFS (3moPFS and 6moPFS) with overall survival (OS), remains unknown. The quality of efficacy and toxicity reporting in these studies is also uncertain. A systematic review of systemic therapy RCTs in STS was performed. Surrogacy between intermediate end points and OS was explored using weighted linear regression for the hazard ratio for OS with the hazard ratio for PFS or the odds ratio for RR, 3moPFS, and 6moPFS. The quality of reporting for efficacy and toxicity was also evaluated. Fifty-two RCTs published between 1974 and 2014, comprising 9,762 patients, met the inclusion criteria. There were significant correlations between PFS and OS (R = 0.61) and between RR and OS (R = 0.51). Conversely, there were nonsignificant correlations between 3moPFS and 6moPFS with OS. A reduction in the use of RR as the primary end point was observed over time, favoring time-based events (P for trend = .02). In 14% of RCTs, the primary end point was not met, but the study was reported as being positive. Toxicity was comprehensively reported in 47% of RCTs, whereas 14% inadequately reported toxicity. In advanced STS, PFS and RR seem to be appropriate surrogates for OS. There is poor correlation between OS and both 3moPFS and 6moPFS. As such, caution is urged with the use of these as primary end points in randomized STS trials. The quality of toxicity reporting and interpretation of results is suboptimal. © 2016 by American Society of Clinical Oncology.

Medication Effects on Periurethral Sensation and Urethral Sphincter Activity

PubMed Central

Greer, W. Jerod; Gleason, Jonathan L.; Kenton, Kimberly; Szychowski, Jeff M.; Goode, Patricia S; Richter, Holly E

2014-01-01

Aim To characterize urethral neuromuscular function before and 2 weeks after medication therapy. Methods Premenopausal women without lower urinary tract symptoms were randomly allocated to one of six medications for 2 weeks (pseudoephedrine ER 120mg, imipramine 25mg, cyclobenzaprine 10mg, tamsulosin 0.4mg, solifenacin 5mg or placebo). At baseline and after medication, participants underwent testing: quantitative concentric needle EMG (CNE) of the urethral sphincter using automated Multi-Motor Unit Action Potential (MUP) software; current perception threshold (CPT) testing to measure periurethral sensation; and standard urodynamic pressure flow studies (PFS). Nonparametric tests were used to compare pre-post differences. Results 56 women had baseline testing; 48 (85.7%) completed follow-up CNE, and 49 (87.5%) completed follow-up CPT and PFS testing. Demographics showed no significant differences among medication groups with respect to age (mean 34.3 ± 10.1), BMI (mean 31.8 ± 7.5), parity (median 1, range 0–7), or race (14% Caucasian, 80% African American). PFS parameters were not significantly different within medication groups. No significant pre-post changes in CNE values were noted; however, trends in amplitudes were in a direction consistent with the expected physiologic effect of the medications. With CPT testing, a trend toward increased urethral sensation at the 5 Hz stimulation level, was observed following treatment with pseudoephedrine (0.15 to 0.09 mA at 5Hz; P=0.03). Conclusion In women without LUTS, pseudoephedrine improved urethral sensation, but not urethral neuromuscular function on CNE or pressure flow studies. Imipramine, cyclobenzaprine, tamsulosin, solifenacin, and placebo did not change urethral sensation or neuromuscular function. PMID:25185603

A Scheme to Optimize Flow Routing and Polling Switch Selection of Software Defined Networks.

PubMed

Chen, Huan; Li, Lemin; Ren, Jing; Wang, Yang; Zhao, Yangming; Wang, Xiong; Wang, Sheng; Xu, Shizhong

2015-01-01

This paper aims at minimizing the communication cost for collecting flow information in Software Defined Networks (SDN). Since flow-based information collecting method requires too much communication cost, and switch-based method proposed recently cannot benefit from controlling flow routing, jointly optimize flow routing and polling switch selection is proposed to reduce the communication cost. To this end, joint optimization problem is formulated as an Integer Linear Programming (ILP) model firstly. Since the ILP model is intractable in large size network, we also design an optimal algorithm for the multi-rooted tree topology and an efficient heuristic algorithm for general topology. According to extensive simulations, it is found that our method can save up to 55.76% communication cost compared with the state-of-the-art switch-based scheme.

Do patient-reported outcome measures cover personal factors important to people with rheumatoid arthritis? A mixed methods design using the International Classification of Functioning, Disability and Health as frame of reference.

PubMed

Dür, Mona; Coenen, Michaela; Stoffer, Michaela Alexandra; Fialka-Moser, Veronika; Kautzky-Willer, Alexandra; Kjeken, Ingvild; Drăgoi, Răzvan Gabriel; Mattsson, Malin; Boström, Carina; Smolen, Josef; Stamm, Tanja Alexandra

2015-02-25

Personal factors (PFs) are internal factors that determine functioning and the individuals' experience of disability. Their coverage by patient-reported outcome measures (PROMs) has not been examined in rheumatoid arthritis (RA) so far. The aims of this study were to identify PFs important in the life stories of people with RA and to determine their coverage by PROMs used in RA. The qualitative data of people with RA was explored to identify PFs. Additionally a systematic literature search was conducted to find PROMs used in RA. PROMs items were linked to the components, domains and categories of the International Classification of Functioning, Disability and Health (ICF) to determine the coverage of important PFs by PROMs. Twelve PFs were found to be important in the life stories of people with RA. The PFs coping and reflecting about one's life in an optimistic way were covered most frequently, each by 14 of the 42 explored PROMs, while job satisfaction was not covered at all. The London Coping with Rheumatoid Arthritis Questionnaire, General Self-Efficacy Scale, Arthritis Self-Efficacy Scale, Rheumatoid Arthritis Self-Efficacy Questionnaire and Revised Ways of Coping Inventory covered most PFs. Nineteen PROMs did not cover any of the PFs. Several PFs were identified as important in the life stories of people with RA, but only 55% of the PROMS covered some of these PFs. When evaluating PFs important to people with RA, health professionals should be alert on which PROMs can be used to assess which PFs.

Challenges in economic modeling of anticancer therapies: an example of modeling the survival benefit of olaparib maintenance therapy for patients with BRCA-mutated platinum-sensitive relapsed ovarian cancer.

PubMed

Hettle, Robert; Posnett, John; Borrill, John

2015-01-01

The aim of this paper is to describe a four health-state, semi-Markov model structure with health states defined by initiation of subsequent treatment, designed to make best possible use of the data available from a phase 2 clinical trial. The approach is illustrated using data from a sub-group of patients enrolled in a phase 2 clinical trial of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer and a BRCA mutation (NCT00753545). A semi-Markov model was developed with four health states: progression-free survival (PFS), first subsequent treatment (FST), second subsequent treatment (SST), and death. Transition probabilities were estimated by fitting survival curves to trial data for time from randomization to FST, time from FST to SST, and time from SST to death. Survival projections generated by the model are broadly consistent with the outcomes observed in the clinical trial. However, limitations of the trial data (small sample size, immaturity of the PFS and overall survival [OS] end-points, and treatment switching) create uncertainty in estimates of survival. The model framework offers a promising approach to evaluating cost-effectiveness of a maintenance therapy for patients with cancer, which may be generalizable to other chronic diseases.

Performance of circuit switching in the Internet

NASA Astrophysics Data System (ADS)

Molinero-Fernández, Pablo; McKeown, Nick

2003-04-01

We study the performance of an Internet that uses circuit switching (CS) instead of, or in addition to, packet switching (PS). On the face of it, this would seem a pointless exercise; the Internet is packet switched, and it was deliberately built that way to enable the efficiencies afforded by statistical multiplexing and the robustness of fast rerouting around failures. But link utilization is low particularly at the core of the Internet, which makes statistical multiplexing less important than it once was. Moreover, circuit switches today are capable of rapid reconfiguration around failures. There is also renewed interest in CS because of the ease of building very-high-capacity optical circuit switches. Although several proposals have suggested ways in which CS may be introduced into the Internet, the research presented here is based on Transmission Control Protocol (TCP) switching, in which a new circuit is created for each application flow. Here we explore the performance of a network that uses TCP switching, with particular emphasis on the response time experienced by users. We use simple M/GI/1 and M/GI/N queues to model application flows in both packet-switched and circuit-switched networks, as well as ns-2 simulations. We conclude that because of high-bandwidth long-lived flows, it does not make sense to use CS in shared-access or local area networks. But our results suggest that in the core of the network, where high capacity is needed most, and where peak flow rate is limited by the access link, there is little or no difference in performance between CS and PS. Given that circuit switches can be built to be much faster than packet switches, this suggests that a circuit-switched core warrants further investigation.

TLR-adjuvanted nanoparticle vaccines differentially influence the quality and longevity of responses to malaria antigen Pfs25.

PubMed

Thompson, Elizabeth A; Ols, Sebastian; Miura, Kazutoyo; Rausch, Kelly; Narum, David L; Spångberg, Mats; Juraska, Michal; Wille-Reece, Ulrike; Weiner, Amy; Howard, Randall F; Long, Carole A; Duffy, Patrick E; Johnston, Lloyd; O'Neil, Conlin P; Loré, Karin

2018-05-17

Transmission-blocking vaccines (TBVs) are considered an integral element of malaria eradication efforts. Despite promising evaluations of Plasmodium falciparum Pfs25-based TBVs in mice, clinical trials have failed to induce robust and long-lived Ab titers, in part due to the poorly immunogenic nature of Pfs25. Using nonhuman primates, we demonstrate that multiple aspects of Pfs25 immunity were enhanced by antigen encapsulation in poly(lactic-co-glycolic acid)-based [(PLGA)-based] synthetic vaccine particles (SVP[Pfs25]) and potent TLR-based adjuvants. SVP[Pfs25] increased Ab titers, Pfs25-specific plasmablasts, circulating memory B cells, and plasma cells in the bone marrow when benchmarked against the clinically tested multimeric form Pfs25-EPA given with GLA-LSQ. SVP[Pfs25] also induced the first reported Pfs25-specific circulating Th1 and Tfh cells to our knowledge. Multivariate correlative analysis indicated several mechanisms for the improved Ab responses. While Pfs25-specific B cells were responsible for increasing Ab titers, T cell responses stimulated increased Ab avidity. The innate immune activation differentially stimulated by the adjuvants revealed a strong correlation between type I IFN polarization, induced by R848 and CpG, and increased Ab half-life and longevity. Collectively, the data identify ways to improve vaccine-induced immunity to poorly immunogenic proteins, both by the choice of antigen and adjuvant formulation, and highlight underlying immunological mechanisms.

P02.03INCREASED COUNTS OF NK AND NKT CELLS ARE ASSOCIATED WITH PROLONGED SURVIVAL IN PRIMARY GLIOBLASTOMA PATIENTS TREATED WITH DENDRITIC CELL IMMUNOTHERAPY IN COMBINATION WITH RADIO- AND CHEMO-THERAPY

PubMed Central

Pellegatta, S.; Eoli, M.; Cantini, G.; Anghileri, E.; Antozzi, C.; Frigerio, S.; Bruzzone, M.; Pollo, B.; Parati, E.; Finocchiaro, G.

2014-01-01

Two clinical studies, DENDR1 and DENDR2 including, respectively, the treatment of first diagnosis and recurrent glioblastoma (GB) patients with dendritic cells (DCs) loaded with autologous tumor lysate are currently active at Istituto Neurologico Besta, Milan. Our first results obtained on a group of recurrent GB patients demonstrated that the response of NK cells correlates with significantly prolonged survival. Here we provide results of the interim analysis on 22 patients affected by primary GB. Patients with post-surgery volume ≤10 cc underwent leukapheresis before radiotherapy and chemotherapy with temozolomide (TMZ). Three intradermal injections of mature DC were done before adjuvant chemotherapy. The subsequent 4 injections were performed 17 ± 3 days after adjuvant TMZ. MRI, clinical and immunological follow-up were performed every 2 months. The median age at surgery was 54.5 years (28-69). RT-TMZ induced significant lymphopenia (<1000 lymphocytes/microl) in 17/22 patients (77.2%). Patients with >1000 lymphocytes/microl (5/22) before first vaccination had shorter PFS than others (p < 0.005). Peripheral Blood Lymphocytes (PBLs) were analyzed by flow cytometry to identify CD8+ T cells, NK and NKT cells before and after DC vaccines. The ratio of vaccination/baseline frequencies and counts (V/B ratio) of all of the immunological parameters for each patient was calculated, and the median of all of the observations used as the cut off value to separate patients. V/B ratio was correlated with the progression free survival (PFS) of each patient. Increased V/B ratio for NK cells and in particular NKT cells, but not for CD8 T lymphocytes, was significantly associated with prolonged PFS (median PFS 14 vs 8.0 mo, p = 0.01; 15.0 vs 8.0 mo, respectively). Interferon (IFN)-γ in PBLs was significantly higher in patients with PFS12 (p < 0.02), increasing immediately after the second vaccination as evaluated by real time-PCR. No changes in the expression levels of IFN-γ were observed in the other patients. After a median follow up of 14 months (6-27), the median progression-free survival (PFS) was 9 mo, with PFS6 90% (C. I. 0.78-1.029%) and PFS12 42% (C. I: 0.20-0.64) at Kaplan Meier analysis. Median overall survival (OS) was 22 mo with OS 12 70%. (C. I. 0.50-0.9). 2/4 patients with MGMT methylation were in the group of high V/B ratio. Our results show a positive association between increased peripheral NK and NKT cells response and prolonged survival. Further investigations are required on possible interference of radio-chemotherapy on activation of CD8+ T cells.

Preference for Solitude, Social Isolation, Suicidal Ideation, and Self-Harm in Adolescents.

PubMed

Endo, Kaori; Ando, Shuntaro; Shimodera, Shinji; Yamasaki, Syudo; Usami, Satoshi; Okazaki, Yuji; Sasaki, Tsukasa; Richards, Marcus; Hatch, Stephani; Nishida, Atsushi

2017-08-01

Social isolation is associated with suicidal ideation (SI) and self-harm (SH) among adolescents. However, the association between preference for solitude (PfS), SI, and SH is unknown. The prevalence of adolescents who have both of PfS and social isolation and the risks for SI and SH among them are also unknown. Information on PfS, social isolation, SI, and SH was collected in a large-scale school-based survey on adolescents, using a self-report questionnaire. Associations between PfS, SI, and SH were examined by logistic regression analysis. The interactions between PfS and social isolation on SI and SH were also investigated. The odds of SI and SH were examined for groups defined by presence of PfS and social isolation. Responses from 17,437 students (89.3% of relevant classes) were available. After adjusting for demographic characteristics and social isolation, PfS was associated with increased odds of SI (odds ratio [OR] = 3.1) and SH (OR = 1.9). There was no interaction between PfS and social isolation on SI and SH. After adjusting for demographic characteristics, the odds for SI (OR = 8.6) and SH (OR = 3.8) were highest among adolescents with both PfS and social isolation (8.4% of all respondents). PfS was associated with increased odds of SI and SH in adolescents. No interaction effect between PfS and social isolation on SI and SH was found, but adolescents with PfS and social isolation had the highest risk for SI and SH. Parents and professionals should pay attention to suicide risk in adolescents with PfS. Copyright © 2017 Society for Adolescent Health and Medicine. Published by Elsevier Inc. All rights reserved.

A Scheme to Optimize Flow Routing and Polling Switch Selection of Software Defined Networks

PubMed Central

Chen, Huan; Li, Lemin; Ren, Jing; Wang, Yang; Zhao, Yangming; Wang, Xiong; Wang, Sheng; Xu, Shizhong

2015-01-01

This paper aims at minimizing the communication cost for collecting flow information in Software Defined Networks (SDN). Since flow-based information collecting method requires too much communication cost, and switch-based method proposed recently cannot benefit from controlling flow routing, jointly optimize flow routing and polling switch selection is proposed to reduce the communication cost. To this end, joint optimization problem is formulated as an Integer Linear Programming (ILP) model firstly. Since the ILP model is intractable in large size network, we also design an optimal algorithm for the multi-rooted tree topology and an efficient heuristic algorithm for general topology. According to extensive simulations, it is found that our method can save up to 55.76% communication cost compared with the state-of-the-art switch-based scheme. PMID:26690571

A novel Pfs38 protein complex on the surface of Plasmodium falciparum blood-stage merozoites.

PubMed

Paul, Gourab; Deshmukh, Arunaditya; Kaur, Inderjeet; Rathore, Sumit; Dabral, Surbhi; Panda, Ashutosh; Singh, Susheel Kumar; Mohmmed, Asif; Theisen, Michael; Malhotra, Pawan

2017-02-16

The Plasmodium genome encodes for a number of 6-Cys proteins that contain a module of six cysteine residues forming three intramolecular disulphide bonds. These proteins have been well characterized at transmission as well as hepatic stages of the parasite life cycle. In the present study, a large complex of 6-Cys proteins: Pfs41, Pfs38 and Pfs12 and three other merozoite surface proteins: Glutamate-rich protein (GLURP), SERA5 and MSP-1 were identified on the Plasmodium falciparum merozoite surface. Recombinant 6-cys proteins i.e. Pfs38, Pfs12, Pfs41 as well as PfMSP-1 65 were expressed and purified using Escherichia coli expression system and antibodies were raised against each of these proteins. These antibodies were used to immunoprecipitate the native proteins and their associated partners from parasite lysate. ELISA, Far western, surface plasmon resonance and glycerol density gradient fractionation were carried out to confirm the respective interactions. Furthermore, erythrocyte binding assay with 6-cys proteins were undertaken to find out their possible role in host-parasite infection and seropositivity was assessed using Indian and Liberian sera. Immunoprecipitation of parasite-derived polypeptides, followed by LC-MS/MS analysis, identified a large Pfs38 complex comprising of 6-cys proteins: Pfs41, Pfs38, Pfs12 and other merozoite surface proteins: GLURP, SERA5 and MSP-1. The existence of such a complex was further corroborated by several protein-protein interaction tools, co-localization and co-sedimentation analysis. Pfs38 protein of Pfs38 complex binds to host red blood cells (RBCs) directly via glycophorin A as a receptor. Seroprevalence analysis showed that of the six antigens, prevalence varied from 40 to 99%, being generally highest for MSP-1 65 and GLURP proteins. Together the data show the presence of a large Pfs38 protein-associated complex on the parasite surface which is involved in RBC binding. These results highlight the complex molecular interactions among the P. falciparum merozoite surface proteins and advocate the development of a multi-sub-unit malaria vaccine based on some of these protein complexes on merozoite surface.

The prevalence of PFS and prevalence and characteristics of reported food allergy; a survey of UK adults aged 18-75 incorporating a validated PFS diagnostic questionnaire.

PubMed

Skypala, I J; Bull, S; Deegan, K; Gruffydd-Jones, K; Holmes, S; Small, I; Emery, P W; Durham, S R

2013-08-01

Pollen-food syndrome (PFS), a food allergy affecting pollen-sensitized individuals, is likely to be the most prevalent food allergy in adults, estimated to affect 50-90% of people allergic to birch tree pollen. A validated PFS diagnostic questionnaire (PFSDQ2) was used to determine the prevalence of PFS and also to characterize those who report reactions to foods. Five UK General practices each sent the PFSDQ2 by post to 2000 patients aged 18-75 years randomly selected from their practice database. The validated questionnaire was accompanied by an additional set of questions to ascertain the demographic of the population, the foods involved and the age of onset. There were 3590 subjects who returned completed questionnaires, with an average return rate from each practice of 36% (range 22-47%). Of these, 73 were diagnosed with PFS according to the questionnaire (PFS+ve) giving a population prevalence of 2%. A further 482 subjects reported reactions to foods but did not fulfil the diagnostic criteria for PFS. The greatest prevalence of PFS was in the Croydon (SE England) urban practice (4.1%) and the lowest in the Aberdeen (Scotland) urban practice (0.8%) (P < 0.001).The most frequently reported trigger foods were apples, hazelnuts and kiwifruit and the majority of those with PFS first experienced symptoms below the age of 20 years. PFS+ve subjects were also more likely to be female and have a higher socio-economic status than those who did not report reactions to foods. The UK prevalence of PFS was 2%, although this varied according to the location of the practice population. The majority of PFS+ve subjects first reported symptoms in their teens. The reported age of onset has important implications for the diagnosis of primary and cross-reactive peanut and tree nut allergies in teenagers and young adults. The continuing rise in aeroallergen sensitization is likely to result in an increased frequency of PFS presenting in both primary and secondary care. © 2013 Blackwell Publishing Ltd.

Progression-free survival/time to progression as a potential surrogate for overall survival in HR+, HER2- metastatic breast cancer.

PubMed

Forsythe, Anna; Chandiwana, David; Barth, Janina; Thabane, Marroon; Baeck, Johan; Tremblay, Gabriel

2018-01-01

Several recent randomized controlled trials (RCTs) in hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) have demonstrated significant improvements in progression-free survival (PFS); however, few have reported improvement in overall survival (OS). The surrogacy of PFS or time to progression (TTP) for OS has not been formally investigated in HR+, HER2- MBC. A systematic literature review of RCTs in HR+, HER2- MBC was conducted to identify studies that reported both median PFS/TTP and OS. The correlation between PFS/TTP and OS was evaluated using Pearson's product-moment correlation and Spearman's rank correlation. Subgroup analyses were performed to explore possible reasons for heterogeneity. Errors-in-variables weighted least squares regression (LSR) was used to model incremental OS months as a function of incremental PFS/TTP months. An exploratory analysis investigated the impact of three covariates (chemotherapy vs hormonal/targeted therapy, PFS vs TTP, and first-line therapy vs second-line therapy or greater) on OS prediction. The lower 95% prediction band was used to determine the minimum incremental PFS/TTP months required to predict OS benefit (surrogate threshold effect [STE]). Forty studies were identified. There was a statistically significant correlation between median PFS/TTP and OS (Pearson =0.741, P =0.000; Spearman =0.650, P =0.000). These results proved consistent for chemotherapy and hormonal/targeted therapy. Univariate LSR analysis yielded an R 2 of 0.354 with 1 incremental PFS/TTP month corresponding to 1.13 incremental OS months. Controlling the type of treatment (chemotherapy vs hormonal/targeted therapy), line of therapy (first vs subsequent), and progression measure (PFS vs TTP) led to an improved R 2 of 0.569 with 1 PFS/TTP month corresponding to 0.78 OS months. The STE for OS benefit was 5-6 months of incremental PFS/TTP. We demonstrated a significant association between PFS/TTP and OS, which may justify the use of PFS/TTP as a surrogate for OS benefit in HR+, HER2- MBC.

Minimal residual disease in chronic lymphocytic leukaemia.

PubMed

García Vela, José Antonio; García Marco, José Antonio

2018-02-23

Minimal residual disease (MRD) assessment is an important endpoint in the treatment of chronic lymphocytic leukaemia (CLL). It is highly predictive of prolonged progression-free survival (PFS) and overall survival and could be considered a surrogate for PFS in the context of chemoimmunotherapy based treatment. Evaluation of MRD level by flow cytometry or molecular techniques in the era of the new BCR and Bcl-2 targeted inhibitors could identify the most cost-effective and durable treatment sequencing. A therapeutic approach guided by the level of MRD might also determine which patients would benefit from an early stop or consolidation therapy. In this review, we discuss the different MRD methods of analysis, which source of tumour samples must be analysed, the future role of the detection of circulating tumour DNA, and the potential role of MRD negativity in clinical practice in the modern era of CLL therapy. Copyright © 2017 Elsevier España, S.L.U. All rights reserved.

Prognostic Value of CD109+ Circulating Endothelial Cells in Recurrent Glioblastomas Treated with Bevacizumab and Irinotecan

PubMed Central

Cuppini, Lucia; Calleri, Angelica; Bruzzone, Maria Grazia; Prodi, Elena; Anghileri, Elena; Pellegatta, Serena; Mancuso, Patrizia; Porrati, Paola; Di Stefano, Anna Luisa; Ceroni, Mauro; Bertolini, Francesco; Finocchiaro, Gaetano; Eoli, Marica

2013-01-01

Background Recent data suggest that circulating endothelial and progenitor cells (CECs and CEPs, respectively) may have predictive potential in cancer patients treated with bevacizumab, the antibody recognizing vascular endothelial growth factor (VEGF). Here we report on CECs and CEPs investigated in 68 patients affected by recurrent glioblastoma (rGBM) treated with bevacizumab and irinotecan and two Independent Datasets of rGBM patients respectively treated with bevacizumab alone (n=32, independent dataset A: IDA) and classical antiblastic chemotherapy (n=14, independent dataset B: IDB). Methods rGBM patients with KPS ≥50 were treated until progression, as defined by MRI with RANO criteria. CECs expressing CD109, a marker of tumor endothelial cells, as well as other CEC and CEP subtypes, were investigated by six-color flow cytometry. Results A baseline count of CD109+ CEC higher than 41.1/ml (1st quartile) was associated with increased progression free survival (PFS; 20 versus 9 weeks, P=0.008) and overall survival (OS; 32 versus 23 weeks, P=0.03). Longer PFS (25 versus 8 weeks, P=0.02) and OS (27 versus 17 weeks, P=0.03) were also confirmed in IDA with CD109+ CECs higher than 41.1/ml but not in IDB. Patients treated with bevacizumab with or without irinotecan that were free from MRI progression after two months of treatment had significant decrease of CD109+ CECs: median PFS was 19 weeks; median OS 29 weeks. The presence of two non-contiguous lesions (distant disease) at baseline was an independent predictor of shorter PFS and OS (P<0.001). Conclusions Data encourage further studies on the predictive potential of CD109+ CECs in GBM patients treated with bevacizumab. PMID:24069296

Enhancing immunogenicity and transmission-blocking activity of malaria vaccines by fusing Pfs25 to IMX313 multimerization technology.

PubMed

Li, Yuanyuan; Leneghan, Darren B; Miura, Kazutoyo; Nikolaeva, Daria; Brian, Iona J; Dicks, Matthew D J; Fyfe, Alex J; Zakutansky, Sarah E; de Cassan, Simone; Long, Carole A; Draper, Simon J; Hill, Adrian V S; Hill, Fergal; Biswas, Sumi

2016-01-08

Transmission-blocking vaccines (TBV) target the sexual-stages of the malaria parasite in the mosquito midgut and are widely considered to be an essential tool for malaria elimination. High-titer functional antibodies are required against target antigens to achieve effective transmission-blocking activity. We have fused Pfs25, the leading malaria TBV candidate antigen to IMX313, a molecular adjuvant and expressed it both in ChAd63 and MVA viral vectors and as a secreted protein-nanoparticle. Pfs25-IMX313 expressed from viral vectors or as a protein-nanoparticle is significantly more immunogenic and gives significantly better transmission-reducing activity than monomeric Pfs25. In addition, we demonstrate that the Pfs25-IMX313 protein-nanoparticle leads to a qualitatively improved antibody response in comparison to soluble Pfs25, as well as to significantly higher germinal centre (GC) responses. These results demonstrate that antigen multimerization using IMX313 is a very promising strategy to enhance antibody responses against Pfs25, and that Pfs25-IMX313 is a highly promising TBV candidate vaccine.

Safety assessment of plant food supplements (PFS).

PubMed

van den Berg, Suzanne J P L; Serra-Majem, Lluis; Coppens, Patrick; Rietjens, Ivonne M C M

2011-12-01

Botanicals and botanical preparations, including plant food supplements (PFS), are widely used in Western diets. The growing use of PFS is accompanied by an increasing concern because the safety of these PFS is not generally assessed before they enter the market. Regulatory bodies have become more aware of this and are increasing their efforts to ensure the safety of PFS. The present review describes an overview of the general framework for the safety assessment of PFS, focusing on the different approaches currently in use to assess the safety of botanicals and/or botanical compounds, including their history of safe use, the tiered approach proposed by the European Food Safety Authority (EFSA), the Threshold of Toxicological Concern (TTC) and the Margin of Exposure (MOE) concept. Moreover, some examples of botanical compounds in PFS that may be of concern are discussed. Altogether, it is clear that "natural" does not equal "safe" and that PFS may contain compounds of concern at levels far above those found in the regular diet. In addition, the traditional use of a PFS compound as a herb or tea does not guarantee its safety when used as a supplement. This points at a need for stricter regulation and control of botanical containing products, especially given their expanding market volume.

Risk assessment of combined exposure to alkenylbenzenes through consumption of plant food supplements containing parsley and dill.

PubMed

Alajlouni, Abdalmajeed M; Al-Malahmeh, Amer J; Wesseling, Sebastiaan; Kalli, Marina; Vervoort, Jacques; Rietjens, Ivonne M C M

2017-12-01

A risk assessment was performed of parsley- and dill-based plant food supplements (PFS) containing apiol and related alkenylbenzenes. First, the levels of the alkenylbenzenes in the PFS and the resulting estimated daily intake (EDI) resulting from use of the PFS were quantified. Since most PFS appeared to contain more than one alkenylbenzene, a combined risk assessment was performed based on equal potency or using a so-called toxic equivalency (TEQ) approach based on toxic equivalency factors (TEFs) for the different alkenylbenzenes. The EDIs resulting from daily PFS consumption amount to 0.74-125 µg kg -1 bw for the individual alkenylbenzenes, 0.74-160 µg kg -1 bw for the sum of the alkenylbenzenes, and 0.47-64 µg kg -1 bw for the sum of alkenylbenzenes when expressed in safrole equivalents. The margins of exposure (MOEs) obtained were generally below 10,000, indicating a priority for risk management if the PFS were to be consumed on a daily basis. Considering short-term use of the PFS, MOEs would increase above 10,000, indicating low priority for risk management. It is concluded that alkenylbenzene intake through consumption of parsley- and dill-based PFS is only of concern when these PFS are used for long periods of time.

Surrogacy of progression-free survival (PFS) for overall survival (OS) in esophageal cancer trials with preoperative therapy: Literature-based meta-analysis.

PubMed

Kataoka, K; Nakamura, K; Mizusawa, J; Kato, K; Eba, J; Katayama, H; Shibata, T; Fukuda, H

2017-10-01

There have been no reports evaluating progression-free survival (PFS) as a surrogate endpoint in resectable esophageal cancer. This study was conducted to evaluate the trial level correlations between PFS and overall survival (OS) in resectable esophageal cancer with preoperative therapy and to explore the potential benefit of PFS as a surrogate endpoint for OS. A systematic literature search of randomized trials with preoperative chemotherapy or preoperative chemoradiotherapy for esophageal cancer reported from January 1990 to September 2014 was conducted using PubMed and the Cochrane Library. Weighted linear regression using sample size of each trial as a weight was used to estimate coefficient of determination (R 2 ) within PFS and OS. The primary analysis included trials in which the HR for both PFS and OS was reported. The sensitivity analysis included trials in which either HR or median survival time of PFS and OS was reported. In the sensitivity analysis, HR was estimated from the median survival time of PFS and OS, assuming exponential distribution. Of 614 articles, 10 trials were selected for the primary analysis and 15 for the sensitivity analysis. The primary analysis did not show a correlation between treatment effects on PFS and OS (R 2 0.283, 95% CI [0.00-0.90]). The sensitivity analysis did not show an association between PFS and OS (R 2 0.084, 95% CI [0.00-0.70]). Although the number of randomized controlled trials evaluating preoperative therapy for esophageal cancer is limited at the moment, PFS is not suitable for primary endpoint as a surrogate endpoint for OS. Copyright © 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Evaluation of Overall Response Rate and Progression-Free Survival as Potential Surrogate Endpoints for Overall Survival in Immunotherapy Trials.

PubMed

Mushti, Sirisha L; Mulkey, Flora; Sridhara, Rajeshwari

2018-05-15

Purpose: With the approval of immunotherapies for a variety of indications, methods to assess treatment benefit addressing the response patterns observed are important. We evaluated RECIST criteria-based overall response rate (ORR) and progression-free survival (PFS) as potential surrogate endpoints of overall survival (OS), and explored a modified definition of PFS by altering the threshold percentage determining disease progression to assess the association with survival benefit in immunotherapy trials. Experimental Design: Thirteen randomized, multicenter, active-control trials containing immunotherapeutic agents submitted to the FDA were analyzed. Associations between treatment effects of ORR, PFS, modified PFS, and OS were evaluated at individual and trial levels. Patient-level responder analysis was performed for PFS and OS. Results: The coefficient of determination ( R ²) measured the strength of associations, where values near 1 imply surrogacy and values close to 0 suggest no association. At the trial level, the association between hazard ratios (HR) of PFS and OS was R 2 = 0.1303, and between the odds ratio (OR) of ORR and HR of OS was R 2 = 0.1277. At the individual level, the Spearman rank correlation coefficient between PFS and OS was 0.61. Trial-level associations between modified PFS and OS ranged between 0.07 and 0.1, and individual-level correlations were approximately 0.6. HRs of PFS and OS for responders versus nonresponders were 0.129 [95% confidence interval (CI), 0.11-0.15] and 0.118 (95% CI, 0.11-0.13), respectively. Conclusions: Although responders exhibited longer survival and PFS than nonresponders, the trial-level and individual-level associations were weak between PFS/ORR and OS. Modifications to PFS did not improve associations. Clin Cancer Res; 24(10); 2268-75. ©2018 AACR See related commentary by Korn and Freidlin, p. 2239 . ©2018 American Association for Cancer Research.

Risk assessment of plant food supplements and other herbal products containing aristolochic acids using the margin of exposure (MOE) approach.

PubMed

Abdullah, Rozaini; Diaz, Leolean Nyle; Wesseling, Sebastiaan; Rietjens, Ivonne M C M

2017-02-01

After the incidences of induction of aristolochic acid nephropathy after consumption of herbal weight loss preparations that accidentally contained aristolochic acids (AAs), several countries defined national restrictions on the presence of AAs in food, including plant food supplements (PFS) and herbal products. This study investigates whether the risks associated with exposure to AAs via PFS and herbal products are at present indeed negligible. Data reported in literature on AA levels in PFS and other herbal products and also obtained from a new series of PFS in the present study were used to calculate the estimated daily intakes (EDIs) and corresponding margins of exposure (MOEs). Available literature data revealed that 206 out of 573 samples were found to contain aristolochic acid I (AAI) and/or aristolochic acid II (AAII). The results obtained from recently collected PFS revealed that both AAI and AAII were detected in three out of 18 analysed PFS at levels up to 594.8 and 235.3 µg g -1 , respectively, being in line with the levels reported in literature. The EDIs resulting from intake of these PFS resulted in MOEs that were generally below 10,000, corroborating the priority for risk management. Although these results refer to PFS collected by targeted sampling strategies, the data reveal that AA-containing PFS are still freely available. When considering that the use of these samples may be limited to shorter periods of time, the EDIs might be lower, but MOE values would still be lower than 10,000 for more than 50% of the AA-containing PFS and herbal products. In conclusion, the presence of AAs in PFS and herbal products even several years after instalment of the legal restrictions still raises concern, especially for people who frequently use the respective PFS and herbal products.

Naturally acquired antibody responses to recombinant Pfs230 and Pfs48/45 transmission blocking vaccine candidates.

PubMed

Jones, Sophie; Grignard, Lynn; Nebie, Issa; Chilongola, Jaffu; Dodoo, Daniel; Sauerwein, Robert; Theisen, Michael; Roeffen, Will; Singh, Shrawan Kumar; Singh, Rajesh Kumar; Singh, Sanjay; Kyei-Baafour, Eric; Tetteh, Kevin; Drakeley, Chris; Bousema, Teun

2015-07-01

Pfs48/45 and Pfs230 are Plasmodium falciparum sexual stage proteins and promising malaria transmission-blocking vaccine candidates. Antibody responses against these proteins may be naturally acquired and target antigens may be under selective pressure. This has consequences for the future evaluation of vaccine immunogenicity and efficacy in populations naturally exposed to malaria. We determined naturally acquired antibody responses to the recombinant proteins Pfs48/45-10C and Pfs230-230CMB in children from three malaria endemic settings in Ghana, Tanzania and Burkina Faso. We also examined genetic polymorphisms in the P. falciparum gene pfs48/45. Antibody prevalence was 1.1-18.2% for 10C and 6.7-18.9% for 230CMB. In Burkina Faso we observed evidence of an age-dependent acquisition pattern for both 10C (p < 0.001) and 230CMB (p = 0.031). Membrane feeding assays on a separate dataset demonstrated an association between functional transmission reducing activity and antibody prevalence for both 10C (p = 0.017) and 230CMB (p = 0.049). 17 single nucleotide polymorphisms were found in pfs48/45 (from 126 samples), with 5 non-synonymous SNPs in the Pfs48/45 10C region. We conclude there are naturally acquired antibody responses to both vaccine candidates which have functional relevance by reducing the transmissibility of infected individuals. We identified genetic polymorphisms, in pfs48/45 which exhibited geographical specificity. Copyright © 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

Continuation of epidermal growth factor receptor tyrosine kinase inhibitor treatment prolongs disease control in non-small-cell lung cancers with acquired resistance to EGFR tyrosine kinase inhibitors

PubMed Central

Chen, Qi; Quan, Qi; Ding, Lingyu; Hong, Xiangchan; Zhou, Ningning; Liang, Ying; Wu, Haiying

2015-01-01

Objectives Patients with non-small-cell lung cancer (NSCLC) develop acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) after tumor regression. No approved targeted therapies are currently available after initial EGFR TKI treatment. This study investigated the efficacy of continuing EGFR TKI therapy with local treatments for patients with NSCLC and local progression or minimal/slow progression on TKI therapy. Materials and Methods Fifty-five patients with NSCLC treated with EGFR TKIs and developed acquired resistance to the drug were included. Initial response to target therapy, median progression free survival (PFS1), progression pattern, and first progression site were assessed. Median progression free survival to physician assessment progression (PFS2) and difference between PFS1 and PFS2 (PFS difference) were also recorded. Results and Conclusion PFS1 was 11.2 months, PFS2 was 20.3 months, and PFS difference was 8.3 months. Nineteen patients (34.5%) who manifested progression received local therapy, and 16 (28.6%) underwent rebiopsy after progression with six positive EGFR T790M mutations detected. Cox proportional hazards regression model showed that only the first line of treatment was significantly correlated with PFS difference. NSCLC patients with acquired resistance to EGFR TKIs could benefit from the same TKI therapy through months to years of disease control. PMID:26172562

Structural and Immunological Characterization of Recombinant 6-Cysteine Domains of the Plasmodium falciparum Sexual Stage Protein Pfs230*

PubMed Central

MacDonald, Nicholas J.; Nguyen, Vu; Shimp, Richard; Reiter, Karine; Herrera, Raul; Burkhardt, Martin; Muratova, Olga; Kumar, Krishan; Aebig, Joan; Rausch, Kelly; Lambert, Lynn; Dawson, Nikiah; Sattabongkot, Jetsumon; Ambroggio, Xavier; Duffy, Patrick E.; Wu, Yimin; Narum, David L.

2016-01-01

Development of a Plasmodium falciparum (Pf) transmission blocking vaccine (TBV) has the potential to significantly impact malaria control. Antibodies elicited against sexual stage proteins in the human bloodstream are taken up with the blood meal of the mosquitoes and inactivate parasite development in the mosquito. In a phase 1 trial, a leading TBV identified as Pfs25-EPA/Alhydrogel® appeared safe and immunogenic, however, the level of Pfs25-specific antibodies were likely too low for an effective vaccine. Pfs230, a 230-kDa sexual stage protein expressed in gametocytes is an alternative vaccine candidate. A unique 6-cysteine-rich domain structure within Pfs230 have thwarted its recombinant expression and characterization for clinical evaluation for nearly a quarter of a century. Here, we report on the identification, biochemical, biophysical, and immunological characterization of recombinant Pfs230 domains. Rabbit antibodies generated against recombinant Pfs230 domains blocked mosquito transmission of a laboratory strain and two field isolates using an ex vivo assay. A planned clinical trial of the Pfs230 vaccine is a significant step toward the potential development of a transmission blocking vaccine to eliminate malaria. PMID:27432885

Optically triggered high voltage switch network and method for switching a high voltage

DOEpatents

El-Sharkawi, Mohamed A.; Andexler, George; Silberkleit, Lee I.

1993-01-19

An optically triggered solid state switch and method for switching a high voltage electrical current. A plurality of solid state switches (350) are connected in series for controlling electrical current flow between a compensation capacitor (112) and ground in a reactive power compensator (50, 50') that monitors the voltage and current flowing through each of three distribution lines (52a, 52b and 52c), which are supplying three-phase power to one or more inductive loads. An optical transmitter (100) controlled by the reactive power compensation system produces light pulses that are conveyed over optical fibers (102) to a switch driver (110') that includes a plurality of series connected optical triger circuits (288). Each of the optical trigger circuits controls a pair of the solid state switches and includes a plurality of series connected resistors (294, 326, 330, and 334) that equalize or balance the potential across the plurality of trigger circuits. The trigger circuits are connected to one of the distribution lines through a trigger capacitor (340). In each switch driver, the light signals activate a phototransistor (300) so that an electrical current flows from one of the energy reservoir capacitors through a pulse transformer (306) in the trigger circuit, producing gate signals that turn on the pair of serially connected solid state switches (350).

VizieR Online Data Catalog: Radial velocities of HD 133131A and HD 133131B (Teske+, 2016)

NASA Astrophysics Data System (ADS)

Teske, J. K.; Shectman, S. A.; Vogt, S. S.; Diaz, M.; Butler, R. P.; Crane, J. D.; Thompson, I. B.; Arriagada, P.

2017-05-01

The radial velocity observations of HD133131A and B are part of the large Magellan Planet Search Program, which began in 2002 and is surveying a sample of ~500 of the nearest stars (<100pc). The survey was started with observations from the Magellan Inamori Kyocera Echelle (MIKE) echelle spectrograph, mounted for a limited time on the Magellan I (Baade), but mostly on Magellan II (Clay), 6.5m telescopes at Las Campanas Observatory. In 2010, the survey switched to using the Carnegie Planet Finder Spectrograph (PFS), a temperature-controlled high-resolution echelle spectrograph built for precision radial velocity observations, on Magellan II. Only HD133131A observations from MIKE are included here. Using a 0.35*5'' slit, MIKE provides spectra with R~70000 in the blue and ~50000 in the red and covers 3900-6200Å. Only the red MIKE orders are used for radial velocity determination, while the blue orders provide coverage of the CaIIH and K lines for monitoring stellar activity. The MIKE observations of HD133131A span 2003 June to 2009 July, with total exposure times ranging from 150 to 600s, depending on observing conditions. Both HD133131A and B were observed with PFS, the former observations ranging from 2010 February to 2015 September, and the latter from 2010 August to 2015 September. PFS has a more limited wavelength range than MIKE (3880-6680Å), but still covers the entire iodine wavelength region, CaIIH and K, and Hα. We use a 0.5*2.5'' slit for target observations, providing R~80000 in the iodine region. The total exposure times for the A component range from 285 to 720s, and for the B component range from 282 to 800s. (6 data files).

Simulations of flow induced structural transition of the β-switch region of glycoprotein Ibα.

PubMed

Han, Mengzhi; Xu, Ji; Ren, Ying; Li, Jinghai

2016-02-01

Binding of glycoprotein Ibα to von Willebrand factor induces platelet adhesion to injured vessel walls and initiates a multistep hemostatic process. It has been hypothesized that the flow condition could induce a loop to β-sheet conformational change in the β-switch region of glycoprotein Ibα, which regulates it binding to the von Willebrand factor and facilitates the blood clot formation and wound healing. In this work, direct molecular dynamics (MD), flow MD and metadynamics, were employed to investigate the mechanisms of this flow induced conformational transition process. Specifically, the free energy landscape of the whole transition process was drawn by metadynamics with the path collective variable approach. The results reveal that without flow, the free energy landscape has two main basins, including a random loop basin stabilized by large conformational entropy and a partially folded β-sheet basin. The free energy barrier separating these two basins is relatively high and the β-switch could not fold from loop to β-sheet state spontaneously. The fully β-sheet conformations located in high free energy regions, which are also unstable and gradually unfold into partially folded β-sheet state with flow. Relatively weak flow could trigger some folding of the β-switch but could not fold it into fully β-sheet state. Under strong flow conditions, the β-switch could readily overcome the high free energy barrier and fold into fully β-sheet state. Copyright © 2015 Elsevier B.V. All rights reserved.

Power of Food Scale in association with weight outcomes and dieting in a nationally representative cohort of U.S. young adults.

PubMed

Lipsky, L M; Nansel, T R; Haynie, D L; Liu, D; Eisenberg, M H; Simons-Morton, B

2016-10-01

Food reward sensitivity may influence susceptibility to overeating in a permissive food environment, contributing to unintended weight gain and intentional weight loss behavior. This study examined associations of food reward sensitivity, assessed by the Power of Food Scale (PFS), with weight outcomes and dieting in a nationally representative cohort of U.S. emerging adults. Wave 5 (W5, 5th year of follow-up) respondents from the NEXT Generation Health Study were included (N = 2202, W5 age = 20.3 ± 0.02 years). Baseline and W5 BMI, W5 weight status (normal weight = 18.5 ≤ BMI < 25, overweight = 25 ≤ BMI < 30, obese = BMI ≥ 30), BMI change (W5-baseline BMI) and onset of overweight or obesity (OWOB) were calculated from self-reported height and weight. PFS (aggregate and 3 domain scores: food available, present, and tasted) and dieting for weight-loss were assessed at W5. Adjusted linear regressions estimated associations of PFS with W5 BMI and BMI change. Log-binomial regressions estimated associations of high W5 BMI (≥25), OWOB onset and dieting with PFS. Post hoc analyses estimated associations of PFS with W5 perceived weight status (overweight vs. about right or underweight). W5 BMI = 25.73 ± 0.32 kg/m(2), and OWOB onset occurred in 27.7% of participants. The PFS-food available score was associated with BMI change, β ± SE = 0.41 ± 0.19. Other PFS scores were not associated with weight outcomes. Dieting prevalence was higher in participants with high versus low W5 BMI (61% versus 32%), and was positively associated with all PFS scores except the PFS-food tasted score, e.g., relative risk (RR) of dieting for PFS-aggregate = 1.13, 95%CI [1.01-1.26]. Post-hoc analyses indicated perceived overweight was positively associated with PFS-food available, 1.12, [1.01-1.24], and PFS-food present, 1.13, [1.03-1.24]. PFS was positively related to dieting and perceived overweight, but not concurrent or change in weight status in a representative cohort of U.S. emerging adults. Published by Elsevier Ltd.

Progression of soot cake layer properties during the systematic regeneration of diesel particulate filters measured with neutron tomography

DOE PAGES

Toops, Todd J.; Pihl, Josh A.; Finney, Charles E. A.; ...

2015-01-16

Although particulate filters (PFs) have been a key component of the emission control system for modern diesel engines, there remain significant questions about the basic regeneration behavior of the filters and how it changes with accumulation of increasing soot layers. This effort describes a systematic deposition and regeneration of particulate matter in 25-mm diameter × 76-mm long wall-flow PFs composed of silicon carbide (SiC) material. The initial soot distributions were analyzed for soot cake thickness using a nondestructive neutron imaging technique. With the PFs intact, it was then possible to sequentially regenerate the samples and reanalyze them, which was performedmore » after nominal 20, 50, and 70 % regenerations. The loaded samples show a relatively uniform distribution of particulate with an increasing soot cake thickness and nearly identical initial density of 70 mg/cm 3. Throughout regeneration, the soot cake thickness initially decreases significantly while the density increases to 80–90 mg/cm 3. After ~50 % regeneration, the soot cake thickness stays relatively constant, but instead, the density decreases as pores open up in the layer (~35 mg/cm 3 at 70 % regeneration). Here, complete regeneration initially occurs at the rear of the PF channels. With this information, a conceptual model of the regeneration is proposed.« less

Progression of soot cake layer properties during the systematic regeneration of diesel particulate filters measured with neutron tomography

DOE Office of Scientific and Technical Information (OSTI.GOV)

Toops, Todd J.; Pihl, Josh A.; Finney, Charles E. A.

Although particulate filters (PFs) have been a key component of the emission control system for modern diesel engines, there remain significant questions about the basic regeneration behavior of the filters and how it changes with accumulation of increasing soot layers. This effort describes a systematic deposition and regeneration of particulate matter in 25-mm diameter × 76-mm long wall-flow PFs composed of silicon carbide (SiC) material. The initial soot distributions were analyzed for soot cake thickness using a nondestructive neutron imaging technique. With the PFs intact, it was then possible to sequentially regenerate the samples and reanalyze them, which was performedmore » after nominal 20, 50, and 70 % regenerations. The loaded samples show a relatively uniform distribution of particulate with an increasing soot cake thickness and nearly identical initial density of 70 mg/cm 3. Throughout regeneration, the soot cake thickness initially decreases significantly while the density increases to 80–90 mg/cm 3. After ~50 % regeneration, the soot cake thickness stays relatively constant, but instead, the density decreases as pores open up in the layer (~35 mg/cm 3 at 70 % regeneration). Here, complete regeneration initially occurs at the rear of the PF channels. With this information, a conceptual model of the regeneration is proposed.« less

Protein aggregation and particle formation in prefilled glass syringes.

PubMed

Gerhardt, Alana; Mcgraw, Nicole R; Schwartz, Daniel K; Bee, Jared S; Carpenter, John F; Randolph, Theodore W

2014-06-01

The stability of therapeutic proteins formulated in prefilled syringes (PFS) may be negatively impacted by the exposure of protein molecules to silicone oil-water interfaces and air-water interfaces. In addition, agitation, such as that experienced during transportation, may increase the detrimental effects (i.e., protein aggregation and particle formation) of protein interactions with interfaces. In this study, surfactant-free formulations containing either a monoclonal antibody or lysozyme were incubated in PFS, where they were exposed to silicone oil-water interfaces (siliconized syringe walls), air-water interfaces (air bubbles), and agitation stress (occurring during end-over-end rotation). Using flow microscopy, particles (≥2 μm diameter) were detected under all conditions. The highest particle concentrations were found in agitated, siliconized syringes containing an air bubble. The particles formed in this condition consisted of silicone oil droplets and aggregated protein, as well as agglomerates of protein aggregates and silicone oil. We propose an interfacial mechanism of particle generation in PFS in which capillary forces at the three-phase (silicone oil-water-air) contact line remove silicone oil and gelled protein aggregates from the interface and transport them into the bulk. This mechanism explains the synergistic effects of silicone oil-water interfaces, air-water interfaces, and agitation in the generation of particles in protein formulations. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.

Assessment of Correlation Between Early and Late Efficacy Endpoints to Identify Potential Surrogacy Relationships in Non-Hodgkin Lymphoma: a Literature-Based Meta-analysis of 108 Phase II and Phase III Studies.

PubMed

Zhu, Rui; Lu, Dan; Chu, Yu-Waye; Chai, Akiko; Green, Michelle; Zhang, Nancy; Jin, Jin Yan

2017-05-01

Correlations between early and late efficacy endpoints were assessed to identify potential surrogate endpoints for overall survival (OS) or progression-free survival (PFS) with clinical trial-level data in three non-Hodgkin lymphoma (NHL) subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). One hundred and eight phase II-III trials (129 trial arms) in DLBCL, FL, and MCL were identified and included in the database. Correlations between efficacy endpoints were analyzed using weighted linear regression and Pearson's coefficient of determination (R 2 ). In newly diagnosed DLBCL, 6-month PFS was strongly correlated with 2-year OS (R 2  = 0.81, 95% confidence interval [CI] 0.51-0.96). Six-month PFS was strongly correlated with 3-year PFS (R 2  = 0.89, 95% CI 0.62-0.96) in FL and was moderately correlated with 2-year OS (R 2  = 0.69, 95% CI 0.40-0.91) in MCL trials. Linear regression determined that a 10% increase in 6-month PFS would yield a 13% ± 1.2% increase in 2-year OS in DLBCL, a 23% ± 1.1% increase in 3-year PFS in FL, or a 6.7% ± 1.0% increase in 2-year OS in MCL. Both 6-month PFS and complete response (CR) rate were moderately correlated with median PFS in FL trials with R 2  = 0.66 (95% CI 0.52-0.98) and R 2  = 0.69 (95% CI 0.22-0.89), respectively. Six-month PFS is a potential surrogate endpoint for 2-year OS in newly diagnosed DLBCL and MCL and for 3-year PFS in FL. Both 6-month PFS and CR rate are potential surrogate endpoints for median PFS in FL patients. Confirmation and validation of these correlations may facilitate early interpretation of NHL trials.

Progression-free survival as a surrogate endpoint for overall survival in glioblastoma: a literature-based meta-analysis from 91 trials

PubMed Central

Han, Kelong; Ren, Melanie; Wick, Wolfgang; Abrey, Lauren; Das, Asha; Jin, Jin; Reardon, David A.

2014-01-01

Background The aim of this study was to determine correlations between progression-free survival (PFS) and the objective response rate (ORR) with overall survival (OS) in glioblastoma and to evaluate their potential use as surrogates for OS. Method Published glioblastoma trials reporting OS and ORR and/or PFS with sufficient detail were included in correlative analyses using weighted linear regression. Results Of 274 published unique glioblastoma trials, 91 were included. PFS and OS hazard ratios were strongly correlated; R2 = 0.92 (95% confidence interval [CI], 0.71–0.99). Linear regression determined that a 10% PFS risk reduction would yield an 8.1% ± 0.8% OS risk reduction. R2 between median PFS and median OS was 0.70 (95% CI, 0.59–0.79), with a higher value in trials using Response Assessment in Neuro-Oncology (RANO; R2 = 0.96, n = 8) versus Macdonald criteria (R2 = 0.70; n = 83). No significant differences were demonstrated between temozolomide- and bevacizumab-containing regimens (P = .10) or between trials using RANO and Macdonald criteria (P = .49). The regression line slope between median PFS and OS was significantly higher in newly diagnosed versus recurrent disease (0.58 vs 0.35, P = .04). R2 for 6-month PFS with 1-year OS and median OS were 0.60 (95% CI, 0.37–0.77) and 0.64 (95% CI, 0.42–0.77), respectively. Objective response rate and OS were poorly correlated (R2 = 0.22). Conclusion In glioblastoma, PFS and OS are strongly correlated, indicating that PFS may be an appropriate surrogate for OS. Compared with OS, PFS offers earlier assessment and higher statistical power at the time of analysis. PMID:24335699

Surrogate endpoints for overall survival in combined chemotherapy and radiotherapy trials in nasopharyngeal carcinoma: Meta-analysis of randomised controlled trials.

PubMed

Chen, Yu-Pei; Sun, Ying; Chen, Lei; Mao, Yan-Ping; Tang, Ling-Long; Li, Wen-Fei; Liu, Xu; Zhang, Wen-Na; Zhou, Guan-Qun; Guo, Rui; Lin, Ai-Hua; Ma, Jun

2015-08-01

We used a literature-based meta-analysis to assess whether failure-free survival (FFS) or progression-free survival (PFS) could be reliable surrogate endpoints for overall survival (OS) in trials of combined chemotherapy and radiotherapy for nasopharyngeal carcinoma (NPC). We identified randomised trials that evaluated combined chemoradiotherapy strategies, and reported FFS or PFS and OS in NPC. We analysed the treatment effects on FFS or PFS, and OS. We used the coefficient of determination (R(2)), and the surrogate threshold effect (STE) to assess the trial-level correlation. Twenty-one trials (5212 patients), with sixteen treatment-control comparisons for FFS, and nine for PFS, were analysed. FFS was strongly correlated with OS (R(2)=0.88, STE=0.84), as was PFS (R(2)=0.90, STE=0.88). Moreover, FFS and PFS at 3 years were still strongly correlated with 5-year OS (R(2)=0.80, STE=0.83; R(2)=0.85, STE=0.84). Both FFS and PFS could be valid surrogate endpoints for OS in trials of combined chemotherapy and radiotherapy for NPC; PFS may be a more acceptable surrogate endpoint compared with FFS. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Circulating Plasma Cells at the Time of Collection of Autologous PBSC for Transplant in Multiple Myeloma Patients is a Negative Prognostic Factor Even in the Age of Post-Transplant Maintenance Therapy.

PubMed

Cowan, Andrew J; Stevenson, Philip A; Libby, Edward N; Becker, Pamela S; Coffey, David G; Green, Damian J; Hyun, Teresa S; Fromm, Jonathan R; Gopal, Ajay K; Holmberg, Leona A

2018-03-01

Circulating plasma cells (CPCs) have been detected in patients with multiple myeloma (MM) at various stages of disease and associated with worse outcomes. Little data exist regarding the impact of CPCs at the time of autologous peripheral blood stem cell (PBSC) collection on outcomes, and the impact of maintenance therapy after autologous stem cell transplantation (ASCT) on prognosis in patients with CPC-containing collections. All patients with MM who underwent first ASCT at Fred Hutchinson Cancer Research Center from 2012 to 2015 and had evaluation for CPCs at the time of PBSC collection were included in our analysis. Seven-color flow cytometry was used to detect the presence of CPCs. Kaplan-Meier estimates were used to generate overall survival (OS) and progression-free survival (PFS) rates from the time of ASCT. A multivariate analysis, including receipt of maintenance therapy post-ASCT, high-risk cytogenetics, and international staging system (ISS) stage, was included in a Cox proportional hazards regression model for associations with OS and PFS. We identified 227 patients with MM who underwent ASCT; of these, 144 (63.4%) patients had routine assessment of CPCs at the time of PBSC collection. One hundred seventeen (81.3%) patients did not have CPCs and 27 (18.8%) did have CPCs. The presence of CPCs was highly associated with poorer PFS (P = .031 by log-rank analysis), but did not affect OS. The median PFS for those patients without CPCs was 39.4 months (95% confidence interval [CI], 31.1 to not reached), while the median PFS for those patients with CPCs was 16.5 months (95% CI, 13.7 to not reached). A subgroup analysis of patients achieving VGPR or better at time of collection, showed the median PFS for patients without CPCs was 38.3 months (95% CI, 29 to not reached), as compared with those patients with CPCs, where it was only 16.5 months (95% CI, 12 months to not reached; P = .02). There was no statistically significant difference in PFS or OS among those patients achieving PR at the time of collection. In a Cox proportional hazards model, adjusting for post-ASCT maintenance therapy, high-risk cytogenetics, and ISS stage at time of initial diagnosis, there was a 43% higher risk of progression or death among the patients with CPCs (P = .04). The presence of CPCs at the time of autologous PBSC collection is a negative prognostic factor for risk of early relapse or death despite the advent of novel agents and maintenance strategies. The impact of CPCs was most significant among patients achieving a VGPR or better at time of collection. The presence of CPCs denotes a unique group of high-risk MM patients for whom alternative treatment strategies are needed to overcome resistance to current standard therapies. Copyright © 2018. Published by Elsevier Inc.

Primary Gastrointestinal Lymphoma

PubMed Central

Chen, Yinting; Chen, Yanzhu; Chen, Shaojie; Wu, Lili; Xu, Lishu; Lian, Guoda; Yang, Kege; Li, Yaqing; Zeng, Linjuan; Huang, Kaihong

2015-01-01

Abstract Primary gastrointestinal lymphoma (PGIL) is a rare malignant tumor without standard diagnosis and treatment methods. This study is aimed to systematically analyze its clinical characteristics and draw out an appropriate flow chart of diagnosis and treatment process for PGIL in China. This study retrospectively analyzed the clinicopathological characteristics, diagnostic approaches, prognostic factors, and therapeutic modalities in 415 cases of PGIL in Chinese province of Guangdong. A systematic review was conducted in 118 studies containing 5075 patients to further identify clinical manifestations and mortalities of therapeutic modalities. The most common clinical presentations were abdominal pain and bloody stools. Endoscopic biopsy was an important diagnostic means, and usually more than once to make a definite diagnosis. Retrospective multicenter clinical study showed that younger onset age (<60 years), female, one region involved, one lesion, early stage, International Prognostic Index (IPI ≤1), normal lactate dehydrogenase (LDH), normal albumin, and nonemergency operation were significant prognostic factors for B-cell lymphoma; non-B symptom, tumor restricted to gastric or ileocecal region, one lesion, performance status (PS ≤1), normal LDH, and nonsurgery alone were significant prognostic factors for T-cell lymphoma. Site of origin and IPI were independent prognostic factors for B-cell lymphoma; PS was the independent prognostic factor for T-cell lymphoma. And T-cell lymphoma had worse overall survival (OS) and progression-free survival (PFS) than B-cell lymphoma. Among different therapeutic modalities, chemotherapy alone or combined with surgery showed better OS and PFS than surgery alone for diffuse large B-cell lymphoma (DLBCL) of stage I/II E and T-cell lymphoma. For DLBCL of stage III E/IV and mucosa-associated lymphoid tissue lymphoma, OS and PFS did not differ among different therapeutic groups. In meta-analysis, surgery plus chemotherapy showed lowest mortality. Chemotherapy alone or combined with surgery may be the first-line treatment for DLBCL of stage I/II E and T-cell lymphoma. A flow chart of diagnosis and treatment process for PGIL was approximately drew out. PMID:26632732

Subjective assessments of floor slipperiness before and after walk under two lighting conditions.

PubMed

Li, Kai Way; Zhao, Caijun; Peng, Lu; Liu, Ai-Qun

2018-06-01

A gait experiment was performed. The participants were tested under shoes, floors, surface and lighting conditions. They gave floor slipperiness ratings before and after a gait trial. The perceived sense of slip (PSOS) was collected. It was found that the perceived floor slipperiness (PFS) before walking was affected significantly by the lighting, floor and surface conditions. Relative low PFS values were recorded under wet and detergent-contaminated conditions in the normal daylight condition as compared with those in the dimmed condition. The PFS after the gait was significantly affected by the floor and surface conditions. The PSOS was highly correlated with the PFS after trial. The regression analyses results indicated that both the coefficient of friction (COF) of the floor and lighting were primary predictors of the PFS before a gait. The COF and walking speed were the primary predictors of the PFS after a gait.

Usage of Plant Food Supplements (PFS) for weight control in six European countries: results from the PlantLIBRA PFS Consumer Survey 2011-2012.

PubMed

Garcia-Alvarez, Alicia; Mila-Villarroel, Raimon; Ribas-Barba, Lourdes; Egan, Bernadette; Badea, Mihaela; Maggi, Franco M; Salmenhaara, Maija; Restani, Patrizia; Serra-Majem, Lluis

2016-07-28

Obesity is increasing worldwide and weight-control strategies, including the consumption of plant food supplements (PFS), are proliferating. This article identifies the herbal ingredients in PFS consumed for weight control and by overweight/obese dieters in six European countries, and explores the relationship between their consumption and their self-reported BMI. Data used were a subset from the PlantLIBRA PFS Consumer Survey 2011-2012, a retrospective survey of 2359 PFS consumers. The survey used a bespoke frequency-of-PFS-usage questionnaire. Analyses were performed in two consumer subsamples of 1) respondents taking the products for "body weight reasons", and 2) "dieters for overweight/obesity", to identify the herbal ingredients consumed for these reasons. The relationship between the 5 most consumed herbal ingredients and self-reported BMI in groups 1 and 2 is explored by comparing BMI proportions of consumers vs. non-consumers (using Chi-squared test). 252 PFS (8.8 %) were consumed for "body weight reasons" (by 240 PFS consumers); 112 PFS consumers (4.8 %) were "dieting for overweight/obesity". Spain is the country where consuming herbal ingredients for body weight control and dieting were most popular. Artichoke was the most consumed herbal ingredient. Considering only the 5 top products consumed by those who responded "body weight", when using the total survey sample, a greater proportion of BMI ≥ 25 was observed among consumers of PFS containing artichoke and green tea as compared to non-consumers (58.4 % vs. 49.1 % and 63.2 % vs. 49.7 % respectively). Considering only the 5 top products consumed by "dieters" and using only the "dieters" sample, a lower proportion of BMI ≥ 25 was observed among pineapple-containing PFS consumers (38.5 % vs. 81.5 %); however, when using the entire survey sample, a greater proportion of BMI ≥ 25 was observed among artichoke-containing PFS consumers (58.4 % vs. 49.1 %). A comparison of results among the scarce publications evaluating the use of weight-loss supplements at the population level is limited. Nevertheless every hint is important in finding out which are the self-treatment strategies used by overweight/obese individuals in European countries. Although limited by a small sample size, our study represents a first attempt at analysing such data in six EU countries. Our findings should encourage the conduction of further studies on this topic, long-term and large sample-sized studies, ideally conducted in the general population.

Diffuse thyroid 18F-FDG uptake after R-CHOP therapy predicts favorable outcome in patients with DLBCL.

PubMed

Song, Moo-Kon; Chung, Joo-Seop; Kim, Seong-Jang; Kim, Sang-Soo; Shin, Ho-Jin

2015-06-01

Therapy-induced autoimmunity may mediate the destruction of cancer cells. Previous studies have demonstrated that presence of autoimmune thyroid disorder is associated with favorable outcome in patients with solid cancer. Patients with diffuse large B cell lymphoma (DLBCL) who achieved complete response on positron emission tomography/computed tomography (PET/CT) after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy were enrolled in this study. The patients with and without diffuse thyroid uptake (DTU) were classified by PET/CT. A total of 270 patients were enrolled in this study. DTU related to autoimmune thyroiditis was present in 61 patients. The median time to DTU detection was 5.7 months (range, 0-21.3 months). High International Prognostic Index (IPI) score (progression-free survival [PFS], p = 0.001; overall survival [OS], p = 0.008), bulky mass ≥10 cm (PFS, p = 0.001; OS, p = 0.001), bone marrow involvement (PFS, p < 0.001; OS, p = 0.001), and DTU after R-CHOP therapy (PFS, p < 0.001; OS, p = 0.001) were significantly associated with PFS and OS. High IPI score (PFS, p = 0.003; OS, p = 0.014), BM involvement (PFS, p = 0.009; OS, p = 0.039), and DTU after R-CHOP therapy (PFS, p = 0.002; OS, p = 0.002) were independently associated with PFS and OS. DTU after R-CHOP therapy independently predicted favorable outcomes in patients with DLBCL.

Clinical benefit of continuing crizotinib therapy after initial disease progression in Chinese patients with advanced ALK-rearranged non-small-cell lung cancer.

PubMed

Hong, Xiangchan; Chen, Qi; Ding, Lingyu; Liang, Ying; Zhou, Ningning; Fang, Wenfeng; Chen, Xinru; Wu, Haiying

2017-06-20

Although most patients with ALK-positive non-small-cell lung cancer (NSCLC) who benefit from treatment with crizotinib ultimately develop progressive disease (PD), continuing crizotinb beyond the initial PD (CBPD) in these patients may be beneficial. In this study, we investigated whether Chinese patients with advanced ALK-positive NSCLC benefit from CBPD, and whether any factors are predictive of a longer post-initial progression-free survival time (PFS2). Data on 33 patients with ALK-positive NSCLC who achieved disease control with crizotinib were analyzed retrospectively. The impact of continued crizotinib therapy on the patients' PFS2 time was assessed after adjusting for potential confounding factors. With initial crizotinib therapy, the objective response rate (ORR) and median PFS time (PFS1) in the 33 patients were 63.6% and 8.6 months, respectively. With continued crizotinib therapy after documentation of PD, the median PFS2 for all 33 patients was 16 weeks, and in those with CNS progression but systemic disease control it was 30 weeks. Patients who received local therapy after disease progression had a significantly longer PFS2 compared with those who did not (P = 0.039). Multivariable Cox regression analysis showed that the PFS1 with initial crizotinib treatment and local therapy were independent predictors of PFS2. This study provides further evidence of the benefit of continuing crizotinib therapy in Chinese patients with progressive ALK-positive NSCLC. Patients with a longer PFS1 and those who received local brain therapy would have a longer period of continuing crizotinib.

Millimeter-scale liquid metal droplet thermal switch

NASA Astrophysics Data System (ADS)

Yang, Tianyu; Kwon, Beomjin; Weisensee, Patricia B.; Kang, Jin Gu; Li, Xuejiao; Braun, Paul; Miljkovic, Nenad; King, William P.

2018-02-01

Devices capable of actively controlling heat flow have been desired by the thermal management community for decades. The need for thermal control has become particularly urgent with power densification resulting in devices with localized heat fluxes as high as 1 kW/cm2. Thermal switches, capable of modulating between high and low thermal conductances, enable the partitioning and active control of heat flow pathways. This paper reports a millimeter-scale thermal switch with a switching ratio >70, at heat fluxes near 10 W/cm2. The device consists of a silicone channel filled with a reducing liquid or vapor and an immersed liquid metal Galinstan slug. Galinstan has a relatively high thermal conductivity (≈16.5 W/mK at room temperature), and its position can be manipulated within the fluid channel, using either hydrostatic pressure or electric fields. When Galinstan bridges the hot and cold reservoirs (the "ON" state), heat flows across the channel. When the hot and cold reservoirs are instead filled with the encapsulating liquid or vapor (the "OFF" state), the cross-channel heat flow significantly reduces due to the lower thermal conductivity of the solution (≈0.03-0.6 W/mK). We demonstrate switching ratios as high as 15.6 for liquid filled channels and 71.3 for vapor filled channels. This work provides a framework for the development of millimeter-scale thermal switches and diodes capable of spatial and temporal control of heat flows.

Evaluating Expected Costs and Benefits of Granting Access to New Treatments on the Basis of Progression-Free Survival in Non-Small-Cell Lung Cancer.

PubMed

Lakdawalla, Darius N; Chou, Jacquelyn W; Linthicum, Mark T; MacEwan, Joanna P; Zhang, Jie; Goldman, Dana P

2015-05-01

Surrogate end points may be used as proxy for more robust clinical end points. One prominent example is the use of progression-free survival (PFS) as a surrogate for overall survival (OS) in trials for oncologic treatments. Decisions based on surrogate end points may expedite regulatory approval but may not accurately reflect drug efficacy. Payers and clinicians must balance the potential benefits of earlier treatment access based on surrogate end points against the risks of clinical uncertainty. To present a framework for evaluating the expected net benefit or cost of providing early access to new treatments on the basis of evidence of PFS benefits before OS results are available, using non-small-cell lung cancer (NSCLC) as an example. A probabilistic decision model was used to estimate expected incremental social value of the decision to grant access to a new treatment on the basis of PFS evidence. The model analyzed a hypothetical population of patients with NSCLC who could be treated during the period between PFS and OS evidence publication. Estimates for delay in publication of OS evidence following publication of PFS evidence, expected OS benefit given PFS benefit, incremental cost of new treatment, and other parameters were drawn from the literature on treatment of NSCLC. Incremental social value of early access for each additional patient per month (in 2014 US dollars). For "medium-value" model parameters, early reimbursement of drugs with any PFS benefit yields an incremental social cost of more than $170,000 per newly treated patient per month. In contrast, granting early access on the basis of PFS benefit between 1 and 3.5 months produces more than $73,000 in incremental social value. Across the full range of model parameter values, granting access for drugs with PFS benefit between 3 and 3.5 months is robustly beneficial, generating incremental social value ranging from $38,000 to more than $1 million per newly treated patient per month, whereas access for all drugs with any PFS benefit is usually not beneficial. The value of providing access to new treatments on the basis of surrogate end points, and PFS in particular, likely varies considerably. Payers and clinicians should carefully consider how to use PFS data in balancing potential benefits against costs in each particular disease.

Compensation of voltage drops in solid-state switches used with thermoelectric generators

NASA Technical Reports Server (NTRS)

Shimada, K.

1972-01-01

Seebeck effect solid state switch was developed eliminating thermoelectric generator switch voltage drops. Semiconductor switches were fabricated from materials with large Seebeck coefficients, arranged such that Seebeck potential is generated with such polarity that current flow is aided.

[Assessing the treatment for sacroiliac joint dysfunction, piriformis syndrome and tarsal tunnel syndrome associated with lumbar degenerative disease].

PubMed

Morimoto, Daijiro; Isu, Toyohiko; Shimoda, Yuusuke; Hamauchi, Shuuji; Sasamori, Tooru; Sugawara, Atsushi; Kim, Kyongsong; Matsumoto, Ryouji; Isobe, Masanori

2009-09-01

Sacroiliac joint (SIJ) dysfunction, piriformis syndrome (PFS) and tarsal tunnel syndrome (TTS) produce symptoms similar to lumbar degenerative disease (LDD). Patients who have these diseases plus LDD sometimes experience residual symptoms after surgery for LDD. We therefore assessed the results of treatment of SIJ dysfunction, PFS and TTS associated with LDD. We assessed 25 patients who underwent surgery for LDD and were affected with SIJ dysfunction (12 patients), PFS (7 patients) or TTS (6 patients). SIJ dysfunction was treated with rest, drugs, pelvic band and sacroiliac joint block. PFS was treated with rest, drugs, physical exercise, injection of local anesthetic into the piriformis muscle, and surgical resection of the piriformis muscle. TTS was treated with drugs and tarsal tunnel opening. We analyzed the improvement score and recovery rate (JOA score) for both LDD surgery and the treatment of SIJ dysfunction, PFS and TTS. Symptom improvement was observed in all patients with SIJ dysfunction and PFS and in 4 patients with TTS. The improvement score and recovery rate of treatments for SIJ dysfunction, PFS and TTS were lower than those of surgery for LDD. The improvement score and recovery rate of treatment for SIJ dysfunction, PFS and TTS were not as high as those for LDD. To enhance patient satisfaction, it is important to consider these complicating diseases when designing treatments for LDD.

Effect of fit testing on the protection offered by n95 filtering facepiece respirators against fine particles in a laboratory setting.

PubMed

Reponen, Tiina; Lee, Shu-An; Grinshpun, Sergey A; Johnson, Erik; McKay, Roy

2011-04-01

This study investigated particle-size-selective protection factors (PFs) of four models of N95 filtering facepiece respirators (FFRs) that passed and failed fit testing. Particle size ranges were representative of individual viruses and bacteria (aerodynamic diameter d(a) = 0.04-1.3 μm). Standard respirator fit testing was followed by particle-size-selective measurement of PFs while subjects wore N95 FFRs in a test chamber. PF values obtained for all subjects were then compared to those obtained for the subjects who passed the fit testing. Overall fit test passing rate for all four models of FFRs was 67%. Of these, 29% had PFs <10 (the Occupational Safety and Health Administration Assigned Protection Factor designated for this type of respirator). When only subjects that passed fit testing were included, PFs improved with 9% having values <10. On average, the PFs were 1.4 times (29.5/21.5) higher when only data for those who passed fit testing were included. The minimum PFs were consistently observed in the particle size range of 0.08-0.2 μm. Overall PFs increased when subjects passed fit testing. The results support the value of fit testing but also show for the first time that PFs are dependent on particle size regardless of fit testing status.

Plant food supplement (PFS) market structure in EC Member States, methods and techniques for the assessment of individual PFS intake.

PubMed

Vargas-Murga, Liliana; Garcia-Alvarez, Alicia; Roman-Viñas, Blanca; Ngo, Joy; Ribas-Barba, Lourdes; van den Berg, Suzanne J P L; Williamson, Gary; Serra-Majem, Lluis

2011-12-01

The popularity of herbal products, especially plant food supplements (PFS) and herbal medicine is on the rise in Europe and other parts of the world, with increased use in the general population as well as among specific subgroups encompassing children, women or those suffering from diseases such as cancer. The aim of this paper is to examine the PFS market structures in European Community (EC) Member States as well as to examine issues addressing methodologies and consumption data relating to PFS use in Europe. A revision of recent reports on market data, trends and main distribution channels, in addition an example of the consumption of PFS in Spain, is presented. An overview of the methods and administration techniques used to assess individual food consumption as a starting point, including their uses and limitations, as well as some examples of studies that collect Food Supplement (FS) information, including herbal/botanical/plant-derived products are also discussed. Additionally, the intake estimation process of food nutrients is described and used to propose the PFS ingredients intake estimation process. Nationally representative PFS consumption data is scarce in Europe. The majority of studies have been conducted in Scandinavia and the UK. However the heterogeneity of definitions, study design and objectives make it difficult to compare results and extrapolate conclusions.

Better Gas-Gap Thermal Switches For Sorption Compressors

NASA Technical Reports Server (NTRS)

Bhandari, Pradeep; Rodriguez, Jose

1995-01-01

Gas-gap thermal switches associated with sorption compressors of some heat pumps and cryogenic systems designed for higher performance, according to proposal, by introducing controlled turbulent flows into gas gaps. Utilizes convection in turbulent flow to transfer heat at greater rate. Design takes advantage of flow of working fluid. Working fluid also serve as heat transfer medium in gas gap.

Respiratory analysis system and method

NASA Technical Reports Server (NTRS)

Liu, F. F. (Inventor)

1973-01-01

A system is described for monitoring the respiratory process in which the gas flow rate and the frequency of respiration and expiration cycles can be determined on a real time basis. A face mask is provided with one-way inlet and outlet valves where the gas flow is through independent flowmeters and through a mass spectrometer. The opening and closing of a valve operates an electrical switch, and the combination of the two switches produces a low frequency electrical signal of the respiratory inhalation and exhalation cycles. During the time a switch is operated, the corresponsing flowmeter produces electric pulses representative of the flow rate; the electrical pulses being at a higher frequency than that of the breathing cycle and combined with the low frequency signal. The high frequency pulses are supplied to conventional analyzer computer which also receives temperature and pressure inputs and computes mass flow rate and totalized mass flow of gas. From the mass spectrometer, components of the gas are separately computed as to flow rate. The electrical switches cause operation of up-down inputs of a reversible counter. The respective up and down cycles can be individually monitored and combined for various respiratory measurements.

Integrated Heat Switch/Oxide Sorption Compressor

NASA Technical Reports Server (NTRS)

Bard, Steven

1989-01-01

Thermally-driven, nonmechanical compressor uses container filled with compressed praseodymium cerium oxide powder (PrCeOx) to provide high-pressure flow of oxygen gas for driving closed-cycle Joule-Thomson-expansion refrigeration unit. Integrated heat switch/oxide sorption compressor has no moving parts except check valves, which control flow of oxygen gas between compressor and closed-cycle Joule-Thomson refrigeration system. Oxygen expelled from sorbent at high pressure by evacuating heat-switch gap and turning on heater.

Algae-Produced Pfs25 Elicits Antibodies That Inhibit Malaria Transmission

PubMed Central

Gregory, James A.; Li, Fengwu; Tomosada, Lauren M.; Cox, Chesa J.; Topol, Aaron B.; Vinetz, Joseph M.; Mayfield, Stephen

2012-01-01

Subunit vaccines are significantly more expensive to produce than traditional vaccines because they are based primarily on recombinant proteins that must be purified from the expression system. Despite the increased cost, subunit vaccines are being developed because they are safe, effective, and can elicit antibodies that confer protection against diseases that are not currently vaccine-preventable. Algae are an attractive platform for producing subunit vaccines because they are relatively inexpensive to grow, genetically tractable, easily scaled to large volumes, have a short generation time, and are devoid of inflammatory, viral, or prion contaminants often present in other systems. We tested whether algal chloroplasts can produce malaria transmission blocking vaccine candidates, Plasmodium falciparum surface protein 25 (Pfs25) and 28 (Pfs28). Antibodies that recognize Pfs25 and Pfs28 disrupt the sexual development of parasites within the mosquito midgut, thus preventing transmission of malaria from one human host to the next. These proteins have been difficult to produce in traditional recombinant systems because they contain tandem repeats of structurally complex epidermal growth factor-like domains, which cannot be produced in bacterial systems, and because they are not glycosylated, so they must be modified for production in eukaryotic systems. Production in algal chloroplasts avoids these issues because chloroplasts can fold complex eukaryotic proteins and do not glycosylate proteins. Here we demonstrate that algae are the first recombinant system to successfully produce an unmodified and aglycosylated version of Pfs25 or Pfs28. These antigens are structurally similar to the native proteins and antibodies raised to these recombinant proteins recognize Pfs25 and Pfs28 from P. falciparum. Furthermore, antibodies to algae-produced Pfs25 bind the surface of in-vitro cultured P. falciparum sexual stage parasites and exhibit transmission blocking activity. Thus, algae are promising organisms for producing cysteine-disulfide-containing malaria transmission blocking vaccine candidate proteins. PMID:22615931

Usage of Plant Food Supplements across Six European Countries: Findings from the PlantLIBRA Consumer Survey

PubMed Central

Garcia-Alvarez, Alicia; Egan, Bernadette; de Klein, Simone; Dima, Lorena; Maggi, Franco M.; Isoniemi, Merja; Ribas-Barba, Lourdes; Raats, Monique M.; Meissner, Eva Melanie; Badea, Mihaela; Bruno, Flavia; Salmenhaara, Maija; Milà-Villarroel, Raimon; Knaze, Viktoria; Hodgkins, Charo; Marculescu, Angela; Uusitalo, Liisa; Restani, Patrizia; Serra-Majem, Lluís

2014-01-01

Background The popularity of botanical products is on the rise in Europe, with consumers using them to complement their diets or to maintain health, and products are taken in many different forms (e.g. teas, juices, herbal medicinal products, plant food supplements (PFS)). However there is a scarcity of data on the usage of such products at European level. Objective To provide an overview of the characteristics and usage patterns of PFS consumers in six European countries. Design Data on PFS usage were collected in a cross-sectional, retrospective survey of PFS consumers using a bespoke frequency of PFS usage questionnaire. Subjects/setting A total sample of 2359 adult PFS consumers from Finland, Germany, Italy, Romania, Spain and the United Kingdom. Data analyses Descriptive analyses were conducted, with all data stratified by gender, age, and country. Absolute frequencies, percentages and 95% confidence intervals are reported. Results Overall, an estimated 18.8% of screened survey respondents used at least one PFS. Characteristics of PFS consumers included being older, well-educated, never having smoked and self-reporting health status as “good or very good”. Across countries, 491 different botanicals were identified in the PFS products used, with Ginkgo biloba (Ginkgo), Oenothera biennis (Evening primrose) and Cynara scolymus (Artichoke) being most frequently reported; the most popular dose forms were capsules and pills/tablets. Most consumers used one product and half of all users took single-botanical products. Some results varied across countries. Conclusions The PlantLIBRA consumer survey is unique in reporting on usage patterns of PFS consumers in six European countries. The survey highlights the complexity of measuring the intake of such products, particularly at pan-European level. Incorporating measures of the intake of botanicals in national dietary surveys would provide much-needed data for comprehensive risk and benefit assessments at the European level. PMID:24642692

Investigation of the hypothalamo-pituitary-adrenal axis (HPA) by 1 microg ACTH test and metyrapone test in patients with primary fibromyalgia syndrome.

PubMed

Calis, M; Gökçe, C; Ates, F; Ulker, S; Izgi, H B; Demir, H; Kirnap, M; Sofuoglu, S; Durak, A C; Tutus, A; Kelestimur, F

2004-01-01

Primary fibromyalgia syndrome (PFS) is characterized by widespread chronic pain that affects the musculoskeletal system, fatigue, anxiety, sleep disturbance, headache and postural hypotension. The pathophysiology of PFS is unknown. The hypothalamic-pituitary-adrenal (HPA) axis seems to play an important role in PFS. Both hyperactivity and hypoactivity of the HPA axis have been reported in patients with PFS. In this study we assessed the HPA axis by 1 microg ACTH stimulation test and metyrapone test in 22 patients with PFS and in 15 age-, sex-, and body mass index (BMI)- matched controls. Metyrapone (30 mg/kg) was administered orally at 23:00 h and blood was sampled at 08:30 h the following morning for 11-deoxycortisol. ACTH stimulation test was carried out by using 1 microg (iv) ACTH as a bolus injection after an overnight fast, and blood samples were drawn at 0, 30 and 60 min. Peak cortisol level (659.4 +/- 207.2 nmol/l) was lower in the patients with PFS than peak cortisol level (838.7 +/- 129.6 nmol/l) in the control subjects (p < 0.05). Ten patients (45%) with PFS had peak cortisol responses to 1 microg ACTH test lower than the lowest peak cortisol detected in healthy controls. After metyrapone test 11-deoxycortisol level was 123.7 +/- 26 nmol/l in patients with PFS and 184.2 +/- 17.3 nmol/l in the controls (p < 0.05). Ninety five percent of the patients with PFS had lower 11-deoxycortisol level after metyrapone than the lowest 11-deoxycortisol level after metyrapone detected in healthy controls. We also compared the adrenal size of the patients with that of the healthy subjects and we found that the adrenal size between the groups was similar. This study clearly shows that HPA axis is underactivated in PFS, rather than overactivated.

Epitope analysis of the malaria surface antigen pfs48/45 identifies a subdomain that elicits transmission blocking antibodies.

PubMed

Outchkourov, Nikolay; Vermunt, Adriaan; Jansen, Josephine; Kaan, Anita; Roeffen, Will; Teelen, Karina; Lasonder, Edwin; Braks, Anneke; van de Vegte-Bolmer, Marga; Qiu, Li Yan; Sauerwein, Robert; Stunnenberg, Hendrik G

2007-06-08

Pfs48/45, a member of a Plasmodium-specific protein family, displays conformation-dependent epitopes and is an important target for malaria transmission-blocking (TB) immunity. To design a recombinant Pfs48/45-based TB vaccine, we analyzed the conformational TB epitopes of Pfs48/45. The Pfs48/45 protein was found to consist of a C-terminal six-cysteine module recognized by anti-epitope I antibodies, a middle four-cysteine module recognized by anti-epitopes IIb and III, and an N-terminal module recognized by anti-epitope V antibodies. Refolding assays identified that a fragment of 10 cysteines (10C), comprising the middle four-cysteine and the C-terminal six-cysteine modules, possesses superior refolding capacity. The refolded and partially purified 10C conformer elicited antibodies in mice that targeted at least two of the TB epitopes (I and III). The induced antibodies could block the fertilization of Plasmodium falciparum gametes in vivo in a concentration-dependent manner. Our results provide important insight into the structural organization of the Pfs48/45 protein and experimental support for a Pfs48/45-based subunit vaccine.

Bidirectional buck boost converter

DOEpatents

Esser, Albert Andreas Maria

1998-03-31

A bidirectional buck boost converter and method of operating the same allows regulation of power flow between first and second voltage sources in which the voltage level at each source is subject to change and power flow is independent of relative voltage levels. In one embodiment, the converter is designed for hard switching while another embodiment implements soft switching of the switching devices. In both embodiments, first and second switching devices are serially coupled between a relatively positive terminal and a relatively negative terminal of a first voltage source with third and fourth switching devices serially coupled between a relatively positive terminal and a relatively negative terminal of a second voltage source. A free-wheeling diode is coupled, respectively, in parallel opposition with respective ones of the switching devices. An inductor is coupled between a junction of the first and second switching devices and a junction of the third and fourth switching devices. Gating pulses supplied by a gating circuit selectively enable operation of the switching devices for transferring power between the voltage sources. In the second embodiment, each switching device is shunted by a capacitor and the switching devices are operated when voltage across the device is substantially zero.

Bidirectional buck boost converter

DOEpatents

Esser, A.A.M.

1998-03-31

A bidirectional buck boost converter and method of operating the same allows regulation of power flow between first and second voltage sources in which the voltage level at each source is subject to change and power flow is independent of relative voltage levels. In one embodiment, the converter is designed for hard switching while another embodiment implements soft switching of the switching devices. In both embodiments, first and second switching devices are serially coupled between a relatively positive terminal and a relatively negative terminal of a first voltage source with third and fourth switching devices serially coupled between a relatively positive terminal and a relatively negative terminal of a second voltage source. A free-wheeling diode is coupled, respectively, in parallel opposition with respective ones of the switching devices. An inductor is coupled between a junction of the first and second switching devices and a junction of the third and fourth switching devices. Gating pulses supplied by a gating circuit selectively enable operation of the switching devices for transferring power between the voltage sources. In the second embodiment, each switching device is shunted by a capacitor and the switching devices are operated when voltage across the device is substantially zero. 20 figs.

Progression-Free and Overall Survival in ALK-Positive NSCLC Patients Treated with Sequential Crizotinib and Ceritinib.

PubMed

Gainor, Justin F; Tan, Daniel S W; De Pas, Tomasso; Solomon, Benjamin J; Ahmad, Aziah; Lazzari, Chiara; de Marinis, Filippo; Spitaleri, Gianluca; Schultz, Katherine; Friboulet, Luc; Yeap, Beow Y; Engelman, Jeffrey A; Shaw, Alice T

2015-06-15

Anaplastic lymphoma kinase (ALK) rearrangements are important therapeutic targets in non-small cell lung cancer (NSCLC) that confer sensitivity to the ALK inhibitors crizotinib and ceritinib. To determine the outcome of sequential treatment with crizotinb and ceritinib, we retrospectively evaluated a cohort of ALK-positive patients treated with both agents. We identified 73 ALK-positive NSCLC patients treated with crizotinib followed by ceritinib at four institutions. Medical records were reviewed to determine overall survival (OS) and progression-free survival (PFS) on crizotinib and ceritinib. Among 73 ALK-positive patients, the median PFS (mPFS) on crizotinib was 8.2 months [95% confidence interval (CI), 7.4-10.6]. The median interval from crizotinib discontinuation to initiation of ceritinib was 25 days (range, 1-694). The mPFS on ceritinib was 7.8 months (6.5-9.1). Among 53 patients with no interval therapies between crizotinib and ceritinib, the mPFS on ceritinib was similar at 7.8 months (5.4-9.8). The median combined PFS for sequential treatment with crizotinib and ceritinib was 17.4 months (15.5-19.4). Among 23 patients who underwent post-crizotinib/pre-ceritinib biopsies, there was no difference in PFS on ceritinib between patients with or without ALK resistance mutations (mPFS 5.8 vs. 6.5 months, respectively; P = 0.510). In the overall study population, median OS was 49.4 months (35.5-63.1). Ceritinib has significant antitumor activity in ALK-positive NSCLC-even when crizotinib immediately precedes treatment with ceritinib (median combined PFS 17.0 months). Additional studies are necessary to further define the impact of specific ALK resistance mutations on duration of response to ceritinib. ©2015 American Association for Cancer Research.

Testing a Theoretical Model of Perceived Self-Efficacy for Cancer-Related Fatigue Self-Management and Optimal Physical Functional Status

PubMed Central

Hoffman, Amy J.; von Eye, Alexander; Gift, Audrey G.; Given, Barbara A.; Given, Charles W.; Rothert, Marilyn

2009-01-01

Background Critical gaps exist in the understanding of cancer symptoms, particularly for cancer-related fatigue (CRF). Existing theories and models do not examine the key role perceived self-efficacy (PSE) plays in a person's ability to manage symptoms. Objectives To test the hypothesis that physical functional status (PFS) is predicted through patient characteristics, CRF, other symptoms, and PSE for fatigue self-management in persons with cancer. Methods This study is a secondary data analysis from the baseline observation of two randomized control trials. The combined data set includes 298 subjects who were undergoing a course of chemotherapy. Key variables included physiological and contextual patient characteristics, the severity from CRF and other symptoms, PSE, and PFS. Path analysis examined the relationships among the variables in the proposed theoretical model. Results Persons with cancer reported CRF as the most prevalent symptom among a mean of 7.4 other concurrent symptoms. The severity from CRF had a direct and indirect effect on PFS, with CRF having a direct adverse impact on PFS (t = -7.02) and an indirect adverse effect as part of the severity from the other symptoms (t = 9.69) which also adversely impacted PFS (t = -2.71). Consistent with the proposed theoretical model, PSE had a positive effect on the PFS (t = 2.87) of persons with cancer while serving as a mediator between CRF severity and PFS. Discussion Cancer-related fatigure is prevalent and related to the presence of other symptoms, and PSE for fatigue self-management is an important factor influencing CRF and PFS. A foundation is provided for future intervention studies to increase PSE to achieve optimal PFS in persons with cancer. PMID:19092553

Clinical benefit of continuing crizotinib therapy after initial disease progression in Chinese patients with advanced ALK-rearranged non-small-cell lung cancer

PubMed Central

Hong, Xiangchan; Chen, Qi; Ding, Lingyu; Liang, Ying; Zhou, Ningning; Fang, Wenfeng; Chen, Xinru; Wu, Haiying

2017-01-01

Purpose Although most patients with ALK-positive non?small-cell lung cancer (NSCLC) who benefit from treatment with crizotinib ultimately develop progressive disease (PD), continuing crizotinb beyond the initial PD (CBPD) in these patients may be beneficial. In this study, we investigated whether Chinese patients with advanced ALK-positive NSCLC benefit from CBPD, and whether any factors are predictive of a longer post-initial progression-free survival time (PFS2). Materials and Methods Data on 33 patients with ALK-positive NSCLC who achieved disease control with crizotinib were analyzed retrospectively. The impact of continued crizotinib therapy on the patients’ PFS2 time was assessed after adjusting for potential confounding factors. Results With initial crizotinib therapy, the objective response rate (ORR) and median PFS time (PFS1) in the 33 patients were 63.6% and 8.6 months, respectively. With continued crizotinib therapy after documentation of PD, the median PFS2 for all 33 patients was 16 weeks, and in those with CNS progression but systemic disease control it was 30 weeks. Patients who received local therapy after disease progression had a significantly longer PFS2 compared with those who did not (P = 0.039). Multivariable Cox regression analysis showed that the PFS1 with initial crizotinib treatment and local therapy were independent predictors of PFS2. Discussion This study provides further evidence of the benefit of continuing crizotinib therapy in Chinese patients with progressive ALK-positive NSCLC. Patients with a longer PFS1 and those who received local brain therapy would have a longer period of continuing crizotinib. PMID:28427213

Anti-inflammatory and anti-arthritic activity of total flavonoids of the roots of Sophora flavescens.

PubMed

Jin, Jeong Ho; Kim, Ju Sun; Kang, Sam Sik; Son, Kun Ho; Chang, Hyun Wook; Kim, Hyun Pyo

2010-02-17

The roots of Sophora flavescens have long been used in Chinese medicine for the treatment of fever, inflammatory disorders, ulcers and skin burns. Sophora flavescens contains flavonoids and alkaloids. This study was conducted to develop a plant-based anti-inflammatory agent focused on chronic inflammatory disorders. To accomplish this, the alkaloid-free prenylated flavonoid-enriched fraction (PFS) of rhizomes of Sophora flavescens was prepared and its in vitro and in vivo anti-inflammatory activities were then evaluated for the first time. The inhibitory activity of PFS on PGE(2), NO, IL-6 and TNF-alpha production of lipopolysaccharide (LPS)-treated RAW 264.7 cells was measured. Additionally, adjuvant-induced arthritis in rats was used as an animal model of chronic inflammation to establish the in vivo anti-inflammatory effects of PFS. PFS inhibited cyclooxygenase-2 (COX-2)-catalyzed PGE(2) and inducible nitric oxide synthase (iNOS)-catalyzed NO production by lipopolysaccharide (LPS)-treated RAW 264.7 cells at 10-50 microg/ml, and these effects primarily occurred via COX-2 inhibition and iNOS down-regulation, respectively. PFS also inhibited IL-6 and TNF-alpha production. When tested against adjuvant-induced arthritis in rats (chronic inflammation), PFS strongly inhibited arthritic inflammation when administered orally at doses of 10-100mg/kg/day. In addition, PFS administered orally potently inhibited acetic acid-induced writhing in mice. Our results suggest that PFS inhibits chronic inflammatory response and the inhibition of proinflammatory molecules such as COX-2, iNOS and IL-6 may contribute, at least in part, to the anti-inflammatory activity in vivo. Overall, these results indicate that PFS from Sophora flavescens may have the potential for treatment of chronic inflammatory disorders such as rheumatoid arthritis. Copyright 2009 Elsevier Ireland Ltd. All rights reserved.

Power flow control based solely on slow feedback loop for heart pump applications.

PubMed

Wang, Bob; Hu, Aiguo Patrick; Budgett, David

2012-06-01

This paper proposes a new control method for regulating power flow via transcutaneous energy transfer (TET) for implantable heart pumps. Previous work on power flow controller requires a fast feedback loop that needs additional switching devices and resonant capacitors to be added to the primary converter. The proposed power flow controller eliminates these additional components, and it relies solely on a slow feedback loop to directly drive the primary converter to meet the heart pump power demand and ensure zero voltage switching. A controlled change in switching frequency varies the resonant tank shorting period of a current-fed push-pull resonant converter, thus changing the magnitude of the primary resonant voltage, as well as the tuning between primary and secondary resonant tanks. The proposed controller has been implemented successfully using an analogue circuit and has reached an end-to-end power efficiency of 79.6% at 10 W with a switching frequency regulation range of 149.3 kHz to 182.2 kHz.

Potent malaria transmission-blocking antibody responses elicited by Plasmodium falciparum Pfs25 expressed in Escherichia coli after successful protein refolding.

PubMed

Kumar, Rajesh; Angov, Evelina; Kumar, Nirbhay

2014-04-01

Production of Pfs25, a Plasmodium falciparum transmission-blocking vaccine target antigen, in functional conformation with the potential to elicit effective immunogenicity still remains a major challenge. In the current study, codon-harmonized recombinant Pfs25 (CHrPfs25) was expressed in Escherichia coli, and purified protein after simple oxidative refolding steps retained reduction-sensitive conformational epitopes of transmission-blocking monoclonal antibodies. CHrPfs25 formulated in several adjuvants elicited strong immunogenicity in preclinical studies in mice. Antibodies elicited after immunization recognized native Pfs25 on the surface of live gametes of P. falciparum and demonstrated complete malaria transmission-blocking activity. The transmission-blocking efficacy was 100% even after a 1:128 dilution of sera from immunized mice in the complete Freund's adjuvant and Montanide ISA51 groups and after a 1:16 dilution of sera from mice in the alum group. The blocking was mediated by antibodies; purified IgG at concentrations as low as 31.25 μg/ml exhibited 100% transmission blocking in membrane feeding assays employing two different species of mosquitoes, Anopheles gambiae and Anopheles stephensi. This study provides the first evidence for successful expression of biologically functional rPfs25 in E. coli. The extremely potent malaria transmission-blocking activity of antibodies elicited by immunization with purified protein provides strong support for further evaluation of E. coli-derived CHrPfs25 as a malaria transmission-blocking vaccine in human clinical trials.

Post-operative diffusion weighted imaging as a predictor of posterior fossa syndrome permanence in paediatric medulloblastoma.

PubMed

Chua, Felicia H Z; Thien, Ady; Ng, Lee Ping; Seow, Wan Tew; Low, David C Y; Chang, Kenneth T E; Lian, Derrick W Q; Loh, Eva; Low, Sharon Y Y

2017-03-01

Posterior fossa syndrome (PFS) is a serious complication faced by neurosurgeons and their patients, especially in paediatric medulloblastoma patients. The uncertain aetiology of PFS, myriad of cited risk factors and therapeutic challenges make this phenomenon an elusive entity. The primary objective of this study was to identify associative factors related to the development of PFS in medulloblastoma patient post-tumour resection. This is a retrospective study based at a single institution. Patient data and all related information were collected from the hospital records, in accordance to a list of possible risk factors associated with PFS. These included pre-operative tumour volume, hydrocephalus, age, gender, extent of resection, metastasis, ventriculoperitoneal shunt insertion, post-operative meningitis and radiological changes in MRI. Additional variables included molecular and histological subtypes of each patient's medulloblastoma tumour. Statistical analysis was employed to determine evidence of each variable's significance in PFS permanence. A total of 19 patients with appropriately complete data was identified. Initial univariate analysis did not show any statistical significance. However, multivariate analysis for MRI-specific changes reported bilateral DWI restricted diffusion changes involving both right and left sides of the surgical cavity was of statistical significance for PFS permanence. The authors performed a clinical study that evaluated possible risk factors for permanent PFS in paediatric medulloblastoma patients. Analysis of collated results found that post-operative DWI restriction in bilateral regions within the surgical cavity demonstrated statistical significance as a predictor of PFS permanence-a novel finding in the current literature.

Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small-cell lung cancer and multiple brain metastases (BRAIN): a multicentre, phase 3, open-label, parallel, randomised controlled trial.

PubMed

Yang, Jin-Ji; Zhou, Caicun; Huang, Yisheng; Feng, Jifeng; Lu, Sun; Song, Yong; Huang, Cheng; Wu, Gang; Zhang, Li; Cheng, Ying; Hu, Chengping; Chen, Gongyan; Zhang, Li; Liu, Xiaoqing; Yan, Hong Hong; Tan, Fen Lai; Zhong, Wenzhao; Wu, Yi-Long

2017-09-01

For patients with non-small-cell lung cancer (NSCLC) and multiple brain metastases, whole-brain irradiation (WBI) is a standard-of-care treatment, but its effects on neurocognition are complex and concerning. We compared the efficacy of an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), icotinib, versus WBI with or without chemotherapy in a phase 3 trial of patients with EGFR-mutant NSCLC and multiple brain metastases. We did a multicentre, open-label, parallel randomised controlled trial (BRAIN) at 17 hospitals in China. Eligible participants were patients with NSCLC with EGFR mutations, who were naive to treatment with EGFR-TKIs or radiotherapy, and had at least three metastatic brain lesions. We randomly assigned participants (1:1) to either icotinib 125 mg orally (three times per day) or WBI (30 Gy in ten fractions of 3 Gy) plus concurrent or sequential chemotherapy for 4-6 cycles, until unacceptable adverse events or intracranial disease progression occurred. The randomisation was done by the Chinese Thoracic Oncology Group with a web-based allocation system applying the Pocock and Simon minimisation method; groups were stratified by EGFR gene mutation status, treatment line (first line or second line), brain metastases only versus both intracranial and extracranial metastases, and presence or absence of symptoms of intracranial hypertension. Clinicians and patients were not masked to treatment assignment, but individuals involved in the data analysis did not participate in the treatments and were thus masked to allocation. Patients receiving icotinib who had intracranial progression only were switched to WBI plus either icotinib or chemotherapy until further progression; those receiving icotinib who had extracranial progression only were switched to icotinib plus chemotherapy. Patients receiving WBI who progressed were switched to icotinib until further progression. Icotinib could be continued beyond progression if a clinical benefit was observed by the investigators (eg, an improvement in cognition or intracranial pressure). The primary endpoint was intracranial progression-free survival (PFS), defined as the time from randomisation to either intracranial disease progression or death from any cause. We assessed efficacy and safety in the intention-to-treat population (all participants who received at least one dose of study treatment), hypothesising that intracranial PFS would be 40% longer (hazard ratio [HR] 0·60) with icotinib compared with WBI. This trial is registered with ClinicalTrials.gov, number NCT01724801. Between Dec 10, 2012, and June 30, 2015, we assigned 176 participants to treatment: 85 to icotinib and 91 to WBI. 18 withdrew from the WBI group before treatment, leaving 73 for assessment. Median follow-up was 16·5 months (IQR 11·5-21·5). Median intracranial PFS was 10·0 months (95% CI 5·6-14·4) with icotinib versus 4·8 months (2·4-7·2) with WBI (equating to a 44% risk reduction with icotinib for an event of intracranial disease progression or death; HR 0·56, 95% CI 0·36-0·90; p=0·014). Adverse events of grade 3 or worse were reported in seven (8%) of 85 patients in the icotinib group and 28 (38%) of 73 patients in the WBI group. Raised concentrations of alanine aminotransferase and rash were the most common adverse events of any grade in both groups, occurring in around 20-30% of each group. At the time of final analysis, 42 (49%) patients in the icotinib group and 37 (51%) in the WBI group had died. 78 of these patients died from disease progression, and one patient in the WBI group died from thrombogenesis related to chemotherapy. In patients with EGFR-mutant NSCLC and multiple brain metastases, icotinib was associated with significantly longer intracranial PFS than WBI plus chemotherapy, indicating that icotinib might be a better first-line therapeutic option for this patient population. Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine, National Health and Family Planning Commission of China, Guangzhou Science and Technology Bureau, Betta Pharmaceuticals, and the Chinese Thoracic Oncology Group. Copyright © 2017 Elsevier Ltd. All rights reserved.

A new day for patient financial services.

PubMed

Canfield, David P; Johnston, Scott

2002-09-01

The patient financial services (PFS) department plays a crucial role in the financial health of a provider organization. Complete, accurate data are a competitive advantage. Data should be obtained and validated as early as possible in the process of providing a healthcare service. A redefined revenue cycle should emphasize interdepartmental collaboration, technology, and patient satisfaction. The PFS department should expand its role to emphasize the merging of clinical and financial data in support of the organization's goals. PFS professionals require educational and career opportunities to fulfill the PFS department's expanded role.

Progression-free survival as surrogate and as true end point: insights from the breast and colorectal cancer literature.

PubMed

Saad, E D; Katz, A; Hoff, P M; Buyse, M

2010-01-01

Significant achievements in the systemic treatment of both advanced breast cancer and advanced colorectal cancer over the past 10 years have led to a growing number of drugs, combinations, and sequences to be tested. The choice of surrogate and true end points has become a critical issue and one that is currently the subject of much debate. Many recent randomized trials in solid tumor oncology have used progression-free survival (PFS) as the primary end point. PFS is an attractive end point because it is available earlier than overall survival (OS) and is not influenced by second-line treatments. PFS is now undergoing validation as a surrogate end point in various disease settings. The question of whether PFS can be considered an acceptable surrogate end point depends not only on formal validation studies but also on a standardized definition and unbiased ascertainment of disease progression in clinical trials. In advanced breast cancer, formal validation of PFS as a surrogate for OS has so far been unsuccessful. In advanced colorectal cancer, in contrast, current evidence indicates that PFS is a valid surrogate for OS after first-line treatment with chemotherapy. The other question is whether PFS sufficiently reflects clinical benefit to be considered a true end point in and of itself.

Removal of total cyanide in coking wastewater during a coagulation process: significance of organic polymers.

PubMed

Shen, Jian; Zhao, He; Cao, Hongbin; Zhang, Yi; Chen, Yongsheng

2014-02-01

Whether a cationic organic polymer can remove more total cyanide (TCN) than a non-ionic organic polymer during the same flocculation system has not been reported previously. In this study, the effects of organic polymers with different charge density on the removal mechanisms of TCN in coking wastewater are investigated by polyferric sulfate (PFS) with a cationic organic polymer (PFS-C) or a non-ionic polymer (PFS-N). The coagulation experiments results show that residual concentrations of TCN (Fe(CN)6(3-)) after PFS-C flocculation (TCN < 0.2 mg/L) are much lower than that after PFS-N precipitation. This can be attributed to the different TCN removal mechanisms of the individual organic polymers. To investigate the roles of organic polymers, physical and structural characteristics of the flocs are analyzed by FT-IR, XPS, TEM and XRD. Owing to the presence of N+ in PFS-C, Fe(CN)6(3-) and negative flocs (Fe(CN)6(3-) adsorbed on ferric hydroxides) can be removed via charge neutralization and electrostatic patch flocculation by the cationic organic polymer. However, non-ionic N in PFS-N barely reacts with cyanides through sweeping or bridging, which indicates that the non-ionic polymer has little influence on TCN removal.

Analysis and Evaluation of German Attainments and Research in the Liquid Rocket Engine Field. Volume 8. Rocket Engine Control and Safety Circuits

DTIC Science & Technology

1951-02-01

the pressure switch (16) is activated. This causes the-electrical circuit to open valve (11) and start the igniter (17). The nitrogen pressure...activates the pressure switch (11) at approximately 7 psi before it flows through the Injector (9) into the chamber. ATI-85«’󈧕 - -A 11...precluded. Accordingly, pressure switch (11) is inserted in the system in parallel (electrically) with the flow indicator (17), and the circuit may

Interconnecting network for switching data packets and method for switching data packets

DOEpatents

Benner, Alan Frederic; Minkenberg, Cyriel Johan Agnes; Stunkel, Craig Brian

2010-05-25

The interconnecting network for switching data packets, having data and flow control information, comprises a local packet switch element (S1) with local input buffers (I(1,1) . . . I(1,y)) for buffering the incoming data packets, a remote packet switch element (S2) with remote input buffers (I(2,1) . . . I(2,y)) for buffering the incoming data packets, and data lines (L) for interconnecting the local and the remote packet switch elements (S1, S2). The interconnecting network further comprises a local and a remote arbiter (A1, A2) which are connected via control lines (CL) to the input buffers (I(1,1) . . . I(1,y), I(2,1) . . . I(2,y)), and which are formed such that they can provide that the flow control information is transmitted via the data lines (L) and the control lines (CL).

Genetic Susceptibility to Dental Caries on Pit and Fissure and Smooth Surfaces

PubMed Central

Shaffer, J.R.; Wang, X.; DeSensi, R.S.; Wendell, S.; Weyant, R.J.; Cuenco, K.T.; Crout, R.; McNeil, D.W.; Marazita, M.L.

2012-01-01

Carious lesions are distributed nonuniformly across tooth surfaces of the complete dentition, suggesting that the effects of risk factors may be surface-specific. Whether genes differentially affect caries risk across tooth surfaces is unknown. We investigated the role of genetics on two classes of tooth surfaces, pit and fissure surfaces (PFS) and smooth surfaces (SMS), in more than 2,600 subjects from 740 families. Participants were examined for surface-level evidence of dental caries, and caries scores for permanent and/or primary teeth were generated separately for PFS and SMS. Heritability estimates (h2, i.e. the proportion of trait variation due to genes) of PFS and SMS caries scores were obtained using likelihood methods. The genetic correlations between PFS and SMS caries scores were calculated to assess the degree to which traits covary due to common genetic effects. Overall, the heritability of caries scores was similar for PFS (h2 = 19–53%; p < 0.001) and SMS (h2 = 17–42%; p < 0.001). Heritability of caries scores for both PFS and SMS in the primary dentition was greater than in the permanent dentition and total dentition. With one exception, the genetic correlation between PFS and SMS caries scores was not significantly different from 100%, indicating that (mostly) common genes are involved in the risk of caries for both surface types. Genetic correlation for the primary dentition dfs (decay + filled surfaces) was significantly less than 100% (p < 0.001), indicating that genetic factors may exert differential effects on caries risk in PFS versus SMS in the primary dentition. PMID:22286298

Current limiter circuit system

DOEpatents

Witcher, Joseph Brandon; Bredemann, Michael V.

2017-09-05

An apparatus comprising a steady state sensing circuit, a switching circuit, and a detection circuit. The steady state sensing circuit is connected to a first, a second and a third node. The first node is connected to a first device, the second node is connected to a second device, and the steady state sensing circuit causes a scaled current to flow at the third node. The scaled current is proportional to a voltage difference between the first and second node. The switching circuit limits an amount of current that flows between the first and second device. The detection circuit is connected to the third node and the switching circuit. The detection circuit monitors the scaled current at the third node and controls the switching circuit to limit the amount of the current that flows between the first and second device when the scaled current is greater than a desired level.

Advanced Technical Data Study

DTIC Science & Technology

1975-01-29

will shut down automatically when condenser high pressure causes Pressure Limit Control high pressure switch to release. Press START switch (3...power cable (1) from facility pow- er. Troubleshoot cooling unit, for HI-LOW pressure switch repeated cutout. Refer to AGE ECU Cooling Unit...acti- vate when loss of air flow oc- curred, the pressure switch (3) failed to open circuit. Adjust or replace pressure switch . Refer to

Progression-free survival as primary endpoint in randomized clinical trials of targeted agents for advanced renal cell carcinoma. Correlation with overall survival, benchmarking and power analysis.

PubMed

Bria, Emilio; Massari, Francesco; Maines, Francesca; Pilotto, Sara; Bonomi, Maria; Porta, Camillo; Bracarda, Sergio; Heng, Daniel; Santini, Daniele; Sperduti, Isabella; Giannarelli, Diana; Cognetti, Francesco; Tortora, Giampaolo; Milella, Michele

2015-01-01

A correlation, power and benchmarking analysis between progression-free and overall survival (PFS, OS) of randomized trials with targeted agents or immunotherapy for advanced renal cell carcinoma (RCC) was performed to provide a practical tool for clinical trial design. For 1st-line of treatment, a significant correlation was observed between 6-month PFS and 12-month OS, between 3-month PFS and 9-month OS and between the distributions of the cumulative PFS and OS estimates. According to the regression equation derived for 1st-line targeted agents, 7859, 2873, 712, and 190 patients would be required to determine a 3%, 5%, 10% and 20% PFS advantage at 6 months, corresponding to an absolute increase in 12-month OS rates of 2%, 3%, 6% and 11%, respectively. These data support PFS as a reliable endpoint for advanced RCC receiving up-front therapies. Benchmarking and power analyses, on the basis of the updated survival expectations, may represent practical tools for future trial' design. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Evidence for the Sequestration of Hydrogen-Bearing Volatiles Towards the Moons Southern Pole-Facing Slopes

NASA Technical Reports Server (NTRS)

McClanahan, T. P.; Mitrofanov, I. G.; Boynton, W. V.; Chin, G.; Bodnarik, J.; Droege, G.; Evans, L. G.; Golovin, D.; Hamara, D.; Harshman, K.;

Relationship between venetoclax exposure, rituximab coadministration, and progression-free survival in patients with relapsed or refractory chronic lymphocytic leukemia: demonstration of synergy.

PubMed

Freise, Kevin J; Jones, Aksana K; Menon, Rajeev M; Verdugo, Maria E; Humerickhouse, Rod A; Awni, Walid M; Salem, Ahmed Hamed

2017-12-01

Venetoclax is indicated at a dosage of 400 mg daily (QD) for the treatment of patients with chronic lymphocytic leukemia (CLL) with 17p deletion who have received at least 1 prior therapy. Ongoing trials are evaluating venetoclax in combination with CD20 targeting monoclonal antibodies, such as rituximab. The objective of this research was to characterize the relationship between venetoclax exposures and progression-free survival (PFS) and to evaluate the effect of rituximab coadministration on PFS in patients with relapsed or refractory (R/R) CLL/small lymphocytic lymphoma (SLL). A total of 323 patients from 3 clinical studies of venetoclax, with and without rituximab coadministration, were pooled for the analyses. A time-variant relative risk survival model was used to relate plasma venetoclax concentrations and rituximab administration to PFS. Demographics and baseline disease characteristics were evaluated for their effect on PFS. A concentration-dependent effect of venetoclax on PFS and a prolonged synergistic effect of 6 cycles of concomitant rituximab were identified. The 17p deletion chromosomal aberration was not identified to affect the PFS of patients treated with venetoclax. A venetoclax dose of 400 mg daily QD was estimated to result in a substantial median PFS of 1.8 years (95% confidence interval [CI], 1.7-2.1), whereas the addition of 6 cycles of rituximab was estimated to increase the median PFS to 3.9 years (95% CI, 2.8-5.6). The analysis demonstrates a concentration-dependent effect of venetoclax on PFS and also a synergistic effect with rituximab. Combining venetoclax with the CD20 targeting monoclonal antibody rituximab in R/R CLL/SLL patients provides substantial synergistic benefit compared with increasing the venetoclax monotherapy dose. Copyright © 2016 John Wiley & Sons, Ltd.

Lactate dehydrogenase predicts combined progression-free survival after sequential therapy with abiraterone and enzalutamide for patients with castration-resistant prostate cancer.

PubMed

Mori, Keiichiro; Kimura, Takahiro; Onuma, Hajime; Kimura, Shoji; Yamamoto, Toshihiro; Sasaki, Hiroshi; Miki, Jun; Miki, Kenta; Egawa, Shin

2017-07-01

An array of clinical issues remains to be resolved for castration-resistant prostate cancer (CRPC), including the sequence of drug use and drug cross-resistance. At present, no clear guidelines are available for the optimal sequence of use of novel agents like androgen-receptor axis-targeted (ARAT) agents, particularly enzalutamide, and abiraterone. This study retrospectively analyzed a total of 69 patients with CRPC treated with sequential therapy using enzalutamide followed by abiraterone or vice versa. The primary outcome measure was the comparative combined progression-free survival (PFS) comprising symptomatic and/or radiographic PFS. Patients were also compared for total prostate-specific antigen (PSA)-PFS, overall survival (OS), and PSA response. The predictors of combined PFS and OS were analyzed with a backward-stepwise multivariate Cox model. Of the 69 patients, 46 received enzalutamide first, followed by abiraterone (E-A group), and 23 received abiraterone, followed by enzalutamide (A-E group). The two groups were not significantly different with regard to basic data, except for hemoglobin values. In a comparison with the E-A group, the A-E group was shown to be associated with better combined PFS in Kaplan-Meier analysis (P = 0.043). Similar results were obtained for total PSA-PFS (P = 0.049), while OS did not differ between groups (P = 0.62). Multivariate analysis demonstrated that pretreatment lactate dehydrogenase (LDH) values and age were significant predictors of longer combined PFS (P < 0.05). Likewise, multivariate analysis demonstrated that pretreatment hemoglobin values and performance status were significant predictors of longer OS (P < 0.05). The results of this study suggested the A-E sequence had longer combined PSA and total PSA-PFS compared to the E-A sequence in patients with CRPC. LDH values in sequential therapy may serve as a predictor of longer combined PFS. © 2017 Wiley Periodicals, Inc.

Differences in Treatment Effect Size Between Overall Survival and Progression-Free Survival in Immunotherapy Trials: A Meta-Epidemiologic Study of Trials With Results Posted at ClinicalTrials.gov.

PubMed

Tan, Aidan; Porcher, Raphael; Crequit, Perrine; Ravaud, Philippe; Dechartres, Agnes

2017-05-20

Purpose We aimed to compare treatment effect sizes between overall survival (OS) and progression-free survival (PFS) in trials of US Food and Drug Administration-approved oncology immunotherapy drugs with results posted at ClinicalTrials.gov . Methods We searched ClinicalTrials.gov for phase II to IV cancer trials of Food and Drug Administration-approved immunotherapy drugs and selected those reporting results for both OS and PFS. For each trial, we extracted the hazard ratios (HRs) with 95% CIs for both outcomes and evaluated the differences by a ratio of HRs (rHRs): the HR for PFS to that for OS. We performed a random effects meta-analysis across trials to obtain a summary rHR. We also evaluated surrogacy of PFS for OS by the coefficient of determination and the surrogacy threshold effect, the minimal value of HR for PFS to predict a non-null effect on OS. Results We identified 51 trials assessing 14 drugs across 15 conditions. Treatment effect sizes were 17% greater, on average, with PFS than with OS (rHR, 0.83; 95% CI, 0.79 to 0.88; I 2 = 34.4%; P = .01; τ 2 = 0.0129). Nearly one half of the trials (n = 23, 45%) showed statistically significant benefits for PFS but not for OS. Differences were great for trials of obinutuzumab (rHR, 0.21; 95% CI, 0.08 to 0.54), bevacizumab (rHR, 0.75; 95% CI, 0.67 to 0.84), and rituximab (rHR, 0.79; 95% CI, 0.64 to 0.98). The coefficient of determination was 38% and the surrogacy threshold effect was 0.50. Conclusion Treatment effect sizes in trials of immunotherapy drugs were greater for PFS than for OS, with important differences for some drugs, which is consistent with surrogacy metrics. Caution must be taken when interpreting PFS in the absence of OS data.

The Piper Fatigue Scale-12 (PFS-12): psychometric findings and item reduction in a cohort of breast cancer survivors.

PubMed

Reeve, Bryce B; Stover, Angela M; Alfano, Catherine M; Smith, Ashley Wilder; Ballard-Barbash, Rachel; Bernstein, Leslie; McTiernan, Anne; Baumgartner, Kathy B; Piper, Barbara F

2012-11-01

Brief, valid measures of fatigue, a prevalent and distressing cancer symptom, are needed for use in research. This study's primary aim was to create a shortened version of the revised Piper Fatigue Scale (PFS-R) based on data from a diverse cohort of breast cancer survivors. A secondary aim was to determine whether the PFS captured multiple distinct aspects of fatigue (a multidimensional model) or a single overall fatigue factor (a unidimensional model). Breast cancer survivors (n = 799; stages in situ through IIIa; ages 29-86 years) were recruited through three SEER registries (New Mexico, Western Washington, and Los Angeles, CA) as part of the Health, Eating, Activity, and Lifestyle (HEAL) study. Fatigue was measured approximately 3 years post-diagnosis using the 22-item PFS-R that has four subscales (Behavior, Affect, Sensory, and Cognition). Confirmatory factor analysis was used to compare unidimensional and multidimensional models. Six criteria were used to make item selections to shorten the PFS-R: scale's content validity, items' relationship with fatigue, content redundancy, differential item functioning by race and/or education, scale reliability, and literacy demand. Factor analyses supported the original 4-factor structure. There was also evidence from the bi-factor model for a dominant underlying fatigue factor. Six items tested positive for differential item functioning between African-American and Caucasian survivors. Four additional items either showed poor association, local dependence, or content validity concerns. After removing these 10 items, the reliability of the PFS-12 subscales ranged from 0.87 to 0.89, compared to 0.90-0.94 prior to item removal. The newly developed PFS-12 can be used to assess fatigue in African-American and Caucasian breast cancer survivors and reduces response burden without compromising reliability or validity. This is the first study to determine PFS literacy demand and to compare PFS-R responses in African-Americans and Caucasian breast cancer survivors. Further testing in diverse populations is warranted.

Comparison of coagulation pretreatment of produced water from natural gas well by polyaluminium chloride and polyferric sulphate coagulants.

PubMed

Zhai, Jun; Huang, Zejin; Rahaman, Md Hasibur; Li, Yue; Mei, Longyue; Ma, Hongpu; Hu, Xuebin; Xiao, Haiwen; Luo, Zhiyong; Wang, Kunping

2017-05-01

This study aimed to optimise coagulation pretreatment of the produced water (PW) collected from a natural gas field. Two coagulants, polyferric sulphate (PFS) and polyaluminium chloride (PACl), were applied separately for the organics, suspended solids (SS), and colour removal. Treatment performance at different coagulant dosages, initial pH values, stirring patterns, and the addition of cationic polyacrylamide (PAM) was investigated in jar tests. The optimal coagulation conditions were dosage of PACl 25 g/L or PFS 20 g/L with that of PAM 30 mg/L, initial pH of 11, and fast mixing of 1.5 min (for PACl) or 2 min (for PFS) at 250 rpm followed by slow mixing of 15 min at 50 rpm for both coagulants. PACl performed better than PFS to remove chemical oxygen demand (COD), total organic carbon (TOC), SS, and colour, and achieved a removal efficiency of 90.1%, 89.4%, 99.0%, and 99.9%, respectively, under the optimal condition; while PFS efficiency was 86.1%, 86.1%, 99.0%, and 98.2%, respectively. However, oil removal was higher in PFS coagulation compared to PACl and showed 98.9% and 95.3%, respectively. Biodegradability, ratio of the biological oxygen demand (five-day) (BOD 5 )/COD, of the PW after pretreatment increased from 0.08 to 0.32 for PFS and 0.43 for PACl. Zeta potential (Z-potential) analysis at the optimum coagulant dosage of PACl and PFS suggests that charge neutralisation was the predominant mechanism during coagulation. Better efficiency was observed at higher pH. The addition of PAM and starring pattern had a minor influence on the removal performance of both coagulants. The results suggest that PACl or PFS can be applied for the pretreatment of PW, which can provide substantial removal of carbon, oil, and colour, a necessary first step for subsequent main treatment units such as chemical oxidation or biological treatment.

Novel flat datacenter network architecture based on scalable and flow-controlled optical switch system.

PubMed

Miao, Wang; Luo, Jun; Di Lucente, Stefano; Dorren, Harm; Calabretta, Nicola

2014-02-10

We propose and demonstrate an optical flat datacenter network based on scalable optical switch system with optical flow control. Modular structure with distributed control results in port-count independent optical switch reconfiguration time. RF tone in-band labeling technique allowing parallel processing of the label bits ensures the low latency operation regardless of the switch port-count. Hardware flow control is conducted at optical level by re-using the label wavelength without occupying extra bandwidth, space, and network resources which further improves the performance of latency within a simple structure. Dynamic switching including multicasting operation is validated for a 4 x 4 system. Error free operation of 40 Gb/s data packets has been achieved with only 1 dB penalty. The system could handle an input load up to 0.5 providing a packet loss lower that 10(-5) and an average latency less that 500 ns when a buffer size of 16 packets is employed. Investigation on scalability also indicates that the proposed system could potentially scale up to large port count with limited power penalty.

Access control mechanism of wireless gateway based on open flow

NASA Astrophysics Data System (ADS)

Peng, Rong; Ding, Lei

2017-08-01

In order to realize the access control of wireless gateway and improve the access control of wireless gateway devices, an access control mechanism of SDN architecture which is based on Open vSwitch is proposed. The mechanism utilizes the features of the controller--centralized control and programmable. Controller send access control flow table based on the business logic. Open vSwitch helps achieve a specific access control strategy based on the flow table.

3D Heart Model and 4D Flow MRI 20 Years after Spiral Arterial Switch Operation.

PubMed

Sievers, Hans-Hinrich; Kheradvar, Arash; Kramer, Hans-Heiner; Rickers, Carsten

2016-12-01

Case of a patient is presented here 20 years after spiral direct anastomosis of the great arteries in an arterial switch operation. Three-dimensional model of the heart combined with four-dimensional flow magnetic resonance imaging presents a novel comprehensive way to assess surgical results.

A critical prognostic analysis of neutrophil-lymphocyte ratio for patients undergoing nephroureterectomy due to upper urinary tract urothelial carcinoma.

PubMed

Altan, Mesut; Haberal, Hakan Bahadır; Akdoğan, Bülent; Özen, Haluk

2017-10-01

To determine preoperative serum complete blood count parameters that affects survival of patients who underwent surgery for upper urinary tract urothelial cancer (UUT-UC). Since 1990, 150 patients underwent nephroureterectomy with bladder cuff excision for UUT-UC at Hacettepe University. Patients with a history of muscle-invasive bladder cancer, adjuvant chemotherapy or metastasis at the time of diagnosis were excluded. One hundred and thirteen patients without infective symptoms and with a full set of serum data were evaluated retrospectively. Effects of the neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio (PLR), and leukocyte count on disease-free survival (DFS) and progression-free survival (PFS) were investigated. Threshold values for each parameter to predict PFS were calculated. The mean age and median follow-up were 63.7 ± 11.1 years and 34 (3-186) months, respectively. Male to female ratio was 86/27. The 5-years PFS (bladder recurrence was excluded) and DFS were 59.6 and 38.4%, respectively. In multivariate analysis, NLR was independent prognostic factor for PFS and DFS (p = 0.006 and p = 0.021, respectively) while LMR was prognostic only for PFS (p = 0.037). For UUT-UC, NLR is a prognostic factor for PFS and DFS, while LMR is a prognostic indicator for PFS in present series.

Application of ultrasound in the assessment of plantar fascia in patients with plantar fasciitis: a systematic review.

PubMed

Mohseni-Bandpei, Mohammad Ali; Nakhaee, Masoomeh; Mousavi, Mohammad Ebrahim; Shakourirad, Ali; Safari, Mohammad Reza; Vahab Kashani, Reza

2014-08-01

Plantar fasciitis (PFS) is one of the most common causes of heel pain, estimated to affect 10% of the general population during their lifetime. Ultrasound (US) imaging technique is increasingly being used to assess plantar fascia (PF) thickness, monitor the effect of different interventions and guide therapeutic interventions in patients with PFS. The purpose of the present study was to systematically review previously published studies concerning the application of US in the assessment of PF in patients with PFS. A literature search was performed for the period 2000-2012 using the Science Direct, Scopus, PubMed, CINAHL, Medline, Embase and Springer databases. The key words used were: ultrasound, sonography, imaging techniques, ultrasonography, interventional ultrasonography, plantar fascia and plantar fasciitis. The literature search yielded 34 relevant studies. Sixteen studies evaluated the effect of different interventions on PF thickness in patients with PFS using US; 12 studies compared PF thickness between patients with and without PFS using US; 6 studies investigated the application of US as a guide for therapeutic intervention in patients with PFS. There were variations among studies in terms of methodology used. The results indicated that US can be considered a reliable imaging technique for assessing PF thickness, monitoring the effect of different interventions and guiding therapeutic interventions in patients with PFS. Copyright © 2014 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.

Denitrification and N2O emissions in annual croplands, perennial grass buffers, and restored perennial grasslands

USDA-ARS?s Scientific Manuscript database

Inclusion of perennial vegetation filter strips (PFS) in the toeslope of annual cropland watersheds can decrease nitrate (NO3) losses to ground and surface waters. Although PFS are similar to riparian buffers, PFS are a relatively new conservation tool and the processes responsible for NO3 removal f...

Racial disparities in molecular subtypes of endometrial cancer.

PubMed

Dubil, Elizabeth A; Tian, Chunqiao; Wang, Guisong; Tarney, Christopher M; Bateman, Nicholas W; Levine, Douglas A; Conrads, Thomas P; Hamilton, Chad A; Maxwell, George Larry; Darcy, Kathleen M

2018-04-01

Racial differences in the molecular subtypes of endometrial cancer and associations with progression-free survival (PFS) were evaluated. Molecular, clinical and PFS data were acquired from the Cancer Genome Atlas (TCGA) including classification into the integrative, somatic copy number alteration and transcript-based subtypes. The prevalence and prognostic value of the aggressive molecular subtypes (copy number variant [CNV]-high, cluster 4 or mitotic) were evaluated in Black and White patients. There were 337 patients including 14% self-designated as Black, 27% with advanced stage, and 82% with endometrioid histology. The CNV-high subtype was more common in Black than White patients (61.9% vs. 23.5%, P=0.0005) and suggested worse PFS in Black patients (hazard ratio [HR]=3.4, P=0.189). The cluster 4 subtype was more prevalent in Black patients (56.8% vs. 20.9%, P<0.0001) and associated with worse PFS in Black patients (HR=3.4, P=0.049). The mitotic subtype was more abundant in Black patients (64.1% vs. 33.7%, P=0.002), indicated worse PFS in Black patients (HR=4.1, P=0.044) including the endometrioid histology (HR=6.1, P=0.024) and exhibited race-associated enrichment in cell cycle signaling and pathways in cancer including PLK1 and BIRC7. All of these aggressive molecular subtypes also indicated worse PFS in White patients, with unique enrichments in mitotic signaling different from Black patients. The aggressive molecular subtypes from TCGA were more common in Black endometrial cancer patients and indicated worse PFS in both Black and White patients. The mitotic subtypes also indicated worse PFS in Black patients with endometrioid histology. Enrichment patterns in mitotic signaling may represent therapeutic opportunities. Copyright © 2017. Published by Elsevier Inc.

Mogamulizumab for relapsed adult T-cell leukemia-lymphoma: Updated follow-up analysis of phase I and II studies.

PubMed

Ishida, Takashi; Utsunomiya, Atae; Jo, Tatsuro; Yamamoto, Kazuhito; Kato, Koji; Yoshida, Shinichiro; Takemoto, Shigeki; Suzushima, Hitoshi; Kobayashi, Yukio; Imaizumi, Yoshitaka; Yoshimura, Kenichi; Kawamura, Kouichi; Takahashi, Takeshi; Tobinai, Kensei; Ueda, Ryuzo

2017-10-01

The present study sought to elucidate the prognosis of adult T-cell leukemia-lymphoma (ATL) patients receiving mogamulizumab, a defucosylated anti-CCR4 monoclonal antibody. Progression-free survival (PFS) and overall survival (OS) of ATL patients enrolled in two studies are herein updated, namely NCT00355472 (phase I study of mogamulizumab in relapsed patients with ATL and peripheral T-cell lymphoma) and NCT00920790 (phase II study for relapsed ATL). Of 13 patients with relapsed aggressive ATL in the phase I study, four (31%) survived >3 years. For 26 relapsed patients with aggressive ATL in the phase II study, median PFS was 5.2 months and 1-year PFS was 26%, whereas median OS was 14.4 months, and 3-year OS was 23%. For patients without a rash or who developed a grade 1 rash only, median PFS was 0.8 months, and 1-year PFS was zero, with a median OS of 6.0 months, and 3-year OS of 8%. In contrast, for patients who developed a rash ≥grade 2, median PFS was 11.7 months, and 1-year PFS was 50%, with a median OS of 25.6 months, and 3-year OS of 36%. Thus, we conclude that mogamulizumab monotherapy may improve PFS and OS in some patients with relapsed aggressive ATL, especially those who develop a skin rash as a moderate immune-related adverse event. Therefore, further investigation is warranted to validate the present observations and to clarify the mechanisms involved in the activity of mogamulizumab. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Prediction of survival benefits from progression-free survival benefits in advanced non-small-cell lung cancer: evidence from a meta-analysis of 2334 patients from 5 randomised trials

PubMed Central

Laporte, Silvy; Squifflet, Pierre; Baroux, Noémie; Fossella, Frank; Georgoulias, Vassilis; Pujol, Jean-Louis; Douillard, Jean-Yves; Kudoh, Shinzohy; Pignon, Jean-Pierre; Quinaux, Emmanuel; Buyse, Marc

2013-01-01

Objectives To investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in advanced non-small-cell lung cancer (NSCLC). Design Meta-analysis of individual patient data from randomised trials. Setting Five randomised controlled trials comparing docetaxel-based chemotherapy with vinorelbine-based chemotherapy for the first-line treatment of NSCLC. Participants 2331 patients with advanced NSCLC. Primary and secondary outcome measures Surrogacy of PFS for OS was assessed through the association between these endpoints and between the treatment effects on these endpoints. The surrogate threshold effect was the minimum treatment effect on PFS required to predict a non-zero treatment effect on OS. Results The median follow-up of patients still alive was 23.4 months. Median OS was 10 months and median PFS was 5.5 months. The treatment effects on PFS and OS were correlated, whether using centres (R²=0.62, 95% CI 0.52 to 0.72) or prognostic strata (R²=0.72, 95% CI 0.60 to 0.84) as units of analysis. The surrogate threshold effect was a PFS hazard ratio (HR) of 0.49 using centres or 0.53 using prognostic strata. Conclusions These analyses provide only modest support for considering PFS as an acceptable surrogate for OS in patients with advanced NSCLC. Only treatments that have a major impact on PFS (risk reduction of at least 50%) would be expected to also have a significant effect on OS. Whether these results also apply to targeted therapies is an open question that requires independent evaluation. PMID:23485717

Conjugating recombinant proteins to Pseudomonas aeruginosa ExoProtein A: a strategy for enhancing immunogenicity of malaria vaccine candidates.

PubMed

Qian, Feng; Wu, Yimin; Muratova, Olga; Zhou, Hong; Dobrescu, Gelu; Duggan, Peter; Lynn, Lambert; Song, Guanhong; Zhang, Yanling; Reiter, Karine; MacDonald, Nicholas; Narum, David L; Long, Carole A; Miller, Louis H; Saul, Allan; Mullen, Gregory E D

2007-05-16

Conjugation of polysaccharides to carrier proteins has been a successful approach for producing safe and effective vaccines. In an attempt to increase the immunogenicity of two malarial vaccine candidate proteins of Plasmodium falciparum, apical membrane antigen 1 (AMA1) to a blood stage vaccine candidate and surface protein 25 (Pfs25) a mosquito stage vaccine candidate, were each independently chemically conjugated to the mutant, nontoxic Pseudomonas aeruginosa ExoProtein A (rEPA). AMA1 is a large (66kD) relatively good immunogen in mice; Pfs25 is a poorly immunogenic protein when presented on alum to mice. Mice were immunized on days 0 and 28 with AMA1- or Pfs25-rEPA conjugates or unconjugated AMA1 or Pfs25, all formulated on Alhydrogel. Remarkably, sera from mice 14 days after the second immunization with Pfs25-rEPA conjugates displayed over a 1000-fold higher antibody titers as compared to unconjugated Pfs25. In contrast, AMA1 conjugated under the same conditions induced only a three-fold increase in antibody titers. When tested for functional activity, antibodies elicited by the AMA1-rEPA inhibited invasion of erythrocytes by blood-stage parasites and antibodies elicited by the Pfs25-rEPA conjugates blocked the development of the sexual stage parasites in the mosquito midgut. These results demonstrate that conjugation to rEPA induces a marked improvement in the antibody titer in mice for the poor immunogen (Pfs25) and for the larger protein (AMA1). These conjugates now need to be tested in humans to determine if mice are predictive of the response in humans.

Evaluation of High Ipsilateral Subventricular Zone Radiation Therapy Dose in Glioblastoma: A Pooled Analysis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lee, Percy, E-mail: percylee@mednet.ucla.edu; UCLA Jonsson Comprehensive Cancer Center, Los Angeles, California; Eppinga, Wietse

Purpose: Cancer stem cells (CSCs) may play a role in the recurrence of glioblastoma. They are believed to originate from neural stem cells in the subventricular zone (SVZ). Because of their radioresistance, we hypothesized that high doses of radiation (>59.4 Gy) to the SVZ are necessary to control CSCs and improve progression-free survival (PFS) or overall survival (OS) in glioblastoma. Methods and Materials: 173 patients with glioblastoma pooled from 2 academic centers were treated with resection followed by chemoradiation therapy. The SVZ was segmented on computed tomography to calculate radiation doses delivered to the presumptive CSC niches. The relationships betweenmore » high SVZ doses and PFS and OS were examined using Cox proportional hazards models. Five covariates were included to estimate their impact on PFS or OS: ipsilateral and contralateral SVZ doses, clinical target volume dose, age, and extent of resection. Results: Median PFS and OS were 10.4 and 19.6 months for the cohort. The mean ipsilateral SVZ, contralateral SVZ, and clinical target volume doses were 49.2, 35.2, and 60.1 Gy, respectively. Twenty-one patients who received high ipsilateral SVZ dose (>59.4 Gy) had significantly longer median PFS (12.6 vs 9.9 months, P=.042) and longer OS (25.8 vs 19.2 months, P=.173). On multivariate analysis, high radiation therapy doses to ipsilateral SVZ remained a statistically significant independent predictor of improved PFS but not of OS. The extent of surgery affected both PFS and OS on multivariate analysis. Conclusion: High radiation therapy doses to ipsilateral CSC niches are associated with improved PFS in glioblastoma.« less

Experimental Studies of Radiation and Plasma Effects behind the Incident Shock in LENS XX, and the Unsteady Flow Characteristics associated with Free Flight Shroud and Stage Separation and Mode Switching in LENS II

DTIC Science & Technology

2010-04-01

Characteristics associated with “Free Flight” Shroud and Stage Separation and Mode Switching in LENS II Michael S. Holden, PhD CUBRC , Inc. 4455 Genesee...ADDRESS(ES) CUBRC , Inc. 4455 Genesee Street Buffalo, NY 14225, USA 8. PERFORMING ORGANIZATION REPORT NUMBER 9. SPONSORING/MONITORING AGENCY NAME(S) AND...switching and inlet-starting validation • Validation to CFD community ( CUBRC /UM) Figure 32: Numerical Simulation of the Unsteady Flow Dynamics during

Polyferric sulphate: preparation, characterisation and application in coagulation experiments.

PubMed

Zouboulis, A I; Moussas, P A; Vasilakou, F

2008-07-15

The process of coagulation is a core environmental protection technology, which is mainly used in the water or wastewater treatment facilities. Research is now focused on the development of inorganic pre-polymerised coagulants. A characteristic example is PFS (polyferric sulphate), a relatively new pre-polymerised inorganic coagulant with high cationic charge. In this paper, the role of major parameters, including temperature, types of chemical reagents, ratio r=[OH]/[Fe], rate of base addition in the preparation stages of PFS were investigated. Furthermore, the prepared PFS was characterised based on typical properties, such as the percentage of the polymerised iron present in the compound, z-potential, pH, etc. Moreover, dynamics of coagulation process were examined by means of the Photometric Dispersion Analyzer (PDA). Finally, the coagulation efficiency of PFS in treating kaolin suspension and biologically pre-treated wastewater was evaluated in comparison with the respective conventional coagulant agent. The results indicate that certain parameters, such as the r value, the rate of base addition and the duration and temperature of the polymerisation stage, significantly affected the properties of the PFS. Additionally, the prepared PFS polymerised coagulants exhibit a significantly better coagulation performance than the respective non-polymerised one, i.e. ferric sulphate.

Inverting Quasi-Resonant Switched-Capacitor Bidirectional Converter and Its Application to Battery Equalization

NASA Astrophysics Data System (ADS)

Lee, Yuang-Shung; Chiu, Yin-Yuan; Cheng, Ming-Wang; Ko, Yi-Pin; Hsiao, Sung-Hsin

The proposed quasi-resonant (QR) zero current switching (ZCS) switched-capacitor (SC) converter is a new type of bidirectional power flow control conversion scheme. The proposed converter is able to provide voltage conversion ratios from -3/-{1 \\over 3} (triple-mode/trisection-mode) to -n/-{1 \\over n} (-n-mode/-{1 \\over n}-mode) by adding a different number of switched-capacitors and power MOSFET switches with a small series connected resonant inductor for forward and reverse power flow control schemes. It possesses the advantages of low switching losses and current stress in this QR ZCS SC converter. The principle of operation, theoretical analysis of the proposed triple-mode/trisection-mode bidirectional power conversion scheme is described in detail with circuit model analysis. Simulation and experimental studies are carried out to verify the performance of the proposed inverting type ZCS SC QR bidirectional converter. The proposed converters can be applied to battery equalization for battery management system (BMS).

Outcomes of Complete Versus Partial Surgical Stabilization of Flail Chest.

PubMed

Nickerson, Terry P; Thiels, Cornelius A; Kim, Brian D; Zielinski, Martin D; Jenkins, Donald H; Schiller, Henry J

2016-01-01

Rib fractures are common after chest wall trauma. For patients with flail chest, surgical stabilization is a promising technique for reducing morbidity. Anatomical difficulties often lead to an inability to completely repair the flail chest; thus, the result is partial flail chest stabilization (PFS). We hypothesized that patients with PFS have outcomes similar to those undergoing complete flail chest stabilization (CFS). A prospectively collected database of all patients who underwent rib fracture stabilization procedures from August 2009 until February 2013 was reviewed. Abstracted data included procedural and complication data, extent of stabilization, and pulmonary function test results. Of 43 patients who underwent operative stabilization of flail chest, 23 (53%) had CFS and 20 (47%) underwent PFS. Anterior location of the fracture was the most common reason for PFS (45%). Age, sex, operative time, pneumonia, intensive care unit and hospital length of stay, and narcotic use were the same in both groups. Total lung capacity was significantly improved in the CFS group at 3 months. No chest wall deformity was appreciated on follow-up, and no patients underwent additional stabilization procedures following PFS. Despite advances in surgical technique, not all fractures are amenable to repair. There was no difference in chest wall deformity, narcotic use, or clinically significant impairment in pulmonary function tests among patients who underwent PFS compared with CFS. Our data suggest that PFS is an acceptable strategy and that extending or creating additional incisions for CFS is unnecessary.

Fused thiophene and its periphery fluorinated substitution derivatives: a theoretical study for organic semiconductors

NASA Astrophysics Data System (ADS)

Wei, Hui-Ling; Shi, Ya-Rui; Liu, Yu-Fang

2015-06-01

A series of phenyl end-capped derivatives of benzo[d,d‧]thieno[3,2-b4,5- b‧]dithiophene (BTDT) with periphery-fluorinated substitutions (PFS) were systematically investigated by using density functional theory (DFT) combined with the Marcus-Hush electron transfer theory. The substituting effects of PFS were discussed. Compared with the original compounds, (i) the PFS compounds have a relatively higher efficiency of charge transport, lower barriers of electron injection, and larger HOMO-LUMO gaps; (ii) the air-stability and the device performance are enhanced by PFS; and (iii) the HOMO-LUMO transitions in the absorption spectrum of the PFS compounds show an obvious blue-shift trend. The perfluorophenylbisbenzo[d, d‧]thieno[3,2-b4,5-b‧]dithiophene (BpF-BTDT) is found to be the most stable and most effective compound in charge transport among the investigated compounds, and it is suggested as an ambipolar semiconducting material. The results of electronic coupling of the bisbenzo[d, d‧]thieno[3,2-b 4,5- b‧]dithiophene (BBTDT) derivatives show that the orbital interaction is mainly contributed by the neighboring molecule in the two dimensional (2D) layer. The PFS compounds have lower oxidization potential, ionization potential, and electron affinity values than the corresponding original ones, which suggest that fluorination can enhance the performance of the thiophene-based organic solar cells. These findings provide a better understanding of the PFS effects on organic semiconductors and may help to design high-performance semiconductor materials.

Plasmodium evasion of mosquito immunity and global malaria transmission: The lock-and-key theory.

PubMed

Molina-Cruz, Alvaro; Canepa, Gaspar E; Kamath, Nitin; Pavlovic, Noelle V; Mu, Jianbing; Ramphul, Urvashi N; Ramirez, Jose Luis; Barillas-Mury, Carolina

2015-12-08

Plasmodium falciparum malaria originated in Africa and became global as humans migrated to other continents. During this journey, parasites encountered new mosquito species, some of them evolutionarily distant from African vectors. We have previously shown that the Pfs47 protein allows the parasite to evade the mosquito immune system of Anopheles gambiae mosquitoes. Here, we investigated the role of Pfs47-mediated immune evasion in the adaptation of P. falciparum to evolutionarily distant mosquito species. We found that P. falciparum isolates from Africa, Asia, or the Americas have low compatibility to malaria vectors from a different continent, an effect that is mediated by the mosquito immune system. We identified 42 different haplotypes of Pfs47 that have a strong geographic population structure and much lower haplotype diversity outside Africa. Replacement of the Pfs47 haplotypes in a P. falciparum isolate is sufficient to make it compatible to a different mosquito species. Those parasites that express a Pfs47 haplotype compatible with a given vector evade antiplasmodial immunity and survive. We propose that Pfs47-mediated immune evasion has been critical for the globalization of P. falciparum malaria as parasites adapted to new vector species. Our findings predict that this ongoing selective force by the mosquito immune system could influence the dispersal of Plasmodium genetic traits and point to Pfs47 as a potential target to block malaria transmission. A new model, the "lock-and-key theory" of P. falciparum globalization, is proposed, and its implications are discussed.

Expression of FGFR3 and FGFR4 and clinical risk factors associated with progression-free survival in synovial sarcoma.

PubMed

Charbonneau, Bridget; Vogel, Rachel Isaksson; Manivel, J Carlos; Rizzardi, Anthony; Schmechel, Stephen C; Ognjanovic, Simona; Subramanian, Subbaya; Largaespada, David; Weigel, Brenda

2013-09-01

Although rare, synovial sarcoma (SS) is one of the most common soft tissue sarcomas affecting young adults. To investigate potential tumor markers related to synovial sarcoma prognosis, we carried out a single-institution retrospective analysis of 103 patients diagnosed with SS between 1980 and 2009. Clinical outcome data were obtained from medical records, and archived tissue samples were used to evaluate the relationship between progression-free survival (PFS) and several prognostic factors, including tumor expression of FGFR3 and FGFR4. No associations were found between PFS and gender, body mass index, tumor site, SS18-SSX translocation, or FGFR4 expression. As seen in previous studies, age at diagnosis (<35, 63% versus ≥35 years, 31% 10-year PFS; P = .033), histologic subtype (biphasic, 75% versus monophasic 34% 10-year PFS; P = .034), and tumor size (≤5 cm, 70% versus >5 cm, 22% 10-year PFS; P < .0001) were associated with PFS in SS patients. In addition, in a subset of patients with available archived tumor samples taken prior to chemotherapy or radiation (n = 34), higher FGFR3 expression was associated with improved PFS (P = .030). To the best of our knowledge, this is the largest study of SS to date to suggest a potential clinical role for FGFR3. While small numbers make this investigation somewhat exploratory, the findings merit future investigation on a larger scale. Copyright © 2013 Elsevier Inc. All rights reserved.

Using Interferon Alfa Before Tyrosine Kinase Inhibitors May Increase Survival in Patients With Metastatic Renal Cell Carcinoma: A Turkish Oncology Group (TOG) Study.

PubMed

Artaç, Mehmet; Çoşkun, Hasan Şenol; Korkmaz, Levent; Koçer, Murat; Turhal, Nazım Serdar; Engin, Hüseyin; Dede, İsa; Paydaş, Semra; Öksüzoğlu, Berna; Bozcuk, Hakan; Demirkazık, Ahmet

2016-08-01

We aimed to investigate the outcomes of interferon alfa and sequencing tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma. This multicenter study assessing the efficacy of TKIs after interferon alfa therapy in the first-line setting in patients with metastatic renal cell carcinoma. Patients (n = 104) from 8 centers in Turkey, who had been treated with interferon alfa in the first-line setting, were included in the study. Prognostic factors were evaluated for progression-free survival (PFS). The median age of the patients was 57 years. The median PFS of the patients treated with interferon alfa in the first-line was 3.6 months. A total of 61 patients received TKIs (sunitinib, n = 58; sorafenib, n = 3) after progression while on interferon alfa. The median PFS among the TKI-treated patients was 13.2 months. In the univariate analysis for interferon alfa treatment, neutrophil and hemoglobin level, platelet count, and Karnofsky performance status were the significant factors associated with PFS. In the univariate analysis for TKI treatment, neutrophil and hemoglobin levels were the significant factors for PFS. The median total PFS of the patients who had been treated with first-line interferon alfa and second-line TKIs was 24.9 months. This study showed that first-line interferon alfa treatment before TKIs may improve the total PFS in patients with metastatic renal cell carcinoma. Copyright © 2016 Elsevier Inc. All rights reserved.

Microfluidic T-form mixer utilizing switching electroosmotic flow.

PubMed

Lin, Che-Hsin; Fu, Lung-Ming; Chien, Yu-Sheng

2004-09-15

This paper presents a microfluidic T-form mixer utilizing alternatively switching electroosmotic flow. The microfluidic device is fabricated on low-cost glass slides using a simple and reliable fabrication process. A switching DC field is used to generate an electroosmotic force which simultaneously drives and mixes the fluid samples. The proposed design eliminates the requirements for moving parts within the microfluidic device and delicate external control systems. Two operation modes, namely, a conventional switching mode and a novel pinched switching mode, are presented. Computer simulation is employed to predict the mixing performance attainable in both operation modes. The simulation results are then compared to those obtained experimentally. It is shown that a mixing performance as high as 97% can be achieved within a mixing distance of 1 mm downstream from the T-junction when a 60 V/cm driving voltage and a 2-Hz switching frequency are applied in the pinched switching operation mode. This study demonstrates how the driving voltage and switching frequency can be optimized to yield an enhanced mixing performance. The novel methods presented in this study provide a simple solution to mixing problems in the micro-total-analysis-systems field.

The three-dimensional structure of swirl-switching in bent pipe flow

DOE PAGES

Hufnagel, Lorenz; Canton, Jacopo; Örlü, Ramis; ...

2017-11-27

Swirl-switching is a low-frequency oscillatory phenomenon which affects the Dean vortices in bent pipes and may cause fatigue in piping systems. Despite thirty years worth of research, the mechanism that causes these oscillations and the frequencies that characterise them remain unclear. In this paper, we show that a three-dimensional wave-like structure is responsible for the low-frequency switching of the dominant Dean vortex. The present study, performed via direct numerical simulation, focuses on the turbulent flow through amore » $$90^{\\circ }$$pipe bend preceded and followed by straight pipe segments. A pipe with curvature 0.3 (defined as ratio between pipe radius and bend radius) is studied for a bulk Reynolds number $$Re=11\\,700$$, corresponding to a friction Reynolds number $$Re_{\\unicode[STIX]{x1D70F}}\\approx 360$$. Synthetic turbulence is generated at the inflow section and used instead of the classical recycling method in order to avoid the interference between recycling and swirl-switching frequencies. The flow field is analysed by three-dimensional proper orthogonal decomposition (POD) which for the first time allows the identification of the source of swirl-switching: a wave-like structure that originates in the pipe bend. Contrary to some previous studies, the flow in the upstream pipe does not show any direct influence on the swirl-switching modes. Finally, our analysis further shows that a three-dimensional characterisation of the modes is crucial to understand the mechanism, and that reconstructions based on two-dimensional POD modes are incomplete.« less

The three-dimensional structure of swirl-switching in bent pipe flow

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hufnagel, Lorenz; Canton, Jacopo; Örlü, Ramis

Swirl-switching is a low-frequency oscillatory phenomenon which affects the Dean vortices in bent pipes and may cause fatigue in piping systems. Despite thirty years worth of research, the mechanism that causes these oscillations and the frequencies that characterise them remain unclear. In this paper, we show that a three-dimensional wave-like structure is responsible for the low-frequency switching of the dominant Dean vortex. The present study, performed via direct numerical simulation, focuses on the turbulent flow through amore » $$90^{\\circ }$$pipe bend preceded and followed by straight pipe segments. A pipe with curvature 0.3 (defined as ratio between pipe radius and bend radius) is studied for a bulk Reynolds number $$Re=11\\,700$$, corresponding to a friction Reynolds number $$Re_{\\unicode[STIX]{x1D70F}}\\approx 360$$. Synthetic turbulence is generated at the inflow section and used instead of the classical recycling method in order to avoid the interference between recycling and swirl-switching frequencies. The flow field is analysed by three-dimensional proper orthogonal decomposition (POD) which for the first time allows the identification of the source of swirl-switching: a wave-like structure that originates in the pipe bend. Contrary to some previous studies, the flow in the upstream pipe does not show any direct influence on the swirl-switching modes. Finally, our analysis further shows that a three-dimensional characterisation of the modes is crucial to understand the mechanism, and that reconstructions based on two-dimensional POD modes are incomplete.« less

Tuning the resistive switching properties of TiO2-x films

NASA Astrophysics Data System (ADS)

Ghenzi, N.; Rozenberg, M. J.; Llopis, R.; Levy, P.; Hueso, L. E.; Stoliar, P.

2015-03-01

We study the electrical characteristics of TiO2-x-based resistive switching devices fabricated with different oxygen/argon flow ratio during the oxide thin film sputtering deposition. Upon minute changes in this fabrication parameter, three qualitatively different device characteristics were accessed in the same system, namely, standard bipolar resistive switching, electroforming-free devices, and devices with multi-step breakdown. We propose that small variations in the oxygen/ argon flow ratio result in relevant changes of the oxygen vacancy concentration, which is the key parameter determining the resistive switching behavior. The coexistence of percolative or non-percolative conductive filaments is also discussed. Finally, the hypothesis is verified by means of the temperature dependence of the devices in low resistance state.

The Piper Fatigue Scale-12 (PFS-12): Psychometric Findings and Item Reduction in a Cohort of Breast Cancer Survivors

PubMed Central

Reeve, Bryce B.; Stover, Angela M.; Alfano, Catherine M.; Smith, Ashley Wilder; Ballard-Barbash, Rachel; Bernstein, Leslie; McTiernan, Anne; Baumgartner, Kathy B.; Piper, Barbara F.

2013-01-01

Purpose Brief, valid measures of fatigue, a prevalent and distressing cancer symptom, are needed for use in research. This study’s primary aim was to create a shortened version of the revised Piper Fatigue Scale (PFS-R) based on data from a diverse cohort of breast cancer survivors. A secondary aim was to determine whether the PFS captured multiple distinct aspects of fatigue (a multidimensional model) or a single overall fatigue factor (a unidimensional model). Methods Breast cancer survivors (n=799; stages in situ through IIIa; ages 29–86 yrs) were recruited through 3 SEER registries (New Mexico, Western Washington, and Los Angeles, CA) as part of the Health, Eating, Activity, and Lifestyle (HEAL) study. Fatigue was measured approximately 3 years post-diagnosis using the 22-item PFS-R that has 4 subscales (Behavior, Affect, Sensory, and Cognition). Confirmatory factor analysis was used to compare unidimensional and multidimensional models. Six criteria were used to make item selections to shorten the PFS-R: scale’s content validity, items’ relationship with fatigue, content redundancy, differential item functioning by race and/or education, scale reliability, and literacy demand. Results Factor analyses supported the original 4-factor structure. There was also evidence from the bi-factor model for a dominant underlying fatigue factor. Six items tested positive for differential item functioning between African-American and Caucasian survivors. Four additional items either showed poor association, local dependence, or content validity concerns. After removing these 10 items, the reliability of the PFS-12 subscales ranged from 0.87–0.89, compared to 0.90–0.94 prior to item removal. Conclusion The newly developed PFS-12 can be used to assess fatigue in African-American and Caucasian breast cancer survivors and reduces response burden without compromising reliability or validity. This is the first study to determine PFS literacy demand and to compare PFS-R responses in African-Americans and Caucasian breast cancer survivors. Further testing in diverse populations is warranted. PMID:22933027

Axis switching and spreading of an asymmetric jet: Role of vorticity dynamics

NASA Technical Reports Server (NTRS)

Zaman, K. B. M. Q.

1994-01-01

The effects of vortex generators and periodic excitation on vorticity dynamics and the phenomenon of axis switching in a free asymmetric jet are studied experimentally. Most of the data reported are for a 3:1 rectangular jet at a Reynolds number of 450,000 and a Mach number of 0.31. The vortex generators are in the form of 'delta tabs', triangular shaped protrusions into the flow, placed at the nozzle exit. With suitable placement of the tabs, axis switching could be either stopped or augmented. Two mechanisms are identified governing the phenomenon. One, as described by previous researchers and referred to here as the omega(sub theta)-induced dynamics, is due to difference in induced velocities for different segments of a rolled up azimuthal vortical structure. The other, omega(sub x)-induced dynamics, is due to the induced velocities of streamwise vortex pairs in the flow. Both dynamics can be active in a natural asymmetric jet; the tendency for axis switching caused by the omega(sub theta)-induced dynamics may be, depending on the streamwise vorticity distribution, either resisted or enhanced by the omega(sub x)-induced dynamics. While this simple framework qualitatively explains the various observations made on axis switching, mechanisms actually in play may be much more complex. The two dynamics are not independent as the flow field is replete with both azimuthal and streamwise vortical structures which continually interact. Phase averaged flow field data for a periodically forced case, over a volume of the flow field, are presented and discussed in an effort to gain insight into the dynamics of these vortical structures.

Size-sensitive sorting of microparticles through control of flow geometry

NASA Astrophysics Data System (ADS)

Wang, Cheng; Jalikop, Shreyas V.; Hilgenfeldt, Sascha

2011-07-01

We demonstrate a general concept of flow manipulation in microfluidic environments, based on controlling the shape and position of flow domains in order to force switching and sorting of microparticles without moving parts or changes in design geometry. Using microbubble acoustic streaming, we show that regulation of the relative strength of streaming and a superimposed Poiseuille flow allows for size-selective trapping and releasing of particles, with particle size sensitivity much greater than what is imposed by the length scales of microfabrication. A simple criterion allows for quantitative tuning of microfluidic devices for switching and sorting of particles of desired size.

Circuit with a Switch for Charging a Battery in a Battery Capacitor Circuit

NASA Technical Reports Server (NTRS)

Stuart, Thomas A. (Inventor); Ashtiani, Cyrus N. (Inventor)

2008-01-01

A circuit for charging a battery combined with a capacitor includes a power supply adapted to be connected to the capacitor, and the battery. The circuit includes an electronic switch connected to the power supply. The electronic switch is responsive to switch between a conducting state to allow current and a non-conducting state to prevent current flow. The circuit includes a control device connected to the switch and is operable to generate a control signal to continuously switch the electronic switch between the conducting and non-conducting states to charge the battery.

Optical Constituents at the Mouth of the Columbia River: Variability and Signature in Remotely Sensed Reflectance

DTIC Science & Technology

2013-09-30

constructed at BIO, carried the new Machine Vision Floc Camera (MVFC), a Sequoia Scientific LISST 100x Type B, an RBR CTD, and two pressure-actuated...WetStar CDOM fluorometer, a Sequoia Scientific flow control switch, and a SeaBird 37 CTD. The flow-control switch allows the ac- 9 to collect 0.2-um

Research and embedded implementation of Layer 3 switch

NASA Astrophysics Data System (ADS)

Song, Jin; Cheng, Zijing

2009-12-01

In the internetworking world, switches and routers have been deployed for workgroup and enterprise connectivity. In the past, switches mainly operated at Layer 2 (they were extensions of bridges), while routers were clearly Layer3 devices. Recently, the line has blurred and switches operating at Layer 3 are becoming more popular. This paper explains the Linux Bridge, Layer 2 Switches, Virtual LAN (VLAN) and Layer 3 Switches. The flow chart of Layer 3 switches and working routine related to Layer 3 switch technology were investigated in detail. This paper presents a new method to implement layer 3 switching that is entirely accomplished in software and is embedded implemented by code transplanting based on PowerPC 460GT platform.

Pre-filled syringe - a ready-to-use drug delivery system: a review.

PubMed

Ingle, Rahul G; Agarwal, Aayush S

2014-09-01

Fueled by a growing global expectation of the health and medical fields, billions of dollars/euros/pounds are invested every year in the research of new biological and chemical entities. However, little interest is seen in the development of novel drug delivery systems. One such system, pre-filled syringe (PFS), was invented decades ago but is still a rare mode of delivery in many therapeutic segments. This review comprises properties and effects of extractables, leachables and discuss the characteristics of PFS technology; its composition, glass and polymer types, configuration of PFS, advantages over glass, technical and commercial applicability; its significance against patient, industry, quality, environment and cost; and its business potential. We discuss in brief about PFS used in various major and life-threatening disorders and future prospects. It provides showers of knowledge in the field of PFS drug delivery technology to the reader's, industrialist's and researcher's point of view. The PFS drug delivery system offers a wonderful panorama to lifesaving drugs that are currently only available in conventional vials and ampoules in the market. A novel approach of Form Fill Seal technology can be adopted for this particular ready-to-use dosage form also, which opens the new global doors for budding researchers in the field of pre-filled drug delivery system.

Long-term white matter tract reorganization following prolonged febrile seizures.

PubMed

Pujar, Suresh S; Seunarine, Kiran K; Martinos, Marina M; Neville, Brian G R; Scott, Rod C; Chin, Richard F M; Clark, Chris A

2017-05-01

Diffusion magnetic resonance imaging (MRI) studies have demonstrated acute white matter changes following prolonged febrile seizures (PFS), but their longer-term evolution is unknown. We investigated a population-based cohort to determine white matter diffusion properties 8 years after PFS. We used diffusion tensor imaging (DTI) and applied Tract-Based Spatial Statistics for voxel-wise comparison of white matter microstructure between 26 children with PFS and 27 age-matched healthy controls. Age, gender, handedness, and hippocampal volumes were entered as covariates for voxel-wise analysis. Mean duration between the episode of PFS and follow-up was 8.2 years (range 6.7-9.6). All children were neurologically normal, and had normal conventional neuroimaging. On voxel-wise analysis, compared to controls, the PFS group had (1) increased fractional anisotropy in early maturing central white matter tracts, (2) increased mean and axial diffusivity in several peripheral white matter tracts and late-maturing central white matter tracts, and (3) increased radial diffusivity in peripheral white matter tracts. None of the tracts had reduced fractional anisotropy or diffusivity indices in the PFS group. In this homogeneous, population-based sample, we found increased fractional anisotropy in early maturing central white matter tracts and increased mean and axial diffusivity with/without increased radial diffusivity in several late-maturing peripheral white matter tracts 8 years post-PFS. We propose disruption in white matter maturation secondary to seizure-induced axonal injury, with subsequent neuroplasticity and microstructural reorganization as a plausible explanation. © 2017 The Authors. Epilepsia published by Wiley Periodicals, Inc. on behalf of International League Against Epilepsy.

Rain Characteristics and Large-Scale Environments of Precipitation Objects with Extreme Rain Volumes from TRMM Observations

NASA Technical Reports Server (NTRS)

Zhou, Yaping; Lau, William K M.; Liu, Chuntao

2013-01-01

This study adopts a "precipitation object" approach by using 14 years of Tropical Rainfall Measuring Mission (TRMM) Precipitation Feature (PF) and National Centers for Environmental Prediction (NCEP) reanalysis data to study rainfall structure and environmental factors associated with extreme heavy rain events. Characteristics of instantaneous extreme volumetric PFs are examined and compared to those of intermediate and small systems. It is found that instantaneous PFs exhibit a much wider scale range compared to the daily gridded precipitation accumulation range. The top 1% of the rainiest PFs contribute over 55% of total rainfall and have 2 orders of rain volume magnitude greater than those of the median PFs. We find a threshold near the top 10% beyond which the PFs grow exponentially into larger, deeper, and colder rain systems. NCEP reanalyses show that midlevel relative humidity and total precipitable water increase steadily with increasingly larger PFs, along with a rapid increase of 500 hPa upward vertical velocity beyond the top 10%. This provides the necessary moisture convergence to amplify and sustain the extreme events. The rapid increase in vertical motion is associated with the release of convective available potential energy (CAPE) in mature systems, as is evident in the increase in CAPE of PFs up to 10% and the subsequent dropoff. The study illustrates distinct stages in the development of an extreme rainfall event including: (1) a systematic buildup in large-scale temperature and moisture, (2) a rapid change in rain structure, (3) explosive growth of the PF size, and (4) a release of CAPE before the demise of the event.

Real-world data on Len/Dex combination at second-line therapy of multiple myeloma: treatment at biochemical relapse is a significant prognostic factor for progression-free survival.

PubMed

Katroditou, Eirini; Kyrtsonis, Marie-Christine; Delimpasi, Sosana; Kyriakou, Despoina; Symeonidis, Argiris; Spanoudakis, Emmanouil; Vasilopoulos, Georgios; Anagnostopoulos, Achilles; Kioumi, Anna; Zikos, Panagiotis; Aktypi, Anthi; Briasoulis, Evangelos; Megalakaki, Aikaterini; Repousis, Panayiotis; Adamopoulos, Ioannis; Gogos, Dimitrios; Kotsopoulou, Maria; Pappa, Vassiliki; Papadaki, Eleni; Fotiou, Despoina; Nikolaou, Eftychia; Giannopoulou, Evlambia; Hatzimichael, Eleftheria; Giannakoulas, Nikolaos; Douka, Vassiliki; Kokoviadou, Kyriaki; Timotheatou, Despoina; Terpos, Evangelos

2018-05-13

We evaluated progression-free survival (PFS) rate of patients treated with lenalidomide/dexamethasone (Len/Dex), the efficacy of the combination, and the prognostic significance of treatment at biochemical vs. clinical relapse on PFS in 207 consecutive myeloma patients treated with Len/Dex in second line, according to routine clinical practice in Greece. First-line treatment included bortezomib-based (63.3%) or immunomodulatory drug-based (34.8%) therapies; 25% of patients underwent autologous stem cell transplantation. Overall response rate was 73.4% (17.8% complete response and 23.7% very good partial response); median time to best response was 6.7 months. Overall, median PFS and 12-month PFS rate was 19.2 months and 67.6%, respectively. 67.5% of patients had biochemical relapse and 32.5% had clinical relapse prior to initiation of Len/Dex. Median PFS was 24 months for patients treated at biochemical relapse vs. 13.2 months for those treated at clinical relapse (HR:0.63, p = 0.006) and the difference remained significant after adjustment for other prognostic factors. Type of relapse was the strongest prognostic factor for PFS in multivariate analysis. These real-world data confirm the efficacy of Len/Dex combination at first relapse; more importantly, it is demonstrated for the first time outside a clinical trial setting that starting therapy with Len/Dex at biochemical, rather than at clinical relapse, is a significant prognostic factor for PFS, inducing a 37% reduction of the probability of disease progression or death.

Beyond D'Amico risk classes for predicting recurrence after external beam radiotherapy for prostate cancer: the Candiolo classifier.

PubMed

Gabriele, Domenico; Jereczek-Fossa, Barbara A; Krengli, Marco; Garibaldi, Elisabetta; Tessa, Maria; Moro, Gregorio; Girelli, Giuseppe; Gabriele, Pietro

2016-02-24

The aim of this work is to develop an algorithm to predict recurrence in prostate cancer patients treated with radical radiotherapy, getting up to a prognostic power higher than traditional D'Amico risk classification. Two thousand four hundred ninety-three men belonging to the EUREKA-2 retrospective multi-centric database on prostate cancer and treated with external-beam radiotherapy as primary treatment comprised the study population. A Cox regression time to PSA failure analysis was performed in univariate and multivariate settings, evaluating the predictive ability of age, pre-treatment PSA, clinical-radiological staging, Gleason score and percentage of positive cores at biopsy (%PC). The accuracy of this model was checked with bootstrapping statistics. Subgroups for all the variables' combinations were combined to classify patients into five different "Candiolo" risk-classes for biochemical Progression Free Survival (bPFS); thereafter, they were also applied to clinical PFS (cPFS), systemic PFS (sPFS) and Prostate Cancer Specific Survival (PCSS), and compared to D'Amico risk grouping performances. The Candiolo classifier splits patients in 5 risk-groups with the following 10-years bPFS, cPFS, sPFS and PCSS: for very-low-risk 90 %, 94 %, 100 % and 100 %; for low-risk 74 %, 88 %, 94 % and 98 %; for intermediate-risk 60 %, 82 %, 91 % and 92 %; for high-risk 43 %, 55 %, 80 % and 89 % and for very-high-risk 14 %, 38 %, 56 % and 70 %. Our classifier outperforms D'Amico risk classes for all the end-points evaluated, with concordance indexes of 71.5 %, 75.5 %, 80 % and 80.5 % versus 63 %, 65.5 %, 69.5 % and 69 %, respectively. Our classification tool, combining five clinical and easily available parameters, seems to better stratify patients in predicting prostate cancer recurrence after radiotherapy compared to the traditional D'Amico risk classes.

Spark gap switch system with condensable dielectric gas

DOEpatents

Thayer, III, William J.

1991-01-01

A spark gap switch system is disclosed which is capable of operating at a high pulse rate comprising an insulated switch housing having a purging gas entrance port and a gas exit port, a pair of spaced apart electrodes each having one end thereof within the housing and defining a spark gap therebetween, an easily condensable and preferably low molecular weight insulating gas flowing through the switch housing from the housing, a heat exchanger/condenser for condensing the insulating gas after it exits from the housing, a pump for recirculating the condensed insulating gas as a liquid back to the housing, and a heater exchanger/evaporator to vaporize at least a portion of the condensed insulating gas back into a vapor prior to flowing the insulating gas back into the housing.

Prefocal station mechanical design concept study for the E-ELT

NASA Astrophysics Data System (ADS)

Jolley, Paul; Brunetto, Enzo; Frank, Christoph; Lewis, Steffan; Marchetti, Enrico

2016-07-01

The Nasmyth platforms of the E-ELT will contain one Prefocal Station (PFS) each. The main PFS functional requirements are to provide a focal plane to the three Nasmyth focal stations and the Coudé focus, optical sensing supporting telescope low order optimisation and seeing limited image quality, and optical sensing supporting characterising and phasing of M1 and other telescope subsystems. The PFS user requirements are used to derive the PFS technical requirements specification that will form the basis for design, development and production of the system. This specification process includes high-level architectural decisions and technical performance budget allocations. The mechanical design concepts reported here have been developed in order to validate key system specifications and associated technical budgets.

Detection and characterization of multi-filament evolution during resistive switching

DOE PAGES

Mickel, Patrick R.; Lohn, Andrew J.; Marinella, Matthew J.

2014-08-05

We present resistive switching data in TaO x memristors displaying signatures of multi-filament switching modes, and develop a geometrically defined equivalent circuit to separate the individual resistances and powers dissipated in each filament. Using these resolved values, we compare the individual switching curves of each filament and demonstrate that the switching data of each filament collapse onto a single switching curve determined by the analytical steady-state resistive switching solution for filamentary switching. Analyzing our results in terms of this solution, we determine the switching temperature, heat flow, conductivity, and time evolving areas of each filament during resistive switching. Finally, wemore » discuss operational modes which may limit the formation of additional conducting filaments, potentially leading to increased device endurance.« less

Spontaneous oscillations in microfluidic networks

NASA Astrophysics Data System (ADS)

Case, Daniel; Angilella, Jean-Regis; Motter, Adilson

2017-11-01

Precisely controlling flows within microfluidic systems is often difficult which typically results in systems being heavily reliant on numerous external pumps and computers. Here, I present a simple microfluidic network that exhibits flow rate switching, bistablity, and spontaneous oscillations controlled by a single pressure. That is, by solely changing the driving pressure, it is possible to switch between an oscillating and steady flow state. Such functionality does not rely on external hardware and may even serve as an on-chip memory or timing mechanism. I use an analytic model and rigorous fluid dynamics simulations to show these results.

High leukocyte mitochondrial DNA content contributes to poor prognosis in glioma patients through its immunosuppressive effect

PubMed Central

Chen, Y; Zhang, J; Huang, X; Zhang, J; Zhou, X; Hu, J; Li, G; He, S; Xing, J

2015-01-01

Background: Epidemiological studies have indicated significant associations of leukocyte mitochondrial DNA (mtDNA) copy number with risk of several malignancies, including glioma. However, whether mtDNA content can predict the clinical outcome of glioma patients has not been investigated. Methods: The mtDNA content of peripheral blood leukocytes from 336 glioma patients was examined using a real-time PCR-based method. Kaplan–Meier curves and Cox proportional hazards regression model were used to examine the association of mtDNA content with overall survival (OS) and progression-free survival (PFS) of patients. To explore the potential mechanism, the immune phenotypes of peripheral blood mononuclear cells (PBMCs) and plasma concentrations of several cytokines from another 20 glioma patients were detected by flow cytometry and enzyme-linked immunosorbent assay (ELISA), respectively. Results: Patients with high mtDNA content showed both poorer OS and PFS than those with low mtDNA content. Multivariate Cox regression analysis demonstrated that mtDNA content was an independent prognostic factor for both OS and PFS. Stratified analyses showed that high mtDNA content was significantly associated with poor prognosis of patients with younger age, high-grade glioma or adjuvant radiochemotherapy. Immunological analysis indicated that patients with high mtDNA content had significantly lower frequency of natural killer cells in PBMCs and higher plasma concentrations of interleukin-2 and tumour necrosis factor-α, suggesting an immunosuppression-related mechanism involved in mtDNA-mediated prognosis. Conclusions: Our study for the first time demonstrated that leukocyte mtDNA content could serve as an independent prognostic marker and an indicator of immune functions in glioma patients. PMID:26022928

Prediction of survival with multi-scale radiomic analysis in glioblastoma patients.

PubMed

Chaddad, Ahmad; Sabri, Siham; Niazi, Tamim; Abdulkarim, Bassam

2018-06-19

We propose a multiscale texture features based on Laplacian-of Gaussian (LoG) filter to predict progression free (PFS) and overall survival (OS) in patients newly diagnosed with glioblastoma (GBM). Experiments use the extracted features derived from 40 patients of GBM with T1-weighted imaging (T1-WI) and Fluid-attenuated inversion recovery (FLAIR) images that were segmented manually into areas of active tumor, necrosis, and edema. Multiscale texture features were extracted locally from each of these areas of interest using a LoG filter and the relation between features to OS and PFS was investigated using univariate (i.e., Spearman's rank correlation coefficient, log-rank test and Kaplan-Meier estimator) and multivariate analyses (i.e., Random Forest classifier). Three and seven features were statistically correlated with PFS and OS, respectively, with absolute correlation values between 0.32 and 0.36 and p < 0.05. Three features derived from active tumor regions only were associated with OS (p < 0.05) with hazard ratios (HR) of 2.9, 3, and 3.24, respectively. Combined features showed an AUC value of 85.37 and 85.54% for predicting the PFS and OS of GBM patients, respectively, using the random forest (RF) classifier. We presented a multiscale texture features to characterize the GBM regions and predict he PFS and OS. The efficiency achievable suggests that this technique can be developed into a GBM MR analysis system suitable for clinical use after a thorough validation involving more patients. Graphical abstract Scheme of the proposed model for characterizing the heterogeneity of GBM regions and predicting the overall survival and progression free survival of GBM patients. (1) Acquisition of pretreatment MRI images; (2) Affine registration of T1-WI image with its corresponding FLAIR images, and GBM subtype (phenotypes) labelling; (3) Extraction of nine texture features from the three texture scales fine, medium, and coarse derived from each of GBM regions; (4) Comparing heterogeneity between GBM regions by ANOVA test; Survival analysis using Univariate (Spearman rank correlation between features and survival (i.e., PFS and OS) based on each of the GBM regions, Kaplan-Meier estimator and log-rank test to predict the PFS and OS of patient groups that grouped based on median of feature), and multivariate (random forest model) for predicting the PFS and OS of patients groups that grouped based on median of PFS and OS.

Combustion mode switching with a turbocharged/supercharged engine

DOEpatents

Mond, Alan; Jiang, Li

2015-09-22

A method for switching between low- and high-dilution combustion modes in an internal combustion engine having an intake passage with an exhaust-driven turbocharger, a crankshaft-driven positive displacement supercharger downstream of the turbocharger and having variable boost controllable with a supercharger bypass valve, and a throttle valve downstream of the supercharger. The current combustion mode and mass air flow are determined. A switch to the target combustion mode is commanded when an operating condition falls within a range of predetermined operating conditions. A target mass air flow to achieve a target air-fuel ratio corresponding to the current operating condition and the target combustion mode is determined. The degree of opening of the supercharger bypass valve and the throttle valve are controlled to achieve the target mass air flow. The amount of residual exhaust gas is manipulated.

Response to crizotinib in advanced ALK-rearranged non-small cell lung cancers with different ALK-fusion variants.

PubMed

Li, Yan; Zhang, Tongtong; Zhang, Jing; Li, Wenbin; Yuan, Pei; Xing, Puyuan; Zhang, Zhou; Chuai, Shannon; Li, Junling; Ying, Jianming

2018-04-01

Anaplastic lymphoma kinase (ALK) rearrangements are present in approximately 5% of non-small-cell lung cancers (NSCLCs). NSCLCs with ALK-rearrangement can be effectively treated with crizotinib. However, magnitude and duration of responses are found to be heterogeneous. This study explored the clinical efficacy of crizotinib in different ALK variants. Among 96 ALK-rearrangement patients treated with crizotinib, 60 patients were identified with tumor specimens that could be evaluated by next-generation sequencing (NGS). We retrospectively evaluated the efficacy of crizotinib in different ALK variants. The median Progression-free survival (PFS) of the 96 ALK-rearrangement patients was 14.17 months. Among the 60 patients with NGS results, the most frequent variants were variant 3a/b (33.33%), variant 1 (23.33%) and variant 2 (15.00%). The percentage of rare EML4-ALK variants and non EML4-ALK variants were 10.00% and 18.33%. Survival analysis showed that patients with variant 2 appeared to have longer PFS than others (P = .021); also, patients with TP53 mutation seemed to have an unfavorable PFS than those with TP53 wild-type with a borderline p value (P = .068). After adjusting for other baseline characteristics, EML4-ALK variant 2 was identified as an important factor for a better PFS of crizotinib. We also found that patients with variant 3a/b had shorter duration of response to crizotinib; however, no significant difference of PFS was observed between the PFS of variant3a/b and non-v3 EML4-ALK variants. Our results indicate prolonged PFS in patients with EML4-ALK variant 2. Copyright © 2018 Elsevier B.V. All rights reserved.

The prediction of progression-free and overall survival in women with an advanced stage of epithelial ovarian carcinoma.

PubMed

Gerestein, C G; Eijkemans, M J C; de Jong, D; van der Burg, M E L; Dykgraaf, R H M; Kooi, G S; Baalbergen, A; Burger, C W; Ansink, A C

2009-02-01

Prognosis in women with ovarian cancer mainly depends on International Federation of Gynecology and Obstetrics stage and the ability to perform optimal cytoreductive surgery. Since ovarian cancer has a heterogeneous presentation and clinical course, predicting progression-free survival (PFS) and overall survival (OS) in the individual patient is difficult. The objective of this study was to determine predictors of PFS and OS in women with advanced stage epithelial ovarian cancer (EOC) after primary cytoreductive surgery and first-line platinum-based chemotherapy. Retrospective observational study. Two teaching hospitals and one university hospital in the south-western part of the Netherlands. Women with advanced stage EOC. All women who underwent primary cytoreductive surgery for advanced stage EOC followed by first-line platinum-based chemotherapy between January 1998 and October 2004 were identified. To investigate independent predictors of PFS and OS, a Cox' proportional hazard model was used. Nomograms were generated with the identified predictive parameters. The primary outcome measure was OS and the secondary outcome measures were response and PFS. A total of 118 women entered the study protocol. Median PFS and OS were 15 and 44 months, respectively. Preoperative platelet count (P = 0.007), and residual disease <1 cm (P = 0.004) predicted PFS with a optimism corrected c-statistic of 0.63. Predictive parameters for OS were preoperative haemoglobin serum concentration (P = 0.012), preoperative platelet counts (P = 0.031) and residual disease <1 cm (P = 0.028) with a optimism corrected c-statistic of 0.67. PFS could be predicted by postoperative residual disease and preoperative platelet counts, whereas residual disease, preoperative platelet counts and preoperative haemoglobin serum concentration were predictive for OS. The proposed nomograms need to be externally validated.

Greater Biopsy Core Number Is Associated With Improved Biochemical Control in Patients Treated With Permanent Prostate Brachytherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bittner, Nathan; Merrick, Gregory S., E-mail: gmerrick@urologicresearchinstitute.or; Galbreath, Robert W.

2010-11-15

Purpose: Standard prostate biopsy schemes underestimate Gleason score in a significant percentage of cases. Extended biopsy improves diagnostic accuracy and provides more reliable prognostic information. In this study, we tested the hypothesis that greater biopsy core number should result in improved treatment outcome through better tailoring of therapy. Methods and Materials: From April 1995 to May 2006, 1,613 prostate cancer patients were treated with permanent brachytherapy. Patients were divided into five groups stratified by the number of prostate biopsy cores ({<=}6, 7-9, 10-12, 13-20, and >20 cores). Biochemical progression-free survival (bPFS), cause-specific survival (CSS), and overall survival (OS) were evaluatedmore » as a function of core number. Results: The median patient age was 66 years, and the median preimplant prostate-specific antigen was 6.5 ng/mL. The overall 10-year bPFS, CSS, and OS were 95.6%, 98.3%, and 78.6%, respectively. When bPFS was analyzed as a function of core number, the 10-year bPFS for patients with >20, 13-20, 10-12, 7-9 and {<=}6 cores was 100%, 100%, 98.3%, 95.8%, and 93.0% (p < 0.001), respectively. When evaluated by treatment era (1995-2000 vs. 2001-2006), the number of biopsy cores remained a statistically significant predictor of bPFS. On multivariate analysis, the number of biopsy cores was predictive of bPFS but did not predict for CSS or OS. Conclusion: Greater biopsy core number was associated with a statistically significant improvement in bPFS. Comprehensive regional sampling of the prostate may enhance diagnostic accuracy compared to a standard biopsy scheme, resulting in better tailoring of therapy.« less

Activation patterns of Purkinje fibers during long-duration ventricular fibrillation in an isolated canine heart model.

PubMed

Tabereaux, Paul B; Walcott, Greg P; Rogers, Jack M; Kim, Jong; Dosdall, Derek J; Robertson, Peter G; Killingsworth, Cheryl R; Smith, William M; Ideker, Raymond E

2007-09-04

The roles of Purkinje fibers (PFs) and focal wave fronts, if any, in the maintenance of ventricular fibrillation (VF) are unknown. If PFs are involved in VF maintenance, it should be possible to map wave fronts propagating from PFs into the working ventricular myocardium during VF. If wave fronts ever arise focally during VF, it should be possible to map them appearing de novo. Six canine hearts were isolated, and the left main coronary artery was cannulated and perfused. The left ventricular cavity was exposed, which allowed direct endocardial mapping of the anterior papillary muscle insertion. Nonperfused VF was induced, and 6 segments of data, each 5 seconds long, were analyzed during 10 minutes of VF. During 36 segments of data that were analyzed, 1018 PF or focal wave fronts of activation were identified. In 534 wave fronts, activation was mapped propagating from working ventricular myocardium to PF. In 142 wave fronts, activation was mapped propagating from PF to working ventricular myocardium. In 342 wave fronts, activation was mapped arising focally. More than 1 of these 3 patterns could occur in the same wave front. PFs are highly active throughout the first 10 minutes of VF. In addition to retrograde propagation from the working ventricular myocardium to PFs, antegrade propagation occurs from PFs to working ventricular myocardium, which suggests PFs are important in VF maintenance. Prior plunge needle recordings in dogs indicate activation propagates from the endocardium toward the epicardium after 1 minute of VF, which suggests that focal sites on the endocardium may represent foci and not breakthrough. If so, in addition to reentry, abnormal automaticity or triggered activity may also occur during VF.

Consequences of an Early PSA Response to Enzalutamide Treatment for Japanese Patients with Metastatic Castration-resistant Prostate Cancer.

PubMed

Kato, Haruo; Furuya, Yosuke; Miyazawa, Yoshiyuki; Miyao, Takeshi; Syuto, Takahiro; Nomura, Masashi; Sekine, Yoshitaka; Koike, Hidekazu; Matsui, Hiroshi; Shibata, Yasuhiro; Ito, Kazuto; Suzuki, Kazuhiro

2016-11-01

Recent studies have shown that an early prostate-specific antigen (PSA) response to androgen receptor (AR)-targeting agents in metastatic castration-resistant prostate cancer (mCRPC) is associated with a better prognosis. We analyzed early PSA response to enzalutamide and oncological outcomes to study their prognostic significance in the Japanese population. Fifty-one patients with mCRPC (26 of pre-docetaxel and 25 of post-docetaxel status) were treated with enzalutamide. The PSA progression-free survival (PFS), radiographic PFS (rPFS) and overall survival (OS) were assessed. The association of rPFS and OS in patients with an early PSA response at 4 weeks after commencement of enzalutamide was studied. Early PSA responses were significantly associated with a longer rPFS (median of 47.9 vs. 20.1 weeks, p<0.001, in patients exhibiting a 50% PSA response; median of 40.9 vs. 20.1 weeks, p=0.016, in patients exhibiting a 30% PSA response). OS was also significantly associated with an early PSA response (p=0.002 for patients exhibiting a 50% PSA response, p=0.003 for patients exhibiting a 30% PSA response). Multivariate analysis showed that the predictors of a 50% PSA response were an interval to mCRPC and a docetaxel treatment history, while the predictor of a 30% PSA response was a docetaxel treatment history. Furthermore, a 50% PSA response was independently prognostic of rPFS. An early PSA response to enzalutamide was significantly associated with a longer rPFS and OS. This information will aid in the management of patients treated with enzalutamide. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Time-dependent changes in non-COX-1-dependent platelet function with daily aspirin therapy

PubMed Central

Voora, Deepak; Ortel, Thomas L.; Lucas, Joseph E.; Chi, Jen-Tsan; Becker, Richard C.; Ginsburg, Geoffrey S.

2012-01-01

Objectives To develop an integrated metric of non COX-1 dependent platelet function (NCDPF) to measure the temporal response to aspirin in healthy volunteers and diabetics. Background NCDPF on aspirin demonstrates wide variability, despite suppression of COX-1. Although a variety of NCDPF assays are available, no standard exists and their reproducibility is not established. Methods We administered 325mg/day aspirin to two cohorts of volunteers (HV1, n = 52, and HV2, n = 96) and diabetics (DM, n = 74) and measured NCDPF using epinephrine, collagen, and ADP aggregometry and PFA100 (collagen/epi) before (Pre), after one dose (Post), and after several weeks (Final). COX-1 activity was assessed with arachidonic acid aggregometry (AAA). The primary outcome of the study, the platelet function score (PFS), was derived from a principal components analysis of NCDPF measures. Results The PFS strongly correlated with each measure of NCDPF in each cohort. After two or four weeks of daily aspirin the Final PFS strongly correlated (r > 0.7, p<0.0001) and was higher (p < 0.01) than the Post PFS. The magnitude and direction of the change in PFS (Final - Post) in an individual subject was moderately inversely proportional to the Post PFS in HV1 (r = −0.45), HV2 (r = −0.54), DM (r = −0.68), p<0.0001 for all. AAA remained suppressed during aspirin therapy. Conclusions The PFS summarizes multiple measures of NCDPF. Despite suppression of COX-1 activity, NCDPF during aspirin therapy is predictably dynamic: those with heightened NCDPF continue to decline whereas those with low/normal NCDPF return to pre-aspirin levels over time. PMID:22294277

Perennial filter strips reduce nitrate levels in soil and shallow groundwater after grassland-to-cropland conversion.

PubMed

Zhou, Xiaobo; Helmers, Matthew J; Asbjornsen, Heidi; Kolka, Randy; Tomer, Mark D

2010-01-01

Many croplands planted to perennial grasses under the Conservation Reserve Program are being returned to crop production, and with potential consequences for water quality. The objective of this study was to quantify the impact of grassland-to-cropland conversion on nitrate-nitrogen (NO3-N) concentrations in soil and shallow groundwater and to assess the potential for perennial filter strips (PFS) to mitigate increases in NO3-N levels. The study, conducted at the Neal Smith National Wildlife Refuge (NSNWR) in central Iowa, consisted of a balanced incomplete block design with 12 watersheds and four watershed-scale treatments having different proportions and topographic positions of PFS planted in native prairie grasses: 100% rowcrop, 10% PFS (toeslope position), 10% PFS (distributed on toe and as contour strips), and 20 PFS (distributed on toe and as contour strips). All treatments were established in fall 2006 on watersheds that were under bromegrass (Bromus L.) cover for at least 10 yr. Nonperennial areas were maintained under a no-till 2-yr corn (Zea mays L.)--soybean [Glycine max. (L.) Merr.] rotation since spring 2007. Suction lysimeter and shallow groundwater wells located at upslope and toeslope positions were sampled monthly during the growing season to determine NO3-N concentration from 2005 to 2008. The results indicated significant increases in NO3-N concentration in soil and groundwater following grassland-to-cropland conversion. Nitrate-nitrogen levels in the vadose zone and groundwater under PFS were lower compared with 100% cropland, with the most significant differences occurring at the toeslope position. During the years following conversion, PFS mitigated increases in subsurface nitrate, but long-term monitoring is needed to observe and understand the full response to land-use conversion.

Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib.

PubMed

Wongchenko, Matthew J; McArthur, Grant A; Dréno, Brigitte; Larkin, James; Ascierto, Paolo A; Sosman, Jeffrey; Andries, Luc; Kockx, Mark; Hurst, Stephen D; Caro, Ivor; Rooney, Isabelle; Hegde, Priti S; Molinero, Luciana; Yue, Huibin; Chang, Ilsung; Amler, Lukas; Yan, Yibing; Ribas, Antoni

2017-09-01

Purpose: The association of tumor gene expression profiles with progression-free survival (PFS) outcomes in patients with BRAF V600 -mutated melanoma treated with vemurafenib or cobimetinib combined with vemurafenib was evaluated. Experimental Design: Gene expression of archival tumor samples from patients in four trials (BRIM-2, BRIM-3, BRIM-7, and coBRIM) was evaluated. Genes significantly associated with PFS ( P < 0.05) were identified by univariate Cox proportional hazards modeling, then subjected to unsupervised hierarchical clustering, principal component analysis, and recursive partitioning to develop optimized gene signatures. Results: Forty-six genes were identified as significantly associated with PFS in both BRIM-2 ( n = 63) and the vemurafenib arm of BRIM-3 ( n = 160). Two distinct signatures were identified: cell cycle and immune. Among vemurafenib-treated patients, the cell-cycle signature was associated with shortened PFS compared with the immune signature in the BRIM-2/BRIM-3 training set [hazard ratio (HR) 1.8; 95% confidence interval (CI), 1.3-2.6, P = 0.0001] and in the coBRIM validation set ( n = 101; HR, 1.6; 95% CI, 1.0-2.5; P = 0.08). The adverse impact of the cell-cycle signature on PFS was not observed in patients treated with cobimetinib combined with vemurafenib ( n = 99; HR, 1.1; 95% CI, 0.7-1.8; P = 0.66). Conclusions: In vemurafenib-treated patients, the cell-cycle gene signature was associated with shorter PFS. However, in cobimetinib combined with vemurafenib-treated patients, both cell cycle and immune signature subgroups had comparable PFS. Cobimetinib combined with vemurafenib may abrogate the adverse impact of the cell-cycle signature. Clin Cancer Res; 23(17); 5238-45. ©2017 AACR . ©2017 American Association for Cancer Research.

Switch maintenance chemotherapy using S-1 with or without bevacizumab in patients with advanced non-small cell lung cancer: a phase II study.

PubMed

Niho, Seiji; Ohe, Yuichiro; Ohmatsu, Hironobu; Umemura, Shigeki; Matsumoto, Shingo; Yoh, Kiyotaka; Goto, Koichi

2017-06-01

We conducted this single-institute; prospective, non-randomized parallel two-arm phase II study to evaluate the efficacy and safety of switch maintenance chemotherapy with S-1 after induction therapy with a platinum-based regimen in patients with advanced non-small cell lung cancer (NSCLC). Patients not showing disease progression after induction platinum-based chemotherapy received S-1 at the dose of 40mg/m 2 twice daily for 14 consecutive days, every three weeks, with or without bevacizumab (Bev) at the dose of 15mg/kg. In cases where the induction chemotherapy regimen contained Bev, Bev was used as continuation maintenance chemotherapy where appropriate. The efficacy/toxicity of switch maintenance chemotherapy with S-1 and S-1+Bev was evaluated separately. The primary end point of this study was the treatment success rate at three months after the start of S-1 treatment. Between July 2010 and January 2014, 79 patients were enrolled, of which 78 were found to be eligible for inclusion in this study. The treatment success rate at three months was 28.2% (90% confidence interval (CI), 7.1-17.1%) in the S-1 group and 64.1% (90% CI, 50.0-76.8%) in the S-1+Bev group. The primary endpoint was met in the S-1+Bev group. The median PFS and OS were 2.6 months and 11.0 months in the S-1 group, and 4.6 months and 19.9 months in the S-1+Bev group, respectively. The most common grade three toxicity was neutropenia (10% incidence in the S-1+Bev group). There were no cases of febrile neutropenia. Switch maintenance chemotherapy with S-1 in combination with continuation maintenance chemotherapy with bevacizumab yielded modest efficacy with mild and acceptable toxicities. Copyright © 2017. Published by Elsevier B.V.

Potential surrogate endpoints for overall survival in locoregionally advanced nasopharyngeal carcinoma: an analysis of a phase III randomized trial

PubMed Central

Chen, Yu-Pei; Chen, Yong; Zhang, Wen-Na; Liang, Shao-Bo; Zong, Jing-Feng; Chen, Lei; Mao, Yan-Ping; Tang, Ling-Long; Li, Wen-Fei; Liu, Xu; Guo, Ying; Lin, Ai-Hua; Liu, Meng-Zhong; Sun, Ying; Ma, Jun

2015-01-01

The gold standard endpoint in trials of locoregionally advanced nasopharyngeal carcinoma (NPC) is overall survival (OS). Using data from a phase III randomized trial, we evaluated whether progression-free survival (PFS), failure-free survival (FFS), distant failure-free survival (D-FFS) or locoregional failure-free survival (LR-FFS) could be reliable surrogate endpoints for OS. Between July 2002 and September 2005, 316 eligible patients with stage III-IVB NPC were randomly assigned to receive either radiotherapy alone or chemoradiotherapy. 2- and 3-year PFS, FFS, D-FFS, and LR-FFS were tested as surrogate endpoints for 5-year OS using Prentice’s four criteria. The Spearman’s rank correlation coefficient was calculated to assess the strength of the associations. After a median follow-up time of 5.8 years, 2- and 3-year D-FFS and LR-FFS were not significantly different between treatment arms, in rejection of Prentice’s second criterion. Being consistent with all Prentice’s criteria, 2- and 3-year PFS and FFS were valid surrogate endpoints for 5-year OS; the rank correlation coefficient was highest (0.84) between 3-year PFS and 5-year OS. In conclusion, PFS and FFS at 2 and 3 years may be candidate surrogate endpoints for OS at 5 years; 3-year PFS may be more appropriate for early assessment of long-term survival. PMID:26219568

Potential surrogate endpoints for overall survival in locoregionally advanced nasopharyngeal carcinoma: an analysis of a phase III randomized trial.

PubMed

Chen, Yu-Pei; Chen, Yong; Zhang, Wen-Na; Liang, Shao-Bo; Zong, Jing-Feng; Chen, Lei; Mao, Yan-Ping; Tang, Ling-Long; Li, Wen-Fei; Liu, Xu; Guo, Ying; Lin, Ai-Hua; Liu, Meng-Zhong; Sun, Ying; Ma, Jun

2015-07-29

The gold standard endpoint in trials of locoregionally advanced nasopharyngeal carcinoma (NPC) is overall survival (OS). Using data from a phase III randomized trial, we evaluated whether progression-free survival (PFS), failure-free survival (FFS), distant failure-free survival (D-FFS) or locoregional failure-free survival (LR-FFS) could be reliable surrogate endpoints for OS. Between July 2002 and September 2005, 316 eligible patients with stage III-IVB NPC were randomly assigned to receive either radiotherapy alone or chemoradiotherapy. 2- and 3-year PFS, FFS, D-FFS, and LR-FFS were tested as surrogate endpoints for 5-year OS using Prentice's four criteria. The Spearman's rank correlation coefficient was calculated to assess the strength of the associations. After a median follow-up time of 5.8 years, 2- and 3-year D-FFS and LR-FFS were not significantly different between treatment arms, in rejection of Prentice's second criterion. Being consistent with all Prentice's criteria, 2- and 3-year PFS and FFS were valid surrogate endpoints for 5-year OS; the rank correlation coefficient was highest (0.84) between 3-year PFS and 5-year OS. In conclusion, PFS and FFS at 2 and 3 years may be candidate surrogate endpoints for OS at 5 years; 3-year PFS may be more appropriate for early assessment of long-term survival.

The radiometric performances of the Planetary Fourier Spectrometer for Mars exploration

NASA Astrophysics Data System (ADS)

Palomba, E.; Colangeli, L.; Formisano, V.; Piccioni, G.; Cafaro, N.; Moroz, V.

1999-04-01

The Planetary Fourier Spectrometer (PFS) is a Fourier transform interferometer, operating in the range 1.2-45 μm. The instrument, previously included in the payload of the failed mission Mars ‧96, is proposed for the future space mission Mars Express, under study by ESA. The present paper is aimed at presenting the radiometric performances of PFS. The two channels (LW and SW) forming PFS were analysed and characterised in terms of sensitivity and noise equivalent brightness. To cover the wide spectral range of PFS, different blackbodies were used for calibration. The built-in blackbodies, needed for the in-flight calibrations, were also characterised. The results show that the LW channel is comparable with IRIS Mariner 9 in terms of noise equivalent brightness. The SW channel performances, while satisfactorily, could be improved by lowering the sensor operative temperature. A simple model of the Mars radiance is used in order to calculate the signal-to-noise ratio on the spectra in typical observation conditions. The computed signal-to-noise ratio for the LW channel varies between 430 and 40, while for the SW channel it ranges from 150 to 30. The radiometric analyses confirm that PFS performances are compliant with the design requirements of the instrument. PFS is fully validated for future remote exploration of the atmosphere and the surface of Mars.

Harmful algal bloom removal and eutrophic water remediation by commercial nontoxic polyamine-co-polymeric ferric sulfate-modified soils.

PubMed

Dai, Guofei; Zhong, Jiayou; Song, Lirong; Guo, Chunjing; Gan, Nanqin; Wu, Zhenbin

2015-07-01

Harmful algal bloom has posed great threat to drinking water safety worldwide. In this study, soils were combined with commercial nontoxic polyamine poly(epichlorohydrin-dimethylamine) (PN) and polymeric ferric sulfate (PFS) to obtain PN-PFS soils for Microcystis removal and eutrophic water remediation under static laboratory conditions. High pH and temperature in water could enhance the function of PN-PFS soil. Algal removal efficiency increased as soil particle size decreased or modified soil dose increased. Other pollutants or chemicals (such as C, P, and organic matter) in eutrophic water could participate and promote algal removal by PN-PFS soil; these pollutants were also flocculated. During PN-PFS soil application in blooming field samples, the removal efficiency of blooming Microcystis cells exceeded 99 %, the cyanotoxin microcystins reduced by 57 %. Water parameters (as TP, TN, SS, and SPC) decreased by about 90 %. CODMn, PO4-P, and NH4-N also sharply decreased by >45 %. DO and ORP in water improved. Netting and bridging effects through electrostatic attraction and complexation reaction could be the two key mechanisms of Microcystis flocculation and pollutant purification. Considering the low cost of PN-PFS soil and its nontoxic effect on the environment, we proposed that this soil combination could be applied to remove cyanobacterial bloom and remediate eutrophic water in fields.

Mutation abundance affects the therapeutic efficacy of EGFR-TKI in patients with advanced lung adenocarcinoma: A retrospective analysis.

PubMed

Wang, Huijuan; Zhang, Mina; Tang, Wanyu; Ma, Jie; Wei, Bing; Niu, Yuanyuan; Zhang, Guowei; Li, Peng; Yan, Xiangtao; Ma, Zhiyong

2018-03-22

To investigate the influence of mutation abundance and sites of epidermal growth factor receptor (EGFR) on therapeutic efficacies of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) treatments of patients with advanced non-small cell lung carcinoma (NSCLC). EGFR mutational sites and mutation abundance were analyzed by amplification refractory mutation system (ARMS) in paraffin-embedded tissue sections taken from primary or metastatic tumors of 194 NSCLC patients. The median progression-free survival (PFS) time of the enrolled patients was 9.3 months (95% CI, 8.2-10.8 months). The PFS was significantly different with EGFR gene mutation abundance after EGFR-TKI therapy (P = 0.014). The median PFS was significantly longer when the cut-off value of EGFR mutation abundance of exon 19 or exon 21, and solely exon 19 was > 26.7% and 61.8%, respectively. For patients who received EGFR-TKI as first-line treatment, the median PFS was significantly longer in the high mutation abundance group than in the low mutation abundance group (12.7 vs 8.7 months, P = 0.002). The PFS benefits were greater in patients with a higher abundance of exon 19 deletion mutations in the EGFR gene after EGFR-TKI treatment and first line EGFR-TKI treatment led to improved PFS in high mutation abundance patients.

Leukocytosis and neutrophilia predicts outcome in anal cancer.

PubMed

Schernberg, Antoine; Escande, Alexandre; Rivin Del Campo, Eleonor; Ducreux, Michel; Nguyen, France; Goere, Diane; Chargari, Cyrus; Deutsch, Eric

2017-01-01

Leukocytosis and neutrophilia could be the tip of the iceberg in the inflammatory tumor microenvironment. We aimed to validate their prognostic significance in a cohort of patients treated with definitive chemoradiation for anal squamous cell carcinoma (SCC). Clinical records from all consecutive patients treated in a single institution between 2006 and 2016 with curative-intent radiotherapy were retrospectively analyzed. Leukocytosis and neutrophilia, defined as leukocyte or neutrophil count over 10,000 and 7500/mm 3 , respectively, were studied in terms of overall survival (OS), progression (PFS), locoregional (LFS) and distant (DFS)-free survival. We identified 103 non-metastatic HIV-negative patients, with concurrent chemotherapy use in 78%. Twelve and 8% displayed baseline leukocytosis and neutrophilia, respectively. Estimated 3-year OS and PFS were 88% and 67%, respectively. In univariate analysis, both leukocytosis and neutrophilia were strongly associated with inferior OS, PFS, LFS and DFS (p<0.01). In multivariate analysis, leukocytosis and neutrophilia remained strongly associated with patient outcome (p<0.01), independently from tumor T and N-stage. Anemia was an independent predictor of worse OS and PFS, while chemoradiation overall treatment time below 50days improved PFS. Leukocytosis and neutrophilia are strong prognostic factors for OS, PFS, LFS and DFS in anal cancer treated with chemoradiation. These biomarkers could help identify patients with higher risk of tumor relapse that require treatment intensification. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL

PubMed Central

Brown, J R; Hillmen, P; O’Brien, S; Barrientos, J C; Reddy, N M; Coutre, S E; Tam, C S; Mulligan, S P; Jaeger, U; Barr, P M; Furman, R R; Kipps, T J; Cymbalista, F; Thornton, P; Caligaris-Cappio, F; Delgado, J; Montillo, M; DeVos, S; Moreno, C; Pagel, J M; Munir, T; Burger, J A; Chung, D; Lin, J; Gau, L; Chang, B; Cole, G; Hsu, E; James, D F; Byrd, J C

2018-01-01

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations. PMID:28592889

Prognostic Relevance of the Peritoneal Surface Disease Severity Score Compared to the Peritoneal Cancer Index for Colorectal Peritoneal Carcinomatosis

PubMed Central

Ng, Jia Lin; Ong, Whee Sze; Chia, Claramae Shulyn; Tan, Grace Hwei Ching; Soo, Khee-Chee; Teo, Melissa Ching Ching

2016-01-01

Background. Peritoneal Carcinomatosis Index (PCI) is a widely established scoring system that describes disease burden in isolated colorectal peritoneal carcinomatosis (CPC). Its significance may be diminished with complete cytoreduction. We explore the utility of the recently described Peritoneal Surface Disease Severity Score (PSDSS) and compare its prognostic value against PCI. Methods. The endpoints were overall survival (OS), progression-free survival (PFS), and survival less than 18 months (18 MS). Results. Fifty patients underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) for CPC from 2003 to 2014, with 98% achieving complete cytoreduction. Median OS was 28.8 months (95% CI, 18.0–39.1); median PFS was 9.4 months (95% CI, 7.7–13.9). Univariate analysis showed that higher PCI was significantly associated with poorer OS (HR 1.11; 95% CI, 1.03–1.20) and PFS (HR 1.09; 95% CI, 1.03–1.14). Conversely, PSDSS was not associated with either endpoint. Multivariate analysis showed that PCI, but not PSDSS, was predictive of OS and PFS. PCI was also able to discriminate survival outcomes better than PSDSS for both OS and PFS. There was no association between 18 MS and either score. Conclusion. PCI is superior to PSDSS in predicting OS and PFS and remains the prognostic score of choice in CPC patients undergoing CRS/HIPEC. PMID:27006828

Microfluidic magnetic switching valves based on aggregates of magnetic nanoparticles: Effects of aggregate length and nanoparticle sizes

NASA Astrophysics Data System (ADS)

Jiemsakul, Thanakorn; Manakasettharn, Supone; Kanharattanachai, Sivakorn; Wanna, Yongyuth; Wangsuya, Sujint; Pratontep, Sirapat

2017-01-01

We demonstrate microfluidic switching valves using magnetic nanoparticles blended within the working fluid as an alternative microfluidic flow control in microchannels. Y-shaped microchannels have been fabricated by using a CO2 laser cutter to pattern microchannels on transparent poly(methyl methacrylate) (PMMA) sheets covered with thermally bonded transparent polyvinyl chloride (PVC) sheets. To examine the performance of the microfluidic magnetic switching valves, an aqueous magnetic nanoparticle suspension was injected into the microchannels by a syringe pump. Neodymium magnets were then employed to attract magnetic nanoparticles and form an aggregate that blocked the microchannels at a required position. We have found that the maximum volumetric flow rate of the syringe pump that the magnetic nanoparticle aggregate can withstand scales with the square of the external magnetic flux density. The viscosity of the fluid exhibits dependent on the aggregate length and the size of the magnetic nanoparticles. This microfluidic switching valve based on aggregates of magnetic nanoparticles has strong potentials as an on-demand flow control, which may help simplifying microfluidic channel designs.

High speed Deans switch for low duty cycle comprehensive two-dimensional gas chromatography.

PubMed

Ghosh, Abhijit; Bates, Carly T; Seeley, Stacy K; Seeley, John V

2013-05-24

A new high-speed valve-based modulator has been designed and tested for use in comprehensive two-dimensional gas chromatography (GC×GC). The modulator is a Deans switch constructed from two micro-volume fittings and a solenoid valve. Modulator performance was characterized over a wide range of device settings including the magnitude of the switching flow, the gap between the tips of the primary and secondary column, the primary column flow rate, and the carrier gas identity. Under optimized conditions, the modulator was found to be capable of generating narrow pulses (<50ms) of primary effluent with a 2mL/min secondary column flow. This capability will ultimately allow the modulator to be used with GC×GC separations employing a wide range of detectors and secondary column geometries. The main disadvantage of this modulator is that it employs a low sampling duty cycle, and thus it produces separations with sensitivities that are lower than those produced with thermal modulators or differential flow modulators. The efficacy of the new high-speed Deans switch modulator was demonstrated through the GC×GC separation of a hydrocarbon standard and gasoline. Precise quantitation of individual components was possible provided the modulation ratio was kept greater than 2.0. Copyright © 2013 Elsevier B.V. All rights reserved.

Role of rituximab in treatment of patients with primary central nervous system lymphoma: a retrospective analysis of the Czech lymphoma study group registry.

PubMed

Mocikova, Heidi; Pytlik, Robert; Sykorova, Alice; Janikova, Andrea; Prochazka, Vit; Vokurka, Samuel; Berkova, Adela; Belada, David; Campr, Vit; Buresova, Lucie; Trneny, Marek

2016-12-01

We have investigated whether the addition of rituximab to methotrexate, procarbazine, vincristine, radiotherapy and cytarabine was associated with improved outcome of primary central nervous system lymphomas (PCNSL). Of 164 patients, 49 received rituximab. Median age was 63 years, median Karnofsky performance score (KPS) was 60 and median follow-up of living patients was 59.5 months. 1- and 2-year PFS were 49.7 and 37.9%, 1- and 2-year OS were 57.0 and 45.3%. Median progression-free survival (PFS), but not overall survival (OS) was significantly better for patients treated with rituximab (22.9 vs. 10.9 months, p = 0.037). In multivariate analysis, age ≤70 years and KPS ≥90 were predictive for PFS and OS, rituximab was an independent prognostic factor for PFS only. In landmark analyses, rituximab was not found beneficial for long-term survivors and no group particularly benefited from rituximab. In conclusion, addition of rituximab was associated with improved PFS, but not OS in this unselected cohort of PCNSL patients.

Highly Swellable, Dual-Responsive Hydrogels Based on PNIPAM and Redox Active Poly(ferrocenylsilane) Poly(ionic liquid)s: Synthesis, Structure, and Properties.

PubMed

Feng, Xueling; Zhang, Kaihuan; Chen, Peng; Sui, Xiaofeng; Hempenius, Mark A; Liedberg, Bo; Vancso, G Julius

2016-12-01

Highly swellable, dual-responsive hydrogels, consisting of thermo-responsive poly(N-isopropylacrylamide) (PNIPAM) and redox-responsive poly(ferrocenylsilane) (PFS) based poly(ionic liquid)s (PILs) are formed by photo-polymerization. PFS chains bearing cross-linkable vinylimidazolium (VIm) side groups are copolymerized with NIPAM in aqueous solutions under ultraviolet light (λ = 365 nm) in the presence of a photoinitiator. The PFS-PILs serve as a macro-cross-linker and also provide redox responsiveness. The swelling ratio, morphology, and lower critical solution temperature (LCST) of the hydrogels are studied as a function of the PNIPAM/PFS ratio. The value of the LCST is dependent on the choice of the counterion of the PIL and the PNIPAM/PFS ratio. The hydrogel is employed as a reducing environment for the in situ fabrication of gold nanoparticles (AuNPs), forming AuNP-hydrogel composites. The localized surface plasmon resonance peak of the as-synthesized Au nanoparticles inside the hydrogel could be tuned by altering the temperature. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Assessment of Antibodies Induced by Multivalent Transmission-Blocking Malaria Vaccines.

PubMed

Menon, Vinay; Kapulu, Melissa C; Taylor, Iona; Jewell, Kerry; Li, Yuanyuan; Hill, Fergal; Long, Carole A; Miura, Kazutoyo; Biswas, Sumi

2017-01-01

A malaria transmission-blocking vaccine would be a critical tool in achieving malaria elimination and eradication. By using chimpanzee adenovirus serotype 63 and modified vaccinia virus Ankara viral vectored vaccines, we investigated whether incorporating two antigens into one vaccine would result in higher transmission-reducing activity than one antigen. We demonstrated that when Pfs25 was administered with other antigens Pfs28 or Pfs230C, either concurrently as a mixed vaccine or co-expressed as a dual-antigen vaccine, the antibody response in mice to each antigen was comparable to a monoantigen vaccine, without immunological interference. However, we found that the transmission-reducing activity (functional activity) of dual-antigen vaccines was not additive. Dual-antigen vaccines generally only elicited similar transmission-reducing activity to monoantigen vaccines and in one instance had lower transmission-reducing activity. We found that despite the lack of immunological interference of dual-antigen vaccines, they are still not as effective at blocking malaria transmission as Pfs25-IMX313, the current leading candidate for viral vectored vaccines. Pfs25-IMX313 elicited similar quality antibodies to dual-antigen vaccines, but higher antibody titers.

Development of a bivalent conjugate vaccine candidate against malaria transmission and typhoid fever.

PubMed

An, So Jung; Scaria, Puthupparampil V; Chen, Beth; Barnafo, Emma; Muratova, Olga; Anderson, Charles; Lambert, Lynn; Chae, Myung Hwa; Yang, Jae Seung; Duffy, Patrick E

2018-05-17

Immune responses to poorly immunogenic antigens, such as polysaccharides, can be enhanced by conjugation to carriers. Our previous studies indicate that conjugation to Vi polysaccharide of Salmonella Typhi may also enhance immunogenicity of some protein carriers. We therefore explored the possibility of generating a bivalent vaccine against Plasmodium falciparum malaria and typhoid fever, which are co-endemic in many parts of the world, by conjugating Vi polysaccharide, an approved antigen in typhoid vaccine, to Pfs25, a malaria transmission blocking vaccine antigen in clinical trials. Vi-Pfs25 conjugates induced strong immune responses against both Vi and Pfs25 in mice, whereas the unconjugated antigens are poorly immunogenic. Functional assays of immune sera revealed potent transmission blocking activity mediated by anti-Pfs25 antibody and serum bactericidal activity due to anti-Vi antibody. Pfs25 conjugation to Vi modified the IgG isotype distribution of antisera, inducing a Th2 polarized immune response against Vi antigen. This conjugate may be further developed as a bivalent vaccine to concurrently target malaria and typhoid fever. Copyright © 2018. Published by Elsevier Ltd.

Yields of projectile fragments in sulphur-emulsion interactions at 3.7 A GeV

NASA Astrophysics Data System (ADS)

Kamel, S.; Osman, W.; Fayed, M.

2017-05-01

This work presents the basic characteristics of singly, doubly and heavily charged projectile fragments (PFs) emitted in inelastic interactions of 32S ions with photo-emulsion nuclei at Dubna energy (3.7 A GeV). Our experimental data are compared with the corresponding data for other projectiles at the same incident energy. The study of mean multiplicities of different charged PFs against the projectile mass shows a power-law relationship. The multiplicity distributions of singly and doubly charged PFs have been fitted well with a Gaussian distribution function. The yields of PFs broken up from the interactions of 32S projectile nuclei with different target nuclei are studied. The beam energy dependence in terms of the various order moments is studied as well.

Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial.

PubMed

Rathkopf, Dana E; Beer, Tomasz M; Loriot, Yohann; Higano, Celestia S; Armstrong, Andrew J; Sternberg, Cora N; de Bono, Johann S; Tombal, Bertrand; Parli, Teresa; Bhattacharya, Suman; Phung, De; Krivoshik, Andrew; Scher, Howard I; Morris, Michael J

2018-05-01

Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS. PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016. Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment. Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula. In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0.23 (SA5; 95% CI, 0.19-0.30), and 0.23 (SA6; 95% CI, 0.19-0.30) (P < .001 for all). Correlations of rPFS and OS in enzalutamide-treated patients were 0.89 (95% CI, 0.86-0.92) by Spearman ρ and 0.72 (95% CI, 0.68-0.77) by Kendall τ. Sensitivity analyses in PREVAIL demonstrated the robustness of the PCWG2 rPFS definition using additional measures of progression. There was concordance between central and investigator review and a positive correlation between rPFS and OS among enzalutamide-treated patients. clinicaltrials.gov Identifier: NCT01212991.

Synergistic atmospheric retrievals: Using OMEGA and PFS to retrieve martian CO

NASA Astrophysics Data System (ADS)

Robert, S.; Aoki, S.; Piccialli, A.; Audouard, J.; Montmessin, F.; Ferron, S.; Altieri, F.; Bellucci, G.; Geminale, A.; Giuranna, M.; Sindoni, G.; Vandaele, A. C.

2017-09-01

Recently, a theoretical study was published showing how science return can benefit from synergistic retrievals [Robert et al., 2017]. The same approach is here applied to experimental data. OMEGA and PFS instruments, both on Mars Express spacecraft, have collected high-quality data enabling us to retrieve CO volume mixing ratio, among others. The synergy between OMEGA and PFS channels will be presented and the benefits of the synergy will be described by comparing synergistic spectral retrievals and non-synergistic ones.

Bariatric surgery and the changing current scope of general surgery practice: implications for general surgery residency training.

PubMed

Mostaedi, Rouzbeh; Ali, Mohamed R; Pierce, Jonathan L; Scherer, Lynette A; Galante, Joseph M

2015-02-01

The scope of general surgery practice has evolved tremendously in the last 20 years. However, clinical experience in general surgery residency training has undergone relatively little change. To evaluate the current scope of academic general surgery and its implications on surgical residency. The University HealthSystem Consortium and Association of American Medical Colleges established the Faculty Practice Solution Center (FPSC) to characterize physician productivity. The FPSC is a benchmarking tool for academic medical centers created from revenue data collected from more than 90,000 physicians who practice at 95 institutions across the United States. The FPSC database was queried to evaluate the annual mean procedure frequency per surgeon (PFS) in each calendar year from 2006 through 2011. The associated work relative value units (wRVUs) were also examined to measure physician effort and skill. During the 6-year period, 146 distinct Current Procedural Terminology codes were among the top 100 procedures, and 16 of these procedures ranked in the top 10 procedures in at least 1 year. The top 10 procedures accounted for more than half (range, 52.5%-57.2%) of the total 100 PFS evaluated for each year. Laparoscopic Roux-en-Y gastric bypass was consistently among the top 10 procedures in each year (PFS, 18.2-24.6). The other most frequently performed procedures included laparoscopic cholecystectomy (PFS, 30.3-43.5), upper gastrointestinal tract endoscopy (PFS, 26.5-34.3), mastectomy (PFS, 16.5-35.0), inguinal hernia repair (PFS, 15.5-22.1), and abdominal wall hernia repair (PFS, 21.6-26.1). In all years, laparoscopic Roux-en-Y gastric bypass generated the highest number of wRVUs (wRVUs, 491.0-618.2), and laparoscopic cholecystectomy was regularly the next highest (wRVUs, 335.8-498.7). A significant proportion of academic general surgery is composed of bariatric surgery, yet surgical training does not sufficiently emphasize the necessary exposure to technical expertise and clinical management of the patient undergoing bariatric surgery. As the scope of general surgery practice continues to evolve, general surgery residency training will need to better integrate the exposure to bariatric surgery.

Is progression-free survival a more relevant endpoint than overall survival in first-line HR+/HER2- metastatic breast cancer?

PubMed

Forsythe, Anna; Chandiwana, David; Barth, Janina; Thabane, Marroon; Baeck, Johan; Shor, Anastasiya; Tremblay, Gabriel

2018-01-01

Hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-), metastatic breast cancer (MBC) accounts for 73% of all MBCs. Endocrine therapy (ET) is the basis of first-line (1L) therapy for patients with HR+/HER2- MBC. Novel therapies have demonstrated improvements in progression-free survival (PFS) compared to ET. The clinical relevance of PFS is being debated, as there is no proven direct correlation with overall survival (OS) benefit to date. We reviewed studies of HR+/HER2- MBC to assess PFS and other factors that influence OS and treatment response, and health-related quality of life (HRQoL). The Embase ® , Medline ® , and Cochrane databases were systematically searched to identify studies in adult women with HR+/HER2- MBC, published between January 2006 and January 2017, and written in English. Phase II and III randomized controlled trials (RCTs), observational, and retrospective studies were included. Seventy-nine RCTs were identified: 58 (73%) in the 1L+ setting and 21 (27%) in second-line or greater settings. PFS hazard ratios (HRs) were reported in 61 (77%) studies; 31 (39%) reported significant PFS improvements. OS was reported in 44 (41%) studies; 12 (15%) reported significant OS improvements. Significant improvements in both PFS and OS were reported in only 6 (8%) studies (1 Phase II; 5 Phase III). Patients with HER2- MBC received, on average, ≥5 lines of therapy, with no consistent treatment pathway. Baseline characteristics, prior therapies, and the type and number of post-progression therapies significantly impacted OS. PFS, response rates, and HRQoL decreased with each line of therapy (EuroQol 5 Dimensions: 0.78 1L vs. 0.70 post-progression). Few RCTs in HR+/HER2- MBC have demonstrated significant improvements in OS. Factors other than choice of 1L therapy impact OS, including post-progression therapies, which cannot be controlled in RCTs. This study emphasizes the importance of PFS improvement in 1L treatment of HR+/HER2- MBC.

Simulation and comparison of progression-free survival among patients with non-squamous non-small-cell lung cancer receiving sequential therapy.

PubMed

Walzer, Stefan; Chouaid, Christos; Lister, Johanna; Gultyaev, Dmitry; Vergnenegre, Alain; de Marinis, Filippo; Meng, Jie; de Castro Carpeno, Javier; Crott, Ralph; Kleman, Martin; Ngoh, Charles

2015-01-01

In recent years, the treatment landscape in advanced non-squamous non-small-cell lung cancer (nsNSCLC) has changed. New therapies (e.g., bevacizumab indicated in first line) have become available and other therapies (e.g., pemetrexed in first line and second line) moved into earlier lines in the treatment paradigm. While there has been an expansion of the available treatment options, it is still a key research question which therapy sequence results in the best survival outcomes for patients with nsNSCLC. A therapy-sequencing disease model that approximates treatment outcomes in up to five lines of treatment was developed for patients with nsNSCLC. The primary source of data for progression-free survival (PFS) and time to death was published pivotal trial data. All patients were treatment-naïve and in the PFS state, received first-line treatment with either bevacizumab-based therapy or doublet chemotherapy (including the option of pemetrexed + cisplatin). Patients would then progress to a subsequent line of therapy, remain in PFS or die. In case of progression, it was assumed that each survivor would receive a subsequent line of therapy, based on EMA licensed therapies. Weibull distribution curves were fitted to the data. All bevacizumab-based first-line therapy sequences analyzed achieved total PFS of around 15 months. Bevacizumab + carboplatin + paclitaxel (first line) → pemetrexed (second line) → erlotinib (third line) → docetaxel (fourth line) resulted in total mean PFS time of 15.7 months, for instance. Sequences with pemetrexed in combination with cisplatin in first line achieved total PFS times between 12.6 and 12.8 months with a slightly higher total PFS time achieved when assuming pemetrexed continuation therapy in maintenance after pemetrexed + cisplatin in first-line induction. Overall survival results followed the same trend as PFS. The model suggests that treatment-sequencing strategies starting with a bevacizumab-based combination in first line yield better survival outcomes than those starting with pemetrexed-based combinations, a result that is attributable to the possibility of one further line of treatment with first-line bevacizumab-based treatment sequences.

Optical multicast system for data center networks.

PubMed

Samadi, Payman; Gupta, Varun; Xu, Junjie; Wang, Howard; Zussman, Gil; Bergman, Keren

2015-08-24

We present the design and experimental evaluation of an Optical Multicast System for Data Center Networks, a hardware-software system architecture that uniquely integrates passive optical splitters in a hybrid network architecture for faster and simpler delivery of multicast traffic flows. An application-driven control plane manages the integrated optical and electronic switched traffic routing in the data plane layer. The control plane includes a resource allocation algorithm to optimally assign optical splitters to the flows. The hardware architecture is built on a hybrid network with both Electronic Packet Switching (EPS) and Optical Circuit Switching (OCS) networks to aggregate Top-of-Rack switches. The OCS is also the connectivity substrate of splitters to the optical network. The optical multicast system implementation requires only commodity optical components. We built a prototype and developed a simulation environment to evaluate the performance of the system for bulk multicasting. Experimental and numerical results show simultaneous delivery of multicast flows to all receivers with steady throughput. Compared to IP multicast that is the electronic counterpart, optical multicast performs with less protocol complexity and reduced energy consumption. Compared to peer-to-peer multicast methods, it achieves at minimum an order of magnitude higher throughput for flows under 250 MB with significantly less connection overheads. Furthermore, for delivering 20 TB of data containing only 15% multicast flows, it reduces the total delivery energy consumption by 50% and improves latency by 55% compared to a data center with a sole non-blocking EPS network.

Preliminary Engineering Design Package for the Basin A Neck Groundwater Intercept and Treatment System Interim Response Action

DTIC Science & Technology

1989-02-01

INDICATOR pPOST-FILTERED VITER RPUESIC POST-FILTRATION POLYMER SOLUTION MCUUM BREAKER FILTRATION POLYMER D*+RENTALkL PRESSURE SWITCH FEED PUMPS POLYMER...differential pressure switch signals the need for backwash of the operating filter. At this time, flow is S automatically switched to the standby filter...filter is undergoing backwash or on standby. High differential pressure across the filter bed, as sensed by a differential pressure switch , signals

Harnessing the polariton drag effect to design an electrically controlled optical switch.

PubMed

Berman, Oleg L; Kezerashvili, Roman Ya; Kolmakov, German V

2014-10-28

We propose a design of a Y-shaped electrically controlled optical switch based on the studies of propagation of an exciton-polariton condensate in a patterned optical microcavity with an embedded quantum well. The polaritons are driven by a time-independent force due to the microcavity wedge shape and by a time-dependent drag force owing to the interaction of excitons in a quantum well and the electric current running in a neighboring quantum well. It is demonstrated that by applying the drag force one can direct more than 90% of the polariton flow toward the desired branch of the switch with no hysteresis. By considering the transient dynamics of the polariton condensate, we estimate the response speed of the switch as 9.1 GHz. We also propose a design of the polariton switch in a flat microcavity based on the geometrically identical Y-shaped quantum wells where the polariton flow is only induced by the drag force. The latter setup enables one to design a multiway switch that can act as an electrically controlled optical transistor with on and off functions. Finally, we performed the simulations for a microcavity with an embedded gapped graphene layer and demonstrated that in this case the response speed of the switch can be increased up to 14 GHz for the same switch size. The simulations also show that the energy gap in the quasiparticle spectrum in graphene can be utilized as an additional parameter that controls the propagation of the signals in the switch.

Pulsed laser triggered high speed microfluidic switch

NASA Astrophysics Data System (ADS)

Wu, Ting-Hsiang; Gao, Lanyu; Chen, Yue; Wei, Kenneth; Chiou, Pei-Yu

2008-10-01

We report a high-speed microfluidic switch capable of achieving a switching time of 10 μs. The switching mechanism is realized by exciting dynamic vapor bubbles with focused laser pulses in a microfluidic polydimethylsiloxane (PDMS) channel. The bubble expansion deforms the elastic PDMS channel wall and squeezes the adjacent sample channel to control its fluid and particle flows as captured by the time-resolved imaging system. A switching of polystyrene microspheres in a Y-shaped channel has also been demonstrated. This ultrafast laser triggered switching mechanism has the potential to advance the sorting speed of state-of-the-art microscale fluorescence activated cell sorting devices.

Polyfluorinated surfactants (PFS) in paper and board coatings for food packaging.

PubMed

Trier, Xenia; Granby, Kit; Christensen, Jan H

2011-08-01

In this study, we explore the identity of a range of polyfluorinated surfactants (PFS) used for food contact materials, primarily to impart oil and water repellency on paper and board. PFS are of interest, as they can be precursors of poly- and perfluorinated alkyl substances (PFAS), of which several are persistent and are found worldwide in human blood and in the environment. To determine the elemental composition of PFS, we combined information from patents, chemical suppliers and analyses of industrial blends using ultra performance liquid chromatography-negative electrospray ionisation quadrupole time-of-flight mass spectrometry. At a high pH of 9.7, both non-ionic and anionic PFS were ionised and were recognised by negative mass defects of exact masses, and neutral fragment losses of n × 20 or n × 100 Da. More than 115 molecular structures were found in industrial blends from the EU, US and China, belonging to the groups of polyfluoroalkyl-mono- and di-ester phosphates (monoPAPS, diPAPS and S-diPAPS), -ethoxylates, -acrylates, -amino acids, -sulfonamide phosphates and -thio acids, together with residuals and synthesis byproducts. In addition, a number of starting materials such as perfluorooctane sulfonamide N-alkyl esters were analysed. Di- and trialkylated PAPS and S-diPAPS were found in migrates from European food contact materials. This study highlights the need to monitor for more types of PFS in order to map the sources of PFAS in humans and the environment.

Progression-free survival in advanced ovarian cancer: a Canadian review and expert panel perspective

PubMed Central

Oza, A.M.; Castonguay, V.; Tsoref, D.; Diaz–Padilla, I.; Karakasis, K.; Mackay, H.; Welch, S.; Weberpals, J.; Hoskins, P.; Plante, M.; Provencher, D.; Tonkin, K.; Covens, A.; Ghatage, P.; Gregoire, J.; Hirte, H.; Miller, D.; Rosen, B.; Maroun, J.; Buyse, M.; Coens, C.; Brady, M.F.; Stuart, G.C.E.

2011-01-01

Ovarian cancer is leading cause of gynecologic cancer mortality in Canada. To date, overall survival (os) has been the most-used endpoint in oncology trials because of its relevance and objectivity. However, as a result of various factors, including the pattern of sequential salvage therapies, measurement of os and collection of os data are becoming particularly challenging. Phase ii and iii trials have therefore adopted progression-free survival (pfs) as a more convenient surrogate endpoint; however, the clinical significance of pfs remains unclear. This position paper presents discussion topics and findings from a pan-Canadian meeting of experts that set out to evaluate the relevance of pfs as a valid endpoint in ovarian cancer;reach a Canadian consensus on the relevance of pfs in ovarian cancer; andtry to address how pfs translates into clinical benefit in ovarian cancer. Overall, the findings and the group consensus posit that future studies should ensure that trials are designed to evaluate pfs, os, and other clinically relevant endpoints such as disease-related symptoms or quality of life;incorporate interim futility analyses intended to stop accrual early when the experimental regimen is not active;stop trials early to declare superiority only when compelling evidence suggests that a new treatment provides benefit for a pre-specified, clinically relevant endpoint such as os or symptom relief; anddiscourage early release of secondary endpoint results when such a release might increase the frequency of crossover to the experimental intervention. PMID:21969808

Functional evaluation of malaria Pfs25 DNA vaccine by in vivo electroporation in olive baboons.

PubMed

Kumar, Rajesh; Nyakundi, Ruth; Kariuki, Thomas; Ozwara, Hastings; Nyamongo, Onkoba; Mlambo, Godfree; Ellefsen, Barry; Hannaman, Drew; Kumar, Nirbhay

2013-06-28

Plasmodium falciparum Pfs25 antigen, expressed on the surface of zygotes and ookinetes, is one of the leading targets for the development of a malaria transmission-blocking vaccine (TBV). Our laboratory has been evaluating DNA plasmid based Pfs25 vaccine in mice and non-human primates. Previously, we established that in vivo electroporation (EP) delivery is an effective method to improve the immunogenicity of DNA vaccine encoding Pfs25 in mice. In order to optimize the in vivo EP procedure and test for its efficacy in more clinically relevant larger animal models, we employed in vivo EP to evaluate the immune response and protective efficacy of Pfs25 encoding DNA vaccine in nonhuman primates (olive baboons, Papio anubis). The results showed that at a dose of 2.5mg DNA vaccine, antibody responses were significantly enhanced with EP as compared to without EP resulting in effective transmission blocking efficiency. Similar immunogenicity enhancing effect of EP was also observed with lower doses (0.5mg and 1mg) of DNA plasmids. Further, final boosting with a single dose of recombinant Pfs25 protein resulted in dramatically enhanced antibody titers and significantly increased functional transmission blocking efficiency. Our study suggests priming with DNA vaccine via EP along with protein boost regimen as an effective method to elicit potent immunogenicity of malaria DNA vaccines in nonhuman primates and provides the basis for further evaluation in human volunteers. Copyright © 2013 Elsevier Ltd. All rights reserved.

Spool Valve for Switching Air Flows Between Two Beds

NASA Technical Reports Server (NTRS)

Dean, W. Clark

2005-01-01

U.S. Patent 6,142,151 describes a dual-bed ventilation system for a space suit, with emphasis on a multiport spool valve that switches air flows between two chemical beds that adsorb carbon dioxide and water vapor. The valve is used to alternately make the air flow through one bed while exposing the other bed to the outer-space environment to regenerate that bed through vacuum desorption of CO2 and H2O. Oxygen flowing from a supply tank is routed through a pair of periodically switched solenoid valves to drive the spool valve in a reciprocating motion. The spool valve equalizes the pressures of air in the beds and the volumes of air flowing into and out of the beds during the alternations between the adsorption and desorption phases, in such a manner that the volume of air that must be vented to outer space is half of what it would be in the absence of pressure equalization. Oxygen that has been used to actuate the spool valve in its reciprocating motion is released into the ventilation loop to replenish air lost to vacuum during the previous desorption phase of the operating cycle.

Objective rapid delineation of areas at risk from block-and-ash pyroclastic flows and surges

USGS Publications Warehouse

Widiwijayanti, C.; Voight, B.; Hidayat, D.; Schilling, S.P.

2009-01-01

Assessments of pyroclastic flow (PF) hazards are commonly based on mapping of PF and surge deposits and estimations of inundation limits, and/or computer models of varying degrees of sophistication. In volcanic crises a PF hazard map may be sorely needed, but limited time, exposures, or safety aspects may preclude fieldwork, and insufficient time or baseline data may be available for reliable dynamic simulations. We have developed a statistically constrained simulation model for block-and-ash type PFs to estimate potential areas of inundation by adapting methodology from Iverson et al. (Geol Soc America Bull 110:972-984, (1998) for lahars. The predictive equations for block-and-ash PFs are calibrated with data from several volcanoes and given by A = (0.05 to 0.1) V2/3, B = (35 to 40) V2/3, where A is cross-sectional area of inundation, B is planimetric area and V is deposit volume. The proportionality coefficients were obtained from regression analyses and comparison of simulations to mapped deposits. The method embeds the predictive equations in a GIS program coupled with DEM topography, using the LAHARZ program of Schilling (1998). Although the method is objective and reproducible, any PF hazard zone so computed should be considered as an approximate guide only, due to uncertainties on the coefficients applicable to individual PFs, the authenticity of DEM details, and the volume of future collapses. The statistical uncertainty of the predictive equations, which imply a factor of two or more in predicting A or B for a specified V, is superposed on the uncertainty of forecasting V for the next PF to descend a particular valley. Multiple inundation zones, produced by simulations using a selected range of volumes, partly accommodate these uncertainties. The resulting maps show graphically that PF inundation potentials are highest nearest volcano sources and along valley thalwegs, and diminish with distance from source and lateral distance from thalweg. The model does not explicitly consider dynamic behavior, which can be important. Ash-cloud surge impact limits must be extended beyond PF hazard zones and we provide several approaches to do this. The method has been used to supply PF and surge hazard maps in two crises: Merapi 2006; and Montserrat 2006-2007. ?? Springer-Verlag 2008.

A hybrid optical switch architecture to integrate IP into optical networks to provide flexible and intelligent bandwidth on demand for cloud computing

NASA Astrophysics Data System (ADS)

Yang, Wei; Hall, Trevor J.

2013-12-01

The Internet is entering an era of cloud computing to provide more cost effective, eco-friendly and reliable services to consumer and business users. As a consequence, the nature of the Internet traffic has been fundamentally transformed from a pure packet-based pattern to today's predominantly flow-based pattern. Cloud computing has also brought about an unprecedented growth in the Internet traffic. In this paper, a hybrid optical switch architecture is presented to deal with the flow-based Internet traffic, aiming to offer flexible and intelligent bandwidth on demand to improve fiber capacity utilization. The hybrid optical switch is capable of integrating IP into optical networks for cloud-based traffic with predictable performance, for which the delay performance of the electronic module in the hybrid optical switch architecture is evaluated through simulation.

Epidemiology, clinical features, and outcome of HTLV-1–related ATLL in an area of prevalence in the United States

PubMed Central

Pimentel, Agustin; Reis, Isildinha M.; Gotuzzo, Eduardo; Lekakis, Lazaros; Komanduri, Krishna; Harrington, Thomas; Barber, Glen N.

2018-01-01

Adult T-cell leukemia/lymphoma (ATLL) is a fatal disease caused by human T-cell leukemia virus type 1 (HTLV-1). We retrospectively analyzed 195 patients with ATLL (lymphomatous n = 96, acute n = 80, unfavorable chronic n = 7, chronic n = 5, smoldering n = 3, and unclassified n = 4) diagnosed between 1987 and 2016 (median age 52 years, 77% Afro-Caribbean). Hypercalcemia was associated with acute ATLL (65%, vs 23% lymphomatous) (P = .012). The median survival for patients treated with modern therapies between 2000 and 2016 was 4.1 months for acute, 10.2 months for lymphomatous, 72 months for chronic/smoldering, and not reached for unfavorable chronic type, with 4-year survival rates of 10%, 4%, 60%, and 83%, respectively. The overall response rate (ORR) after first-line multiagent chemotherapy was 78% (complete response [CR] 39%) for acute vs 67% (CR 33%) for lymphomatous ATLL. First-line zidovudine interferon-α (AZT-IFN) resulted in ORR of 56% (CR 23%) for acute (n = 43), 33% (CR 16.5%) for lymphomatous (n = 6), and 86% (CR 29%) for unfavorable chronic ATLL. The median progression-free survival (PFS) in patients with aggressive ATLL who achieved CR after AZT-IFN was 48 months vs 11 months after chemotherapy (P = .003). Allogeneic hematopoietic stem cell transplant (allo-HSCT) resulted in a PFS of 24 and 28 months in 2 patients with lymphomatous ATLL. Our results suggest high-dose AZT-IFN is a reasonable up-front option for patients with aggressive leukemic ATLL followed by chemotherapy switch in nonresponders, whereas chemotherapy should be used in lymphomatous type followed by allo-HSCT when feasible. PMID:29545256

A new inorganic-organic composite coagulant, consisting of polyferric sulphate (PFS) and polyacrylamide (PAA).

PubMed

Moussas, P A; Zouboulis, A I

2009-08-01

Currently, research is focused on the synthesis of new composite coagulants, which are constituted of both inorganic and organic materials. In this paper, the development of relevant reagents was investigated, by combining the inorganic pre-polymerised iron-based coagulant Polyferric Sulphate (PFS) with an organic, non-ionic polymer (Polyacrylamide, PAA) under different PAA/Fe (mg/l) and OH/Fe molar ratios. Moreover, the new reagents were characterised in terms of typical properties, stability and morphological analysis (XRD, FTIR, SEM). Their coagulation performance, when treating low or high turbid kaolin-humic acid suspensions, was also investigated, whereas the applied coagulation mechanisms were discussed by using the Photometric Dispersion Analysis (PDA) analysis. The results show that the new coagulation reagents present improved properties, including increased effective polymer species concentration, and they exhibit very good stability. The respective tests using PDA confirmed that the predominant coagulation mechanism of PFS-PAA is the bridge formation mechanism. Coagulation experiments in low or high turbid kaolin-humic acid suspensions reveal that the novel composite reagent PFS-PAA exhibits better coagulation performance, when compared with simple PFS, in terms of zeta-potential reduction, turbidity and organic matter removal and residual iron concentration.

Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.

PubMed

McDermott, David F; Huseni, Mahrukh A; Atkins, Michael B; Motzer, Robert J; Rini, Brian I; Escudier, Bernard; Fong, Lawrence; Joseph, Richard W; Pal, Sumanta K; Reeves, James A; Sznol, Mario; Hainsworth, John; Rathmell, W Kimryn; Stadler, Walter M; Hutson, Thomas; Gore, Martin E; Ravaud, Alain; Bracarda, Sergio; Suárez, Cristina; Danielli, Riccardo; Gruenwald, Viktor; Choueiri, Toni K; Nickles, Dorothee; Jhunjhunwala, Suchit; Piault-Louis, Elisabeth; Thobhani, Alpa; Qiu, Jiaheng; Chen, Daniel S; Hegde, Priti S; Schiff, Christina; Fine, Gregg D; Powles, Thomas

2018-06-01

We describe results from IMmotion150, a randomized phase 2 study of atezolizumab (anti-PD-L1) alone or combined with bevacizumab (anti-VEGF) versus sunitinib in 305 patients with treatment-naive metastatic renal cell carcinoma. Co-primary endpoints were progression-free survival (PFS) in intent-to-treat and PD-L1+ populations. Intent-to-treat PFS hazard ratios for atezolizumab + bevacizumab or atezolizumab monotherapy versus sunitinib were 1.0 (95% confidence interval (CI), 0.69-1.45) and 1.19 (95% CI, 0.82-1.71), respectively; PD-L1+ PFS hazard ratios were 0.64 (95% CI, 0.38-1.08) and 1.03 (95% CI, 0.63-1.67), respectively. Exploratory biomarker analyses indicated that tumor mutation and neoantigen burden were not associated with PFS. Angiogenesis, T-effector/IFN-γ response, and myeloid inflammatory gene expression signatures were strongly and differentially associated with PFS within and across the treatments. These molecular profiles suggest that prediction of outcomes with anti-VEGF and immunotherapy may be possible and offer mechanistic insights into how blocking VEGF may overcome resistance to immune checkpoint blockade.

Association between hedonic hunger and body-mass index versus obesity status.

PubMed

Ribeiro, Gabriela; Camacho, Marta; Santos, Osvaldo; Pontes, Cristina; Torres, Sandra; Oliveira-Maia, Albino J

2018-04-11

Obesity-associated differences in hedonic hunger, while consistently reported, have not been adequately quantified, with most studies failing to demonstrate strong correlations between Body Mass Index (BMI) and hedonic hunger indicators. Here, we quantified and assessed the nature of the relationship between hedonic hunger and BMI, in a cross-sectional study using the Portuguese version of the PFS (P-PFS) to measure hedonic hunger. Data were collected from 1266 participants belonging to non-clinical, clinical (candidates for weight-loss surgery) and population samples. Across samples, significant but weak positive associations were found between P-PFS scores and BMI, in adjusted linear regression models. However, in logistic regression models of data from the clinical and non-clinical samples, the P-PFS Food Available domain score was significantly and robustly associated with belonging to the clinical sample (OR = 1.8, 95%CI: 1.2-2.8; p = 0.008), while in the population sample it was associated to being obese (OR = 2.1, 95%CI: 1.6-2.7; p < 0.001). Thus, hedonic hunger levels are associated with obesity status with the odds of being obese approximately doubling for each unit increase in the P-PFS Food Available score.

Smooth invariant densities for random switching on the torus

NASA Astrophysics Data System (ADS)

Bakhtin, Yuri; Hurth, Tobias; Lawley, Sean D.; Mattingly, Jonathan C.

2018-04-01

We consider a random dynamical system obtained by switching between the flows generated by two smooth vector fields on the 2d-torus, with the random switchings happening according to a Poisson process. Assuming that the driving vector fields are transversal to each other at all points of the torus and that each of them allows for a smooth invariant density and no periodic orbits, we prove that the switched system also has a smooth invariant density, for every switching rate. Our approach is based on an integration by parts formula inspired by techniques from Malliavin calculus.

Thermal Simulation of Switching Pulses in an Insulated Gate Bipolar Transistor (IGBT) Power Module

DTIC Science & Technology

2015-02-01

executed with SolidWorks Flow Simulation , a computational fluid-dynamics code. The graph in Fig. 2 shows the timing and amplitudes of power pulses...defined a convective flow of air perpendicular to the bottom surface of the mounting plate, with a velocity of 10 ft/s. The thermal simulations were...Thermal Simulation of Switching Pulses in an Insulated Gate Bipolar Transistor (IGBT) Power Module by Gregory K Ovrebo ARL-TR-7210

Levels of circulating CD45dimCD34+VEGFR2+ progenitor cells correlate with outcome in metastatic renal cell carcinoma patients treated with tyrosine kinase inhibitors

PubMed Central

Farace, F; Gross-Goupil, M; Tournay, E; Taylor, M; Vimond, N; Jacques, N; Billiot, F; Mauguen, A; Hill, C; Escudier, B

2011-01-01

Background: Predicting the efficacy of antiangiogenic therapy would be of clinical value in patients (pts) with metastatic renal cell carcinoma (mRCC). We tested the hypothesis that circulating endothelial cell (CEC), bone marrow-derived CD45dimCD34+VEGFR2+ progenitor cell or plasma angiogenic factor levels are associated with clinical outcome in mRCC pts undergoing treatment with tyrosine kinase inhibitors (TKI). Methods: Fifty-five mRCC pts were prospectively monitored at baseline (day 1) and day 14 during treatment (46 pts received sunitinib and 9 pts received sorafenib). Circulating endothelial cells (CD45−CD31+CD146+7-amino-actinomycin (7AAD)− cells) were measured in 1 ml whole blood using four-color flow cytometry (FCM). Circulating CD45dimCD34+VEGFR2+7AAD− progenitor cells were measured in progenitor-enriched fractions by four-color FCM. Plasma VEGF, sVEGFR2, SDF-1α and sVCAM-1 levels were determined by ELISA. Correlations between baseline CEC, CD45dimCD34+VEGFR2+7AAD− progenitor cells, plasma factors, as well as day 1–day 14 changes in CEC, CD45dimCD34+VEGFR2+7AAD− progenitor, plasma factor levels, and response to TKI, progression-free survival (PFS) and overall survival (OS) were examined. Results: No significant correlation between markers and response to TKI was observed. No association between baseline CEC, plasma VEGF, sVEGFR-2, SDF-1α, sVCAM-1 levels with PFS and OS was observed. However, baseline CD45dimCD34+VEGFR2+7AAD− progenitor cell levels were associated with PFS (P=0.01) and OS (P=0.006). Changes in this population and in SDF-1α levels between day 1 and day 14 were associated with PFS (P=0.03, P=0.002). Changes in VEGF and SDF-1α levels were associated with OS (P=0.02, P=0.007). Conclusion: Monitoring CD45dimCD34+VEGFR2+ progenitor cells, plasma VEGF and SDF-1α levels could be of clinical interest in TKI-treated mRCC pts to predict outcome. PMID:21386843

Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer

PubMed Central

Rathkopf, Dana E.; Beer, Tomasz M.; Loriot, Yohann; Higano, Celestia S.; Armstrong, Andrew J.; Sternberg, Cora N.; de Bono, Johann S.; Tombal, Bertrand; Parli, Teresa; Bhattacharya, Suman; Phung, De; Krivoshik, Andrew; Scher, Howard I.

2018-01-01

Importance Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. Objective To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS. Design, Setting, and Participants PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016. Interventions Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment. Main Outcomes and Measures Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman ρ and Kendall τ via Clayton copula. Results In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0.23 (SA5; 95% CI, 0.19-0.30), and 0.23 (SA6; 95% CI, 0.19-0.30) (P < .001 for all). Correlations of rPFS and OS in enzalutamide-treated patients were 0.89 (95% CI, 0.86-0.92) by Spearman ρ and 0.72 (95% CI, 0.68-0.77) by Kendall τ. Conclusions and Relevance Sensitivity analyses in PREVAIL demonstrated the robustness of the PCWG2 rPFS definition using additional measures of progression. There was concordance between central and investigator review and a positive correlation between rPFS and OS among enzalutamide-treated patients. Trial Registration clinicaltrials.gov Identifier: NCT01212991 PMID:29522174

Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials

PubMed Central

Vidriales, Maria-Belen; Cordón, Lourdes; Cedena, Maria-Teresa; Puig, Noemi; Martinez-Lopez, Joaquin; Rosiñol, Laura; Gutierrez, Norma C.; Martín-Ramos, María-Luisa; Oriol, Albert; Teruel, Ana-Isabel; Echeveste, María-Asunción; de Paz, Raquel; de Arriba, Felipe; Hernandez, Miguel T.; Palomera, Luis; Martinez, Rafael; Martin, Alejandro; Alegre, Adrian; De la Rubia, Javier; Orfao, Alberto; Mateos, María-Victoria; Blade, Joan; San-Miguel, Jesus F.

2017-01-01

Purpose To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of “operational cure” was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM. PMID:28498784

Depth of Response in Multiple Myeloma: A Pooled Analysis of Three PETHEMA/GEM Clinical Trials.

PubMed

Lahuerta, Juan-Jose; Paiva, Bruno; Vidriales, Maria-Belen; Cordón, Lourdes; Cedena, Maria-Teresa; Puig, Noemi; Martinez-Lopez, Joaquin; Rosiñol, Laura; Gutierrez, Norma C; Martín-Ramos, María-Luisa; Oriol, Albert; Teruel, Ana-Isabel; Echeveste, María-Asunción; de Paz, Raquel; de Arriba, Felipe; Hernandez, Miguel T; Palomera, Luis; Martinez, Rafael; Martin, Alejandro; Alegre, Adrian; De la Rubia, Javier; Orfao, Alberto; Mateos, María-Victoria; Blade, Joan; San-Miguel, Jesus F

2017-09-01

Purpose To perform a critical analysis on the impact of depth of response in newly diagnosed multiple myeloma (MM). Patients and Methods Data were analyzed from 609 patients who were enrolled in the GEM (Grupo Español de Mieloma) 2000 and GEM2005MENOS65 studies for transplant-eligible MM and the GEM2010MAS65 clinical trial for elderly patients with MM who had minimal residual disease (MRD) assessments 9 months after study enrollment. Median follow-up of the series was 71 months. Results Achievement of complete remission (CR) in the absence of MRD negativity was not associated with prolonged progression-free survival (PFS) and overall survival (OS) compared with near-CR or partial response (median PFS, 27, 27, and 29 months, respectively; median OS, 59, 64, and 65 months, respectively). MRD-negative status was strongly associated with prolonged PFS (median, 63 months; P < .001) and OS (median not reached; P < .001) overall and in subgroups defined by prior transplantation, disease stage, and cytogenetics, with prognostic superiority of MRD negativity versus CR particularly evident in patients with high-risk cytogenetics. Accordingly, Harrell C statistics showed higher discrimination for both PFS and OS in Cox models that included MRD (as opposed to CR) for response assessment. Superior MRD-negative rates after different induction regimens anticipated prolonged PFS. Among 34 MRD-negative patients with MM and a phenotypic pattern of bone marrow involvement similar to monoclonal gammopathy of undetermined significance at diagnosis, the probability of "operational cure" was high; median PFS was 12 years, and the 10-year OS rate was 94%. Conclusion Our results demonstrate that MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group. MRD negativity should be considered as one of the most relevant end points for transplant-eligible and elderly fit patients with MM.

Pretreatment neutrophil to lymphocyte ratio is associated with response to therapy and prognosis of advanced non-small cell lung cancer patients treated with first-line platinum-based chemotherapy.

PubMed

Yao, Yanwen; Yuan, Dongmei; Liu, Hongbing; Gu, Xiaoling; Song, Yong

2013-03-01

Neutrophil to lymphocyte ratio (NLR) has been shown to be a prognosis indicator in different types of cancer. We aimed to investigate the association between NLR and therapy response, progression free survival (PFS) and overall survival (OS) in advanced non-small cell lung cancer (NSCLC) patients treated with first-line platinum-based chemotherapy. Patients who were hospitalized between January 2007 and December 2010 were enrolled and eliminated according to the inclusion and exclusion criteria. The NLR was defined as the absolute neutrophil count divided by the absolute lymphocyte count. Logistic regression analysis was applied for response rate and Cox regression analysis was adopted for PFS and OS. A P value of ≤0.05 was considered to be statistically significant. A total of 182 patients were enrolled in the current study. The median PFS was 164.5 days and median OS was 439.5 days. The statistical analysis data indicated that low pretreatment NLR (≤ 2.63) (OR = 2.043, P = 0.043), decreased posttreatment NLR (OR = 2.368, P = 0.013), well and moderate differentiation (OR = 2.773, P = 0.021) and normal CEA level (≤ 9.6 ng/ml) (OR = 2.090, P = 0.046) were associated with response to first-line platinum-based chemotherapy. A high pretreatment NLR (HR = 1.807, P = 0.018 for PFS, HR = 1.761, P = 0.020 for OS) and distant metastasis (HR = 2.118, P = 0.008 for PFS, HR = 2.753, P = 0.000 for OS) were independent prognostic factors for PFS and OS. Elevated pretreatment NLR might be a potential biomarker of worse response to first-line platinum-based chemotherapy and shorter PFS and OS for advanced NSCLC patients. To confirm these findings, larger, prospective and randomized studies are needed.

Phase II trial of the mTOR inhibitor, temsirolimus and evaluation of circulating tumor cells and tumor biomarkers in persistent and recurrent epithelial ovarian and primary peritoneal malignancies: a Gynecologic Oncology Group study

PubMed Central

Behbakht, Kian; Sill, Michael W.; Darcy, Kathleen M.; Rubin, Stephen C.; Mannel, Robert S.; Waggoner, Steven; Schilder, Russell J.; Cai, Kathy Q.; Godwin, Andrew K.; Alpaugh, R. Katherine

2012-01-01

Purpose Patients with persistent/recurrent epithelial ovarian cancer/primary peritoneal cancer (EOC/PPC) have limited treatment options. AKT and PI3K pathway activation is common in EOC/PPC, resulting in constitutive activation of downstream mTOR. The GOG conducted a phase II evaluation of efficacy and safety for the mTOR inhibitor, temsirolimus in EOC/PPC and explored circulating tumor cells (CTC) and AKT/mTOR/downstream tumor markers. Methods Eligible women with measurable, persistent/recurrent EOC/PPC who had received 1–3 prior regimens were treated with 25 mg weekly IV temsirolimus until progression or intolerable toxicity. Primary endpoints were progression-free survival (PFS) ≥6-months, tumor response, and toxicity. CellSearch® system was used to examine CTC, and AKT/mTOR/downstream markers were evaluated by archival tumor immunohistochemistry. Kendall’s tau-b correlation coefficient (r) and Cox regression modeling were used to explore marker associations with baseline characteristics and outcome. Results Sixty patients were enrolled in a two-stage sequential design. Of 54 eligible and evaluable patients, 24.1% (90%CI 14.9%–38.6%) had PFS ≥6 months (median 3.1 months), 9.3% (90%CI 3.7%–23.4%) experienced a partial response. Grade 3/4 adverse events included metabolic(8), gastrointestinal(8), pain(6), constitutional(5) and pulmonary(4). Suggested associations were between cyclin D1 and PFS ≥6 months, PFS or survival; positive CTC pre-treatment and lack of response; and high CTC expression of M30 and PFS ≥6 months/longer PFS. Conclusions Temsirolimus appears to have modest activity in persistent/recurrent EOC/PPC; however, PFS is just below that required to warrant inclusion in phase III studies in unselected patients. Cyclin D1 as a selection marker and CTC measures merit further study. PMID:21752435

Phase II study of monthly pasireotide LAR (SOM230C) for recurrent or progressive meningioma

PubMed Central

Norden, Andrew D.; Ligon, Keith L.; Hammond, Samantha N.; Muzikansky, Alona; Reardon, David A.; Kaley, Thomas J.; Batchelor, Tracy T.; Plotkin, Scott R.; Raizer, Jeffrey J.; Wong, Eric T.; Drappatz, Jan; Lesser, Glenn J.; Haidar, Sam; Beroukhim, Rameen; Lee, Eudocia Q.; Doherty, Lisa; Lafrankie, Debra; Gaffey, Sarah C.; Gerard, Mary; Smith, Katrina H.; McCluskey, Christine; Phuphanich, Surasak

2015-01-01

Objective: A subset of meningiomas recur after surgery and radiation therapy, but no medical therapy for recurrent meningioma has proven effective. Methods: Pasireotide LAR is a long-acting somatostatin analog that may inhibit meningioma growth. This was a phase II trial in patients with histologically confirmed recurrent or progressive meningioma designed to evaluate whether pasireotide LAR prolongs progression-free survival at 6 months (PFS6). Patients were stratified by histology (atypical [World Health Organization grade 2] and malignant [grade 3] meningiomas in cohort A and benign [grade 3] in cohort B). Results: Eighteen patients were accrued in cohort A and 16 in cohort B. Cohort A had median age 59 years, median Karnofsky performance status 80, 17 (94%) had previous radiation therapy, and 11 (61%) showed high octreotide uptake. Cohort B had median age 52 years, median Karnofsky performance status 90, 11 (69%) had previous radiation therapy, and 12 (75%) showed high octreotide uptake. There were no radiographic responses to pasireotide LAR therapy in either cohort. Twelve patients (67%) in cohort A and 13 (81%) in cohort B achieved stable disease. In cohort A, PFS6 was 17% and median PFS 15 weeks (95% confidence interval: 8–20). In cohort B, PFS6 was 50% and median PFS 26 weeks (12–43). Treatment was well tolerated. Octreotide uptake and insulin-like growth factor–1 levels did not predict outcome. Expression of somatostatin receptor 3 predicted favorable PFS and overall survival. Conclusions: Pasireotide LAR has limited activity in recurrent meningiomas. The finding that somatostatin receptor 3 is associated with favorable outcomes warrants further investigation. Classification of evidence: This study provides Class IV evidence that in patients with recurrent or progressive meningioma, pasireotide LAR does not significantly increase the proportion of patients with PFS at 6 months. PMID:25527270

Additional Survival Benefit of Involved-Lesion Radiation Therapy After R-CHOP Chemotherapy in Limited Stage Diffuse Large B-Cell Lymphoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kwon, Jeanny; Kim, Il Han, E-mail: ihkim@snu.ac.kr; Cancer Research Institute, Seoul National University College of Medicine, Seoul

Purpose: The purpose of this study was to evaluate the role of involved-lesion radiation therapy (ILRT) after rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy in limited stage diffuse large B-cell lymphoma (DLBCL) by comparing outcomes of R-CHOP therapy alone with R-CHOP followed by ILRT. Methods and Materials: We identified 198 patients treated with R-CHOP (median, 6 cycles) for pathologically confirmed DLBCL of limited stage from July 2004 to December 2012. Clinical characteristics of these patients were 33% with stage I and 66.7% with stage II; 79.8% were in the low or low-intermediate risk group; 13.6% had B symptoms; 29.8%more » had bulky tumors (≥7 cm); and 75.3% underwent ≥6 cycles of R-CHOP therapy. RT was given to 43 patients (21.7%) using ILRT technique, which included the prechemotherapy tumor volume with a median margin of 2 cm (median RT dose: 36 Gy). Results: After a median follow-up of 40 months, 3-year progression-free survival (PFS) and overall survival (OS) were 85.8% and 88.9%, respectively. Multivariate analysis showed ≥6 cycles of R-CHOP (PFS, P=.004; OS, P=.004) and ILRT (PFS, P=.021; OS, P=.014) were favorable prognosticators of PFS and OS. A bulky tumor (P=.027) and response to R-CHOP (P=.012) were also found to be independent factors of OS. In subgroup analysis, the effect of ILRT was prominent in patients with a bulky tumor (PFS, P=.014; OS, P=.030) or an elevated level of serum lactate dehydrogenase (LDH; PFS, P=.004; OS, P=.012). Conclusions: Our results suggest that ILRT after R-CHOP therapy improves PFS and OS in patients with limited stage DLBCL, especially in those with bulky disease or an elevated serum LDH level.« less

Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study

PubMed Central

Fackler, MaryJo S.; Zhang, Zhe; Lopez-Bujanda, Zoila A.; Jeter, Stacie C.; Sokoll, Lori J.; Garrett-Mayer, Elizabeth; Cope, Leslie M.; Umbricht, Christopher B.; Euhus, David M.; Forero, Andres; Storniolo, Anna M.; Nanda, Rita; Lin, Nancy U.; Carey, Lisa A.; Ingle, James N.; Sukumar, Saraswati; Wolff, Antonio C.

2017-01-01

Purpose Epigenetic alterations measured in blood may help guide breast cancer treatment. The multisite prospective study TBCRC 005 was conducted to examine the ability of a novel panel of cell-free DNA methylation markers to predict survival outcomes in metastatic breast cancer (MBC) using a new quantitative multiplex assay (cMethDNA). Patients and Methods Ten genes were tested in duplicate serum samples from 141 women at baseline, at week 4, and at first restaging. A cumulative methylation index (CMI) was generated on the basis of six of the 10 genes tested. Methylation cut points were selected to maximize the log-rank statistic, and cross-validation was used to obtain unbiased point estimates. Logistic regression or Cox proportional hazard models were used to test associations between the CMI and progression-free survival (PFS), overall survival (OS), and disease status at first restaging. The added value of the CMI in predicting survival outcomes was evaluated and compared with circulating tumor cells (CellSearch). Results Median PFS and OS were significantly shorter in women with a high CMI (PFS, 2.1 months; OS, 12.3 months) versus a low CMI (PFS, 5.8 months; OS, 21.7 months). In multivariable models, among women with MBC, a high versus low CMI at week 4 was independently associated with worse PFS (hazard ratio, 1.79; 95% CI, 1.23 to 2.60; P = .002) and OS (hazard ratio, 1.75; 95% CI, 1.21 to 2.54; P = .003). An increase in the CMI from baseline to week 4 was associated with worse PFS (P < .001) and progressive disease at first restaging (P < .001). Week 4 CMI was a strong predictor of PFS, even in the presence of circulating tumor cells (P = .004). Conclusion Methylation of this gene panel is a strong predictor of survival outcomes in MBC and may have clinical usefulness in risk stratification and disease monitoring. PMID:27870562

A Martian PFS average spectrum: Comparison with ISO SWS

NASA Astrophysics Data System (ADS)

Formisano, V.; Encrenaz, T.; Fonti, S.; Giuranna, M.; Grassi, D.; Hirsh, H.; Khatuntsev, I.; Ignatiev, N.; Lellouch, E.; Maturilli, A.; Moroz, V.; Orleanski, P.; Piccioni, G.; Rataj, M.; Saggin, B.; Zasova, L.

2005-08-01

The evaluation of the planetary Fourier spectrometer performance at Mars is presented by comparing an average spectrum with the ISO spectrum published by Lellouch et al. [2000. Planet. Space Sci. 48, 1393.]. First, the average conditions of Mars atmosphere are compared, then the mixing ratios of the major gases are evaluated. Major and minor bands of CO 2 are compared, from the point of view of features characteristics and bands depth. The spectral resolution is also compared using several solar lines. The result indicates that PFS radiance is valid to better than 1% in the wavenumber range 1800-4200 cm -1 for the average spectrum considered (1680 measurements). The PFS monochromatic transfer function generates an overshooting on the left-hand side of strong narrow lines (solar or atmospheric). The spectral resolution of PFS is of the order of 1.3 cm -1 or better. A large number of narrow features to be identified are discovered.

Assessment of early response to imatinib 800 mg after 400 mg progression by ¹⁸F-fluorodeoxyglucose PET in patients with metastatic gastrointestinal stromal tumors.

PubMed

Chacón, Matías; Eleta, Martín; Espindola, Adriel Rodríguez; Roca, Enrique; Méndez, Guillermo; Rojo, Sandra; Pupareli, Carmen

2015-01-01

Imatinib is the standard first-line therapy for advanced gastrointestinal stromal tumor. (18)F-fluorodeoxyglucose PET computed tomography (FDG PET/CT) shows a faster response than computed tomography in nonpretreated patients. After disease progression on imatinib 400 mg, 16 patients were exposed to 800 mg. Tumor response was evaluated by FDG PET/CT on days 7 and 37. Primary objective was to correlate early metabolic response (EMR) with progression-free survival (PFS). EMR by FDG PET/CT scan was not predictive of PFS. Median PFS in these patients was 3 months. Overall survival was influenced by gastric primary site (p = 0.05). The assessment of EMR by FDG PET/CT in patients with advanced gastrointestinal stromal tumor exposed to imatinib 800 mg was not predictive of PFS or overall survival.

Gravimetric system using high-speed double switching valves for low liquid flow rates

NASA Astrophysics Data System (ADS)

Cheong, Kar-Hooi; Doihara, Ryouji; Shimada, Takashi; Terao, Yoshiya

2018-07-01

This paper presents a gravimetric system developed to perform the static weighing with flying-start-and-stop (SW-FSS) calibration method at low liquid flow rates using a pair of identical high-speed switching valves as a flow diverter. Features of the gravimetric system comprise three main components: a pair of switching valves that divert the working liquid between two symmetrical flow paths; a weighing vessel equipped with an overflow inner vessel and enclosed in a weighing chamber; and a liquid discharge mechanism comprising a discharge tube and a discharge pump, used with a multi-purpose bin. These are described with an explanation of the design considerations behind each feature. The overflow inner vessel is designed with a notch in its wall and is positioned so that it does not come into contact with the liquid surface of the accumulated liquid in the weighing vessel or the side wall of the weighing vessel to obtain a good repeatability of the interactive effects between the feeding tube and the submerging working liquid, thus ensuring a correct mass reading of the liquid collection. A performance test showed that, in terms of contribution to the overall uncertainty of the standard flow rate, the pair of switching valves is capable of performing SW-FSS satisfactorily with small relative timing errors within %. However, the mass loss due to evaporation is considered a major source of error of the gravimetric system, showing a maximum error of 0.011% under the most evaporative condition tested for the longest liquid collection time of the gravimetric system.

Apparent diffusion coefficient histogram metrics correlate with survival in diffuse intrinsic pontine glioma: a report from the Pediatric Brain Tumor Consortium

PubMed Central

Poussaint, Tina Young; Vajapeyam, Sridhar; Ricci, Kelsey I.; Panigrahy, Ashok; Kocak, Mehmet; Kun, Larry E.; Boyett, James M.; Pollack, Ian F.; Fouladi, Maryam

2016-01-01

Background Diffuse intrinsic pontine glioma (DIPG) is associated with poor survival regardless of therapy. We used volumetric apparent diffusion coefficient (ADC) histogram metrics to determine associations with progression-free survival (PFS) and overall survival (OS) at baseline and after radiation therapy (RT). Methods Baseline and post-RT quantitative ADC histograms were generated from fluid-attenuated inversion recovery (FLAIR) images and enhancement regions of interest. Metrics assessed included number of peaks (ie, unimodal or bimodal), mean and median ADC, standard deviation, mode, skewness, and kurtosis. Results Based on FLAIR images, the majority of tumors had unimodal peaks with significantly shorter average survival. Pre-RT FLAIR mean, mode, and median values were significantly associated with decreased risk of progression; higher pre-RT ADC values had longer PFS on average. Pre-RT FLAIR skewness and standard deviation were significantly associated with increased risk of progression; higher pre-RT FLAIR skewness and standard deviation had shorter PFS. Nonenhancing tumors at baseline showed higher ADC FLAIR mean values, lower kurtosis, and higher PFS. For enhancing tumors at baseline, bimodal enhancement histograms had much worse PFS and OS than unimodal cases and significantly lower mean peak values. Enhancement in tumors only after RT led to significantly shorter PFS and OS than in patients with baseline or no baseline enhancement. Conclusions ADC histogram metrics in DIPG demonstrate significant correlations between diffusion metrics and survival, with lower diffusion values (increased cellularity), increased skewness, and enhancement associated with shorter survival, requiring future investigations in large DIPG clinical trials. PMID:26487690

Clinical outcomes of WBRT plus EGFR-TKIs versus WBRT or TKIs alone for the treatment of cerebral metastatic NSCLC patients: a meta-analysis

PubMed Central

Hou, Bin; Zhou, Dong; Li, Jing-Meng; Lu, Xiao; Wu, Qiu-Ping; Dai, Ji-Gang

2017-01-01

Whether WBRT plus EGFR-TKIs has a greater survival benefit than EGFR-TKIs alone or WBRT alone remains controversial in NSCLC patients with multiple brain metastases. To rectify this, we conducted a systematic meta-analysis based on 9 retrospective studies and 1 randomized controlled study published between 2012 and 2016, comprising 1041 patients. Five studies were included in the comparison of WBRT plus EGFR-TKIs and EGFR-TKIs alone. The combined HR for OS of patients with EGFR mutation was 1.25 [95% CI 0.98–2.15; P = 0.08] and for intracranial PFS was 1.30 [95% CI 1.03–1.65; P = 0.03], which revealed that EGFR-TKIs alone produced a superior intracranial PFS than WBRT plus EGFR-TKIs. Five studies were included in the comparison of WBRT plus EGFR-TKIs and WBRT alone. The combined HR for OS, intracranial PFS and extracranial PFS were 0.52 [95% CI 0.37–0.75; P = 0.0004], 0.36 [95% CI 0.24–0.53; P < 0.001] and 0.52 [95% CI 0.38–0.71; P < 0.001], respectively, which revealed a significant benefit of WBRT plus EGFR-TKIs compared with WBRT alone. The results indicated that EGFR-TKIs alone should be the first option for the treatment of NSCLC patients with multiple BM, especially with EGFR mutation, since it provides similar OS and extracranial PFS but superior intracranial PFS compared with WBRT plus EGFR-TKIs. PMID:28915676

Clinical outcomes of WBRT plus EGFR-TKIs versus WBRT or TKIs alone for the treatment of cerebral metastatic NSCLC patients: a meta-analysis.

PubMed

Zheng, Hong; Liu, Quan-Xing; Hou, Bin; Zhou, Dong; Li, Jing-Meng; Lu, Xiao; Wu, Qiu-Ping; Dai, Ji-Gang

2017-08-22

Whether WBRT plus EGFR-TKIs has a greater survival benefit than EGFR-TKIs alone or WBRT alone remains controversial in NSCLC patients with multiple brain metastases. To rectify this, we conducted a systematic meta-analysis based on 9 retrospective studies and 1 randomized controlled study published between 2012 and 2016, comprising 1041 patients. Five studies were included in the comparison of WBRT plus EGFR-TKIs and EGFR-TKIs alone. The combined HR for OS of patients with EGFR mutation was 1.25 [95% CI 0.98-2.15; P = 0.08] and for intracranial PFS was 1.30 [95% CI 1.03-1.65; P = 0.03], which revealed that EGFR-TKIs alone produced a superior intracranial PFS than WBRT plus EGFR-TKIs. Five studies were included in the comparison of WBRT plus EGFR-TKIs and WBRT alone. The combined HR for OS, intracranial PFS and extracranial PFS were 0.52 [95% CI 0.37-0.75; P = 0.0004], 0.36 [95% CI 0.24-0.53; P < 0.001] and 0.52 [95% CI 0.38-0.71; P < 0.001], respectively, which revealed a significant benefit of WBRT plus EGFR-TKIs compared with WBRT alone. The results indicated that EGFR-TKIs alone should be the first option for the treatment of NSCLC patients with multiple BM, especially with EGFR mutation, since it provides similar OS and extracranial PFS but superior intracranial PFS compared with WBRT plus EGFR-TKIs.

Adult medulloblastoma: clinical characters, prognostic factors, outcomes and patterns of relapse.

PubMed

Zhang, Na; Ouyang, Taohui; Kang, Huicong; Long, Wang; Thomas, Benjamin; Zhu, Suiqiang

2015-09-01

To analyze the clinical characters, prognostic factors, patterns of relapse and treatment outcomes for medulloblastoma in adults. The clinical materials of 73 consecutive adult patients (age, ≥16 years) with medulloblastoma were analyzed retrospectively. Follow-up data were available in 62 patients, ranging from 10 to 142 months (median, 78.4 months). Outcome in survival was assessed by the progression-free survival (PFS) and overall survival (OS). Univariate and multivariate analysis were performed to determine the prognostic factors. Total or near-total tumor resection was achieved in 37 cases (59.7 %), subtotal in 19 cases (30.6 %), and partial resection in 6 cases (9.7 %).Twenty-two patients experienced recurrences, and 45 % percent of all recurrences occurred more than 4 years after initial surgery. The PFS rates at 5 and 8 years were 60.1 and 37.0 %, respectively. The OS rates at 5 and 8 years were 82.6 and 57.3 %, respectively. In univariate analysis, less tumor resection, non-desmoplastic pathology, and brainstem involvement were risk factors for worse PFS and OS (P < 0.05). High-risk category was associated with just lower PFS, but not OS. In multivariate analysis, complete resection and desmoplastic pathology were independently predictive factors of improved PFS and OS. In adult medulloblastoma, late relapse is common and therefore long-term follow-up is important for evaluating the real impact of treatments. Risk category had prognostic value just for PFS, but not for OS. Complete resection and desmoplastic histology are independently predictive factors for favorable outcomes.

Surrogate Endpoints in Second-Line Trials of Targeted Agents in Metastatic Colorectal Cancer: A Literature-Based Systematic Review and Meta-Analysis.

PubMed

Cremolini, Chiara; Antoniotti, Carlotta; Pietrantonio, Filippo; Berenato, Rosa; Tampellini, Marco; Baratelli, Chiara; Salvatore, Lisa; Marmorino, Federica; Borelli, Beatrice; Nichetti, Federico; Bironzo, Paolo; Sonetto, Cristina; Bartolomeo, Maria Di; Braud, Filippo de; Loupakis, Fotios; Falcone, Alfredo; Di Maio, M

2017-07-01

The purpose of this study was to evaluate progression-free survival (PFS) and objective response rate (ORR) as surrogate endpoints of overall survival (OS) in modern clinical trials investigating the efficacy of targeted agents in the second-line treatment of metastatic colorectal cancer (mCRC). A systematic search of literature pertaining to randomized phase II and III trials evaluating targeted agents as second-line treatments for mCRC was performed. The strength of the correlation between both PFS and ORR and OS was assessed based on the Pearson's correlation coefficient (R) and the coefficient of determination (R 2 ). Twenty trials, including a total of 7,571 patients, met the search criteria. The median duration of post-progression survival (PPS) was 7.6 months. The median differences between experimental and control arms were 0.65 months (range, -2.4 to 3.4) for the median PFS and 0.7 months (range, -5.8 to 3.9) for the median OS. PFS and ORR showed moderate (R=0.734, R 2 =0.539, p < 0.001) and poor correlation (R=0.169, R 2 =0.029, p=0.476) with OS, respectively. No differences between anti-angiogenic agents and other drugs were evident. Targeted agents investigated in the second-line treatment of mCRC provided minimal PFS gains translating into modest OS improvements. Considering both the moderate correlation between PFS and OS and the short duration of PPS, the OS should remain the preferred primary endpoint for randomized clinical trials in the second-line treatment of mCRC.

RF-photonic chirp encoder and compressor for seamless analysis of information flow.

PubMed

Zalevsky, Zeev; Shemer, Amir; Zach, Shlomo

2008-05-26

In this paper we realize an RF photonic chirp compression system that compresses a continuous stream of incoming RF data (modulated on top of an optical carrier) into a train of temporal short pulses. Each pulse in the train can be separated and treated individually while being sampled by low rate optical switch and without temporal loses of the incoming flow of information. Each such pulse can be filtered and analyzed differently. The main advantage of the proposed system is its capability of being able to handle, seamlessly, high rate information flow with all-optical means and with low rate optical switches.

Standardized added metabolic activity (SAM) IN ¹⁸F-FDG PET assessment of treatment response in colorectal liver metastases.

PubMed

Mertens, Jeroen; De Bruyne, S; Van Damme, N; Smeets, P; Ceelen, W; Troisi, R; Laurent, S; Geboes, K; Peeters, M; Goethals, I; Van de Wiele, C

2013-08-01

Standardized added metabolic activity (SAM) is a PET parameter for assessing the total metabolic load of malignant processes, avoiding partial volume effects and lesion segmentation. The potential role of this parameter in the assessment of response to chemotherapy and bevacizumab was tested in patients with metastatic colorectal cancer with potentially resectable liver metastases (mCRC). (18)F-FDG PET/CT was performed in 18 mCRC patients with liver metastases before treatment and after five cycles of FOLFOX/FOLFIRI and bevacizumab. Of the 18 patients, 16 subsequently underwent resection of liver metastases. Baseline and follow-up SUVmax, and SAM as well as reduction in SUVmax (∆SUVmax) and SAM (∆SAM) of all liver metastases were correlated with morphological response, and progression-free and overall survival (PFS and OS). A significant reduction in metabolic activity of the liver metastases was seen after chemotherapy with a median ∆SUVmax of 25.3% and ∆SAM of 94.5% (p = 0.033 and 0.003). Median baseline SUVmax and SAM values were significantly different between morphological responders and nonresponders (3.8 vs. 7.2, p = 0.021; and 34 vs. 211, p = 0.002, respectively), but neither baseline PET parameters nor morphological response was correlated with PFS or OS. Follow-up SUVmax and SAM as well as ∆SAM were found to be prognostic factors. The median PFS and OS in the patient group with a high follow-up SUVmax were 10.4 months and 32 months, compared to a median PFS of 14.7 months and a median OS which had not been reached in the group with a low follow-up SUVmax (p = 0.01 and 0.003, respectively). The patient group with a high follow-up SAM and a low ∆SAM had a median PFS and OS of 9.4 months and 32 months, whereas the other group had a median PFS of 14.7 months and a median OS which had not been reached (p = 0.002 for both PFS and OS). (18)F-FDG PET imaging is a useful tool to assess treatment response and predict clinical outcome in patients with mCRC who undergo chemotherapy before liver metastasectomy. Follow-up SUVmax, follow-up SAM and ∆SAM were found to be significant prognostic factors for PFS and OS.

Do Surrogate Endpoints Better Correlate with Overall Survival in Studies That Did Not Allow for Crossover or Reported Balanced Postprogression Treatments? An Application in Advanced Non-Small Cell Lung Cancer.

PubMed

Hashim, Mahmoud; Pfeiffer, Boris M; Bartsch, Robert; Postma, Maarten; Heeg, Bart

2018-01-01

In previous studies, correlation between overall survival (OS) and surrogate endpoints like objective response rate (ORR) or progression-free survival (PFS) in advanced non-small cell lung cancer (NSCLC) was poor. This can be biased by crossover and postprogression treatments. To evaluate the relationship between these two surrogate endpoints and OS in advanced NSCLC studies that did not allow for crossover or reported balanced post-progression treatments. A systematic review in patients with advanced NSCLC receiving second- and further-line therapy was performed. The relationship between the absolute difference in ORR or median PFS (mPFS) and the absolute difference in median OS (mOS) was assessed using the correlation coefficient (R) and weighted regression models. The analysis was repeated in predefined data cuts based on crossover and balance of postprogression treatments. When the upper limit of R's 95% confidence interval (CI) was more than 0.7, the surrogate threshold effect (STE) was estimated. In total, 146 randomized clinical trials (43,061 patients) were included. The mean ORR, mPFS, and mOS were 12.2% ± 11.2%, 3.2 ± 1.3 months, and 9.6 ± 4.1 months, respectively. The correlation coefficients of ORR and mPFS were 0.181 (95% CI 0.016-0.337) and 0.254 (95% CI 0.074-0.418), respectively, with mOS. Nevertheless, in trials that did not allow crossover and reported balanced postprogression treatments, the correlation coefficients of ORR and mPFS were 0.528 (95% CI 0.081-0.798) and 0.778 (95% CI 0.475-0.916), respectively, with mOS. On the basis of STE estimation, in trials showing significant treatment effect size of 41.0% or more ORR or 4.15 or more mPFS months, OS benefit can be expected with sufficient certainty. Crossover and postprogression treatments may bias the relationship between surrogate endpoints and OS. Presented STE calculation can be used to interpret treatment effect on either ORR or PFS when used as primary endpoints. Copyright © 2018 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.

Low-grade Glioma Surgery in Intraoperative Magnetic Resonance Imaging: Results of a Multicenter Retrospective Assessment of the German Study Group for Intraoperative Magnetic Resonance Imaging.

PubMed

Coburger, Jan; Merkel, Andreas; Scherer, Moritz; Schwartz, Felix; Gessler, Florian; Roder, Constantin; Pala, Andrej; König, Ralph; Bullinger, Lars; Nagel, Gabriele; Jungk, Christine; Bisdas, Sotirios; Nabavi, Arya; Ganslandt, Oliver; Seifert, Volker; Tatagiba, Marcos; Senft, Christian; Mehdorn, Maximilian; Unterberg, Andreas W; Rössler, Karl; Wirtz, Christian Rainer

2016-06-01

The ideal treatment strategy for low-grade gliomas (LGGs) is a controversial topic. Additionally, only smaller single-center series dealing with the concept of intraoperative magnetic resonance imaging (iMRI) have been published. To investigate determinants for patient outcome and progression-free-survival (PFS) after iMRI-guided surgery for LGGs in a multicenter retrospective study initiated by the German Study Group for Intraoperative Magnetic Resonance Imaging. A retrospective consecutive assessment of patients treated for LGGs (World Health Organization grade II) with iMRI-guided resection at 6 neurosurgical centers was performed. Eloquent location, extent of resection, first-line adjuvant treatment, neurophysiological monitoring, awake brain surgery, intraoperative ultrasound, and field-strength of iMRI were analyzed, as well as progression-free survival (PFS), new permanent neurological deficits, and complications. Multivariate binary logistic and Cox regression models were calculated to evaluate determinants of PFS, gross total resection (GTR), and adjuvant treatment. A total of 288 patients met the inclusion criteria. On multivariate analysis, GTR significantly increased PFS (hazard ratio, 0.44; P < .01), whereas "failed" GTR did not differ significantly from intended subtotal-resection. Combined radiochemotherapy as adjuvant therapy was a negative prognostic factor (hazard ratio: 2.84, P < .01). Field strength of iMRI was not associated with PFS. In the binary logistic regression model, use of high-field iMRI (odds ratio: 0.51, P < .01) was positively and eloquent location (odds ratio: 1.99, P < .01) was negatively associated with GTR. GTR was not associated with increased rates of new permanent neurological deficits. GTR was an independent positive prognostic factor for PFS in LGG surgery. Patients with accidentally left tumor remnants showed a similar prognosis compared with patients harboring only partially resectable tumors. Use of high-field iMRI was significantly associated with GTR. However, the field strength of iMRI did not affect PFS. EoR, extent of resectionFLAIR, fluid-attenuated inversion recoveryGTR, gross total resectionIDH1, isocitrate dehydrogenase 1iMRI, intraoperative magnetic resonance imagingLGG, low-grade gliomaMGMT, methylguanine-deoxyribonucleic acid methyltransferasenPND, new permanent neurological deficitOS, overall survivalPFS, progression-free survivalSTR, subtotal resectionWHO, World Health Organization.

Final results of the TANIA randomised phase III trial of bevacizumab after progression on first-line bevacizumab therapy for HER2-negative locally recurrent/metastatic breast cancer.

PubMed

Vrdoljak, E; Marschner, N; Zielinski, C; Gligorov, J; Cortes, J; Puglisi, F; Aapro, M; Fallowfield, L; Fontana, A; Inbar, M; Kahan, Z; Welt, A; Lévy, C; Brain, E; Pivot, X; Putzu, C; González Martín, A; de Ducla, S; Easton, V; von Minckwitz, G

2016-11-01

The randomised phase III TANIA trial demonstrated that continuing bevacizumab with second-line chemotherapy for locally recurrent/metastatic breast cancer (LR/mBC) after progression on first-line bevacizumab-containing therapy significantly improved progression-free survival (PFS) compared with chemotherapy alone [hazard ratio (HR) = 0.75, 95% confidence interval (CI) 0.61-0.93]. We report final results from the TANIA trial, including overall survival (OS) and health-related quality of life (HRQoL). Patients with HER2-negative LR/mBC that had progressed on or after first-line bevacizumab plus chemotherapy were randomised to receive standard second-line chemotherapy either alone or with bevacizumab. At second progression, patients initially randomised to bevacizumab continued bevacizumab with their third-line chemotherapy, but those randomised to chemotherapy alone were not allowed to cross over to receive third-line bevacizumab. The primary end point was second-line PFS; secondary end points included third-line PFS, combined second- and third-line PFS, OS, HRQoL and safety. Of the 494 patients randomised, 483 received second-line therapy; 234 patients (47% of the randomised population) continued to third-line study treatment. The median duration of follow-up at the final analysis was 32.1 months in the chemotherapy-alone arm and 30.9 months in the bevacizumab plus chemotherapy arm. There was no statistically significant difference between treatment arms in third-line PFS (HR = 0.79, 95% CI 0.59-1.06), combined second- and third-line PFS (HR = 0.85, 95% CI 0.68-1.05) or OS (HR = 0.96, 95% CI 0.76-1.21). Third-line safety results showed increased incidences of proteinuria and hypertension with bevacizumab, consistent with safety results for the second-line treatment phase. No differences in HRQoL were detected. In this trial, continuing bevacizumab beyond first and second progression of LR/mBC improved second-line PFS, but no improvement in longer term efficacy was observed. The second-line PFS benefit appears to be achieved without detrimentally affecting quality of life. NCT01250379. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Redox responsive nanotubes from organometallic polymers by template assisted layer by layer fabrication

NASA Astrophysics Data System (ADS)

Song, Jing; Jańczewski, Dominik; Guo, Yuanyuan; Xu, Jianwei; Vancso, G. Julius

2013-11-01

Redox responsive nanotubes were fabricated by the template assisted layer-by-layer (LbL) assembly method and employed as platforms for molecular payload release. Positively and negatively charged organometallic poly(ferrocenylsilane)s (PFS) were used to construct the nanotubes, in combination with other polyions. During fabrication, multilayers of these polyions were deposited onto the inner pores of template porous membranes, followed by subsequent removal of the template. Anodized porous alumina and track-etched polycarbonate membranes were used as templates. The morphology, electrochemistry, composition and other properties of the obtained tubular structure were characterized by fluorescence microscopy, scanning (SEM) and transmission electron microscopy (TEM) and energy-dispersive X-ray (EDX) spectroscopy. Composite nanotubes, consisting of poly(acrylic acid) anions with PFS+ and nanoparticles including fluorophore labelled dextran and decorated quantum dots, with PFS polyelectrolytes were also fabricated, broadening the scope of the structures. Cyclic voltammograms of PFS containing nanotubes showed similar redox responsive behaviour to thin LbL assembled films. Redox triggered release of labelled macromolecules from these tubular structures demonstrated application potential in controlled molecular delivery.Redox responsive nanotubes were fabricated by the template assisted layer-by-layer (LbL) assembly method and employed as platforms for molecular payload release. Positively and negatively charged organometallic poly(ferrocenylsilane)s (PFS) were used to construct the nanotubes, in combination with other polyions. During fabrication, multilayers of these polyions were deposited onto the inner pores of template porous membranes, followed by subsequent removal of the template. Anodized porous alumina and track-etched polycarbonate membranes were used as templates. The morphology, electrochemistry, composition and other properties of the obtained tubular structure were characterized by fluorescence microscopy, scanning (SEM) and transmission electron microscopy (TEM) and energy-dispersive X-ray (EDX) spectroscopy. Composite nanotubes, consisting of poly(acrylic acid) anions with PFS+ and nanoparticles including fluorophore labelled dextran and decorated quantum dots, with PFS polyelectrolytes were also fabricated, broadening the scope of the structures. Cyclic voltammograms of PFS containing nanotubes showed similar redox responsive behaviour to thin LbL assembled films. Redox triggered release of labelled macromolecules from these tubular structures demonstrated application potential in controlled molecular delivery. Electronic supplementary information (ESI) available: Nanotube wall thickness determination protocol. See DOI: 10.1039/c3nr03927g

Propellant Feed Subsystem for a 26 kW flight arcjet propulsion system

NASA Astrophysics Data System (ADS)

Vaughan, C. E.; Morris, J. P.

1993-06-01

The USAF arcjet ATTD program demanded the development of a low-cost ammonia Propellant Feed Subsystem (PFS). A flow rate of 240 +/- 5 mg/sec during a total of ten 15-min ammonia outflows was required for the flight mission. The precision of the flow tolerance required a departure from the design of previous ammonia propellant feed systems. Since a propellant management device was not used, thermocapillary forces were explored as a means to limit outflow of liquid phase ammonia. A high energy density feedline heater with an internal wick was developed to guarantee that only gas phase propellant would reach the arcjet. A digital control algorithm was developed to implement bang-bang control of mass flow rate metered by a sonic venturi. Development tests of this system have been completed. The system is capable of continuous gas phase outflows regardless of orientation. Integrated tests with the arcjet and power conditioning unit have also been successfully completed.

Outcomes of Pediatric Low-grade Gliomas Treated With Radiation Therapy: A Single-institution Study

PubMed Central

Raikar, Sunil S.; Halloran, Donna R.; Elliot, Michael; McHugh, Michele; Patel, Shaun; Gauvain, Karen M.

2014-01-01

Summary Radiation therapy is often considered the treatment of choice for low-grade gliomas. However, given the long-term effects of radiation on the developing brain, the appropriate use of radiation therapy in pediatric patients remains controversial. The purpose of this study was to evaluate progression-free survival (PFS) of pediatric low-grade glioma patients treated with radiation therapy. Data were obtained through a retrospective chart review of patients treated between 1991 and 2008 from a single tertiary care center in the midwest. The study population consisted of 17 patients, of whom 8 (47%) had tumor recurrence after radiation therapy. The median follow-up time was 8.2 years, with a range of 2.3 to 17.2 years. The median age at diagnosis was 5.4 years, and the median age at radiation therapy was 9.4 years. The 3- and the 10-year PFS were 69% ± 11.7% and 46% ± 13.3%, respectively. A significant difference in PFS was seen when comparing brainstem tumors with hypothalamic/optic pathway tumors (P = 0.019). Differences in PFS based on the age at diagnosis, the extent of initial surgery, and indication for radiation therapy were not significant. A larger multicenter study is needed to better assess PFS in these patients. PMID:24714505

Properties of Hail Storms over China and the United States from the Tropical Rainfall Measuring Mission

NASA Technical Reports Server (NTRS)

Ni, Xiang; Liu, Chuntao; Zhang, Qinghong; Cecil, Daniel J.

2016-01-01

A 16-yr record of hail reports over the southeast US and from weather stations in China are collocated with Precipitation Features (PF) derived from the Tropical Rainfall Measurement Mission (TRMM) radar and passive microwave observations. While U.S. hail reports are dominated by cases with hail size greater than 19 mm, hail reports in China mostly include diameters of 1-10 nm and mostly occur over the Tibetan Plateau. The fraction of PFs collocated with hail reports (hail PFs) reaches 3% in the plains of the U.S. In China, the fraction is higher in high elevation regions than low elevation regions. Hail PFs in the U.S. show lower brightness temperatures, higher lightning flash rates, stronger maximum reflectivity, and higher echo tops than those in China, consistent with the larger hail diameters in the U.S. reports. The average near surface maximum reflectivity of hail PFs at higher elevations (greater than or equal to 2000 m) in China is about 5 dB smaller than those at low elevations. Larger hail is reported with PFs having stronger maximum reflectivity above 6 km, though the median of maximum reflectivity values at levels below 5 km is close among the storms with large and small hail sizes.

Correlation of 18F-FDG PET and MRI Apparent Diffusion Coefficient Histogram Metrics with Survival in Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium.

PubMed

Zukotynski, Katherine A; Vajapeyam, Sridhar; Fahey, Frederic H; Kocak, Mehmet; Brown, Douglas; Ricci, Kelsey I; Onar-Thomas, Arzu; Fouladi, Maryam; Poussaint, Tina Young

2017-08-01

The purpose of this study was to describe baseline 18 F-FDG PET voxel characteristics in pediatric diffuse intrinsic pontine glioma (DIPG) and to correlate these metrics with baseline MRI apparent diffusion coefficient (ADC) histogram metrics, progression-free survival (PFS), and overall survival. Methods: Baseline brain 18 F-FDG PET and MRI scans were obtained in 33 children from Pediatric Brain Tumor Consortium clinical DIPG trials. 18 F-FDG PET images, postgadolinium MR images, and ADC MR images were registered to baseline fluid attenuation inversion recovery MR images. Three-dimensional regions of interest on fluid attenuation inversion recovery MR images and postgadolinium MR images and 18 F-FDG PET and MR ADC histograms were generated. Metrics evaluated included peak number, skewness, and kurtosis. Correlation between PET and MR ADC histogram metrics was evaluated. PET pixel values within the region of interest for each tumor were plotted against MR ADC values. The association of these imaging markers with survival was described. Results: PET histograms were almost always unimodal (94%, vs. 6% bimodal). None of the PET histogram parameters (skewness or kurtosis) had a significant association with PFS, although a higher PET postgadolinium skewness tended toward a less favorable PFS (hazard ratio, 3.48; 95% confidence interval [CI], 0.75-16.28 [ P = 0.11]). There was a significant association between higher MR ADC postgadolinium skewness and shorter PFS (hazard ratio, 2.56; 95% CI, 1.11-5.91 [ P = 0.028]), and there was the suggestion that this also led to shorter overall survival (hazard ratio, 2.18; 95% CI, 0.95-5.04 [ P = 0.067]). Higher MR ADC postgadolinium kurtosis tended toward shorter PFS (hazard ratio, 1.30; 95% CI, 0.98-1.74 [ P = 0.073]). PET and MR ADC pixel values were negatively correlated using the Pearson correlation coefficient. Further, the level of PET and MR ADC correlation was significantly positively associated with PFS; tumors with higher values of ADC-PET correlation had more favorable PFS (hazard ratio, 0.17; 95% CI, 0.03-0.89 [ P = 0.036]), suggesting that a higher level of negative ADC-PET correlation leads to less favorable PFS. A more significant negative correlation may indicate higher-grade elements within the tumor leading to poorer outcomes. Conclusion: 18 F-FDG PET and MR ADC histogram metrics in pediatric DIPG demonstrate different characteristics with often a negative correlation between PET and MR ADC pixel values. A higher negative correlation is associated with a worse PFS, which may indicate higher-grade elements within the tumor. © 2017 by the Society of Nuclear Medicine and Molecular Imaging.

Indirect Treatment Comparisons of Ibrutinib Versus Physician's Choice and Idelalisib Plus Ofatumumab in Patients With Previously Treated Chronic Lymphocytic Leukemia.

PubMed

Sorensen, Sonja; Wildgust, Mark; Sengupta, Nishan; Trambitas, Cristina; Diels, Joris; van Sanden, Suzy; Xu, Yingxin; Dorman, Emily

2017-01-01

Treatment options for patients with relapsed or refractory chronic lymphocytic leukemia (R/R CLL) are limited. Until recently, few effective treatment options existed, and even with the advent of new agents, studies evaluating comparative efficacy are scarce. In the Ibrutinib Versus Ofatumumab in Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia (RESONATE) Phase III study, ibrutinib, an oral, once-a-day, first-in-class covalent Bruton tyrosine kinase inhibitor, improved progression-free survival (PFS) and overall survival (OS) compared with ofatumumab (PFS hazard ratio [HR] = 0.106 and OS HR = 0.369 [adjusted for crossover] at a median of 16 months' follow-up). We sought to establish the relative efficacy of ibrutinib versus other treatment options for patients with R/R CLL using indirect comparison methods. A systematic literature review was conducted to identify clinical trials sharing a common treatment arm with the RESONATE Phase III trial such that a network meta-analysis or indirect treatment comparisons (ITCs) could be conducted. Two trials were identified, each using the same comparator (ofatumumab) as the RESONATE study. Two pairwise ITCs were conducted using the Bucher method to establish the relative treatment efficacy of ibrutinib versus (1) idelalisib plus ofatumumab in the first study and (2) physician's choice, defined as a mix of therapies commonly used in R/R CLL, in the second study. Odds ratios for these ITCs were calculated for overall response rate (ORR) and HRs for PFS and OS. A strong and consistent trend of superiority for ibrutinib was observed via these ITC models with idelalisib plus ofatumumab and physician's choice for ORR, PFS, and OS. Ibrutinib revealed prolonged PFS and OS versus comparators (PFS HR = 0.06; 95% CI, 0.04-0.11; and OS HR = 0.25; 95% CI, 0.12-0.54), physician's choice (PFS HR = 0.41; 95% CI, 0.25-0.66; and OS HR = 0.50; 95% CI, 0.23-1.08), and idelalisib plus ofatumumab. These findings were robust and continued to favor ibrutinib when adjusting (where appropriate) for underlying differences in patient population between the trials. Some trial differences were not accounted for in the models and thus some limitations remain; however, consistency of results supports the overall findings. In a randomized Phase III study, ibrutinib significantly improved ORR, PFS, and OS in patients with R/R CLL versus ofatumumab. In ITC models that used ofatumumab as the common comparator, ibrutinib appears to have higher ORR and longer PFS and OS versus both idelalisib plus ofatumumab and physician's choice. In the absence of head-to-head studies and taking into consideration inherent limitations of ITCs, these models provide useful estimates of comparative efficacy. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

On the primary variable switching technique for simulating unsaturated-saturated flows

NASA Astrophysics Data System (ADS)

Diersch, H.-J. G.; Perrochet, P.

Primary variable switching appears as a promising numerical technique for variably saturated flows. While the standard pressure-based form of the Richards equation can suffer from poor mass balance accuracy, the mixed form with its improved conservative properties can possess convergence difficulties for dry initial conditions. On the other hand, variable switching can overcome most of the stated numerical problems. The paper deals with variable switching for finite elements in two and three dimensions. The technique is incorporated in both an adaptive error-controlled predictor-corrector one-step Newton (PCOSN) iteration strategy and a target-based full Newton (TBFN) iteration scheme. Both schemes provide different behaviors with respect to accuracy and solution effort. Additionally, a simplified upstream weighting technique is used. Compared with conventional approaches the primary variable switching technique represents a fast and robust strategy for unsaturated problems with dry initial conditions. The impact of the primary variable switching technique is studied over a wide range of mostly 2D and partly difficult-to-solve problems (infiltration, drainage, perched water table, capillary barrier), where comparable results are available. It is shown that the TBFN iteration is an effective but error-prone procedure. TBFN sacrifices temporal accuracy in favor of accelerated convergence if aggressive time step sizes are chosen.

Clustering and Flow Conservation Monitoring Tool for Software Defined Networks.

PubMed

Puente Fernández, Jesús Antonio; García Villalba, Luis Javier; Kim, Tai-Hoon

2018-04-03

Prediction systems present some challenges on two fronts: the relation between video quality and observed session features and on the other hand, dynamics changes on the video quality. Software Defined Networks (SDN) is a new concept of network architecture that provides the separation of control plane (controller) and data plane (switches) in network devices. Due to the existence of the southbound interface, it is possible to deploy monitoring tools to obtain the network status and retrieve a statistics collection. Therefore, achieving the most accurate statistics depends on a strategy of monitoring and information requests of network devices. In this paper, we propose an enhanced algorithm for requesting statistics to measure the traffic flow in SDN networks. Such an algorithm is based on grouping network switches in clusters focusing on their number of ports to apply different monitoring techniques. Such grouping occurs by avoiding monitoring queries in network switches with common characteristics and then, by omitting redundant information. In this way, the present proposal decreases the number of monitoring queries to switches, improving the network traffic and preventing the switching overload. We have tested our optimization in a video streaming simulation using different types of videos. The experiments and comparison with traditional monitoring techniques demonstrate the feasibility of our proposal maintaining similar values decreasing the number of queries to the switches.

Modelling, fabrication and characterization of a polymeric micromixer based on sequential segmentation.

PubMed

Nguyen, Nam-Trung; Huang, Xiaoyang

2006-06-01

Effective and fast mixing is important for many microfluidic applications. In many cases, mixing is limited by molecular diffusion due to constrains of the laminar flow in the microscale regime. According to scaling law, decreasing the mixing path can shorten the mixing time and enhance mixing quality. One of the techniques for reducing mixing path is sequential segmentation. This technique divides solvent and solute into segments in axial direction. The so-called Taylor-Aris dispersion can improve axial transport by three orders of magnitudes. The mixing path can be controlled by the switching frequency and the mean velocity of the flow. Mixing ratio can be controlled by pulse width modulation of the switching signal. This paper first presents a simple time-dependent one-dimensional analytical model for sequential segmentation. The model considers an arbitrary mixing ratio between solute and solvent as well as the axial Taylor-Aris dispersion. Next, a micromixer was designed and fabricated based on polymeric micromachining. The micromixer was formed by laminating four polymer layers. The layers are micro machined by a CO(2) laser. Switching of the fluid flows was realized by two piezoelectric valves. Mixing experiments were evaluated optically. The concentration profile along the mixing channel agrees qualitatively well with the analytical model. Furthermore, mixing results at different switching frequencies were investigated. Due to the dynamic behavior of the valves and the fluidic system, mixing quality decreases with increasing switching frequency.

“U-Method” TVT-Secur Slings: Are they obstructive?

PubMed Central

Richard, Patrick; Gagnon, Louis-Olivier; Tu, Le Mai

2012-01-01

Introduction: The TVT-Secur, a single incision sling, was introduced in 2006. It is implanted using either the “hammock” or the “U-method” technique. With the latter, the sling is tightened to create a “pillowing effect” on the urethra until a negative stress test is obtained. Short-term results seem promising. However, no study has ever reported on the voiding pattern 12 months after its implantation. Our objective was to assess whether the “U-method” technique creates an obstructive voiding pattern on pressure-flow study (PFS) 12 months after the surgery. Methods: In this retrospective study, we reviewed the charts of 33 women who underwent the “U-method” TVT-Secur. Patients were evaluated before and 12 months postoperatively with regard to different urodynamic studies (UDS). The incontinence status was also assessed 12 months after surgery. Results: At 12 months after the operation, 12.5% (4/32) of the patients reported an improvement of their stress urinary incontinence, while 78.1% (25/32) reported being cured from it. The objective cure rate was 63% (19/30). One patient had a suspected bladder outlet obstruction (BOO) based on PFS. Maximal flow rate (Qmax) was significantly lower 12 months after surgery (26.0 mL/s [range: 19.0–36.5] vs. 21.5 mL/s [range: 16.0–32.3]). However, median voided volume was lower on the postoperative uroflowmetry (446 mL [range: 348–605] vs. 320 mL [range: 243–502]). Furthermore, none of the patients complained of voiding symptoms after surgery. Conclusions: Although one patient had findings compatible with BOO, none complained of voiding symptoms. TVT-Secur may result in a lower Qmax. However, this finding may be due to a lower voiding volume on the postoperative UDS. PMID:22511425

The association of BMI and outcomes in metastatic melanoma: A retrospective, multicohort analysis of patients treated with targeted therapy, immunotherapy, or chemotherapy

PubMed Central

McQuade, Jennifer L.; Daniel, Carrie R.; Hess, Kenneth R.; Mak, Carmen; Wang, Daniel Y.; Rai, Rajat R.; Park, John J.; Haydu, Lauren E.; Spencer, Christine; Wongchenko, Matthew; Lane, Stephen; Lee, Dung-Yang; Kaper, Mathilde; McKean, Meredith; Beckermann, Kathryn E; Rubinstein, Samuel M.; Rooney, Isabelle; Musib, Luna; Budha, Nageshwar; Hsu, Jessie; Nowicki, Theodore S.; Avila, Alexandre; Haas, Tomas; Puligandla, Maneka; Lee, Sandra; Fang, Shenying; Wargo, Jennifer A.; Gershenwald, Jeffrey E; Lee, Jeffrey E.; Hwu, Patrick; Chapman, Paul B.; Sosman, Jeffrey A.; Schadendorf, Dirk; Grob, Jean-Jacques; Flaherty, Keith T.; Walker, Dana; Yan, Yibing; McKenna, Edward; Legos, Jeffrey J.; Carlino, Matteo S.; Ribas, Antoni; Kirkwood, John M.; Long, Georgina V.; Johnson, Douglas B.; Menzies, Alexander M; Davies, Michael A.

2018-01-01

Background Obesity has been linked to increased mortality in several cancer types; however, the relationship between obesity and survival in metastatic melanoma is unknown. The aim of this study was to examine the association between BMI, progression-free survival (PFS), and overall survival (OS) in metastatic melanoma. Methods This study included 6 independent cohorts for a total of 1918 metastatic melanoma patients. These included two targeted therapy cohorts [randomized control trials (RCTs) of dabrafenib and trametinib (n=599) and vemurafenib and cobimetinib (n=240)], two immunotherapy cohorts [RCT of ipilimumab + dacarbazine (DTIC) (n=207) and a retrospective cohort treated with anti-PD-1/PDL-1 (n=331)], and two chemotherapy cohorts [RCT DTIC cohorts (n=320 and n=221)]. BMI was classified as normal (BMI 18 to <25; n=694 of 1918, 36.1%) overweight (BMI 25-29.9; n=711, 37.1%) or obese (BMI≥30; n=513, 26.7%). The primary outcomes were the association between BMI, PFS, and OS, stratified by treatment type and sex. These exploratory analyses were based on previously reported intention-to-treat data from the RCTs. The effect of BMI on PFS and OS was assessed by multivariable-adjusted Cox models in independent cohorts. In order to provide a more precise estimate of the association between BMI and outcomes, as well as the interaction between BMI, sex, and therapy type, adjusted hazard ratios were combined in mixed-effects meta-analyses and heterogeneity was explored with meta-regression analyses. Findings In the pooled analysis, obesity, as compared to normal BMI, was associated with improved survival in patients with metastatic melanoma [average adjusted hazard ratio (HR) and 95% CI: 0.77 (0.66-0.90) and 0.74 (0.58-0.95) for PFS and OS, respectively]. The survival benefit associated with obesity was restricted to patients treated with targeted therapy [0.72 (0.57-0.91) and 0.60 (0.45-0.79) for PFS and OS, respectively] and immunotherapy [0.75 (0.56-1.00) and 0.64 (0.47-0.86)]. No associations were observed with chemotherapy [0.87 (0.65-1.17) and 1.03 (0.80-1.34); treatment p for interaction = 0.61 and 0.01, for PFS and OS, respectively]. The prognostic effect of BMI with targeted and immune therapies differed by sex with pronounced inverse associations in males [PFS 0.67 (0.53-0.84) and OS 0.53 (0.40-0.70)], but not females [PFS 0.92 (0.70-1.23) and OS 0.85 (0.61-1.18), sex p for interaction= 0.08 and 0.03, for PFS and OS, respectively] Interpretation Obesity is associated with improved PFS and OS in metastatic melanoma, driven by strong associations observed in males treated with targeted or immune therapy. The magnitude of the benefit detected supports the need for investigation into the underlying mechanism of these unexpected observations Funding ASCO/CCF Young Investigator Award and ASCO/CCF Career Development Award to JLM PMID:29449192

Safety evaluation of intersection conflict warning systems (ICWS), TechBrief

DOT National Transportation Integrated Search

2016-02-02

The Federal Highway Administration (FHWA) organized 40 States to participate in the FHWA Evaluation of LowCost Safety Improvements Pooled Fund Study (ELCSI-PFS) as part of its strategic highway safety plan support effort. The goal of the ELCSI-PFS re...

BMS-777607 promotes megakaryocytic differentiation and induces polyploidization in the CHRF-288-11 cells.

PubMed

Nurhayati, Retno Wahyu; Ojima, Yoshihiro; Taya, Masahito

2015-04-01

Introduction of a polyploidy inducer is a promising strategy to achieve a high level of polyploidization during megakaryocytic (MK) differentiation. Here, we report that a multi-kinase inhibitor, BMS-777607, is a potent polyploidy inducer for elevating high ploidy cell formation in the MK-differentiated CHRF-288-11 (CHRF) cells. Our result showed that BMS-777607 strongly inhibited cell division without affecting cell viability when detected at day 1 after treatment. As a consequence, the high ploidy (≥8N) cells were accumulated in culture for 8 days, with an increase from 16.2 to 75.2 % of the total cell population. The elevated polyploidization was accompanied by the increased expression level of MK marker, CD41 (platelet glycoprotein IIb/IIIa, GPIIb/IIIa), suggesting that BMS-777607 promoted both polyploidization and commitment of MK-differentiated CHRF cells. Platelet-like fragments (PFs) were released by mature CHRF cells. Based on a flow cytometry assay, it was found that the PFs produced from BMS-777607-treated cells tended to have larger size and higher expression of GPIIb/IIIa, a receptor for platelet adhesion. Taken together, these results suggested that BMS-777607 promoted MK differentiation of CHRF cells and increased the functional property of platelet-like fragments.

Zener diode controls switching of large direct currents

NASA Technical Reports Server (NTRS)

1965-01-01

High-current zener diode is connected in series with the positive input terminal of a dc supply to block the flow of direct current until a high-frequency control signal is applied across the zener diode. This circuit controls the switching of large dc signals.

Altered expression of HER-2 and the mismatch repair genes MLH1 and MSH2 predicts the outcome of T1 high-grade bladder cancer.

PubMed

Sanguedolce, Francesca; Cormio, Antonella; Massenio, Paolo; Pedicillo, Maria C; Cagiano, Simona; Fortunato, Francesca; Calò, Beppe; Di Fino, Giuseppe; Carrieri, Giuseppe; Bufo, Pantaleo; Cormio, Luigi

2018-04-01

The identification of factors predicting the outcome of stage T1 high-grade bladder cancer (BC) is a major clinical issue. We performed immunohistochemistry to assess the role of human epidermal growth factor receptor-2 (HER-2) and microsatellite instability (MSI) factors MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in predicting recurrence and progression of T1 high-grade BCs having undergone transurethral resection of bladder tumor (TURBT) alone or TURBT + intravesical instillations of bacillus Calmette-Guerin (BCG). HER-2 overexpression was a significant predictor of disease-free survival (DFS) in the overall as well as in the two patients' population; as for progression-free survival (PFS), it was significant in the overall but not in the two patients' population. MLH1 was an independent predictor of PFS only in patients treated with BCG and MSH2 failed to predict DFS and PFS in all populations. Most importantly, the higher the number of altered markers the lowers the DFS and PFS. In multivariate Cox proportional-hazards regression analysis, the number of altered molecular markers and BCG treatment were significant predictors (p = 0.0004 and 0.0283, respectively) of DFS, whereas the number of altered molecular markers was the only significant predictor (p = 0.0054) of PFS. Altered expression of the proto-oncogene HER-2 and the two molecular markers of genetic instability MLH1 and MSH2 predicted T1 high-grade BC outcome with the higher the number of altered markers the lower the DFS and PFS. These findings provide grounds for further testing them in predicting the outcome of this challenging disease.

The prognostic value of CT radiomic features for patients with pulmonary adenocarcinoma treated with EGFR tyrosine kinase inhibitors

PubMed Central

Kim, Hyungjin; Park, Sang Joon; Kim, Miso; Kim, Tae Min; Kim, Dong-Wan; Heo, Dae Seog; Goo, Jin Mo

2017-01-01

Purpose To determine if the radiomic features on CT can predict progression-free survival (PFS) in epidermal growth factor receptor (EGFR) mutant adenocarcinoma patients treated with first-line EGFR tyrosine kinase inhibitors (TKIs) and to identify the incremental value of radiomic features over conventional clinical factors in PFS prediction. Methods In this institutional review board–approved retrospective study, pretreatment contrast-enhanced CT and first follow-up CT after initiation of TKIs were analyzed in 48 patients (M:F = 23:25; median age: 61 years). Radiomic features at baseline, at 1st first follow-up, and the percentage change between the two were determined. A Cox regression model was used to predict PFS with nonredundant radiomic features and clinical factors, respectively. The incremental value of radiomic features over the clinical factors in PFS prediction was also assessed by way of a concordance index. Results Roundness (HR: 3.91; 95% CI: 1.72, 8.90; P = 0.001) and grey-level nonuniformity (HR: 3.60; 95% CI: 1.80, 7.18; P<0.001) were independent predictors of PFS. For clinical factors, patient age (HR: 2.11; 95% CI: 1.01, 4.39; P = 0.046), baseline tumor diameter (HR: 1.03; 95% CI: 1.01, 1.05; P = 0.002), and treatment response (HR: 0.46; 95% CI: 0.24, 0.87; P = 0.017) were independent predictors. The addition of radiomic features to clinical factors significantly improved predictive performance (concordance index; combined model = 0.77, clinical-only model = 0.69, P<0.001). Conclusions Radiomic features enable PFS estimation in EGFR mutant adenocarcinoma patients treated with first-line EGFR TKIs. Radiomic features combined with clinical factors provide significant improvement in prognostic performance compared with using only clinical factors. PMID:29099855

The prognostic and predictive value of vascular response parameters measured by dynamic contrast-enhanced-CT, -MRI and -US in patients with metastatic renal cell carcinoma receiving sunitinib.

PubMed

Hudson, John M; Bailey, Colleen; Atri, Mostafa; Stanisz, Greg; Milot, Laurent; Williams, Ross; Kiss, Alex; Burns, Peter N; Bjarnason, Georg A

2018-06-01

To identify dynamic contrast-enhanced (DCE) imaging parameters from MRI, CT and US that are prognostic and predictive in patients with metastatic renal cell cancer (mRCC) receiving sunitinib. Thirty-four patients were monitored by DCE imaging on day 0 and 14 of the first course of sunitinib treatment. Additional scans were performed with DCE-US only (day 7 or 28 and 2 weeks after the treatment break). Perfusion parameters that demonstrated a significant correlation (Spearman p < 0.05) with progression-free survival (PFS) and overall survival (OS) were investigated using Cox proportional hazard models/ratios (HR) and Kaplan-Meier survival analysis. A higher baseline and day 14 value for Ktrans (DCE-MRI) and a lower pre-treatment vascular heterogeneity (DCE-US) were significantly associated with a longer PFS (HR, 0.62, 0.37 and 5.5, respectively). A larger per cent decrease in blood volume on day 14 (DCE-US) predicted a longer OS (HR, 1.45). We did not find significant correlations between any of the DCE-CT parameters and PFS/OS, unless a cut-off analysis was used. DCE-MRI, -CT and ultrasound produce complementary parameters that reflect the prognosis of patients receiving sunitinib for mRCC. Blood volume measured by DCE-US was the only parameter whose change during early anti-angiogenic therapy predicted for OS and PFS. • DCE-CT, -MRI and ultrasound are complementary modalities for monitoring anti-angiogenic therapy. • The change in blood volume measured by DCE-US was predictive of OS/PFS. • Baseline vascular heterogeneity by DCE-US has the strongest prognostic value for PFS.

Model-based prediction of progression-free survival in patients with first-line renal cell carcinoma using week 8 tumor size change from baseline.

PubMed

Claret, Laurent; Zheng, Jenny; Mercier, Francois; Chanu, Pascal; Chen, Ying; Rosbrook, Brad; Yazdi, Pithavala; Milligan, Peter A; Bruno, Rene

2016-09-01

To assess the link between early tumor shrinkage (ETS) and progression-free survival (PFS) based on historical first-line metastatic renal cell carcinoma (mRCC) data. Tumor size data from 921 patients with first-line mRCC who received interferon-alpha, sunitinib, sorafenib or axitinib in two Phase III studies were modeled. The relationship between model-based estimates of ETS at week 8 as well as the baseline prognostic factors and PFS was tested in multivariate log-logistic models. Model performance was evaluated using simulations of PFS distributions and hazard ratio (HR) across treatments for the two studies. In addition, an external validation was conducted using data from an independent Phase II RCC study. The relationship between expected HR of an investigational treatment vs. sunitinib and the differences in ETS was simulated. A model with a nonlinear ETS-PFS link was qualified to predict PFS distribution by ETS quartiles as well as to predict HRs of sunitinib vs. interferon-alpha and axitinib vs. sorafenib. The model also performed well in simulations of an independent study of axitinib (external validation). The simulations suggested that if a new investigational treatment could further reduce the week 8 ETS by 30 % compared with sunitinib, an expected HR [95 % predictive interval] of the new treatment vs. sunitinib would be 0.59 [0.46, 0.79]. A model has been developed that uses early changes in tumor size to predict the HR for PFS differences between treatment arms for first-line mRCC. Such a model may have utility in predicting the outcome of ongoing studies (e.g., as part of interim futility analyses), supporting early decision making and future study design for investigational agents in development for this indication.

Impact of timing of radiotherapy in patients with newly diagnosed glioblastoma.

PubMed

Randolph, David M; McTyre, Emory R; Paulsson, Anna K; Holmes, Jordan A; Hinson, William H; Lesser, Glenn J; Strowd, Roy; Lo, Hui-Wen; Laxton, Adrian W; Tatter, Stephen B; Debinski, Waldemar; Chan, Michael D

2016-12-01

To further evaluate if a delay in the start of radiation therapy (RT) affects patient outcomes for glioblastoma (GBM). From May 1999 to May 2010, a total of 161 patients underwent surgery followed by RT for GBM. We assessed overall survival (OS) and progression free survival (PFS), stratified by extent of surgical resection. Included in the analysis were genomic predictors of progression. Median time from surgery to start of RT was 20days for biopsy alone, 28days for subtotal resection (STR) and 28days for gross total resection (GTR). For all patients, a delay >28days did not result in a difference in PFS when compared to no delay (6.7 vs. 6.9 months, p=0.07). PFS was improved in biopsy or STR patients with a >28day delay to start of RT (4.2 vs. 6.7 months, p=0.006). OS was also improved in patients receiving biopsy or STR with a >28day delay to start of RT (12.3 vs. 7.8 months, p=0.005). Multivariable analysis (MVA) demonstrated an improvement in OS and PFS with time to RT >28days for biopsy or STR patients (HR 0.52 p=0.008 and HR 0.48 p=0.02, respectively). In this retrospective review of GBM patients treated at a single institution, OS and PFS were not different between time to RT >28days compared to <28 days. There was a modest improvement in both PFS and OS in patients who received biopsy or STR with time to RT >28 days. Copyright © 2016 Elsevier B.V. All rights reserved.

[Efficacy of chemotherapy after EGFR-TKIs resistance in 191 patients with Unknow EGFR gene mutation in advanced lung adenocarcinoma].

PubMed

He, Ping; Wang, Yan; Yang, Sheng; Yu, Shufei; Wang, Ziping; Li, Junling; Wang, Bin; Hao, Xuezhi; Wang, Hongyu; Hu, Xingsheng; Zhang, Xiangru; Shi, Yuankai

2013-10-20

Subsequent chemotherapy were needed in patients with advanced pulmonary adenocarcinoma experiencing disease progression after epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment. The study is to explore factors potentially influencing efficacy of subsequent chemotherapy. One hundred and ninety-one patients with advanced lung adenocarcinoma, who were resistant from EGFR-TKIs and then received subsequent chemotherapy, were identified. Data of patient's characteristics, responses to chemotherapy and survival time were analyzed retrospectively. The overall response rate of the pemetrexed-based chemotherapy (9.3%) was higher than non-pemetrexed-based regimen (1.1%), P=0.011. Furthermore, the response in the second-line was more obvisous [objective response rate (ORR) 14.3% vs 3.7%, P=0.041]. The patients who achieved response of partial response (PR) showed longer progression-free survival (PFS) than those who achieved non-PR (PFS 10.1 months and 2.3 months, P=0.012). The patients treated with platinum-based chemotherapy had longer PFS and OS than those with non-platinum-based chemotherapy, therefore platinum-based regimen was independent prognosis factors for PFS and OS (PFS: RR=0.634, 95%CI: 0.466-0.832, P=0.004; OS: RR=0.666, 95%CI: 0.460-0.960, P=0.030), especially the pateients who were aquired EGFR-TKIs resistance and who got drmatic progression from EGFR-TKIs treatment might got more benefits from platinum-based chemotherapy. However there was no significant difference in ORR, PFS or OS between patients with TKIs primary resistance and acquired resistance, or between dramtic progression and gradual/local progression. The patients with advanced lung adenocarcinoma might get benefits from pemetrexed-based or platinum-based chemotherapy after they were EGFR-TKIs resistace.

Improving the malaria transmission-blocking activity of a Plasmodium falciparum 48/45 based vaccine antigen by SpyTag/SpyCatcher mediated virus-like display.

PubMed

Singh, Susheel K; Thrane, Susan; Janitzek, Christoph M; Nielsen, Morten A; Theander, Thor G; Theisen, Michael; Salanti, Ali; Sander, Adam F

2017-06-27

Malaria is a devastating disease caused by Plasmodium parasites, resulting in almost 0.5 million deaths per year. The Pfs48/45 protein exposed on the P. falciparum sexual stages is one of the most advanced antigen candidates for a transmission-blocking (TB) vaccine in the clinical pipeline. However, it remains essential to identify an optimal vaccine formulation that can facilitate induction of a long-lasting TB anti-Pfs48/45 response. Here we report on the development and evaluation of two Pfs48/45-based virus-like particle (VLP) vaccines generated using the AP205 SpyTag/Catcher VLP system. Two different recombinant proteins (SpyCatcher-R0.6C and SpyCatcher-6C), comprising the Pfs48/45-6C region, were covalently attached to the surface of Spy-tagged Acinetobacter phage AP205 VLPs. Resulting Pfs48/45-VLP complexes appeared as non-aggregated particles of ∼30nm, each displaying an average of 216 (R0.6C) or 291 (6C) copies of the antigens. Both R0.6C and 6C VLP conjugates were strongly reactive with a monoclonal antibody (mAb45.1) targeting a conformational TB Pfs48/45 epitope, suggesting that the TB epitope is accessible for immune recognition on the particles. To select the most suitable vaccine formulation for downstream clinical studies the two VLP vaccines were tested in CD1 mice using different adjuvant formulations. The study demonstrates that VLP-display of R0.6C and 6C significantly increases antigen immunogenicity when using Montanide ISA 720 VG as extrinsic adjuvant. Copyright © 2017 Elsevier Ltd. All rights reserved.

Incidence, Risks, and Sequelae of Posterior Fossa Syndrome in Pediatric Medulloblastoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Korah, Mariam P., E-mail: mariam@radonc.emory.or; Esiashvili, Natia; Mazewski, Claire M.

2010-05-01

Purpose: To investigate the incidence, risks, severity, and sequelae of posterior fossa syndrome (PFS) in children with medulloblastoma. Methods and Materials: Between 1990 and 2007, 63 children with medulloblastoma at Emory University and Children's Healthcare of Atlanta were treated with craniectomy followed by radiation. Fifty-one patients were assigned to a standard-risk group, and 12 patients were assigned to a high-risk group. Five patients had <1.5-cm{sup 2} residual tumor, 4 had >=1.5-cm{sup 2} residual tumor, and the remainder had no residual tumor. Eleven patients had disseminated disease. Patients received craniospinal irradiation at a typical dose of 23.4 Gy or 36 Gymore » for standard- or high-risk disease, respectively. The posterior fossa was given a total dose of 54 or 55.8 Gy. Nearly all patients received chemotherapy following cooperative group protocols. Results: Median follow-up was 7 years. PFS developed in 18 patients (29%). On univariate analysis, brainstem invasion, midline tumor location, younger age, and the absence of radiographic residual tumor were found to be predictors of PFS; the last two variables remained significant on multivariate analysis. From 1990 to 2000 and from 2001 to 2007, the proportions of patients with no radiographic residual tumor were 77% and 94%, respectively. During the same eras, the proportions of patients with PFS were 17% and 39%. Only 4 patients had complete recovery at last follow-up. Conclusions: The incidence of PFS increased in the latter study period and is proportional to more aggressive surgery. Children with midline tumors exhibiting brainstem invasion are at increased risk. With the increased incidence of PFS and the permanent morbidity in many patients, the risks and benefits of complete tumor removal in all patients need to be reexamined.« less

Alga-Produced Cholera Toxin-Pfs25 Fusion Proteins as Oral Vaccines

PubMed Central

Gregory, James A.; Topol, Aaron B.; Doerner, David Z.

2013-01-01

Infectious diseases disproportionately affect indigent regions and are the greatest cause of childhood mortality in developing countries. Practical, low-cost vaccines for use in these countries are paramount to reducing disease burdens and concomitant poverty. Algae are a promising low-cost system for producing vaccines that can be orally delivered, thereby avoiding expensive purification and injectable delivery. We engineered the chloroplast of the eukaryotic alga Chlamydomonas reinhardtii to produce a chimeric protein consisting of the 25-kDa Plasmodium falciparum surface protein (Pfs25) fused to the β subunit of the cholera toxin (CtxB) to investigate an alga-based whole-cell oral vaccine. Pfs25 is a promising malaria transmission-blocking vaccine candidate that has been difficult to produce in traditional recombinant systems due to its structurally complex tandem repeats of epidermal growth factor-like domains. The noncatalytic CtxB domain of the cholera holotoxin assembles into a pentameric structure and acts as a mucosal adjuvant by binding GM1 ganglioside receptors on gut epithelial cells. We demonstrate that CtxB-Pfs25 accumulates as a soluble, properly folded and functional protein within algal chloroplasts, and it is stable in freeze-dried alga cells at ambient temperatures. In mice, oral vaccination using freeze-dried algae that produce CtxB-Pfs25 elicited CtxB-specific serum IgG antibodies and both CtxB- and Pfs25-specific secretory IgA antibodies. These data suggest that algae are a promising system for production and oral delivery of vaccine antigens, but as an orally delivered adjuvant, CtxB is best suited for eliciting secretory IgA antibodies for vaccine antigens against pathogens that invade mucosal surfaces using this strategy. PMID:23603678

Long-Term Efficacy of Maintenance Therapy for Multiple Myeloma: A Quantitative Synthesis of 22 Randomized Controlled Trials.

PubMed

Li, Jie-Li; Fan, Guang-Yu; Liu, Yu-Jie; Zeng, Zi-Hang; Huang, Jing-Juan; Yang, Zong-Ming; Meng, Xiang-Yu

2018-01-01

We aimed to quantitatively synthesize data from randomized controlled trials (RCTs) concerning maintenance for multiple myeloma (MM). We searched electronic literature databases and conference proceedings to identify relevant RCTs. We selected eligible RCTs using predefined selection criteria. We conducted meta-analysis comparing maintenance containing new agents and conventional maintenance, and subgroup analysis by transplantation status and mainstay agent as well. We performed trial sequential analysis (TSA) to determine adequacy of sample size for overall and subgroup meta-analyses. We performed network meta-analysis (NMA) to compare and rank included regimens. A total of 22 RCTs involving 9,968 MM patients and 15 regimens were included, the overall quality of which was adequate. Significant heterogeneity was detected for progression-free survival (PFS) but not overall survival (OS). Meta-analyses showed that maintenance containing new agents significantly improved PFS but not OS [PFS: Hazard Ratio (HR) = 0.59, 95% Confidence Interval (CI) = 0.54 to 0.64; OS: HR = 0.93, 95% CI = 0.87 to 1.00], compared with controls. Subgroup analyses revealed lenalidomide (Len)-based therapies better than thalidomide-based ones (HR = 0.50 and 0.66, respectively; P = 0.001). NMA revealed that most of the maintenance regimens containing new agents were significantly better than simple observation in terms of PFS but not OS. Len single agent was the most effective, considering PFS and OS both. We concluded that conventional maintenance has very limited effect. Maintenance containing new agents is highly effective in improving PFS, but has very limited effect on OS. Maintenance with Len may have the largest survival benefits. Emerging strategies may further change the landscape of maintenance of MM.

Clogging in staked-in needle pre-filled syringes (SIN-PFS): Influence of water vapor transmission through the needle shield.

PubMed

De Bardi, M; Müller, R; Grünzweig, C; Mannes, D; Rigollet, M; Bamberg, F; Jung, T A; Yang, K

2018-06-01

Staked-in needle pre-fillable syringes (SIN-PFS) are a convenient delivery system widely established in the growing pharmaceutical market. Under specific storage conditions, the needle of PFS containing high concentration drug product (DP) solution is prone to clogging, which prevents administration of the liquid. The purpose of this study is to clarify the clogging phenomenon of SIN-PFS and to elucidate the role of water vapor transmission via the needle shield. The presence of liquid within needles is a prerequisite condition for clogging and was investigated non-invasively by neutron imaging (NI) to confirm that liquid can migrate into the needle under certain processing conditions. The water vapor transmission rate (WVTR) of different needle shields was measured and the impact of temperature and relative humidity (rH) on the WVTR was investigated on sheets with the same composition as used in commercial needle shields. Our study clearly showed that the partial vapor pressure difference (ΔPP) across the needle shield is the dominant driving factor for water vapor transmission. A linear correlation between ΔPP and WVTR was found and a model to predict the water vapor transmission for PFS under specific storage conditions was developed. The impact of the WVTR on needle clogging was confirmed by clogging tests performed on SIN-PFS stored under different conditions. Thereby, we clearly show that high water loss induced by higher WVTR can be correlated to an increased occurrence of needle clogging. In conclusion, the WVTR of the needle shield plays a key role in needle clogging and the established WVTR model can be employed to assess the clogging risk for product development. Copyright © 2018 Elsevier B.V. All rights reserved.

Impact of Time to Treatment Initiation in Patients with Human Papillomavirus-positive and -negative Oropharyngeal Squamous Cell Carcinoma.

PubMed

Grønhøj, C; Jensen, D; Dehlendorff, C; Nørregaard, C; Andersen, E; Specht, L; Charabi, B; von Buchwald, C

2018-06-01

The distinct difference in disease phenotype of human papillomavirus-positive (HPV+) and -negative (HPV-) oropharyngeal squamous cell cancer (OPSCC) patients might also be apparent when assessing the effect of time to treatment initiation (TTI). We assessed the overall survival and progression-free survival (PFS) effect from increasing TTI for HPV+ and HPV- OPSCC patients. We examined patients who received curative-intended therapy for OPSCC in eastern Denmark between 2000 and 2014. TTI was the number of days from diagnosis to the initiation of curative treatment. Overall survival and PFS were measured from the start of treatment and estimated with the Kaplan-Meier estimator. Hazard ratios and 95% confidence intervals were estimated with Cox proportional hazard regression. At a median follow-up of 3.6 years (interquartile range 1.86-6.07 years), 1177 patients were included (59% HPV+). In the adjusted analysis for the HPV+ and HPV- patient population, TTI influenced overall survival and PFS, most evident in the HPV- group, where TTI >60 days statistically significantly influenced overall survival but not PFS (overall survival: hazard ratio 1.60; 95% confidence interval 1.04-2.45; PFS: hazard ratio 1.46; 95% confidence interval 0.96-2.22). For patients with a TTI >60 days in the HPV+ group, TTI affected overall survival and PFS similarly, with slightly lower hazard ratio estimates of 1.44 (95% confidence interval 0.83-2.51) and 1.15 (95% confidence interval 0.70-1.88), respectively. For patients treated for a HPV+ or HPV- OPSCC, TTI affects outcome, with the strongest effect for overall survival among HPV- patients. Reducing TTI is an important tool to improve the prognosis. Copyright © 2018. Published by Elsevier Ltd.

Randomized Phase III Placebo-Controlled Trial of Letrozole Plus Oral Temsirolimus As First-Line Endocrine Therapy in Postmenopausal Women With Locally Advanced or Metastatic Breast Cancer

PubMed Central

Wolff, Antonio C.; Lazar, Ann A.; Bondarenko, Igor; Garin, August M.; Brincat, Stephen; Chow, Louis; Sun, Yan; Neskovic-Konstantinovic, Zora; Guimaraes, Rodrigo C.; Fumoleau, Pierre; Chan, Arlene; Hachemi, Soulef; Strahs, Andrew; Cincotta, Maria; Berkenblit, Anna; Krygowski, Mizue; Kang, Lih Lisa; Moore, Laurence; Hayes, Daniel F.

2013-01-01

Purpose Recent data showed improvement in progression-free survival (PFS) when adding everolimus to exemestane in patients with advanced breast cancer experiencing recurrence/progression after nonsteroidal aromatase inhibitor (AI) therapy. Here, we report clinical outcomes of combining the mammalian target of rapamycin (mTOR) inhibitor temsirolimus with letrozole in AI-naive patients. Patients and Methods This phase III randomized placebo-controlled study tested efficacy/safety of first-line oral letrozole 2.5 mg daily/temsirolimus 30 mg daily (5 days every 2 weeks) versus letrozole/placebo in 1,112 patients with AI-naive, hormone receptor–positive advanced disease. An independent data monitoring committee recommended study termination for futility at the second preplanned interim analysis (382 PFS events). Results Patients were balanced (median age, 63 years; 10% stage III, 40% had received adjuvant endocrine therapy). Those on letrozole/temsirolimus experienced more grade 3 to 4 events (37% v 24%). There was no overall improvement in primary end point PFS (median, 9 months; hazard ratio [HR], 0.90; 95% CI, 0.76 to 1.07; P = .25) nor in the 40% patient subset with prior adjuvant endocrine therapy. An exploratory analysis showed improved PFS favoring letrozole/temsirolimus in patients ≤ age 65 years (9.0 v 5.6 months; HR, 0.75; 95% CI, 0.60 to 0.93; P = .009), which was separately examined by an exploratory analysis of 5-month PFS using subpopulation treatment effect pattern plot methodology (P = .003). Conclusion Adding temsirolimus to letrozole did not improve PFS as first-line therapy in patients with AI-naive advanced breast cancer. Exploratory analyses of benefit in younger postmenopausal patients require external confirmation. PMID:23233719

The prognostic value of derived neutrophil to lymphocyte ratio in oesophageal cancer treated with definitive chemoradiotherapy.

PubMed

Cox, Samantha; Hurt, Christopher; Grenader, Tal; Mukherjee, Somnath; Bridgewater, John; Crosby, Thomas

2017-10-01

The derived neutrophil-lymphocyte ratio (dNLR) is a validated prognostic biomarker for cancer survival but has not been extensively studied in locally-advanced oesophageal cancer treated with definitive chemoradiotherapy (dCRT). We aimed to identify the prognostic value of dNLR in patients recruited to the SCOPE1 trial. 258 patients were randomised to receive dCRT±cetuximab. Kaplan-Meier's curves and both univariable and multivariable Cox regression models were calculated for overall survival (OS), progression free survival (PFS), local PFS inside the radiation volume (LPFSi), local PFS outside the radiation volume (LPFSo), and distant PFS (DPFS). An elevated pre-treatment dNLR≥2 was significantly associated with decreased OS in univariable (HR 1.74 [95% CI 1.29-2.35], p<0.001) and multivariable analyses (HR 1.64 [1.17-2.29], p=0.004). Median OS was 36months (95% CI 27.8-42.4) if dNLR<2 and 18.4months (95% CI 14.1-24.9) if dNLR≥2. All measures of PFS were also significantly reduced with an elevated dNLR. dNLR was prognostic for OS in cases of squamous cell carcinoma with a non-significant trend for adenocarcinoma/undifferentiated tumours. An elevated pre-treatment dNLR may be an independent prognostic biomarker for OS and PFS in oesophageal cancer patients treated with definitive CRT. dNLR is a simple, inexpensive and readily available tool for risk-stratification and should be considered for use in future oesophageal cancer clinical trials. The SCOPE1 trial was an International Standard Randomised Controlled Trial [number 47718479]. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Mesospheric CO2 ice clouds on Mars observed by Planetary Fourier Spectrometer onboard Mars Express

NASA Astrophysics Data System (ADS)

Aoki, S.; Sato, Y.; Giuranna, M.; Wolkenberg, P.; Sato, T. M.; Nakagawa, H.; Kasaba, Y.

2018-03-01

We have investigated mesospheric CO2 ice clouds on Mars through analysis of near-infrared spectra acquired by Planetary Fourier Spectrometer (PFS) onboard the Mars Express (MEx) from MY 27 to MY 32. With the highest spectral resolution achieved thus far in the relevant spectral range among remote-sensing experiments orbiting Mars, PFS enables precise identification of the scattering peak of CO2 ice at the bottom of the 4.3 μm CO2 band. A total of 111 occurrences of CO2 ice cloud features have been detected over the period investigated. Data from the OMEGA imaging spectrometer onboard MEx confirm all of PFS detections from times when OMEGA operated simultaneously with PFS. The spatial and seasonal distributions of the CO2 ice clouds detected by PFS are consistent with previous observations by other instruments. We find CO2 ice clouds between Ls = 0° and 140° in distinct longitudinal corridors around the equatorial region (± 20°N). Moreover, CO2 ice clouds were preferentially detected at the observational LT range between 15-16 h in MY 29. However, observational biases prevent from distinguishing local time dependency from inter-annual variation. PFS also enables us to investigate the shape of mesospheric CO2 ice cloud spectral features in detail. In all cases, peaks were found between 4.240 and 4.265 μm. Relatively small secondary peaks were occasionally observed around 4.28 μm (8 occurrences). These spectral features cannot be reproduced using our radiative transfer model, which may be because the available CO2 ice refractive indices are inappropriate for the mesospheric temperatures of Mars, or because of the assumption in our model that the CO2 ice crystals are spherical and composed by pure CO2 ice.

Expression, Purification and Characterization of GMZ2'.10C, a Complex Disulphide-Bonded Fusion Protein Vaccine Candidate against the Asexual and Sexual Life-Stages of the Malaria-Causing Plasmodium falciparum Parasite.

PubMed

Mistarz, Ulrik H; Singh, Susheel K; Nguyen, Tam T T N; Roeffen, Will; Yang, Fen; Lissau, Casper; Madsen, Søren M; Vrang, Astrid; Tiendrebeogo, Régis W; Kana, Ikhlaq H; Sauerwein, Robert W; Theisen, Michael; Rand, Kasper D

2017-09-01

Production and characterization of a chimeric fusion protein (GMZ2'.10C) which combines epitopes of key malaria parasite antigens: glutamate-rich protein (GLURP), merozoite surface protein 3 (MSP3), and the highly disulphide bonded Pfs48/45 (10C). GMZ2'.10C is a potential candidate for a multi-stage malaria vaccine that targets both transmission and asexual life-cycle stages of the parasite. GMZ2'.10C was produced in Lactococcus lactis and purified using either an immunoaffinity purification (IP) or a conventional purification (CP) method. Protein purity and stability was analysed by RP-HPLC, SEC-HPLC, 2-site ELISA, gel-electrophoresis and Western blotting. Structural characterization (mass analysis, peptide mapping and cysteine connectivity mapping) was performed by LC-MS/MS. CP-GMZ2'.10C resulted in similar purity, yield, structure and stability as compared to IP-GMZ2'.10C. CP-GMZ2'.10C and IP-GMZ2'.10C both elicited a high titer of transmission blocking (TB) antibodies in rodents. The intricate disulphide-bond connectivity of C-terminus Pfs48/45 was analysed by tandem mass spectrometry and was established for GMZ2'.10C and two reference fusion proteins encompassing similar parts of Pfs48/45. GMZ2'.10C, combining GMZ2' and correctly-folded Pfs48/45 can be produced by the Lactoccus lactis P170 based expression system in purity and quality for pharmaceutical development and elicit high level of TB antibodies. The cysteine connectivity for the 10C region of Pfs48/45 was revealed experimentally, providing an important guideline for employing the Pfs48/45 antigen in vaccine design.

Three-Year Follow-Up of an Alectinib Phase I/II Study in ALK-Positive Non-Small-Cell Lung Cancer: AF-001JP.

PubMed

Tamura, Tomohide; Kiura, Katsuyuki; Seto, Takashi; Nakagawa, Kazuhiko; Maemondo, Makoto; Inoue, Akira; Hida, Toyoaki; Yoshioka, Hiroshige; Harada, Masao; Ohe, Yuichiro; Nogami, Naoyuki; Murakami, Haruyasu; Kuriki, Hiroshi; Shimada, Tadashi; Tanaka, Tomohiro; Takeuchi, Kengo; Nishio, Makoto

2017-05-10

Purpose Alectinib is an anaplastic lymphoma kinase (ALK) -specific kinase inhibitor that seems to be effective against non-small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor-naïve, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment.

Three-Year Follow-Up of an Alectinib Phase I/II Study in ALK-Positive Non–Small-Cell Lung Cancer: AF-001JP

PubMed Central

Tamura, Tomohide; Kiura, Katsuyuki; Seto, Takashi; Nakagawa, Kazuhiko; Maemondo, Makoto; Inoue, Akira; Hida, Toyoaki; Yoshioka, Hiroshige; Harada, Masao; Ohe, Yuichiro; Nogami, Naoyuki; Murakami, Haruyasu; Kuriki, Hiroshi; Shimada, Tadashi; Tanaka, Tomohiro; Takeuchi, Kengo; Nishio, Makoto

2017-01-01

Purpose Alectinib is an anaplastic lymphoma kinase (ALK) –specific kinase inhibitor that seems to be effective against non–small-cell lung cancer (NSCLC) with a variety of ALK mutations. The primary analysis of AF-001JP reported a promising overall response rate. To assess progression-free survival (PFS) and overall survival (OS), patients from the phase II part of AF-001JP were followed up for approximately 3 years. Patients and Methods Oral alectinib 300 mg was administered twice per day to patients with ALK inhibitor–naïve, ALK-positive NSCLC who had progressed after one or more regimens of previous chemotherapy. In this long-term follow-up, efficacy (PFS, OS), correlation between tumor shrinkage and PFS, safety of alectinib, and relief of cancer symptoms were evaluated. Results At the updated data cutoff (September 10, 2015; first patient in August 30, 2011, last patient in April 18, 2012), 25 of 46 phase II patients were still receiving alectinib. Disease progression was confirmed in 18 patients (39%); median PFS was not reached (3-year PFS rate, 62%; 95% CI, 45 to 75). Fourteen patients had brain metastases at baseline; of these, 6 remained in the study without CNS and systemic progression. Tumor shrinkage and PFS showed no correlation. The 3-year OS rate was 78% (13 events). The most common treatment-related adverse event (all grades) was increased blood bilirubin (36.2%). Most cancer symptoms were relieved early, and medication for symptoms was dramatically decreased during alectinib therapy. Conclusion Alectinib was effective in this 3-year follow-up with a favorable safety profile over a long administration period in ALK-positive NSCLC without previous ALK inhibitor treatment. PMID:28296581

VEGF-A polymorphisms predict progression-free survival among advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide

PubMed Central

Orlandi, P; Fontana, A; Fioravanti, A; Di Desidero, T; Galli, L; Derosa, L; Canu, B; Marconcini, R; Biasco, E; Solini, A; Francia, G; Danesi, R; Falcone, A; Bocci, G

2013-01-01

Background: No data are available on the pharmacogenetics of metronomic chemotherapy in prostate cancer. The aim of this study was to evaluate the association between VEGF-A sequence variants and prostate-specific antigen (PSA) progression, progression-free survival (PFS) and overall survival (OS), in advanced castration-resistant prostate cancer patients treated with metronomic cyclophosphamide (CTX), celecoxib and dexamethasone. Methods: Forty-three patients were enrolled, and genomic DNA was extracted. VEGF-A gene SNPs (−2578A/C, −634C/G, +936C/T) were analysed using TaqMan PCR assays. Hardy–Weinberg equilibrium was tested for each SNP, and genetic effects were evaluated by Fisher's exact test. PFS and OS were analysed with GraphPad Prism software, using the product limit method of Kaplan and Meier, and comparing survival curves using both the log-rank test and the Gehan–Wilcoxon test. We used Bonferroni correction to account for multiple testing, and a two-tailed P-value of <0.017 was considered statistically significant. Results: Overall, 20 patients (46%) experienced a reduction in PSA levels from baseline and, among them, 14 (32%) showed a confirmed PSA ≥50% decrease. In non-responders, the −2578CC genotype was more frequent (18.60% vs 2.33% in responders; P=0.0212) whereas the −634CC genotype frequency was 22.73% vs 0% in responders (P=0.0485). With regard to PFS, patients harbouring the −634CC genotype had a median PFS of 2.2 months whereas patients with the genotype −634CG/GG had a median PFS of 6.25 months (P=0.0042). Conclusion: The −634CC genotype is significantly associated with a shorter PFS in patients treated with a metronomic CTX schedule. PMID:23860526

Experimental investigation of magnetically actuated separation using tangential microfluidic channels and magnetic nanoparticles.

PubMed

Munir, Ahsan; Zhu, Zanzan; Wang, Jianlong; Zhou, Hong Susan

2014-06-01

A novel continuous switching/separation scheme of magnetic nanoparticles (MNPs) in a sub-microlitre fluid volume surrounded by neodymium permanent magnet is studied in this work using tangential microfluidic channels. Polydimethylsiloxane tangential microchannels are fabricated using a novel micromoulding technique that can be done without a clean room and at much lower cost and time. Negligible switching of MNPs is seen in the absence of magnetic field, whereas 90% of switching is observed in the presence of magnetic field. The flow rate of MNPs solution had dramatic impact on separation performance. An optimum value of the flow rate is found that resulted in providing effective MNP separation at much faster rate. Separation performance is also investigated for a mixture containing non-magnetic polystyrene particles and MNPs. It is found that MNPs preferentially moved from lower microchannel to upper microchannel resulting in efficient separation. The proof-of-concept experiments performed in this work demonstrates that microfluidic bioseparation can be efficiently achieved using functionalised MNPs, together with tangential microchannels, appropriate magnetic field strength and optimum flow rates. This work verifies that a simple low-cost magnetic switching scheme can be potentially of great utility for the separation and detection of biomolecules in microfluidic lab-on-a-chip systems.

Near-optimality of special periodic protocols for fluid models of single server switched networks with switchover times

NASA Astrophysics Data System (ADS)

Matveev, A. S.; Ishchenko, R.

2017-11-01

We consider a generic deterministic time-invariant fluid model of a single server switched network, which consists of finitely many infinite size buffers (queues) and receives constant rate inflows of jobs from the outside. Any flow undergoes a multi-phase service, entering a specific buffer after every phase, and ultimately leaves the network; the route of the flow over the buffers is pre-specified, and flows may merge inside the network. They share a common source of service, which can serve at most one buffer at a time and has to switch among buffers from time to time; any switch consumes a nonzero switchover period. With respect to the long-run maximal scaled wip (work in progress) performance metric, near-optimality of periodic scheduling and service protocols is established: the deepest optimum (that is over all feasible processes in the network, irrespective of the initial state) is furnished by such a protocol up to as small error as desired. Moreover, this can be achieved with a special periodic protocol introduced in the paper. It is also shown that the exhaustive policy is optimal for any buffer whose service at the maximal rate does not cause growth of the scaled wip.

Missing data and censoring in the analysis of progression-free survival in oncology clinical trials.

PubMed

Denne, J S; Stone, A M; Bailey-Iacona, R; Chen, T-T

2013-01-01

Progression-free survival (PFS) is increasingly used as a primary endpoint in oncology clinical trials. However, trial conduct is often such that PFS data on some patients may be partially missing either due to incomplete follow-up for progression, or due to data that may be collected but confounded by patients stopping randomized therapy or starting alternative therapy prior to progression. Regulatory guidance on how to handle these patients in the analysis and whether to censor these patients differs between agencies. We present results of a reanalysis of 28 Phase III trials from 12 companies or institutions performed by the Pharmaceutical Research and Manufacturers Association-sponsored PFS Expert Team. We show that analyses not adhering to the intention-to-treat principle tend to give hazard ratio estimates further from unity and describe several factors associated with this shift. We present illustrative simulations to support these findings and provide recommendations for the analysis of PFS.

Towards clinical development of a Pfs48/45-based transmission blocking malaria vaccine.

PubMed

Theisen, Michael; Jore, Matthijs M; Sauerwein, Robert

2017-04-01

Malaria is a devastating vector-borne disease caused by the Plasmodium parasite, resulting in almost 0.5 million casualties per year. The parasite has a complex life-cycle that includes asexual replication in human red blood cells, causing symptomatic malaria, and sexual stages which are essential for the transmission to the mosquito vector. A vaccine targeting the sexual stages of the parasite and thus blocking transmission will be instrumental for the eradication of malaria. One of the leading transmission blocking vaccine candidates is the sexual stage antigen Pfs48/45. Areas covered: PubMed was searched to review the progress and future prospects for clinical development of a Pfs48/45-based subunit vaccine. We will focus on biological function, naturally acquired immunity, functional activity of specific antibodies, sequence diversity, production of recombinant protein and preclinical studies. Expert commentary: Pfs48/45 is one of the lead-candidates for a transmission blocking vaccine and should be further explored in clinical trials.

Structural, morphological and mechanical properties of niobium nitride thin films grown by ion and electron beams emanated from plasma

NASA Astrophysics Data System (ADS)

Siddiqui, Jamil; Hussain, Tousif; Ahmad, Riaz; Umar, Zeeshan A.; Abdus Samad, Ubair

2016-05-01

The influence of variation in plasma deposition parameters on the structural, morphological and mechanical characteristics of the niobium nitride films grown by plasma-emanated ion and electron beams are investigated. Crystallographic investigation made by X-ray diffractometer shows that the film synthesized at 10 cm axial distance with 15 plasma focus shots (PFS) exhibits better crystallinity when compared to the other deposition conditions. Morphological analysis made by scanning electron microscope reveals a definite granular pattern composed of homogeneously distributed nano-spheroids grown as clustered particles for the film synthesized at 10 cm axial distance for 15 PFS. Roughness analysis demonstrates higher rms roughness for the films synthesized at shorter axial distance and by greater number of PFS. Maximum niobium atomic percentage (35.8) and maximum average hardness (19.4 ± 0.4 GPa) characterized by energy-dispersive spectroscopy and nano-hardness analyzer respectively are observed for film synthesized at 10 cm axial distance with 15 PFS.

Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non–Small-Cell Lung Cancer

PubMed Central

Thress, Kenneth S.; Alden, Ryan S.; Lawrance, Rachael; Paweletz, Cloud P.; Cantarini, Mireille; Yang, James Chih-Hsin; Barrett, J. Carl; Jänne, Pasi A.

2016-01-01

Purpose Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated potent activity against TKI resistance mediated by EGFR T790M. We studied whether noninvasive genotyping of cell-free plasma DNA (cfDNA) is a useful biomarker for prediction of outcome from a third-generation EGFR-TKI, osimertinib. Methods Plasma was collected from all patients in the first-in-man study of osimertinib. Patients who were included had acquired EGFR-TKI resistance and evidence of a common EGFR-sensitizing mutation. Genotyping of cell-free plasma DNA was performed by using BEAMing. Plasma genotyping accuracy was assessed by using tumor genotyping from a central laboratory as reference. Objective response rate (ORR) and progression-free survival (PFS) were analyzed in all T790M-positive or T790M-negative patients. Results Sensitivity of plasma genotyping for detection of T790M was 70%. Of 58 patients with T790M-negative tumors, T790M was detected in plasma of 18 (31%). ORR and median PFS were similar in patients with T790M-positive plasma (ORR, 63%; PFS, 9.7 months) or T790M-positive tumor (ORR, 62%; PFS, 9.7 months) results. Although patients with T790M-negative plasma had overall favorable outcomes (ORR, 46%; median PFS, 8.2 months), tumor genotyping distinguished a subset of patients positive for T790M who had better outcomes (ORR, 69%; PFS, 16.5 months) as well as a subset of patients negative for T790M with poor outcomes (ORR, 25%; PFS, 2.8 months). Conclusion In this retrospective analysis, patients positive for T790M in plasma have outcomes with osimertinib that are equivalent to patients positive by a tissue-based assay. This study suggests that, upon availability of validated plasma T790M assays, some patients could avoid a tumor biopsy for T790M genotyping. As a result of the 30% false-negative rate of plasma genotyping, those with T790M-negative plasma results still need a tumor biopsy to determine presence or absence of T790M. PMID:27354477

Association Between Plasma Genotyping and Outcomes of Treatment With Osimertinib (AZD9291) in Advanced Non-Small-Cell Lung Cancer.

PubMed

Oxnard, Geoffrey R; Thress, Kenneth S; Alden, Ryan S; Lawrance, Rachael; Paweletz, Cloud P; Cantarini, Mireille; Yang, James Chih-Hsin; Barrett, J Carl; Jänne, Pasi A

2016-10-01

Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have demonstrated potent activity against TKI resistance mediated by EGFR T790M. We studied whether noninvasive genotyping of cell-free plasma DNA (cfDNA) is a useful biomarker for prediction of outcome from a third-generation EGFR-TKI, osimertinib. Plasma was collected from all patients in the first-in-man study of osimertinib. Patients who were included had acquired EGFR-TKI resistance and evidence of a common EGFR-sensitizing mutation. Genotyping of cell-free plasma DNA was performed by using BEAMing. Plasma genotyping accuracy was assessed by using tumor genotyping from a central laboratory as reference. Objective response rate (ORR) and progression-free survival (PFS) were analyzed in all T790M-positive or T790M-negative patients. Sensitivity of plasma genotyping for detection of T790M was 70%. Of 58 patients with T790M-negative tumors, T790M was detected in plasma of 18 (31%). ORR and median PFS were similar in patients with T790M-positive plasma (ORR, 63%; PFS, 9.7 months) or T790M-positive tumor (ORR, 62%; PFS, 9.7 months) results. Although patients with T790M-negative plasma had overall favorable outcomes (ORR, 46%; median PFS, 8.2 months), tumor genotyping distinguished a subset of patients positive for T790M who had better outcomes (ORR, 69%; PFS, 16.5 months) as well as a subset of patients negative for T790M with poor outcomes (ORR, 25%; PFS, 2.8 months). In this retrospective analysis, patients positive for T790M in plasma have outcomes with osimertinib that are equivalent to patients positive by a tissue-based assay. This study suggests that, upon availability of validated plasma T790M assays, some patients could avoid a tumor biopsy for T790M genotyping. As a result of the 30% false-negative rate of plasma genotyping, those with T790M-negative plasma results still need a tumor biopsy to determine presence or absence of T790M. © 2016 by American Society of Clinical Oncology.

Baseline Characteristics Predicting Very Good Outcome of Allogeneic Hematopoietic Cell Transplantation in Young Patients With High Cytogenetic Risk Chronic Lymphocytic Leukemia - A Retrospective Analysis From the Chronic Malignancies Working Party of the EBMT.

PubMed

van Gelder, Michel; Ziagkos, Dimitris; de Wreede, Liesbeth; van Biezen, Anja; Dreger, Peter; Gramatzki, Martin; Stelljes, Matthias; Andersen, Niels Smedegaard; Schaap, Nicolaas; Vitek, Antonin; Beelen, Dietrich; Lindström, Vesa; Finke, Jürgen; Passweg, Jacob; Eder, Matthias; Machaczka, Maciej; Delgado, Julio; Krüger, William; Raida, Luděk; Socié, Gerard; Jindra, Pavel; Afanasyev, Boris; Wagner, Eva; Chalandon, Yves; Henseler, Anja; Schoenland, Stefan; Kröger, Nicolaus; Schetelig, Johannes

2017-10-01

Patients with genetically high-risk relapsed/refractory chronic lymphocytic leukemia have shorter median progression-free survival (PFS) with kinase- and BCL2-inhibitors (KI, BCL2i). Allogeneic hematopoietic stem cell transplantation (alloHCT) may result in sustained PFS, especially in younger patients because of its age-dependent non-relapse mortality (NRM) risk, but outcome data are lacking for this population. Risk factors for 2-year NRM and 8-year PFS were identified in patients < 50 years in an updated European Society for Blood and Marrow Transplantation registry cohort (n = 197; median follow-up, 90.4 months) by Cox regression modeling, and predicted probabilities of NRM and PFS of 2 reference patients with favorable or unfavorable characteristics were plotted. Predictors for poor 8-year PFS were no remission at the time of alloHCT (hazard ratio [HR], 1.7; 95% confidence interval [CI], 1.1-2.5) and partially human leukocyte antigen (HLA)-mismatched unrelated donor (HR, 2.8; 95% CI, 1.5-5.2). The latter variable also predicted a higher risk of 2-year NRM (HR, 4.0; 95% CI, 1.4-11.6) compared with HLA-matched sibling donors. Predicted 2-year NRM and 8-year PFS of a high cytogenetic risk (del(17p) and/or del(11q)) patient in remission with a matched related donor were 12% (95% CI, 3%-22%) and 54% (95% CI, 38%-69%), and for an unresponsive patient with a female partially HLA-matched unrelated donor 37% (95% CI, 12%-62%) and 38% (95% CI, 13%-63%). Low predicted NRM and high 8-year PFS in favorable transplant high cytogenetic risk patients compares favorably with outcomes with KI or BCL2i. Taking into account the amount of uncertainty for predicting survival after alloHCT and after sequential administration of KI and BCL2i, alloHCT remains a valid option for younger patients with high cytogenetic risk chronic lymphocytic leukemia with a well-HLA-matched donor. Copyright © 2017 Elsevier Inc. All rights reserved.

Tumor response and progression-free survival as potential surrogate endpoints for overall survival in extensive stage small-cell lung cancer: findings on the basis of North Central Cancer Treatment Group trials.

PubMed

Foster, Nathan R; Qi, Yingwei; Shi, Qian; Krook, James E; Kugler, John W; Jett, James R; Molina, Julian R; Schild, Steven E; Adjei, Alex A; Mandrekar, Sumithra J

2011-03-15

The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression-free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS. Individual patient data from 870 untreated extensive stage small-cell lung cancer patients participating in 6 single-arm (274 patients) and 3 randomized trials (596 patients) were pooled. Patient-level associations between putative surrogate endpoints and OS were assessed by Cox models using landmark analyses. Trial-level surrogacy of putative surrogate endpoints were assessed by the association of treatment effects on OS and individual putative surrogate endpoints. Trial-level surrogacy measures included: R(2) from weighted least squares regression model, Spearman correlation coefficient, and R(2) from bivariate survival model (Copula R(2) ). Median OS and PFS were 9.6 (95% confidence interval [CI], 9.1-10.0) and 5.5 (95% CI, 5.2-5.9) months, respectively; best response, CR, and confirmed response rates were 44%, 22%, and 34%, respectively. Patient-level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (hazard ratio [HR], 0.42; 95% CI, 0.35-0.51; concordance index 0.63; P < .01), with 6-month PFS being the strongest (HR, 0.41; 95% CI, 0.35-0.49; concordance index, 0.66, P < .01). At the trial level, PFS showed the highest level of surrogacy for OS (weighted least squares R(2) = 0.79; Copula R(2) = 0.80), explaining 79% of the variance in OS. Tumor response endpoints showed lower surrogacy levels (weighted least squares R(2) ≤0.48). PFS was strongly associated with OS at both the patient and trial levels. PFS also shows promise as a potential surrogate for OS, but further validation is needed using data from a larger number of randomized phase 3 trials. Copyright © 2010 American Cancer Society.

Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials

PubMed Central

Flaherty, Keith T; Hennig, Michael; Lee, Sandra J; Ascierto, Paolo A; Dummer, Reinhard; Eggermont, Alexander M M; Hauschild, Axel; Kefford, Richard; Kirkwood, John M; Long, Georgina V; Lorigan, Paul; Mackensen, Andreas; McArthur, Grant; O'Day, Steven; Patel, Poulam M; Robert, Caroline; Schadendorf, Dirk

2015-01-01

Summary Background Recent phase 3 trials have shown an overall survival benefit in metastatic melanoma. We aimed to assess whether progression-free survival (PFS) could be regarded as a reliable surrogate for overall survival through a meta-analysis of randomised trials. Methods We systematically reviewed randomised trials comparing treatment regimens in metastatic melanoma that included dacarbazine as the control arm, and which reported both PFS and overall survival with a standard hazard ratio (HR). We correlated HRs for overall survival and PFS, weighted by sample size or by precision of the HR estimate, assuming fixed and random effects. We did sensitivity analyses according to presence of crossover, trial size, and dacarbazine dose. Findings After screening 1649 reports and meeting abstracts published before Sept 8, 2013, we identified 12 eligible randomised trials that enrolled 4416 patients with metastatic melanoma. Irrespective of weighting strategy, we noted a strong correlation between the treatment effects for PFS and overall survival, which seemed independent of treatment type. Pearson correlation coefficients were 0.71 (95% CI 0.29–0.90) with a random-effects assumption, 0.85 (0.59–0.95) with a fixed-effects assumption, and 0.89 (0.68–0.97) with sample-size weighting. For nine trials without crossover, the correlation coefficient was 0.96 (0.81–0.99), which decreased to 0.93 (0.74–0.98) when two additional trials with less than 50% crossover were included. Inclusion of mature follow-up data after at least 50% crossover (in vemurafenib and dabrafenib phase 3 trials) weakened the PFS to overall survival correlation (0.55, 0.03–0.84). Inclusion of trials with no or little crossover with the random-effects assumption yielded a conservative statement of the PFS to overall survival correlation of 0.85 (0.51–0.96). Interpretation PFS can be regarded as a robust surrogate for overall survival in dacarbazine-controlled randomised trials of metastatic melanoma; we postulate that this association will hold as treatment standards evolve and are adopted as the control arm in future trials. Funding None. PMID:24485879

Antibodies elicited during natural infection in a predominantly Plasmodium falciparum transmission area cross-react with sexual stage-specific antigen in P. vivax.

PubMed

Bansal, Geetha P; Vengesai, Arthur; Cao, Yi; Mduluza, Takafira; Kumar, Nirbhay

2017-06-01

Infections caused by Plasmodium falciparum and P. vivax account for more than 90% of global malaria burden. Exposure to malaria parasite elicits immune responses during natural infection and it is generally believed that the immunity is not only stage specific but also species specific. However, partial genomic similarity for various antigens in different Plasmodium spp. raises the possibility of immunological cross-reactivity at the level of specific antigens. Serum samples collected from children who were permanent residents of a P. falciparum transmission area in Zimbabwe were screened for antibody reactivity against Pfs48/45, a P. falciparum gametocyte antigen and Pvs48/45, a P. vivax homolog of Pfs48/45 using ELISA. Western blotting was used to further confirm identity of the specific antibody reactivity to the Pfs48/45 and Pvs48/45 proteins. Pan Plasmodium PCR and nested PCR were used to confirm infection with the Plasmodium species. Twenty-seven percent (49/181) of the participants were found to be sero-positive for Pfs48/45 and 73% (n=36) of these Pfs48/45 positive sera also showed reactivity with Pvs48/45. Immune cross-reactivity revealed by ELISA was also confirmed by Western blot analysis using a panel of randomly selected 23 Pfs48/45 and Pvs48/45 ELISA positive samples. Nested PCR analysis of 27 blood samples randomly selected from the 36 that showed positive ELISA reactivity to both Pfs48/45 and Pvs48/45 antigens confirmed infection with P. falciparum and generalized absence of P. vivax except for a single sample which revealed PCR positivity for both P. vivax and P. falciparum. Our studies with sera samples from a predominantly P. falciparum transmission area in Zimbabwe suggest immunological cross-reactivity with Pvs48/45, thus raising the possibility of partial species cross-reactive immunity and possible cross-boosting of immunity during co-infection with P. falciparum and P. vivax. Copyright © 2017 Elsevier B.V. All rights reserved.

Benefit of Consolidative Radiation Therapy for Primary Bone Diffuse Large B-Cell Lymphoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tao, Randa; Allen, Pamela K.; Rodriguez, Alma

Purpose: Outcomes for patients with diffuse large B-cell lymphoma (DLBCL) differ according to the site of presentation. With effective chemotherapy, the need for consolidative radiation therapy (RT) is controversial. We investigated the influence of primary bone presentation and receipt of consolidative RT on progression-free survival (PFS) and overall survival (OS) in patients with DLBCL. Methods and Materials: We identified 102 patients with primary bone DLBCL treated consecutively from 1988 through 2013 and extracted clinical, pathologic, and treatment characteristics from the medical records. Survival outcomes were calculated by the Kaplan-Meier method, with factors affecting survival determined by log-rank tests. Univariate andmore » multivariate analyses were done with a Cox regression model. Results: The median age was 55 years (range, 16-87 years). The most common site of presentation was in the long bones. Sixty-five patients (63%) received R-CHOP–based chemotherapy, and 74 (72%) received rituximab. RT was given to 67 patients (66%), 47 with stage I to II and 20 with stage III to IV disease. The median RT dose was 44 Gy (range, 24.5-50 Gy). At a median follow-up time of 82 months, the 5-year PFS and OS rates were 80% and 82%, respectively. Receipt of RT was associated with improved 5-year PFS (88% RT vs 63% no RT, P=.0069) and OS (91% vs 68%, P=.0064). On multivariate analysis, the addition of RT significantly improved PFS (hazard ratio [HR] = 0.14, P=.014) with a trend toward an OS benefit (HR=0.30, P=.053). No significant difference in PFS or OS was found between patients treated with 30 to 35 Gy versus ≥36 Gy (P=.71 PFS and P=.31 OS). Conclusion: Patients with primary bone lymphoma treated with standard chemotherapy followed by RT can have excellent outcomes. The use of consolidative RT was associated with significant benefits in both PFS and OS.« less

Prognostic factors in patients with advanced renal cell carcinoma.

PubMed

Muriel López, Carolina; Esteban, Emilio; Berros, Jose Pablo; Pardo, Pablo; Astudillo, Aurora; Izquierdo, Marta; Crespo, Guillermo; Sanmamed, Miguel; Fonseca, Paula J; Martínez-Camblor, Pablo

2012-12-01

The purpose of this study was to evaluate prognostic factors in patients with RCC. The expression of several biomarkers were measured by immunohistochemistry (IHC), together with 2 analytic factors (thrombocytosis and neutrophilia), in 135 patients with advanced RCC treated with new targeted drugs (NTDs) (n = 67) and/or cytokines (CKs) (n = 68)-with 23 of the patients who received CKs also receiving NTDs-between July 1996 and February 2010. Relationships with overall survival (OS) and progression-free survival (PFS) were searched for. Univariate statistical analysis revealed that high expression of hypoxia-inducible factor-1α (HIF-1α) correlated with poor prognosis in NTD treatment (PFS, 5.4 vs. 13.5, low expression months; P = .033) and CK treatment (PFS, 3.3 vs. 5.7, low expression; P = .003). Overexpression of carbonic anhydrase IX (CAIX) was associated with better prognosis with NTD treatment (OS, 32.1 vs. 7.8 months; P < .001) and CK treatment (OS, 32.9 vs. 5.9 months; P = .001). Positive PTEN was related to good prognosis with sunitinib (PFS, 15.1 vs. 6.5 months; P = .003) and CKs (OS, 13.7 vs. 7.9 months; P = .039). Increased expression of p21 was related to poor prognosis with NTD treatment (PFS, 5.9 vs. 16.8 months; P = .024) and CK treatment (PFS, 3.9 vs. 7.5 months; P < .001) Thrombocytosis was related to poor prognosis with NTDs (OS, 15.9 vs. 26.7 months; P = .007) and CKs (OS, 5.9 vs. 14.3 months; P = .010). Neutrophilia was related to poor prognosis with NTDs (OS, 17.6 vs. 25.4 months; P = .063) and CKs (OS, 5.9 vs. 12.8 months; P = .035). Multivariate analysis revealed that overexpression of CAIX was a favorable prognostic factor independent of PFS (hazard ratio [HR], 0.107; P < .001) and OS (HR, 0.055; P < .001). HIF-1α, PTEN, p21, thrombocytosis, neutrophilia, and CAIX in particular are useful prognostic factors in patients with advanced RCC. Copyright © 2012 Elsevier Inc. All rights reserved.

Minimal Residual Disease Assessment Improves Prediction of Outcome in Patients With Chronic Lymphocytic Leukemia (CLL) Who Achieve Partial Response: Comprehensive Analysis of Two Phase III Studies of the German CLL Study Group.

PubMed

Kovacs, Gabor; Robrecht, Sandra; Fink, Anna Maria; Bahlo, Jasmin; Cramer, Paula; von Tresckow, Julia; Maurer, Christian; Langerbeins, Petra; Fingerle-Rowson, Günter; Ritgen, Matthias; Kneba, Michael; Döhner, Hartmut; Stilgenbauer, Stephan; Klapper, Wolfram; Wendtner, Clemens-Martin; Fischer, Kirsten; Hallek, Michael; Eichhorst, Barbara; Böttcher, Sebastian

2016-11-01

Purpose To determine the value of minimal residual disease (MRD) assessments, together with the evaluation of clinical response in chronic lymphocytic leukemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia criteria. Patients and Methods Progression-free survival (PFS) and overall survival of 554 patients from two randomized trials of the German CLL Study Group (CLL8: fludarabine and cyclophosphamide [FC] v FC plus rituximab; CLL10: FC plus rituximab v bendamustine plus rituximab) were analyzed according to MRD assessed in peripheral blood at a threshold of 10 -4 and clinical response. The prognostic value of different parameters defining a partial response (PR) was further investigated. Results Patients with MRD-negative complete remission (CR), MRD-negative PR, MRD-positive CR, and MRD-positive PR experienced a median PFS from a landmark at end of treatment of 61 months, 54 months, 35 months, and 21 months, respectively. PFS did not differ significantly between MRD-negative CR and MRD-negative PR; however, PFS was longer for MRD-negative PR than for MRD-positive CR ( P = .048) and for MRD-positive CR compared with MRD-positive PR ( P = .002). Compared with MRD-negative CR, only patients with MRD-positive PR had a significantly shorter overall survival (not reached v 72 months; P = .001), whereas there was no detectable difference for patients with MRD-negative PR or MRD-positive CR ( P = 0.612 and P = 0.853, respectively). Patients with MRD-negative PR who presented with residual splenomegaly had only a similar PFS (63 months) compared with patients with MRD-negative CR (61 months; P = .354), whereas patients with MRD-negative PR with lymphadenopathy showed a shorter PFS (31 months; P < .001). Conclusion MRD quantification allows for improved PFS prediction in both patients who achive PR and CR, which thus supports its application in all responders. In contrast to residual lymphadenopathy, persisting splenomegaly does not impact outcome in patients with MRD-negative PR.

Pemetrexed-Erlotinib, Pemetrexed Alone, or Erlotinib Alone as Second-Line Treatment for East Asian and Non-East Asian Never-Smokers with Locally Advanced or Metastatic Nonsquamous Non-small Cell Lung Cancer: Exploratory Subgroup Analysis of a Phase II Trial

PubMed Central

Lee, Dae Ho; Lee, Jung Shin; Wang, Jie; Hsia, Te-Chun; Wang, Xin; Kim, Jongseok; Orlando, Mauro

2015-01-01

Purpose This subgroup analysis of a phase II trial was conducted to assess possible ethnicity-based trends in efficacy and safety in East Asian (EA) and non-EA populations with nonsquamous non-small cell lung cancer (NSCLC). Materials and Methods Never-smoker patients (n=240) with locally advanced or metastatic nonsquamous NSCLC included 133 EA patients randomized to pemetrexed supplemented with dexamethasone, folic acid, and vitamin B12 plus erlotinib (pemetrexed-erlotinib) (n=41), erlotinib (n=49), or pemetrexed (n=43), and 107 non-EA patients randomized to pemetrexed-erlotinib (n=37), erlotinib (n=33), or pemetrexed (n=37). The primary endpoint, progression-free survival (PFS), was analyzed using a multivariate Cox model. Results Consistent with the results of the overall study, a statistically significant difference in PFS among the three arms was noted in the EA population favoring pemetrexed-erlotinib (overall p=0.003) as compared with either single-agent arm (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.29 to 0.79; p=0.004 vs. erlotinib; HR, 0.40; 95% CI, 0.23 to 0.70; p=0.001 vs. pemetrexed). The EA patients treated with pemetrexed-erlotinib achieved a longer median PFS (7.4 months) compared with erlotinib (4.5 months) and pemetrexed (4.0 months). The PFS results also numerically favored pemetrexed-erlotinib in the non-EA population (overall p=0.210) (HR, 0.62; 95% CI, 0.37 to 1.05; p=0.078 vs. erlotinib; HR, 0.75; 95% CI, 0.42 to 1.32; p=0.320 vs. pemetrexed) (median PFS: pemetrexed-erlotinib, 6.7 months; erlotinib, 3.0 months; pemetrexed, 4.4 months). Conclusion The PFS results from this subset analysis in both EA and non-EA populations are consistent with the results in the overall population. The PFS advantage for pemetrexed-erlotinib is significant compared with the single agents in EA patients. PMID:25672577

Results of a Randomized Controlled Multicenter Phase III Trial of Percutaneous Hepatic Perfusion Compared with Best Available Care for Patients with Melanoma Liver Metastases.

PubMed

Hughes, Marybeth S; Zager, Jonathan; Faries, Mark; Alexander, H Richard; Royal, Richard E; Wood, Bradford; Choi, Junsung; McCluskey, Kevin; Whitman, Eric; Agarwala, Sanjiv; Siskin, Gary; Nutting, Charles; Toomey, Mary Ann; Webb, Carole; Beresnev, Tatiana; Pingpank, James F

2016-04-01

There is no consensus for the treatment of melanoma metastatic to the liver. Percutaneous hepatic perfusion with melphalan (PHP-Mel) is a method of delivering regional chemotherapy selectively to the liver. In this study, we report the results of a multicenter, randomized controlled trial comparing PHP-Mel with best alternative care (BAC) for patients with ocular or cutaneous melanoma metastatic to the liver. A total of 93 patients were randomized to PHP-Mel (n = 44) or BAC (n = 49). On the PHP-Mel arm, melphalan was delivered via the hepatic artery, and the hepatic effluent captured and filtered extracorporeally prior to return to the systemic circulation via a venovenous bypass circuit. PHP-Mel was repeatable every 4-8 weeks. The primary endpoint was hepatic progression-free survival (hPFS), and secondary endpoints included overall PFS (oPFS), overall survival (OS), hepatic objective response (hOR), and safety. hPFS was 7.0 months for PHP-Mel and 1.6 months for BAC (p < 0.0001), while oPFS was 5.4 months for PHP-Mel and 1.6 months for BAC (p < 0.0001). Median OS was not significantly different (PHP-Mel 10.6 months vs. BAC 10.0 months), likely due to crossover to PHP-Mel treatment (57.1 %) from the BAC arm, and the hOR was 36.4 % for PHP-Mel and 2.0 % for BAC (p < 0.001). The majority of adverse events were related to bone marrow suppression. Four deaths were attributed to PHP-Mel, three in the primary PHP-Mel group, and one post-crossover to PHP-Mel from BAC. This randomized, phase III study demonstrated the efficacy of the PHP-Mel procedure. hPFS, oPFS, and hOR were significantly improved with PHP-Mel. PHP with melphalan should provide a new treatment option for unresectable metastatic melanoma in the liver.

Development of a Human Leukocyte Antigen Score to Predict Progression-Free Survival in Head and Neck Squamous Cell Carcinoma Patients.

PubMed

Wichmann, Gunnar; Lehmann, Claudia; Herchenhahn, Cindy; Kolb, Marlen; Hofer, Mathias; Wiegand, Susanne; Dietz, Andreas

2018-01-01

In personalized medicine and treatment stratification of head and neck squamous cell carcinoma (HNSCC), the heterogeneous genetic background of patients is not considered. Human leukocyte antigen (HLA) alleles and HLA haplotypes (HLA traits) are linked to development of HNSCC and affect progression-free survival (PFS) of HNSCC patients but most head and neck oncologists are not familiar with HLA typing. Hence, we developed an HLA-score abstracting from complexity of HLA-typing results to facilitate potential use of HLA-associated hazard ratios (HR) for prognostic stratification. The HR for PFS of 8 HLA traits shown to be independent predictors ( Pi ) of PFS in a test cohort (TC) of 90 HNSCC patients were used to build the HLA-score based on the natural logarithm (ln) of the Pi -associated HR. Crude ln-transformed HR of the eight Pi , alleles B*13 (2), B*35 (1), B*51 (2), DQB1*06 (1), homozygous Cw (1), homozygous DRB4 (2), and haplotypes A*01/B*08 (-6) and B*08/C*07 (4), were summed up to yield the individual patient's HLA-score. Receiver operating characteristic (ROC) and Kaplan-Meier curves were used to proof the suitability of the HLA-score as prognostic marker for PFS. An independent validation cohort (iVC) of 32 patients treated in the larynx-organ preservation trial DeLOS-II was utilized for validation. The individual HLA-scores (range -2 to 6) in TC classified HNSCC patients regarding PFS. ROC analysis (area under the curve = 0.750, 95% CI 0.665-0.836; P  = 0.0000034) demonstrated an optimum cutoff for the HLA-score at 0.5 (97.9% sensitivity, 34.7% specificity), and 70/90 patients in TC with HLA-score > 0 had significant reduced PFS ( P  = 0.001). Applying the same classifier (HLA-score > 0) confirmed these findings in the iVC revealing reduced PFS of 25/32 patients ( P  = 0.040). HLA traits constitute critical Pi . Considering the HLA-score may potentially facilitate the use of genetic information from HLA typing for prognostic stratification, e.g., within clinical trials.

Heat Switches Providing Low-Activation Power and Quick-Switching Time for Use in Adiabatic Demagnetization Refrigerators

NASA Technical Reports Server (NTRS)

Kimball, Mark O.; Shirron, Peter J.

2011-01-01

An adiabatic demagnetization refrigerator (ADR) is a solid-state cooler capable of achieving sub-Kelvin temperatures. It neither requires moving parts nor a density gradient in a working fluid making it ideal for use in space-based instruments. The flow of energy through the cooler is controlled by heat switches that allow heat transfer when on and isolate portions of the cooler when off. One type of switch uses helium gas as the switching medium. In the off state the gas is adsorbed in a getter thus breaking the thermal path through the switch. To activate the switch, the getter is heated to release helium into the switch body allowing it to complete the thermal path. A getter that has a small heat capacity and low thermal conductance to the body of the switch requires low-activation power. The cooler benefits from this in two ways: shorter recycle times and higher efficiency. We describe such a design here.

Heat Switches Providing Low-Activation Power and Quick-Switching Time for Use in Cryogenic Multi-Stage Refrigerators

NASA Technical Reports Server (NTRS)

Kimball, Mark O.; Shirron, Peter J.

2011-01-01

An adiabatic demagnetization refrigerator (ADR) is a solid-state cooler capable of achieving sub-Kelvin temperatures. It neither requires moving parts nor a density gradient in a working fluid making it ideal for use in space-based instruments. The flow of energy through the cooler is controlled by heat switches that allow heat transfer when on and isolate portions of the cooler when off. One type of switch uses helium gas as the switching medium. In the off state the gas is adsorbed in a getter thus breaking the thermal path through the switch. To activate the switch, the getter is heated to release helium into the switch body allowing it to complete the thermal path. A getter that has a small heat capacity and low thermal conductance to the body of the switch requires low-activation power. The cooler benefits from this in two ways: shorter recycle times and higher efficiency. We describe such a design here.

AR-V7 in circulating tumor cells cluster as a predictive biomarker of abiraterone acetate and enzalutamide treatment in castration-resistant prostate cancer patients.

PubMed

Okegawa, Takatsugu; Ninomiya, Naoki; Masuda, Kazuki; Nakamura, Yu; Tambo, Mitsuhiro; Nutahara, Kikuo

2018-06-01

We examined whether androgen receptor splice variant 7 (AR-V7) in circulating tumor cell(CTC)clusters can be used to predict survival in patients with bone metastatic castration resistant-prostate cancer (mCRPC) treated with abiraterone or enzalutamide. We retrospectively enrolled 98 patients with CRPC on abiraterone or enzalutamide, and investigated the prognostic value of CTC cluster detection (+ v -) and AR-V7 detection (+ v -) using a CTC cluster detection - based AR-V7 mRNA assay. We examined ≤50% prostate-specific antigen (PSA) responses, PSA progression-free survival (PSA-PFS), clinical and radiological progression-free survival (radiologic PSF), and overall survival (OS). We then assessed whether AR-V7 expression in CTC clusters identified after On-chip multi-imaging flow cytometry was related to disease progression and survival after first-line systemic therapy. All abiraterone-treated or enzalutamide-treated patients received prior docetaxel. The median follow-up was 20.7 (range: 3.0-37.0) months in the abiraterone and enzalutamide cohorts, respectively. Forty-nine of the 98 men (50.0%) were CTC cluster (-), 23 of the 98 men (23.5%) were CTC cluster(+)/AR-V7(-), and 26 of the 98 men (26.5%) were CTC cluster(+)/AR-V7(+). CTC cluster(+)/AR-V7(+) patients were more likely to have EOD ≥3 at diagnosis (P = 0.003), pain (P = 0.023), higher alkaline phosphatase levels (P < 0.001), and visceral metastases (P < 0.001). On multivariable analysis, pretherapy CTC cluster(+), CTC cluster(+)/AR-V7(-), and ALP >UNL were independently associated with a poor PSA-PFS, radiographic PFS, and OS in abiraterone-treated patients and enzalutamide-treated patients. The CTC clusters and AR-V7-positive CTC clusters detected were important for assessing the response to abiraterone or enzalutamide therapy and for predicting disease outcome. © 2018 Wiley Periodicals, Inc.

Chaotic mixing in microchannels via low frequency switching transverse electroosmotic flow generated on integrated microelectrodes.

PubMed

Song, Hongjun; Cai, Ziliang; Noh, Hongseok Moses; Bennett, Dawn J

2010-03-21

In this paper we present a numerical and experimental investigation of a chaotic mixer in a microchannel via low frequency switching transverse electroosmotic flow. By applying a low frequency, square-wave electric field to a pair of parallel electrodes placed at the bottom of the channel, a complex 3D spatial and time-dependence flow was generated to stretch and fold the fluid. This significantly enhanced the mixing effect. The mixing mechanism was first investigated by numerical and experimental analysis. The effects of operational parameters such as flow rate, frequency, and amplitude of the applied voltage have also been investigated. It is found that the best mixing performance is achieved when the frequency is around 1 Hz, and the required mixing length is about 1.5 mm for the case of applied electric potential 5 V peak-to-peak and flow rate 75 microL h(-1). The mixing performance was significantly enhanced when the applied electric potential increased or the flow rate of fluids decreased.

The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis.

PubMed

Morgan, Gareth J; Gregory, Walter M; Davies, Faith E; Bell, Sue E; Szubert, Alexander J; Brown, Julia M; Coy, Nuria N; Cook, Gordon; Russell, Nigel H; Rudin, Claudius; Roddie, Huw; Drayson, Mark T; Owen, Roger G; Ross, Fiona M; Jackson, Graham H; Child, J Anthony

2012-01-05

Thalidomide maintenance has the potential to modulate residual multiple myeloma (MM) after an initial response. This trial compared the effect of thalidomide maintenance and no maintenance on progression-free survival (PFS) and overall survival (OS) in MM patients. After intensive or nonintensive induction therapy, 820 newly diagnosed MM patients were randomized to open-label thalidomide maintenance until progression, or no maintenance. Interphase FISH (iFISH) analysis was performed at study entry. Median PFS was significantly longer with thalidomide maintenance (log-rank P < .001). Median OS was similar between regimens (log-rank P = .40). Patients with favorable iFISH showed improved PFS (P = .004) and a trend toward a late survival benefit. Patients with adverse iFISH receiving thalidomide showed no significant PFS benefit and worse OS (P = .009). Effective relapse therapy enhanced survival after progression, translating into a significant OS benefit. Meta-analysis of this and other studies show a significant late OS benefit (P < .001, 7-year difference hazard ratio = 12.3; 95% confidence interval, 5.5-19.0). Thalidomide maintenance significantly improves PFS and can be associated with improved OS. iFISH testing is important in assessing the clinical impact of maintenance therapy. Overview analysis demonstrated that thalidomide maintenance was associated with a significant late OS benefit. This trial was registered at www.isrctn.org as #ISRCTN68454111.

Identification of surrogate endpoints in patients with locoregionally advanced nasopharyngeal carcinoma receiving neoadjuvant chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone.

PubMed

Chen, Yu-Pei; Zhang, Wen-Na; Tang, Ling-Long; Mao, Yan-Ping; Liu, Xu; Chen, Lei; Zhou, Guan-Qun; Mai, Hai-Qiang; Shao, Jian-Yong; Jia, Wei-Hua; Kang, Tie-Bang; Zeng, Mu-Sheng; Sun, Ying; Ma, Jun

2015-11-24

In the era of intensity-modulated radiotherapy (IMRT), the efficacy of additional neoadjuvant chemotherapy (NACT) to concurrent chemoradiotherapy (CCRT) in locoregionally advanced nasopharyngeal carcinoma (NPC) is currently being investigated in ongoing trials. Overall survival (OS) is the gold standard endpoint in NPC trials. We performed this analysis to identify surrogate endpoints for OS, which could shorten follow-up duration and speed up assessment of treatment effects. We retrospectively analysed 208 matched-pair patients with locoregionally advanced NPC receiving NACT+CCRT or CCRT. Progression-free survival (PFS), failure-free survival (FFS), distant failure-free survival (D-FFS) and locoregional failure-free survival (LR-FFS) at 2 and 3 years were assessed as surrogates for 5-year OS according to Prentice's criteria. The strength of the associations were assessed using Spearman's rank correlation coefficient. No significant differences were observed between treatment arms for any surrogate endpoint at 2 years, which rejected Prentice's second criterion. In contrast, 3-year LR-FFS, PFS, FFS and D-FFS were consistent with all four of Prentice's criteria; the rank correlation coefficient (0.730) between 3-year PFS and 5-year OS was highest. 3-year PFS, FFS and D-FFS could be valid surrogate endpoints for 5-year OS; 3-year PFS may be the most accurate.

Comparative Assessment of Transmission-Blocking Vaccine Candidates against Plasmodium falciparum

PubMed Central

Kapulu, M. C.; Da, D. F.; Miura, K.; Li, Y; Blagborough, A. M.; Churcher, T. S.; Nikolaeva, D.; Williams, A. R.; Goodman, A. L.; Sangare, I.; Turner, A. V.; Cottingham, M. G.; Nicosia, A.; Straschil, U.; Tsuboi, T.; Gilbert, S. C.; Long, Carole A.; Sinden, R. E.; Draper, S. J.; Hill, A. V. S.; Cohuet, A.; Biswas, S.

2015-01-01

Malaria transmission-blocking vaccines (TBVs) target the development of Plasmodium parasites within the mosquito, with the aim of preventing malaria transmission from one infected individual to another. Different vaccine platforms, mainly protein-in-adjuvant formulations delivering the leading candidate antigens, have been developed independently and have reported varied transmission-blocking activities (TBA). Here, recombinant chimpanzee adenovirus 63, ChAd63, and modified vaccinia virus Ankara, MVA, expressing AgAPN1, Pfs230-C, Pfs25, and Pfs48/45 were generated. Antibody responses primed individually against all antigens by ChAd63 immunization in BALB/c mice were boosted by the administration of MVA expressing the same antigen. These antibodies exhibited a hierarchy of inhibitory activity against the NF54 laboratory strain of P. falciparum in Anopheles stephensi mosquitoes using the standard membrane feeding assay (SMFA), with anti-Pfs230-C and anti-Pfs25 antibodies giving complete blockade. The observed rank order of inhibition was replicated against P. falciparum African field isolates in A. gambiae in direct membrane feeding assays (DMFA). TBA achieved was IgG concentration dependent. This study provides the first head-to-head comparative analysis of leading antigens using two different parasite sources in two different vector species, and can be used to guide selection of TBVs for future clinical development using the viral-vectored delivery platform. PMID:26063320

[Preparation and structural analysis of diatomite-supported SPFS flocculant].

PubMed

Zheng, Huai-li; Fang, Hui-li; Jiang, Shao-jie; Yang, Chun; Ma, Jiang-ya; Zhang, Zhao-qing

2011-07-01

In the presetn study, polymerized ferric sulphate (PFS) flocculant was prepared and tested. In the preparation of PFS flocculant, industrial by-product ferrous sulfate heptahydrate (FeSO4.7H2O) was reused as the main material. By composition with diatomite and drying up at certain temperature in vacuum drying oven, solid PFS flocculant was produced. Structural characteristics of the new flocculant product were examined through infrared spectroscopy and scanning electron microscopy (SEM), which showed that by compositing with diatomite, new group bridging emerged in the structure of PFS, which made the bond of groups stronger. In addition, part of the metalic contents in diatomite was polymerized with PFS, the product of which was polymerized ferric complex. Furthermore, the absorbing and agglomerating capacity of the diatomite carrier was significant. Considering the factors listed above, the new solid polymerized ferric sulphate (SPFS) flocculant was characterized with a larger molecule structure and enhanced absorbing, bridging and rolling sweep capacities. Through orthogonal experiment, optimum conditions of synthesis were as follows: the ratio of FeSO4.7H2O/diatomite in weight was 43/1, the reaction time is 1 h and the reaction temperature is 55 degrees C. By wastewater treatment experiment, it was found that the synthetic products showed good flocculation performance in the treatment of domestic sewage, the removal of COD was 80.00% and the removal of turbidity was 99.98%.

Prognostic Significance of Blood Transfusion in Newly Diagnosed Multiple Myeloma Patients without Autologous Hematopoietic Stem Cell Transplantation

PubMed Central

Fan, Liping; Fu, Danhui; Zhang, Jinping; Wang, Qingqing; Ye, Yamei; Xie, Qianling

2017-01-01

The aim of this study was to evaluate whether blood transfusions affect overall survival (OS) and progression-free survival (PFS) in newly diagnosed multiple myeloma (MM) patients without hematopoietic stem cell transplantation. A total of 181 patients were enrolled and divided into two groups: 68 patients in the transfused group and 113 patients in the nontransfused group. Statistical analyses showed that there were significant differences in ECOG scoring, Ig isotype, platelet (Plt) counts, hemoglobin (Hb) level, serum creatinine (Scr) level, and β2-microglobulin (β2-MG) level between the two groups. Univariate analyses showed that higher International Staging System staging, Plt counts < 100 × 109/L, Scr level ≥ 177 μmol/L, serum β2-MG ≥ 5.5 μmol/L, serum calcium (Ca) ≥ 2.75 mmol/L, and thalidomide use were associated with both OS and PFS in MM patients. Age ≥ 60 was associated with OS and Ig isotype was associated with PFS in MM patients. Moreover, blood transfusion was associated with PFS but not OS in MM patients. Multivariate analyses showed that blood transfusion was not an independent factor for PFS in MM patients. Our preliminary results suggested that newly diagnosed MM patients may benefit from a liberal blood transfusion strategy, since blood transfusion is not an independent impact factor for survival. PMID:28567420

INCREASING AGE IS A RISK FACTOR FOR DECREASED POSTPARTUM PELVIC FLOOR STRENGTH

PubMed Central

Quiroz, Lieschen H.; Pickett, Stephanie D.; Peck, Jennifer D; Rostaminia, Ghazaleh; Stone, Daniel E.; Shobeiri, S. Abbas

2016-01-01

Objectives To determine factors associated with decreased pelvic floor strength (PFS) after the first vaginal delivery in a cohort of low risk women Methods This is a secondary analysis of a prospective study examining the risk of pelvic floor injury in a cohort of primiparous women. All recruited participants underwent an examination, 3D ultrasound and measurement of pelvic floor strength (PFS) in the third trimester and repeated at 4 weeks-6 months postpartum using a perineometer. Results There were 84 women recruited for the study, and 70 completed the postpartum assessment. Average age was 28.4 years (SD, 4.8). There were 46 (66%) subjects with a vaginal delivery (VD) and 24 (34%) with a cesarean delivery (CD) who labored. Decreased PFS was observed more frequently in the VD group compared to the CD group (68% vs. 42%, p=0.03). In modified Poisson regression models controlling for mode of delivery and time of postpartum assessment, women who were age 25-29 (RR=2.80, 95% CI 1.03-7.57) and >=30 (RR=2.53, 95% CI 0.93-6.86)) were over 2.5 times more likely to have decreased postpartum PFS compared to women < 25 yo. Conclusions In this population, women age 25 and older were more than twice as likely to have a decrease in postpartum PFS. PMID:28067746

Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies.

PubMed

Rule, Simon; Dreyling, Martin; Goy, Andre; Hess, Georg; Auer, Rebecca; Kahl, Brad; Cavazos, Nora; Liu, Black; Yang, Shiyi; Clow, Fong; Goldberg, Jenna D; Beaupre, Darrin; Vermeulen, Jessica; Wildgust, Mark; Wang, Michael

2017-11-01

Ibrutinib is highly active in treating mantle cell lymphoma (MCL), an aggressive B-cell lymphoma. We pooled data from three ibrutinib studies to explore the impact of baseline patient characteristics on treatment response. Patients with relapsed/refractory MCL (n = 370) treated with ibrutinib had an objective response rate (ORR) of 66% (20% complete response; 46% partial response); median duration of response (DOR), progression-free survival (PFS) and overall survival (OS) were 18·6, 12·8 and 25·0 months, respectively. Univariate analyses showed patients with one versus >one prior line of therapy had longer OS. Multivariate analyses identified that one prior line of therapy affected PFS; Eastern Cooperative Oncology Group (ECOG) performance status, simplified MCL international prognostic index (sMIPI) score, bulky disease, and blastoid histology affected OS and PFS. Patients with blastoid versus non-blastoid histology had similar time to best response, but lower ORR, DOR, PFS and OS. OS and PFS were longer in patients with better sMIPI, patients with ECOG performance status 0-1, non-bulky disease and non-blastoid histology. Additionally, the proportion of patients with poor prognostic factors increased with increasing lines of therapy. Together, results suggest that patient outcomes following treatment failure with ibrutinib are related to the natural biological evolution of the disease. © 2017 John Wiley & Sons Ltd.

Pre-equilibrium dynamics and heavy-ion observables

NASA Astrophysics Data System (ADS)

Heinz, Ulrich; Liu, Jia

2016-12-01

To bracket the importance of the pre-equilibrium stage on relativistic heavy-ion collision observables, we compare simulations where it is modeled by either free-streaming partons or fluid dynamics. These cases implement the assumptions of extremely weak vs. extremely strong coupling in the initial collision stage. Accounting for flow generated in the pre-equilibrium stage, we study the sensitivity of radial, elliptic and triangular flow on the switching time when the hydrodynamic description becomes valid. Using the hybrid code iEBE-VISHNU [C. Shen, Z. Qiu, H. Song, J. Bernhard, S. Bass and U. Heinz, Comput. Phys. Commun. 199 (2016) 61] we perform a multi-parameter search, constrained by particle ratios, integrated elliptic and triangular charged hadron flow, the mean transverse momenta of pions, kaons and protons, and the second moment < pT2 > of the proton transverse momentum spectrum, to identify optimized values for the switching time τs from pre-equilibrium to hydrodynamics, the specific shear viscosity η / s, the normalization factor of the temperature-dependent specific bulk viscosity (ζ / s) (T), and the switching temperature Tsw from viscous hydrodynamics to the hadron cascade UrQMD. With the optimized parameters, we predict and compare with experiment the pT-distributions of π, K, p, Λ, Ξ and Ω yields and their elliptic flow coefficients, focusing specifically on the mass-ordering of the elliptic flow for protons and Lambda hyperons which is incorrectly described by VISHNU without pre-equilibrium flow.

Clustering and Flow Conservation Monitoring Tool for Software Defined Networks

PubMed Central

Puente Fernández, Jesús Antonio

2018-01-01

Prediction systems present some challenges on two fronts: the relation between video quality and observed session features and on the other hand, dynamics changes on the video quality. Software Defined Networks (SDN) is a new concept of network architecture that provides the separation of control plane (controller) and data plane (switches) in network devices. Due to the existence of the southbound interface, it is possible to deploy monitoring tools to obtain the network status and retrieve a statistics collection. Therefore, achieving the most accurate statistics depends on a strategy of monitoring and information requests of network devices. In this paper, we propose an enhanced algorithm for requesting statistics to measure the traffic flow in SDN networks. Such an algorithm is based on grouping network switches in clusters focusing on their number of ports to apply different monitoring techniques. Such grouping occurs by avoiding monitoring queries in network switches with common characteristics and then, by omitting redundant information. In this way, the present proposal decreases the number of monitoring queries to switches, improving the network traffic and preventing the switching overload. We have tested our optimization in a video streaming simulation using different types of videos. The experiments and comparison with traditional monitoring techniques demonstrate the feasibility of our proposal maintaining similar values decreasing the number of queries to the switches. PMID:29614049

Directional flow induced by synchronized longitudinal and zeta-potential controlling AC-electrical fields.

PubMed

van der Wouden, E J; Hermes, D C; Gardeniers, J G E; van den Berg, A

2006-10-01

Electroosmotic flow (EOF) in a microchannel can be controlled by electronic control of the surface charge using an electrode embedded in the wall of the channel. By setting a voltage to the electrode, the zeta-potential at the wall can be changed locally. Thus, the electrode acts as a "gate" for liquid flow, in analogy with a gate in a field-effect transistor. In this paper we will show three aspects of a Field Effect Flow Control (FEFC) structure. We demonstrate the induction of directional flow by the synchronized switching of the gate potential with the channel axial potential. The advantage of this procedure is that potential gas formation by electrolysis at the electrodes that provide the axial electric field is suppressed at sufficiently large switching frequencies, while the direction and magnitude of the EOF can be maintained. Furthermore we will give an analysis of the time constants involved in the charging of the insulator, and thus the switching of the zeta potential, in order to predict the maximum operating frequency. For this purpose an equivalent electrical circuit is presented and analyzed. It is shown that in order to accurately describe the charging dynamics and pH dependency the traditionally used three capacitor model should be expanded with an element describing the buffer capacitance of the silica wall surface.

Simultaneous determination of amino acids and carbohydrates in culture media of Clostridium thermocellum by valve-switching ion chromatography.

PubMed

Fa, Yun; Yang, Haiyan; Ji, Chengshuai; Cui, He; Zhu, Xinshu; Du, Juan; Gao, Jun

2013-10-10

An improved method for the simultaneous determination of 20 amino acids and 7 carbohydrates using one-valve switching after injection, ion chromatography, and integrated pulsed amperometric detection is proposed. The resolution of the amino acids and carbohydrates in the cation trap column was investigated. In addition, parameters including flow liquid type, flow rate, concentration, and valve-switch timing were optimized. The method is time-saving, effective, and accurate for the simultaneous separation of amino acids and carbohydrates, with a mean correlation coefficient of >0.99 and repeatability of 0.5-4.6% for eight replicates. The method was successfully applied in the analysis of amino acids and carbohydrates in aseptic media and in extracellular culture media of three phenotypes of Clostridium thermocellum. Copyright © 2013 Elsevier B.V. All rights reserved.

Flow-switching device for comprehensive two-dimensional gas chromatography.

PubMed

Bueno, Pedro A; Seeley, John V

2004-02-20

A simple flow-switching device has been developed as a differential flow modulator for comprehensive two-dimensional gas chromatography (GC x GC). The device is assembled from tubing, four tee unions, and a solenoid valve. The solenoid valve is located outside the oven of the gas chromatograph and is not in the sample path. The modulation technique has no inherent temperature restrictions and passes 100% of the primary column effluent to the secondary column(s). Secondary peaks are produced with widths at half maximum less than 100 ms when operating in GC x 2GC mode with a 2.0 s modulation period. The efficacy of this approach is demonstrated through the analysis of a standard mixture of volatile organic compounds (VOCs) and diesel fuel.

Safety Assessment of TACOM’s Ride Motion Simulator

DTIC Science & Technology

1990-01-24

level (1300 to 1800 psi). 24 Step 16. Pressurize the system by moving the main pressure switch to "ON." Wait for the roll, pitch, and yaw error signals...the appropriate seat/shoulder/safety belts and harnesses. Carefully, help the test subject dismount. Step 41. Flip the main pressure switch on the...Dismount the test subject. Step 6. Move the main pressure switch to the "OFF" position. This will block any hydraulic flow to the system. Step 7. Move the

Product Descriptions: Database Software for Science. A MicroSIFT Quarterly Report.

ERIC Educational Resources Information Center

Batey, Anne; And Others

Specific programs and software resources are described in this report on database software for science instruction. Materials are reviewed in the categories of: (1) database management (reviewing AppleWorks, Bank Street School Filer, FileVision, Friendly Filer, MECC DataQuest: The Composer, Scholastic PFS:File, PFS:Report); (2) data files…

Coleman performs VO2 Max PFS Software Calibrations and Instrument Check

NASA Image and Video Library

2011-02-24

ISS026-E-029180 (24 Feb. 2011) --- NASA astronaut Catherine (Cady) Coleman, Expedition 26 flight engineer, performs VO2max portable Pulmonary Function System (PFS) software calibrations and instrument check while using the Cycle Ergometer with Vibration Isolation System (CEVIS) in the Destiny laboratory of the International Space Station.

Childhood CT scans and cancer risk: impact of predisposing factors for cancer on the risk estimates.

PubMed

Journy, N; Roué, T; Cardis, E; Le Pointe, H Ducou; Brisse, H; Chateil, J-F; Laurier, D; Bernier, M-O

2016-03-01

To investigate the role of cancer predisposing factors (PFs) on the associations between paediatric computed tomography (CT) scan exposures and subsequent risk of central nervous system (CNS) tumours and leukaemia. A cohort of children who underwent a CT scan in 2000-2010 in 23 French radiology departments was linked with the national childhood cancers registry and national vital status registry; information on PFs was retrieved through hospital discharge databases. In children without PF, hazard ratios of 1.07 (95% CI 0.99-1.10) for CNS tumours (15 cases) and 1.16 (95% CI 0.77-1.27) for leukaemia (12 cases) were estimated for each 10 mGy increment in CT x-rays organ doses. These estimates were similar to those obtained in the whole cohort. In children with PFs, no positive dose-risk association was observed, possibly related to earlier non-cancer mortality in this group. Our results suggest a modifying effect of PFs on CT-related cancer risks, but need to be confirmed by longer follow-up and other studies.

Perfluorinated surfactants (PFSs) in size-fractionated street dust in Tokyo.

PubMed

Murakami, Michio; Takada, Hideshige

2008-11-01

We investigated perfluorinated surfactants (PFSs) in size-fractionated street dust to identify their occurrence, contributions from traffic, and potential routes of entry into waters. Street dust was collected from residential areas and heavily trafficked areas in Tokyo and sorted into fine (<63 microm) and coarse fractions (63-2000 microm). Five PFS species were analyzed by liquid chromatography-tandem mass spectrometry: perfluorooctanesulfonate (PFOS), perfluorooctanoate (PFOA), perfluorononanoate (PFNA), perfluorodecanoate (PFDA), and perfluoroundecanoate (PFUA). In fine fractions, PFS contents were significantly higher in heavily trafficked street dust than in residential street dust, but in coarse fractions, no significant differences were observed. Additionally, in heavily trafficked areas, PFS contents were significantly higher in fine fractions than in coarse fractions, but in residential areas, no significant differences were observed. PFS compositions differed between size fractions, not locations, indicating differences in sources between size fractions. Fine particles from traffic contributed to PFSs in street dust. Street dust possibly acts as the origin of PFSs in street runoff and eventually enters waters. This is the first report of PFSs in street dust.

Food coloring agents and plant food supplements derived from Vitis vinifera: a new source of human exposure to ochratoxin A.

PubMed

Solfrizzo, Michele; Piemontese, Luca; Gambacorta, Lucia; Zivoli, Rosanna; Longobardi, Francesco

2015-04-08

Grape pomaces are increasingly being used as starting material in the industrial production of plant food supplements (PFS), food coloring, and tartrates, but they are at risk of ochratoxin A (OTA) contamination, a mycotoxin with nephrotoxic and carcinogenic effects. We analyzed 24 commercial PFS and 13 food coloring samples derived from Vitis vinifera, mainly pomaces, using a HPLC-FLD method for OTA determination. OTA was found in 75% of PFS samples and 69% of food coloring samples at levels of <1.16-20.23 μg/kg and <1.16-32.00 μg/kg, respectively. The four commercial leavening agents containing tartrates were found to be negative for OTA. All eight samples collected in two distilleries that use grape pomaces and wine lees to produce tartrates and other byproducts contained OTA at levels of <1.16-240.93 μg/kg. The high incidence of OTA contamination in PFS and food coloring agents derived from V. vinifera suggests that maximum permitted level(s) should be established for this mycotoxin in these products.

Delayed discounting and hedonic hunger in the prediction of lab-based eating behavior.

PubMed

Ely, Alice V; Howard, Janna; Lowe, Michael R

2015-12-01

Research suggests that characteristics identified in obese individuals, such as impulsive decision-making and hedonic hunger, may exist in nonobese populations. This study examined the independent and interactive effects of impulsive decision-making (measured via delay discounting, DD) and hedonic hunger (assessed with the Power of Food Scale, PFS) on food intake. Female participants (N=78) ate a self-determined amount of plain oatmeal, completed self-report measures and the delay discounting task, and participated in a sham taste test of palatable sweet and salty foods. Unexpectedly, PFS and DD scores interacted to predict consumption of the total amount of food consumed, and of oatmeal alone, but not of snack food alone. High-PFS participants consumed more when also high in DD, while low-PFS participants showed the opposite pattern of consumption. The findings identify variables that may increase propensity toward overconsumption and potential weight gain; future research is necessary to evaluate the utility of these constructs to predict increases in BMI over time. Copyright © 2015 Elsevier Ltd. All rights reserved.

Power of food moderates food craving, perceived control, and brain networks following a short-term post-absorptive state in older adults.

PubMed

Rejeski, W Jack; Burdette, Jonathan; Burns, Marley; Morgan, Ashley R; Hayasaka, Satoru; Norris, James; Williamson, Donald A; Laurienti, Paul J

2012-06-01

The Power of Food Scale (PFS) is a new measure that assesses the drive to consume highly palatable food in an obesogenic food environment. The data reported in this investigation evaluate whether the PFS moderates state cravings, control beliefs, and brain networks of older, obese adults following either a short-term post-absorptive state, in which participants were only allowed to consume water, or a short-term energy surfeit treatment condition, in which they consumed BOOST®. We found that the short-term post-absorptive condition, in which participants consumed water only, was associated with increases in state cravings for desired food, a reduction in participants' confidence related to the control of eating behavior, and shifts in brain networks that parallel what is observed with other addictive behaviors. Furthermore, individuals who scored high on the PFS were at an increased risk for experiencing these effects. Future research is needed to examine the eating behavior of persons who score high on the PFS and to develop interventions that directly target food cravings. Copyright © 2012 Elsevier Ltd. All rights reserved.

Motivational Impact of Palatable Food Correlates With Functional Brain Responses to Food Images in Adolescents.

PubMed

Jensen, Chad D; Duraccio, Kara M; Carbine, Kaylie A; Barnett, Kimberly A; Kirwan, C Brock

2017-06-01

To examine associations between motivational impact of palatable foods and neural activity in brain regions involved in inhibitory control among adolescents. Thirty-four adolescents aged 14-20 years underwent functional magnetic resonance imaging while viewing images of high- and low-energy foods. Participants completed the Power of Food Scale (PFS). Whole-brain analyses of variance tested for neural activation differences and correlations between brain activation and PFS scores were tested. We found an interaction between food type (high energy vs. low energy) and PFS scores in the right dorsolateral prefrontal cortex and right inferior parietal lobule. We also found that PFS scores correlated negatively with activation to high-energy foods in prefrontal cortical and parietal regions. These findings suggest that individuals with high motivation for high-energy foods also demonstrate lower neural activation in inhibition-related brain regions when viewing images of high-energy foods, indicating that they may have difficulty inhibiting consumption impulses. © The Author 2016. Published by Oxford University Press on behalf of the Society of Pediatric Psychology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com

Negative differential electrolyte resistance in a solid-state nanopore resulting from electroosmotic flow bistability.

PubMed

Luo, Long; Holden, Deric A; White, Henry S

2014-03-25

A solid-state nanopore separating two aqueous solutions containing different concentrations of KCl is demonstrated to exhibit negative differential resistance (NDR) when a constant pressure is applied across the nanopore. NDR refers to a decrease in electrical current when the voltage applied across the nanopore is increased. NDR results from the interdependence of solution flow (electroosmotic and pressure-engendered) with the distributions of K+ and Cl- within the nanopore. A switch from a high-conductivity state to a low-conductivity state occurs over a very narrow voltage window (<2 mV) that depends on the nanopore geometry, electrolyte concentration, and nanopore surface charge density. Finite element simulations based on a simultaneous solution of the Navier-Stokes, Poisson, and Nernst-Planck equations demonstrate that NDR results from a positive feedback mechanism between the ion distributions and electroosmotic flow, yielding a true bistability in fluid flow and electrical current at a critical applied voltage, i.e., the NDR "switching potential". Solution pH and Ca2+ were separately employed as chemical stimuli to investigate the dependence of the NDR on the surface charge density. The NDR switching potential is remarkably sensitive to the surface charge density, and thus to pH and the presence of Ca2+, suggesting possible applications in chemical sensing.

Evaluation of the Linde Flow Warning Device,

DTIC Science & Technology

1965-12-30

the cause of the failure. It was not possible to disassemble the pressure switch or to determine the cause of failure. The warning device was...simple means of causing an actuat ion of a pressure switch . The sensing device used in the apparatus proved to be too del icate for the operat ion to

Design and Test of Passively Operated Heat Switches for 0.2 to 15 K

NASA Technical Reports Server (NTRS)

DiPirro, M. J.; Shirron, P. J.; Canavan, E. R.; Francis, J. J.; Tuttle, J. G.

2003-01-01

Heat switches have many uses in cryogenics, from regulating heat flow between refrigeration stages to thermally isolating components once they have cooled to low temperature. Among the techniques one can use for thermal switching, the gas-gap technique has the advantages of wide operating temperature range, high switching ratio, and no moving parts. The traditional gas-gap switch uses copper conductors separated by a small gap and an external getter. The switch is activated by heating and cooling the getter by moving gas into and out of the gap, turning the switch on and off. We have designed, built and tested heat switches that use an internal getter to passively turn off at temperatures between 0.2 and 15 K. The getter is thermally anchored to one side of the switch, and when that side of the switch cools through a transition region, gas adsorbs onto the getter and the switch turns off. The challenges are to make the transition region very narrow and tailorable to a wide range of applications, and to achieve high gas conductance when the switch is on. We have made switches using He-3, He-4, hydrogen, and neon gas, and have used charcoal and various metal substrates as getters. Switching ratios range from 1000 to over 10,000. Design and performance of these switches will be discussed in detail.

Design and endpoints of clinical and translational trials in advanced colorectal cancer. a proposal from GROUP Español Multidisciplinar en Cancer Digestivo (GEMCAD).

PubMed

Carrera, Gemma; Garcia-Albeniz, Xabier; Ayuso, Juan Ramón; Aparicio, Jorge; Castells, Antoni; Codony-Servat, Jordi; Feliu, Jaime; Fuster, David; Gallego, Rosa; Pagés, Mario; Torres, Ferran; Maurel, Joan

2011-05-01

Meta-analytic reviews of Randomized Clinical Trials (RCT) have reached contradictory conclusions regarding the benefit of medical interventions in Advanced Colorectal Cancer (ACRC). Surrogate markers of survival benefit, such as response rate (RR) and progression free-survival (PFS) often show contradictory and highly variable correlations. These contradictions can be due to differences in 1) the studies analysed (sources), 2) the quality of clinical trials (intrinsic bias in the design, biased data analysis, heterogeneous PFS definitions) and 3) the second-line strategies between arms. PFS is a more vulnerable target than overall survival (OS), but the latter can also be affected by different biases and additional medical interventions such as secondary resection of metastases or second-line therapies. Therefore the correlation between PFS and survival must be clearly stated if PFS is to be considered as a primary endpoint. Of the differences between studies, only the quality of clinical trials can be improved by a deeper knowledge of both the area of study (i.e. colorectal cancer) and the methodology needed (i.e., clinical and translational trials). The aim of this manuscript is to offer the basic resources to develop experimental trials in ACRC. To this end, techniques for diagnosis and for response assessment are discussed, prognostic factors and treatment standards are critically exposed, and notes about how to design useful translational studies are provided.

Properties of hail storms over China and the United States from the Tropical Rainfall Measuring Mission

PubMed Central

Ni, Xiang; Liu, Chuntao; Zhang, Qinghong; Cecil, Daniel J.

2018-01-01

A 16-yr record of hail reports over the south U.S. and from weather stations in China are collocated with Precipitation Features (PF) derived from the Tropical Rainfall Measuring Mission (TRMM) radar and passive microwave observations. Differences in the way hail is reported in the two nations make it difficult to draw meaningful conclusions about storm frequency. But taking the two together yields a wide spectrum of hail sizes, suitable for comparing with remote sensing measurements. While U.S. hail reports are dominated by cases with hail size greater than 19 mm, hail reports in China mostly include diameters of 1–10 mm and mostly occur over the Tibetan Plateau. The fraction of PFs collocated with hail reports (hail PFs) reaches 3% in the plains of the U.S. In China, the fraction is higher in high elevation regions than low elevation regions. Hail PFs (as reported in the U.S.) show lower brightness temperatures, higher lightning flash rates, stronger maximum reflectivity, and higher echo tops than those with smaller hail, as reported in China. The average near surface maximum reflectivity of hail PFs at high elevations (≥ 2000 m) in China is about 5 dB smaller than those at low elevations. Larger hail is reported with PFs having stronger maximum reflectivity above 6 km, though the median of maximum reflectivity values at levels below 5 km is similar among the storms with large and small hail sizes. PMID:29377045

Outcome of Patients With Pilocytic Astrocytoma and Leptomeningeal Dissemination

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mazloom, Ali; Hodges, Joseph C.; Teh, Bin S.

2012-10-01

Purpose: To determine the patient, tumor, and treatment characteristics of patients with pilocytic astrocytoma (PA) and leptomeningeal dissemination (LMD). Methods and Materials: A PubMed search of English-language studies pertaining to PA with LMD was performed using a combination of keywords that included juvenile pilocytic astrocytoma, low-grade astrocytoma, low-grade glioma, leptomeningeal dissemination, neuraxis spread, and radiotherapy. We found 26 studies with 58 patients between 1976 and 2005 that met these criteria. Results: The median survival for PA patients with LMD was 65 months. The 1-, 2-, and 5-year overall survival (OS) rate after the diagnosis of LMD was 81.1%, 75.7%, andmore » 55.5%. The 1-, 2-, and 5-year progression-free survival (PFS) rate after the diagnosis of LMD was 69.3%, 66.5%, and 34.6%, respectively. Age, gender, primary site location, timing of LMD presentation (synchronous vs. metachronous), and LMD location did not significantly influence OS or PFS. No statistically significant difference was found in OS or PFS between the chemotherapy and radiotherapy groups. Likewise, no difference was found in OS or PFS according to the use of craniospinal irradiation vs. less extensive RT fields. Conclusions: Approximately one-half of PA patients were alive 5 years after the diagnosis of LMD. Both chemotherapy and radiotherapy have efficacy against LMD. Although the use of craniospinal irradiation did not have an effect on PFS, the patient numbers were small and a larger number treated with craniospinal irradiation is needed to determine its efficacy.« less

Glossiness and perishable food quality: visual freshness judgment of fish eyes based on luminance distribution.

PubMed

Murakoshi, Takuma; Masuda, Tomohiro; Utsumi, Ken; Tsubota, Kazuo; Wada, Yuji

2013-01-01

Previous studies have reported the effects of statistics of luminance distribution on visual freshness perception using pictures which included the degradation process of food samples. However, these studies did not examine the effect of individual differences between the same kinds of food. Here we elucidate whether luminance distribution would continue to have a significant effect on visual freshness perception even if visual stimuli included individual differences in addition to the degradation process of foods. We took pictures of the degradation of three fishes over 3.29 hours in a controlled environment, then cropped square patches of their eyes from the original images as visual stimuli. Eleven participants performed paired comparison tests judging the visual freshness of the fish eyes at three points of degradation. Perceived freshness scores (PFS) were calculated using the Bradley-Terry Model for each image. The ANOVA revealed that the PFS for each fish decreased as the degradation time increased; however, the differences in the PFS between individual fish was larger for the shorter degradation time, and smaller for the longer degradation time. A multiple linear regression analysis was conducted in order to determine the relative importance of the statistics of luminance distribution of the stimulus images in predicting PFS. The results show that standard deviation and skewness in luminance distribution have a significant influence on PFS. These results show that even if foodstuffs contain individual differences, visual freshness perception and changes in luminance distribution correlate with degradation time.

Nomograms Predicting Platinum Sensitivity, Progression-Free Survival, and Overall Survival Using Pretreatment Complete Blood Cell Counts in Epithelial Ovarian Cancer

PubMed Central

Paik, E Sun; Sohn, Insuk; Baek, Sun-Young; Shim, Minhee; Choi, Hyun Jin; Kim, Tae-Joong; Choi, Chel Hun; Lee, Jeong-Won; Kim, Byoung-Gie; Lee, Yoo-Young; Bae, Duk-Soo

2017-01-01

Purpose This study was conducted to evaluate the prognostic significance of pre-treatment complete blood cell count (CBC), including white blood cell (WBC) differential, in epithelial ovarian cancer (EOC) patients with primary debulking surgery (PDS) and to develop nomograms for platinum sensitivity, progression-free survival (PFS), and overall survival (OS). Materials and Methods We retrospectively reviewed the records of 757 patients with EOC whose primary treatment consisted of surgical debulking and chemotherapy at Samsung Medical Center from 2002 to 2012. We subsequently created nomograms for platinum sensitivity, 3-year PFS, and 5-year OS as prediction models for prognostic variables including age, stage, grade, cancer antigen 125 level, residual disease after PDS, and pre-treatment WBC differential counts. The models were then validated by 10-fold cross-validation (CV). Results In addition to stage and residual disease after PDS, which are known predictors, lymphocyte and monocyte count were found to be significant prognostic factors for platinum-sensitivity, platelet count for PFS, and neutrophil count for OS on multivariate analysis. The area under the curves of platinum sensitivity, 3-year PFS, and 5-year OS calculated by the 10-fold CV procedure were 0.7405, 0.8159, and 0.815, respectively. Conclusion Prognostic factors including pre-treatment CBC were used to develop nomograms for platinum sensitivity, 3-year PFS, and 5-year OS of patients with EOC. These nomograms can be used to better estimate individual outcomes. PMID:27669704

Nomograms Predicting Platinum Sensitivity, Progression-Free Survival, and Overall Survival Using Pretreatment Complete Blood Cell Counts in Epithelial Ovarian Cancer.

PubMed

Paik, E Sun; Sohn, Insuk; Baek, Sun-Young; Shim, Minhee; Choi, Hyun Jin; Kim, Tae-Joong; Choi, Chel Hun; Lee, Jeong-Won; Kim, Byoung-Gie; Lee, Yoo-Young; Bae, Duk-Soo

2017-07-01

This study was conducted to evaluate the prognostic significance of pre-treatment complete blood cell count (CBC), including white blood cell (WBC) differential, in epithelial ovarian cancer (EOC) patients with primary debulking surgery (PDS) and to develop nomograms for platinum sensitivity, progression-free survival (PFS), and overall survival (OS). We retrospectively reviewed the records of 757 patients with EOC whose primary treatment consisted of surgical debulking and chemotherapy at Samsung Medical Center from 2002 to 2012. We subsequently created nomograms for platinum sensitivity, 3-year PFS, and 5-year OS as prediction models for prognostic variables including age, stage, grade, cancer antigen 125 level, residual disease after PDS, and pre-treatment WBC differential counts. The models were then validated by 10-fold cross-validation (CV). In addition to stage and residual disease after PDS, which are known predictors, lymphocyte and monocyte count were found to be significant prognostic factors for platinum-sensitivity, platelet count for PFS, and neutrophil count for OS on multivariate analysis. The area under the curves of platinum sensitivity, 3-year PFS, and 5-year OS calculated by the 10-fold CV procedure were 0.7405, 0.8159, and 0.815, respectively. Prognostic factors including pre-treatment CBC were used to develop nomograms for platinum sensitivity, 3-year PFS, and 5-year OS of patients with EOC. These nomograms can be used to better estimate individual outcomes.

Leukocytosis and neutrophilia predict outcome in locally advanced esophageal cancer treated with definitive chemoradiation

PubMed Central

Schernberg, Antoine; Moureau-Zabotto, Laurence; Del Campo, Eleonor Rivin; Escande, Alexandre; Ducreux, Michel; Nguyen, France; Goere, Diane; Chargari, Cyrus; Deutsch, Eric

2017-01-01

Purpose To investigate the prognostic value of leukocyte and neutrophil count as biomarkers in patients with locally advanced esophageal squamous cell carcinoma (SCC) undergoing exclusive chemoradiation. Results A total of 126 patients were identified. Respectively, 33% and 35% displayed baseline leukocytosis and neutrophilia. Estimated 3-year OS and PFS from chemoradiation completion were 31% and 25%, respectively. In univariate analysis, both leukocytosis and neutrophilia were associated with worse OS, PFS, and LRC (p < 0.01). In multivariate analysis, leukocytosis remained an independent risk factor associated with poorer OS, PFS and LRC (p < 0.05), independently from tumor stage and length, with higher prognostic value for OS compared with patients’ performance status (PS). Materials and Methods Bi-institutional clinical records from consecutive non-operable patients treated between 2003 and 2015 with definitive chemoradiation for locally advanced esophageal carcinoma were reviewed. Leukocytosis and neutrophilia were defined as a leukocyte or neutrophil count over 10 G/L and 7 G/L, respectively. These parameters were studied for their potential correlation with overall survival (OS), progression free survival (PFS), locoregional control (LRC) and distant metastases control (DMC). Conclusions Leukocytosis and neutrophilia were independent prognostic factors of poor OS, PFS, and LRC in this bi-institutional series of locally advanced esophageal SCC treated with definitive chemoradiation. Although prospective confirmation is warranted, it is suggested that the leukocyte and neutrophil count parameters might be clinically relevant biomarkers to be considered for further clinical investigations. PMID:28086222

Botanical species being used for manufacturing plant food supplements (PFS) and related products in the EU member states and selected third countries.

PubMed

Franz, Chlodwig; Chizzola, Remigius; Novak, Johannes; Sponza, Silvia

2011-12-01

A great wealth of plants and plant derived preparations are used in the intention to supplement the basic nutrition in order to sustain and promote health. They may be used directly or consumed as manufactured plant food supplements (PFS) in dosed form. The use of these plants may already have a long tradition as fruit, vegetable or (folk) medicinal plants. Due to globalisation, more and more plants originating from all over the world are now offered and marketed in European countries, including species from China, South Africa and the American continent. For reasons of security, EU wide lists of plants accepted or prohibited to be used in food supplements are in elaboration. A crucial point is the correct identification of the plant material. The identity can be assessed by morphological, chemical and DNA specific methods. The active substances usable in PFS are secondary plant products that are often characteristic for certain plant groups (taxa), species or plant parts. They comprise not only polyphenols, essential oils, carotenoids and phytosterols, but also glucosinolates or saponins. The quality of the plant material used for PFS depends on a variety of factors, including the natural phytochemical, intraspecific variation with the occurrence of chemotypes, the ontogenetic variation, the considered plant parts and environmental influences during plant growth. In the production of the raw materials for PFS international standards (good agricultural practice, fair trade) should be applied.

BIOMECHANICAL DIFFERENCES IN BRAZILIAN JIU-JITSU ATHLETES: THE ROLE OF COMBAT STYLE.

PubMed

Lima, Pedro Olavo de Paula; Lima, Alane Almeida; Coelho, Anita Camila Sampaio; Lima, Yuri Lopes; Almeida, Gabriel Peixoto Leão; Bezerra, Márcio Almeida; de Oliveira, Rodrigo Ribeiro

2017-02-01

Brazilian Jiu-Jitsu (BJJ) athletes can be divided into two combat styles: pass fighters (PFs) and guard fighters (GFs). Flexibility of the posterior chain muscles is highly necessary in these athletes, especially in GFs. On the other hand, isometric strength of the trunk extensors is required in PFs. Handgrip strength is important in holding the kimono of the opponent, and symmetrical lower-limb strength is important for the prevention of injuries due to the overload caused by training. The aim of this study was to compare the biomechanical profiles of BJJ athletes with different combat styles using the following outcome measures: flexibility, trunk extensor isometric endurance, postural balance, handgrip isometric endurance and lower-limb muscle strength. A cross-sectional study was conducted using 19 GFs and 19 PFs. The sit-and-reach test was used to evaluate the flexibility of the posterior chain muscles. The Biodex Balance System® was used to evaluate balance. A handgrip dynamometer and a dorsal dynamometer were used to evaluate handgrip and trunk extensor endurance, respectively. Quadriceps and hamstring strength were evaluated with an isokinetic dynamometer at 60 °/s. No differences were observed between groups in terms of flexibility, balance, handgrip isometric endurance or quadriceps and hamstring strength; however, PFs (81.33) showed more isometric trunk extension endurance than GFs (68.85) ( p = 0.02). Both groups had low values for hamstring/quadriceps ratio. No significant biomechanical differences were observed between PFs and GFs. 2b.

Light-weight DC to very high voltage DC converter

DOEpatents

Druce, Robert L.; Kirbie, Hugh C.; Newton, Mark A.

1998-01-01

A DC-DC converter capable of generating outputs of 100 KV without a transformer comprises a silicon opening switch (SOS) diode connected to allow a charging current from a capacitor to flow into an inductor. When a specified amount of charge has flowed through the SOS diode, it opens up abruptly; and the consequential collapsing field of the inductor causes a voltage and current reversal that is steered into a load capacitor by an output diode. A switch across the series combination of the capacitor, inductor, and SOS diode closes to periodically reset the SOS diode by inducing a forward-biased current.

Fault-tolerant power distribution system

NASA Technical Reports Server (NTRS)

Volp, Jeffrey A. (Inventor)

1987-01-01

A fault-tolerant power distribution system which includes a plurality of power sources and a plurality of nodes responsive thereto for supplying power to one or more loads associated with each node. Each node includes a plurality of switching circuits, each of which preferably uses a power field effect transistor which provides a diode operation when power is first applied to the nodes and which thereafter provides bi-directional current flow through the switching circuit in a manner such that a low voltage drop is produced in each direction. Each switching circuit includes circuitry for disabling the power field effect transistor when the current in the switching circuit exceeds a preselected value.

SPARK GAP SWITCH

DOEpatents

Neal, R.B.

1957-12-17

An improved triggered spark gap switch is described, capable of precisely controllable firing time while switching very large amounts of power. The invention in general comprises three electrodes adjustably spaced and adapted to have a large potential impressed between the outer electrodes. The central electrode includes two separate elements electrically connected togetaer and spaced apart to define a pair of spark gaps between the end electrodes. Means are provided to cause the gas flow in the switch to pass towards the central electrode, through a passage in each separate element, and out an exit disposed between the two separate central electrode elements in order to withdraw ions from the spark gap.

Traffic protection in MPLS networks using an off-line flow optimization model

NASA Astrophysics Data System (ADS)

Krzesinski, Anthony E.; Muller, Karen E.

2002-07-01

MPLS-based recovery is intended to effect rapid and complete restoration of traffic affected by a fault in an MPLS network. Two MPLS-based recovery models have been proposed: IP re-routing which establishes recovery paths on demand, and protection switching which works with pre-established recovery paths. IP re-routing is robust and frugal since no resources are pre-committed but is inherently slower than protection switching which is intended to offer high reliability to premium services where fault recovery takes place at the 100 ms time scale. We present a model of protection switching in MPLS networks. A variant of the flow deviation method is used to find and capacitate a set of optimal label switched paths. The traffic is routed over a set of working LSPs. Global repair is implemented by reserving a set of pre-established recovery LSPs. An analytic model is used to evaluate the MPLS-based recovery mechanisms in response to bi-directional link failures. A simulation model is used to evaluate the MPLS recovery cycle in terms of the time needed to restore the traffic after a uni-directional link failure. The models are applied to evaluate the effectiveness of protection switching in networks consisting of between 20 and 100 nodes.

Surface switching statistics of rotating fluid: Disk-rim gap effects

NASA Astrophysics Data System (ADS)

Tasaka, Yuji; Iima, Makoto

2017-04-01

We examined the influence of internal noise on the irregular switching of the shape of the free surface of fluids in an open cylindrical vessel driven by a bottom disk rotating at constant speed [Suzuki, Iima, and Hayase, Phys. Fluids 18, 101701 (2006), 10.1063/1.2359740]. A slight increase in the disk-rim gap (less than 3% of the disk radius) was established experimentally to cause significant changes in this system, specifically, frequent appearance of the surface descending event connecting a nonaxisymmetric shape in strong mixing flow (turbulent flow) and an axisymmetric shape in laminar flow, as well as a shift in critical Reynolds number that define the characteristic states. The physical mechanism underlying the change is analyzed in terms of flow characteristics in the disk-rim gap, which acts as a noise source, and a mathematical model established from measurements of the surface height fluctuations with noise term.

Presence of pleural effusion is associated with a poor prognosis in patients with epidermal growth factor receptor-mutated lung cancer receiving tyrosine kinase inhibitors as first-line treatment.

PubMed

Wang, Tso-Fu; Chu, Sung-Chao; Lee, Jen-Jyh; Yang, Gee-Gwo; Huang, Wei-Han; Chang, En-Ting; Low, Tissot; Wu, Yi-Feng; Kao, Ruey-Ho; Lin, Chih-Bin

2017-08-01

This study was conducted to evaluate the effect of clinical factors on the treatment outcomes of lung cancer patients with active epidermal growth factor receptor (EGFR) mutations treated by first-line tyrosine kinase inhibitors (TKIs). Patients of stage IIIb or IV lung adenocarcinoma harboring mutated EGFR were enrolled between March 2010 and June 2014 and followed up until December 2015. The effects of various clinical features, such as age, sex, smoking history, EGFR mutation types, TKIs used, presence of pleural effusion, metastatic sites on progression-free survival (PFS) and overall survival (OS), were analyzed retrospectively. A total of 104 patients were included in this study. Patients with pleural effusion at initial diagnosis had significantly shorter PFS and OS than those without pleural effusion (median PFS: 8.2 months vs 15.3 months, P = 0.0004; median OS: 16.3 months vs 28.2 months, P = 0.0003). Univariate analysis revealed that being male or a smoker was associated with short PFS, whereas smoking history, bony metastasis and malignant pleural effusion were associated with poor OS. Stepwise multivariate Cox regression analysis showed that the presence of pleural effusion and different TKI use were independent prognostic factors for PFS [hazard ratio [HR] = 2.50 (95% confidence interval [CI], 1.53-4.10), P = 0.0003 and HR = 0.55 (95% CI, 0.31-0.97), P = 0.0396, respectively], whereas the presence of pleural effusion and liver metastasis were associated with poor OS [HR = 2.79 (95% CI: 1.46-5.30), P = 0.0018 and HR = 2.12 (95% CI, 1.02-4.40), P = 0.0440, respectively]. The presence of pleural effusion predicts poor PFS and OS in lung adenocarcinoma patients receiving TKIs as the first-line treatment. Additional studies are warranted to elucidate the underlying mechanisms and determine novel strategies for improving the outcome of these patients. © 2017 John Wiley & Sons Australia, Ltd.

Individual patient data analysis of progression-free survival versus overall survival as a first-line end point for metastatic colorectal cancer in modern randomized trials: findings from the analysis and research in cancers of the digestive system database.

PubMed

Shi, Qian; de Gramont, Aimery; Grothey, Axel; Zalcberg, John; Chibaudel, Benoist; Schmoll, Hans-Joachim; Seymour, Matthew T; Adams, Richard; Saltz, Leonard; Goldberg, Richard M; Punt, Cornelis J A; Douillard, Jean-Yves; Hoff, Paulo M; Hecht, Joel Randolph; Hurwitz, Herbert; Díaz-Rubio, Eduardo; Porschen, Rainer; Tebbutt, Niall C; Fuchs, Charles; Souglakos, John; Falcone, Alfredo; Tournigand, Christophe; Kabbinavar, Fairooz F; Heinemann, Volker; Van Cutsem, Eric; Bokemeyer, Carsten; Buyse, Marc; Sargent, Daniel J

2015-01-01

Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination. Individual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti-epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R(2) statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models. Forty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R(2), 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy. In modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents. © 2014 by American Society of Clinical Oncology.

A randomized phase 2 study exploring the role of bevacizumab and a chemotherapy-free approach in HER2-positive metastatic breast cancer: The HAT study (BOOG 2008-2003), a Dutch Breast Cancer Research Group trial.

PubMed

Drooger, Jan C; van Tinteren, Harm; de Groot, Steffen M; Ten Tije, Albert J; de Graaf, Hiltje; Portielje, Johanneke E A; Jager, Agnes; Honkoop, Aafke; Linn, Sabine C; Kroep, Judith R; Erdkamp, Frans L G; Hamberg, Paul; Imholz, Alex L T; van Rossum-Schornagel, Quirine C; Heijns, Joan B; van Leeuwen-Stok, A Elise; Sleijfer, Stefan

2016-10-01

To explore the role of bevacizumab and a chemotherapy-free approach, the authors evaluated the combination of bevacizumab, trastuzumab, and paclitaxel (HAT) and the regimen of trastuzumab and bevacizumab (HA) with the addition of paclitaxel after progression (HA-HAT) as first-line treatment for patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. In a noncomparative phase 2 trial, patients were randomized between HAT and HA-HAT. The primary endpoint was the progression-free rate at 1 year (1-year PFR). In the HA-HAT group, progression-free survival (PFS) was separately established for HA (PFS1) and HAT (PFS2). Eighty-four patients received HAT (n = 39) or HA-HAT (n = 45). The 1-year PFR was 74.4% (95% confidence interval [CI], 61.8%-89.4%) and 62.2% (95% CI, 49.6%-89.4%) in the HAT and HA-HAT arms, respectively. The median PFS was 19.8 months (95% CI, 14.9-25.6 months) in the HAT arm and 19.6 months (95% CI, 12.0-32.0 months) in the HA-HAT arm. In the HA-HAT arm, the median PFS1 was 10.4 months (95% CI, 6.2-15.0 months), and the median PFS2 was 8.2 months (95% CI, 7.0-12.6 months). The number and severity of adverse events were comparable between the arms. Both HAT and HA-HAT have promising activity in patients with HER2-positive metastatic breast cancer. In particular, starting with only targeted agents and delaying chemotherapy is worth further exploration. Cancer 2016;122:2961-2970. © 2016 American Cancer Society. © 2016 American Cancer Society.

Neutrophil to lymphocyte ratio (NLR) improves the risk assessment of ISS staging in newly diagnosed MM patients treated upfront with novel agents.

PubMed

Romano, A; Parrinello, N L; Consoli, M L; Marchionni, L; Forte, S; Conticello, C; Pompa, A; Corso, A; Milone, G; Di Raimondo, F; Borrello, I

2015-11-01

Recent reports identify the ratio between absolute neutrophil count (ANC) and absolute lymphocyte count (ALC), called neutrophil to lymphocyte ratio (NLR), as a predictor of progression-free survival (PFS) and overall survival (OS) in various malignancies. We retrospectively examined the NLR in a cohort of 309 newly diagnosed multiple myeloma (MM) patients treated upfront with novel agents. NLR was calculated using data obtained from the complete blood count (CBC) at diagnosis and subsequently correlated with PFS and OS. The median NLR was 1.9 (range 0.4-15.9). Higher NLR was independent of international staging system (ISS) stage, plasma cell infiltration or cytogenetics. The 5-year PFS and OS estimates were, respectively, 18.2 and 36.4 % for patients with NLR ≥ 2 versus 25.5 and 66.6 % in patients with NLR < 2. Among younger patients (age <65 years, N = 179), NLR ≥ 2 had a negative prognostic impact on both PFS and OS, in all ISS stages. By combining ISS stage and NLR in a model limited to young patients, we found that 19 % of the patients were classified as very low risk, 70 % standard risk and 11 % very high risk. The 5-year estimates were 39.3, 19.4 and 10.9 % for PFS and 95.8, 50.9 and 23.6 % for OS for very low, standard-risk and very high-risk groups. We found NLR to be a predictor of PFS and OS in MM patients treated upfront with novel agents. NLR can be combined with ISS staging system to identify patients with dismal outcome. However, larger cohorts and prospective studies are needed to use NLR as additional parameter to personalise MM therapy in the era of novel agents.

Coronary heart disease risk factors in adult premenopausal white women with polycystic ovary syndrome compared with a healthy female population.

PubMed

Glueck, Charles J; Morrison, John A; Goldenberg, Naila; Wang, Ping

2009-05-01

Our specific aim was to determine whether coronary heart disease (CHD) risk factors in polycystic ovary syndrome (PCOS) patients were independent of their higher body mass index (BMI) and centripetal obesity. In adult, premenopausal, white women, CHD risk factors were compared between 488 patients with well-defined PCOS and 351 healthy free-living population controls from the Princeton Follow-up Study (PFS). After excluding women with irregular menses (putative PCOS phenotypes), comparisons were also made between the 261 PFS women with a history of regular menses and the 488 women with PCOS. Fasting lipids, insulin, glucose, homeostasis model assessment of insulin resistance (HOMA-IR), HOMA insulin secretion, blood pressure, BMI, and waist circumference were measured. Compared with both the full cohort of 351 PFS women and the subgroup of 261 PFS women with regular menses, women with PCOS had higher BMI, waist circumference, total and low-density lipoprotein cholesterol, triglyceride, systolic blood pressure, diastolic blood pressure, insulin, glucose, and HOMA-IR (all Ps < or = .005). After adjusting for age and BMI, women with PCOS, compared with the 351 and 261 PFS women, had lower high-density lipoprotein cholesterol (P < .0001, .0008) and higher systolic blood pressure (P = .0002, < .0001), insulin (P = .017, .039), HOMA-IR (P = .013, .032), and HOMA insulin secretion (P = .022, .037). The small subgroup of PCOS women with normal BMI (<25 kg/m(2)) (36/488, 7%) also had higher age-adjusted insulin, glucose, and HOMA-IR (all Ps < .005) than the subgroup of PFS women with BMI less than 25 kg/m(2) (123/261, 47%). Increased CHD risk factors and high HOMA-IR in PCOS cannot be exclusively attributed to their preponderant centripetal obesity. Identification of women with clinical features of PCOS should alert the clinician to potentially increased risk for CHD and prompt CHD risk factor testing.

A systematic review and meta-analysis of individual patient data on the impact of the BIM deletion polymorphism on treatment outcomes in epidermal growth factor receptor mutant lung cancer.

PubMed

Soh, Sheila X; Siddiqui, Fahad J; Allen, John C; Kim, Go Woon; Lee, Jae Cheol; Yatabe, Yasushi; Soda, Manabu; Mano, Hiroyuki; Soo, Ross A; Chin, Tan-Min; Ebi, Hiromichi; Yano, Seiji; Matsuo, Keitaro; Niu, Xiaomin; Lu, Shun; Isobe, Kazutoshi; Lee, Jih-Hsiang; Yang, James C; Zhao, Mingchuan; Zhou, Caicun; Lee, June-Koo; Lee, Se-Hoon; Lee, Ji Yun; Ahn, Myung-Ju; Tan, Tira J; Tan, Daniel S; Tan, Eng-Huat; Ong, S Tiong; Lim, Wan-Teck

2017-06-20

A germline deletion in the BIM (BCL2L11) gene has been shown to impair the apoptotic response to tyrosine kinase inhibitors (TKIs) in vitro but its association with poor outcomes in TKI-treated non-small cell lung cancer (NSCLC) patients remains unclear. We conducted a systematic review and meta-analysis on both aggregate and individual patient data to address this issue. In an aggregate data meta-analysis (n = 1429), the BIM deletion was associated with inferior PFS (HR = 1.51, 95%CI = 1.06-2.13, P = 0.02). Using individual patient data (n = 1200), we found a significant interaction between the deletion and ethnicity. Amongst non-Koreans, the deletion was an independent predictor of shorter PFS (Chinese: HR = 1.607, 95%CI = 1.251-2.065, P = 0.0002; Japanese: HR = 2.636, 95%CI = 1.603-4.335, P = 0.0001), and OS (HR = 1.457, 95% CI = 1.063-1.997, P = 0.019). In Kaplan-Meier analyses, the BIM deletion was associated with shorter survival in non-Koreans (PFS: 8.0 months v 11.1 months, P < 0.0005; OS: 25.7 v 30.0 months, P = 0.042). In Koreans, the BIM deletion was not predictive of PFS or OS. 10 published and 3 unpublished studies that reported survival outcomes in NSCLC patients stratified according to BIM deletion were identified from PubMed and Embase. Summary risk estimates were calculated from aggregate patient data using a random-effects model. For individual patient data, Kaplan-Meier analyses were supported by multivariate Cox regression to estimate hazard ratios (HRs) for PFS and OS. In selected populations, the BIM deletion is a significant predictor of shorter PFS and OS on EGFR-TKIs. Further studies to determine its effect on response to other BIM-dependent therapeutic agents are needed, so that alternative treatment strategies may be devised.

Individual Patient Data Analysis of Progression-Free Survival Versus Overall Survival As a First-Line End Point for Metastatic Colorectal Cancer in Modern Randomized Trials: Findings From the Analysis and Research in Cancers of the Digestive System Database

PubMed Central

Shi, Qian; de Gramont, Aimery; Grothey, Axel; Zalcberg, John; Chibaudel, Benoist; Schmoll, Hans-Joachim; Seymour, Matthew T.; Adams, Richard; Saltz, Leonard; Goldberg, Richard M.; Punt, Cornelis J.A.; Douillard, Jean-Yves; Hoff, Paulo M.; Hecht, Joel Randolph; Hurwitz, Herbert; Díaz-Rubio, Eduardo; Porschen, Rainer; Tebbutt, Niall C.; Fuchs, Charles; Souglakos, John; Falcone, Alfredo; Tournigand, Christophe; Kabbinavar, Fairooz F.; Heinemann, Volker; Van Cutsem, Eric; Bokemeyer, Carsten; Buyse, Marc; Sargent, Daniel J.

2015-01-01

Purpose Progression-free survival (PFS) has previously been established as a surrogate for overall survival (OS) for first-line metastatic colorectal cancer (mCRC). Because mCRC treatment has advanced in the last decade with extended OS, this surrogacy requires re-examination. Methods Individual patient data from 16,762 patients were available from 22 first-line mCRC studies conducted from 1997 to 2006; 12 of those studies tested antiangiogenic and/or anti–epidermal growth factor receptor agents. The relationship between PFS (first event of progression or death) and OS was evaluated by using R2 statistics (the closer the value is to 1, the stronger the correlation) from weighted least squares regression of trial-specific hazard ratios estimated by using Cox and Copula models. Results Forty-four percent of patients received a regimen that included biologic agents. Median first-line PFS was 8.3 months, and median OS was 18.2 months. The correlation between PFS and OS was modest (R2, 0.45 to 0.69). Analyses limited to trials that tested treatments with biologic agents, nonstrategy trials, or superiority trials did not improve surrogacy. Conclusion In modern mCRC trials, in which survival after the first progression exceeds time to first progression, a positive but modest correlation was observed between OS and PFS at both the patient and trial levels. This finding demonstrates the substantial variability in OS introduced by the number of lines of therapy and types of effective subsequent treatments and the associated challenge to the use of OS as an end point to assess the benefit attributable to a single line of therapy. PFS remains an appropriate primary end point for first-line mCRC trials to detect the direct treatment effect of new agents. PMID:25385741

A comparative analysis of prognostic factor models for follicular lymphoma based on a phase III trial of CHOP-rituximab versus CHOP + 131iodine--tositumomab.

PubMed

Press, Oliver W; Unger, Joseph M; Rimsza, Lisa M; Friedberg, Jonathan W; LeBlanc, Michael; Czuczman, Myron S; Kaminski, Mark; Braziel, Rita M; Spier, Catherine; Gopal, Ajay K; Maloney, David G; Cheson, Bruce D; Dakhil, Shaker R; Miller, Thomas P; Fisher, Richard I

2013-12-01

There is currently no consensus on optimal frontline therapy for patients with follicular lymphoma. We analyzed a phase III randomized intergroup trial comparing six cycles of CHOP-R (cyclophosphamide-Adriamycin-vincristine-prednisone (Oncovin)-rituximab) with six cycles of CHOP followed by iodine-131 tositumomab radioimmunotherapy (RIT) to assess whether any subsets benefited more from one treatment or the other, and to compare three prognostic models. We conducted univariate and multivariate Cox regression analyses of 532 patients enrolled on this trial and compared the prognostic value of the FLIPI (follicular lymphoma international prognostic index), FLIPI2, and LDH + β2M (lactate dehydrogenase + β2-microglobulin) models. Outcomes were excellent, but not statistically different between the two study arms [5-year progression-free survival (PFS) of 60% with CHOP-R and 66% with CHOP-RIT (P = 0.11); 5-year overall survival (OS) of 92% with CHOP-R and 86% with CHOP-RIT (P = 0.08); overall response rate of 84% for both arms]. The only factor found to potentially predict the impact of treatment was serum β2M; among patients with normal β2M, CHOP-RIT patients had better PFS compared with CHOP-R patients, whereas among patients with high serum β2M, PFS by arm was similar (interaction P value = 0.02). All three prognostic models (FLIPI, FLIPI2, and LDH + β2M) predicted both PFS and OS well, though the LDH + β2M model is easiest to apply and identified an especially poor risk subset. In an exploratory analysis using the latter model, there was a statistically significant trend suggesting that low-risk patients had superior observed PFS if treated with CHOP-RIT, whereas high-risk patients had a better PFS with CHOP-R. ©2013 AACR.

Prespecified candidate biomarkers identify follicular lymphoma patients who achieved longer progression-free survival with bortezomib-rituximab versus rituximab.

PubMed

Coiffier, Bertrand; Li, Weimin; Henitz, Erin D; Karkera, Jayaprakash D; Favis, Reyna; Gaffney, Dana; Shapiro, Alice; Theocharous, Panteli; Elsayed, Yusri A; van de Velde, Helgi; Schaffer, Michael E; Osmanov, Evgenii A; Hong, Xiaonan; Scheliga, Adriana; Mayer, Jiri; Offner, Fritz; Rule, Simon; Teixeira, Adriana; Romejko-Jarosinska, Joanna; de Vos, Sven; Crump, Michael; Shpilberg, Ofer; Zinzani, Pier Luigi; Cakana, Andrew; Esseltine, Dixie-Lee; Mulligan, George; Ricci, Deborah

2013-05-01

Identify subgroups of patients with relapsed/refractory follicular lymphoma deriving substantial progression-free survival (PFS) benefit with bortezomib-rituximab versus rituximab in the phase III LYM-3001 study. A total of 676 patients were randomized to five 5-week cycles of bortezomib-rituximab or rituximab. The primary end point was PFS; this prespecified analysis of candidate protein biomarkers and genes was an exploratory objective. Archived tumor tissue and whole blood samples were collected at baseline. Immunohistochemistry and genetic analyses were completed for 4 proteins and 8 genes. In initial pairwise analyses, using individual single-nucleotide polymorphism genotypes, one biomarker pair (PSMB1 P11A C/G heterozygote, low CD68 expression) was associated with a significant PFS benefit with bortezomib-rituximab versus rituximab, controlling for multiple comparison corrections. The pair was analyzed under dominant, recessive, and additive genetic models, with significant association with PFS seen under the dominant model (G/G+C/G). In patients carrying this biomarker pair [PSMB1 P11A G allele, low CD68 expression (≤50 CD68-positive cells), population frequency: 43.6%], median PFS was 14.2 months with bortezomib-rituximab versus 9.1 months with rituximab (HR 0.47, P < 0.0001), and there was a significant overall survival benefit (HR 0.49, P = 0.0461). Response rates were higher and time to next antilymphoma therapy was longer in the bortezomib-rituximab group. In biomarker-negative patients, no significant efficacy differences were seen between treatment groups. Similar proportions of patients had high-risk features in the biomarker-positive and biomarker-negative subsets. Patients with PSMB1 P11A (G allele) and low CD68 expression seemed to have significantly longer PFS and greater clinical benefit with bortezomib-rituximab versus rituximab. ©2013 AACR.

The PlantLIBRA consumer survey: Findings on the use of plant food supplements in Italy.

PubMed

Restani, Patrizia; Di Lorenzo, Chiara; Garcia-Alvarez, Alicia; Frigerio, Gianfranco; Colombo, Francesca; Maggi, Franco M; Milà-Villarroel, Raimon; Serra-Majem, Lluis

2018-01-01

Food supplements, and in particular those containing botanicals (plant food supplements, PFS), have in recent decades been of great interest both to consumers and to food/pharmaceutical industries. The aim of this paper is to examine replies by Italian consumers to the PlantLIBRA consumers' survey in order to: 1) assess the behaviour of an Italian population with respect to the use of PFS, and to compare it with that of other 5 countries involved in the whole survey; 2) identify different habits in the 4 Italian cities selected according to their geographical distribution; 3) collect independent information on the actual intake of PFS and consumers' behaviour. 397 Italian consumers enrolled, 187 males (49.5%) and 191 female (50.5%). The distribution of subjects among the 4 cities included was: Milan 99; Venice 90; Rome 96 and Catania 96. The interest in PFS in Italy is high, the prevalence of "regular" consumers being 22.7%. Some differences were observed between the 4 cities involved: the pattern of use during the year was specific to each city; consumers in Milan reported reasons to use PFS significantly different from those in the whole Italian sample and did not indicate supermarkets as an important place of purchase; respondents from Rome and Catania more frequently used family doctors and pharmacists as a source of recommendation. Some significant difference among cities, sex and age groups were observed when the most frequently used botanicals were ranked. The results provide new insights on the socio-economic characteristics and lifestyle of Italian PFS consumers, on their reasons for and pattern of use, and on their behaviour and expectations. The value of this information is not restricted to the specific country (Italy) but allows for a more general evaluation of the pattern of use, according to habits and geographical area.

Down-regulation of long non-coding RNA MEG3 indicates an unfavorable prognosis in non-small cell lung cancer: Evidence from the GEO database.

PubMed

Zhang, Zichao; Liu, Tiantian; Wang, Kai; Qu, Xiao; Pang, Zhaofei; Liu, Shaorui; Liu, Qi; Du, Jiajun

2017-09-30

Long non-coding RNA (lncRNA) MEG3 (maternally expressed gene 3) is an imprinted gene that suppresses cells growth in various tumors. However, the association between MEG3 expression and prognosis in non-small cell lung cancer (NSCLC) has not been fully investigated. Seven datasets with 1144 patients were obtained from Gene Expression Omnibus (GEO) database (Affymetrix U133 Plus 2.0 platform). Association between MEG3 and other variables was tested using the chi-squared test. Kaplan-Meier survival analysis was carried out to explore the association between MEG3 expression and overall survival (OS)/progression free survival (PFS). Results of univariate and multivariate Cox regression analysis were represented in HR and 95%CI form. Summarized results and publication bias were showed by forest plots and funnel plots respectively. Differential expression of MEG3 was related to stage (GSE31210OS and GSE31210PFS), histology (GSE29013OS and GSE29013PFS) and gender (GSE29013PFS). In summary, low MEG3 expression was associated with shorter long-term survival time in several datasets (GSE3141 (p=0.039), GSE30219 (p=0.008) for OS and GSE30219 (p=0.048) for PFS). We found that MEG3 was an independent prognostic factor in GSE30219 for PFS (HR 0.666, 95%CI 0.458-0.969, p=0.033). The summarized results suggested that low MEG3 expression was a poor prognostic factor in NSCLC (HR=0.77, 95%CI 0.63-0.95). Specifically, the association between low MEG3 expression and poor prognosis was markedly significant in younger patients (≤60years old) (HR0.602, 95%CI 0.417-0.867, p=0.007). These findings indicate that MEG3 could be a novel prognostic factor for NSCLC patients. Copyright © 2017 Elsevier B.V. All rights reserved.

Concurrent Chemoradiotherapy with Temozolomide Followed by Adjuvant Temozolomide for Newly Diagnosed Glioblastoma Patients: A Retrospective Multicenter Observation Study in Korea.

PubMed

Kim, Byung Sup; Seol, Ho Jun; Nam, Do-Hyun; Park, Chul-Kee; Kim, Il Han; Kim, Tae Min; Kim, Jeong Hoon; Cho, Young Hyun; Yoon, Sang Min; Chang, Jong Hee; Kang, Seok-Gu; Kim, Eui Hyun; Suh, Chang-Ok; Jung, Tae-Young; Lee, Kyung-Hwa; Kim, Chae-Yong; Kim, In Ah; Hong, Chang-Ki; Yoo, Heon; Kim, Jin Hee; Kang, Shin-Hyuk; Kang, Min Kyu; Kim, Eun-Young; Kim, Sun-Hwan; Chung, Dong-Sup; Hwang, Sun-Chul; Song, Joon-Ho; Cho, Sung Jin; Lee, Sun-Il; Lee, Youn-Soo; Ahn, Kook-Jin; Kim, Se Hoon; Lim, Do Hun; Gwak, Ho-Shin; Lee, Se-Hoon; Hong, Yong-Kil

2017-01-01

The purpose of this study was to investigate the feasibility and survival benefits of combined treatment with radiotherapy and adjuvant temozolomide (TMZ) in a Korean sample. A total of 750 Korean patients with histologically confirmed glioblastoma multiforme, who received concurrent chemoradiotherapy with TMZ (CCRT) and adjuvant TMZ from January 2006 until June 2011, were analyzed retrospectively. After the first operation, a gross total resection (GTR), subtotal resection (STR), partial resection (PR), biopsy alone were achieved in 388 (51.7%), 159 (21.2%), 96 (12.8%), and 107 (14.3%) patients, respectively. The methylation status of O 6 -methylguanine-DNA methyltransferase (MGMT) was reviewed retrospectively in 217 patients. The median follow-up period was 16.3 months and the median overall survival (OS) was 17.5 months. The actuarial survival rates at the 1-, 3-, and 5-year OS were 72.1%, 21.0%, and 9.0%, respectively. The median progression-free survival (PFS) was 10.1 months, and the actuarial PFS at 1-, 3-, and 5-year PFS were 42.2%, 13.0%, and 7.8%, respectively. The patients who received GTR showed a significantly longer OS and PFS than those who received STR, PR, or biopsy alone, regardless of the methylation status of the MGMT promoter. Patients with a methylated MGMT promoter also showed a significantly longer OS and PFS than those with an unmethylated MGMT promoter. Patients who received more than six cycles of adjuvant TMZ had a longer OS and PFS than those who received six or fewer cycles. Hematologic toxicity of grade 3 or 4 was observed in 8.4% of patients during the CCRT period and in 10.2% during the adjuvant TMZ period. Patients treated with CCRT followed by adjuvant TMZ had more favorable survival rates and tolerable toxicity than those who did not undergo this treatment.

Phase II study of maintenance pembrolizumab in patients with extensive-stage small cell lung cancer (SCLC).

PubMed

Gadgeel, Shirish M; Pennell, Nathan A; Fidler, Mary Jo; Halmos, Balazs; Bonomi, Philip; Stevenson, James; Schneider, Bryan; Sukari, Ammar; Ventimiglia, Jaclyn; Chen, Wei; Galasso, Cathy; Wozniak, Antoinette; Boerner, Julie; Kalemkerian, Gregory P

2018-05-15

To assess the efficacy of maintenance pembrolizumab in extensive-stage small cell lung cancer (SCLC) patients, after treatment with platinum/etoposide. Extensive-stage SCLC patients with a response or stable disease following induction chemotherapy were eligible. Pembrolizumab at a dose of 200 mg IV every 3 weeks was initiated within 8 weeks of the last cycle of chemotherapy. The primary endpoint of the study was progression-free survival (PFS) from study registration, with overall survival (OS) as a key secondary endpoint. Available tumor tissue was assessed for PD-L1 expression both in the tumor cells and surrounding stroma. Blood for circulating tumor cells was collected before the first, second and third cycles of pembrolizumab. Of the 45 patients enrolled, 56% were male and 22% had treated brain metastases. The median PFS was 1.4 months (95%CI- 1.3-2.8), with 1-year PFS of 13%. The median OS was 9.6 months (95%CI- 7.0-12), with 1-year OS of 37%. Of the 30 tumors that could be assessed, 3 had PD-L1 expression (≥ 1%) in the tumor cells. Twenty tumors could be assessed for PD-L1 expression in the stroma. The median PFS in the 8 patients with tumors positive for stromal interface PD-L1 expression was 6.5 months (95% CI-1.1-12.8) compared to 1.3 months (95%CI- 0.6-2.5) in 12 patients with tumors negative for this marker. No unexpected toxicities were observed. Maintenance pembrolizumab did not appear to improve median PFS compared to historical data. However, 1-year PFS of 13% and OS of 37% suggest that a subset of patients did benefit from pembrolizumab. Copyright © 2018 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.

The PlantLIBRA consumer survey: Findings on the use of plant food supplements in Italy

PubMed Central

Di Lorenzo, Chiara; Garcia-Alvarez, Alicia; Frigerio, Gianfranco; Colombo, Francesca; Maggi, Franco M.; Milà-Villarroel, Raimon; Serra-Majem, Lluis

2018-01-01

Background Food supplements, and in particular those containing botanicals (plant food supplements, PFS), have in recent decades been of great interest both to consumers and to food/pharmaceutical industries. Objectives The aim of this paper is to examine replies by Italian consumers to the PlantLIBRA consumers' survey in order to: 1) assess the behaviour of an Italian population with respect to the use of PFS, and to compare it with that of other 5 countries involved in the whole survey; 2) identify different habits in the 4 Italian cities selected according to their geographical distribution; 3) collect independent information on the actual intake of PFS and consumers' behaviour. Subjects/setting 397 Italian consumers enrolled, 187 males (49.5%) and 191 female (50.5%). The distribution of subjects among the 4 cities included was: Milan 99; Venice 90; Rome 96 and Catania 96. Results The interest in PFS in Italy is high, the prevalence of "regular" consumers being 22.7%. Some differences were observed between the 4 cities involved: the pattern of use during the year was specific to each city; consumers in Milan reported reasons to use PFS significantly different from those in the whole Italian sample and did not indicate supermarkets as an important place of purchase; respondents from Rome and Catania more frequently used family doctors and pharmacists as a source of recommendation. Some significant difference among cities, sex and age groups were observed when the most frequently used botanicals were ranked. Conclusions The results provide new insights on the socio-economic characteristics and lifestyle of Italian PFS consumers, on their reasons for and pattern of use, and on their behaviour and expectations. The value of this information is not restricted to the specific country (Italy) but allows for a more general evaluation of the pattern of use, according to habits and geographical area. PMID:29324831

[Clinical effects for patients with recurrent advanced non-small cell lung cancer treated with icotinib hydrochloride].

PubMed

Nong, Jingying; Qin, Na; Wang, Jinghui; Yang, Xinjie; Zhang, Hui; Wu, Yuhua; Lv, Jialin; Zhang, Quan; Zhang, Shucai

2013-05-01

Icotinib hydrochloride is the third single target EGFR-TKI used in clinical treatment of advanced non-small cell lung cancer (NSCLC). Clinical research reports on its efficacy and survival in patients with Recurrent Advanced NSCLC are still little.The aim of this study is to evaluate the efficacy and survival of Icotinib hydrochloride for patients with advanced non-small cell lung cancer who failed to previous chemotherapy and explore the association of clinical features with the efficacy and survival. The clinical data of 60 NSCLC patients referred to the Beijing Chest Hospital, Capital Medical University from March 2009 to July 2012 were retrospectively analyzed. The overall response rate (ORR) was 45.0% and the disease control rate (DCR) was 80.0%. The median progression-free survival (PFS) time was 6.7 months. RR and PFS in female were superior to male (P=0.014, 0.013, respectively). RR, DCR in 2nd-line subgroup were superior to ≥3rd-line subgroup (P=0.020, 0.024, respectively). RR, DCR and PFS in EGFR mutation carriers were significantly superior to wild-type patients (P=0.006, <0.001, 0.002, respectively). There was no statistical difference in RR and PFS between those age<65 and ≥65 or PS<2 and PS≥2. There was no statistical difference in RR and DCR between exon 19 deletion and exon 21 mutations, while the former had much longer PFS (P=0.020). EGFR mutation and exon 19 deletion are the independent prognostic factors to significantly improve the PFS (P=0.009, 0.012, respectively). The side effects were generally mild and consisted of rash and diarrhea. Icotinib hydrochloride is effective especially in EGFR mutation carriers and well tolerated in patients with recurrent advanced non-small-cell lung cancer.

Prognostic factors, patterns of recurrence and toxicity for patients with esophageal cancer undergoing definitive radiotherapy or chemo-radiotherapy.

PubMed

Haefner, Matthias F; Lang, Kristin; Krug, David; Koerber, Stefan A; Uhlmann, Lorenz; Kieser, Meinhard; Debus, Juergen; Sterzing, Florian

2015-07-01

The aim of this study was to evaluate the effectiveness and tolerability of definitive chemo-radiation or radiotherapy alone in patients with esophageal cancer. We retrospectively analyzed the medical records of n = 238 patients with squamous cell carcinoma or adenocarcinoma of the esophagus treated with definitive radiotherapy with or without concomitant chemotherapy at our institution between 2000 and 2012. Patients of all stages were included to represent actual clinical routine. We performed univariate and multivariate analysis to identify prognostic factors for overall survival (OS) and progression-free survival (PFS). Moreover, treatment-related toxicity and patterns of recurrence were assessed. Patients recieved either chemo-radiation (64%), radiotherapy plus cetuximab (10%) or radiotherapy alone (26%). In 69%, a boost was applied, resulting in a median cumulative dose of 55.8 Gy; the remaining 31% received a median total dose of 50 Gy. For the entire cohort, the median OS and PFS were 15.0 and 11.0 months, respectively. In multivariate analysis, important prognostic factors for OS and PFS were T stage (OS: P = 0.005; PFS: P = 0.006), M stage (OS: P = 0.015; PFS: P = 0.003), concomitant chemotherapy (P < 0.001) and radiation doses of >55 Gy (OS: P = 0.019; PFS: P = 0.022). Recurrences occurred predominantly as local in-field relapse or distant metastases. Toxicity was dominated by nutritional impairment (12.6% with G3/4 dysphagia) and chemo-associated side effects. Definitive chemo-radiation in patients with esophageal cancer results in survival rates comparable with surgical treatment approaches. However, local and distant recurrence considerably restrict prognosis. Further advances in radio-oncological treatment strategies are necessary for improving outcome. © The Author 2015. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.

[Response and prognosis of patients with multiple myeloma induced by PAD/TAD].

PubMed

Zeng, Tianmei; He, Haiyan; Shi, Haotian; Xi, Hao; Du, Juan; Zhang, Chunyang; Jiang, Hua; Fu, Weijun; Zhou, Fan; Hou, Jian

2015-03-17

To evaluate the impact of cytogenetic grouping and autologous stem cell transplantation on the prognosis of patients with multiple myeloma (MM) induced by PAD (velcade+epirubicin+dexamethasone) and TAD (thalidomide+epirubicin+dexamethasone). A total of 191 patients with a definite diagnosis of MM were enrolled from May 2008 to December 2013 into this prospective study. They were non-randomly induced by PAD (n = 132) or TAD (n = 59) plus autologous stem cell transplantation or chemotherapy. Response and survival rates were also analyzed between two groups. The overall response rates of PAD and TAD groups were 84.4% (108/128) and 69.5% (41/59) (P = 0.011) respectively. The very good partial remission (VGPR) rates were 70.3% (90/128) and 32.2% (19/59) (P < 0.001) and near complete remission/complete remission (nCR/CR) rates 68.0% (87/128) and 25.4% (15/59) respectively (P < 0.001). Both progression-free survival (PFS) and overall survival (OS) showed no significant inter-group difference (P = 0.223, 0.989). The survival analysis of PAD group showed that FISH high-risk group had shorter PFS and OS than FISH low-risk group (15.2 vs 19.1 months for PFS, P = 0.098; 41.2 months vs non-attaining for OS, P = 0.017). In FISH high-risk group, patients consolidated with autologous stem cell transplantation showed longer PFS than those with chemotherapy (17.8 vs 14.6 months, P = 0.029) while the OS showed no difference (P = 0.840). In FISH low-risk group, no difference were observed in PFS and OS between patients with consolidation therapies alone (P = 0.131, 0.294). The response rates are higher in patients induced by PAD than by TAD. After PAD induction, cytogenetic grouping may further distinguish the prognosis of MM patients. For FISH high-risk patients, their PFS is prolonged by autologous stem cell transplantation.

Promising outcomes of definitive chemoradiation and cetuximab for patients with esophageal squamous cell carcinoma.

PubMed

Chen, Yongshun; Wu, Xiaoyuan; Bu, Shanshan; He, Chunyu; Wang, Wen; Liu, Jinsong; Guo, Wei; Tan, Bo; Wang, Yanxia; Wang, Jianhua

2012-11-01

This study investigated cetuximab added to definitive concurrent chemoradiation for esophageal squamous cell carcinoma (ESCC). Previously untreated patients with stage II-IVa ESCC received cetuximab (400 mg/m(2) per week in week 1, then 250 mg/m(2) per week during weeks 2-8), paclitaxel (45 mg/m(2) per week) and cisplatin (20 mg/m(2) per week) in weeks 2-8 with 59.4 Gy radiotherapy. Epidermal growth factor receptor (EGFR) status in tumor specimens was assessed. Thirty-one patients were enrolled and evaluated for toxicity. Of the 29 patients assessable for a response, 20 (69.0%) had a clinical complete response (CR). Over a median follow up of 23.6 months, disease progression was observed in seven patients. The 1- and 2-year progression-free survival (PFS) rates were 85.5% and 75.1%, respectively. The PFS was shorter for patients with lymphatic metastatic disease than for those with locally confined tumor; the 1-year PFS rates were 78.7% and 92.3%, respectively (P = 0.038). Sixteen (55.2%) patients were immunohistochemically positive for EGFR. The patients with EGFR-expressing tumor had a CR rate of 75.0% compared with 61.5% in those with negative EGFR expression (P = 0.024). The PFS for patients with EGFR-expressing tumor was longer compared with the PFS of patients with negative EGFR (P = 0.133). The patients with prominent cetuximab-induced rash (≥grade 2) had a better CR rate and PFS than those with no or grade 1 rash (P < 0.05). The rates of grades 3/4 esophagitis, hematological and dermatological toxicities were 9.7%, 29.0% and 16.1%, respectively. The regimen of definitive chemoradiation plus cetuximab achieved good clinical response and has an acceptable safety profile in Chinese ESCC patients. © 2012 Japanese Cancer Association.

Phase II study of paclitaxel given once per week along with trastuzumab and pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

PubMed

Dang, Chau; Iyengar, Neil; Datko, Farrah; D'Andrea, Gabriella; Theodoulou, Maria; Dickler, Maura; Goldfarb, Shari; Lake, Diana; Fasano, Julie; Fornier, Monica; Gilewski, Theresa; Modi, Shanu; Gajria, Devika; Moynahan, Mary Ellen; Hamilton, Nicola; Patil, Sujata; Jochelson, Maxine; Norton, Larry; Baselga, Jose; Hudis, Clifford

2015-02-10

The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. Patients with metastatic human epidermal growth factor receptor 2-positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m(2) once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy. © 2014 by American Society of Clinical Oncology.

Primary site and regional lymph node involvement are independent prognostic factors for early-stage extranodal nasal-type natural killer/T cell lymphoma.

PubMed

Niu, Shao-Qing; Yang, Yong; Li, Yi-Yang; Wen, Ge; Wang, Liang; Li, Zhi-Ming; Wang, Han-Yu; Zhang, Lu-Lu; Xia, Yun-Fei; Zhang, Yu-Jing

2016-04-04

Nasal-type extranodal natural killer/T-cell lymphoma (ENKTCL) originates primarily in the nasal cavity or extra-nasal sites within the upper aerodigestive tract. However, it is unclear whether the primary site can serve as an independent prognostic factor or whether the varying clinical outcomes observed with different primary sites can be attributed merely to their propensities of regional lymph node involvement. The aim of this study was to investigate the prognostic implications of the primary site and regional lymph node involvement in patients with early-stage nasal-type ENKTCL. To develop a nomogram, we reviewed the clinical data of 215 consecutively diagnosed patients with early-stage nasal-type ENKTCL who were treated in Sun Yat-sen University Cancer Center with chemotherapy and radiotherapy between 2000 and 2011. The predictive accuracy and discriminative ability of the nomogram were determined using a concordance index (C-index) and calibration curve. The 5-year overall survival (OS) and progression-free survival (PFS) rates of patients with nasal ENKTCL were higher than those of patients with extra-nasal ENKTCL (OS: 68.2% vs. 46.0%, P = 0.030; PFS: 53.4% vs. 26.6%, P = 0.010). The 5-year OS and PFS rates of patients with Ann Arbor stage IE ENKTCL were higher than those of patients with Ann Arbor stage IIE ENKTCL (OS: 66.3% vs. 59.2%, P = 0.003; PFS: 51.4% vs. 40.3%, P = 0.009). Multivariate analysis showed that age >60 years, ECOG performance status score ≥2, elevated lactate dehydrogenase (LDH) level, extra-nasal primary site, and regional lymph node involvement were significantly associated with lower 5-year OS rate; age >60 years, elevated LDH level, extra-nasal primary site, and regional lymph node involvement were significantly associated with lower 5-year PFS rate. The nomogram included the primary site and regional lymph node involvement based on multivariate analysis. The calibration curve showed good agreement between the predicted and actual 5-year OS and PFS rates, and the C-indexes of the nomogram for the OS and PFS rates were 0.697 and 0.634, respectively. The primary site and regional lymph node involvement are independent prognostic factors for early-stage ENKTCL treated with chemotherapy followed by definitive radiotherapy.

Serum Human Epidermal Growth Factor 2 Extracellular Domain as a Predictive Biomarker for Lapatinib Treatment Efficacy in Patients With Advanced Breast Cancer.

PubMed

Lee, Chee Khoon; Davies, Lucy; Gebski, Val J; Lord, Sarah J; Di Leo, Angelo; Johnston, Stephen; Geyer, Charles; Cameron, David; Press, Michael F; Ellis, Catherine; Loi, Sherene; Marschner, Ian; Simes, John; de Souza, Paul

2016-03-20

We examined the prognostic and predictive value of serum human epidermal growth factor 2 (HER2) extracellular domain (sHER2) in patients with advanced breast cancer treated with lapatinib using data from three randomized trials. We analyzed sHER2 and tissue HER2 (tHER2) data from 1,902 patients (84%) who were randomly assigned to receive lapatinib or control in the trials EGF30001, EGF30008, and EGF100151. Cox regression analyses were performed to correlate both biomarkers with progression-free survival (PFS) and overall survival (OS). Median sHER2 levels were 25.1 and 10.1 ng/mL in tHER2-amplified (tHER-positive) and nonamplified (tHER-negative) populations, respectively (r = 0.42 for sHER2-tHER2 correlation). Lapatinib had significant PFS benefit over control (hazard ratio [HR], 0.855; P = .004), but not OS (HR, 0.941; P = .33). Lapatinib PFS benefit is independently predicted by higher sHER2 values (HR per 10-ng/mL increase in sHER2: lapatinib-containing therapies, 1.009 v nonlapatinib-containing therapies, 1.044; P(interaction) < .001) and by positive tHER2 (HR [lapatinib v nonlapatinib]: tHER2 positive, 0.638 v tHER2 negative, 0.940; P(interaction) = .001). Within the tHER2-positive subpopulation (n = 515), higher sHER2 values still independently predicted lapatinib PFS benefit (HR per 10-ng/mL increase in sHER2: lapatinib-containing therapies, 1.017 v nonlapatinib-containing therapies, 1.041; P(interaction) = .008). In control arms (n = 936), higher sHER2 was associated with worse prognosis in multivariable analyses (PFS HR per 10 ng/mL: PFS, 1.024; P < .001; and OS, 1.018; P < .001). Higher sHER2 predicts greater PFS benefit with lapatinib independent of tHER2 status. High sHER2 is also independently prognostic for worse survival in patients who received nonlapatinib-containing therapies. The predictive role of sHER2 for other anti-HER2 agents requires further research. © 2016 by American Society of Clinical Oncology.

Lapatinib or Trastuzumab Plus Taxane Therapy for Human Epidermal Growth Factor Receptor 2-Positive Advanced Breast Cancer: Final Results of NCIC CTG MA.31.

PubMed

Gelmon, Karen A; Boyle, Frances M; Kaufman, Bella; Huntsman, David G; Manikhas, Alexey; Di Leo, Angelo; Martin, Miguel; Schwartzberg, Lee S; Lemieux, Julie; Aparicio, Samuel; Shepherd, Lois E; Dent, Susan; Ellard, Susan L; Tonkin, Katia; Pritchard, Kathleen I; Whelan, Timothy J; Nomikos, Dora; Nusch, Arnd; Coleman, Robert E; Mukai, Hirofumi; Tjulandin, Sergei; Khasanov, Rustem; Rizel, Shulamith; Connor, Anne P; Santillana, Sergio L; Chapman, Judith-Anne W; Parulekar, Wendy R

2015-05-10

The efficacy of lapatinib versus trastuzumab combined with taxanes in the first-line setting of human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer (BC) is unknown. The MA.31 trial compared a combination of first-line anti-HER2 therapy (lapatinib or trastuzumab) and taxane therapy for 24 weeks, followed by the same anti-HER2 monotherapy until progression. Stratification was by prior (neo)adjuvant anti-HER2 therapy, prior (neo)adjuvant taxane, planned taxane, and liver metastases. The primary end point was intention-to-treat (ITT) progression-free survival (PFS), defined as time from random assignment to progression by RECIST (version 1.0) criteria, or death for patients with locally assessed HER2-positive tumors. The primary test statistic was a stratified log-rank test for noninferiority. PFS was also assessed for patients with centrally confirmed HER2-positive tumors. From July 17, 2008, to December 1, 2011, 652 patients were accrued from 21 countries, resulting in 537 patients with centrally confirmed HER2-positive tumors. Median follow-up was 21.5 months. Median ITT PFS was 9.0 months with lapatinib and 11.3 months with trastuzumab. By ITT analysis, PFS was inferior for lapatinib compared with trastuzumab, with a stratified hazard ratio (HR) of 1.37 (95% CI, 1.13 to 1.65; P = .001). In patients with centrally confirmed HER2-positive tumors, median PFS was 9.1 months with lapatinib and 13.6 months with trastuzumab (HR, 1.48; 95% CI, 1.20 to 1.83; P < .001). More grade 3 or 4 diarrhea and rash were observed with lapatinib (P < .001). PFS results were supported by the secondary end point of overall survival, with an ITT HR of 1.28 (95% CI, 0.95 to 1.72; P = .11); in patients with centrally confirmed HER2-positive tumors, the HR was 1.47 (95% CI, 1.03 to 2.09; P = .03). As first-line therapy for HER2-positive metastatic BC, lapatinib combined with taxane was associated with shorter PFS and more toxicity compared with trastuzumab combined with taxane. © 2015 by American Society of Clinical Oncology.

Prognostic and predictive effects of primary versus secondary platinum resistance for bevacizumab treatment for platinum-resistant ovarian cancer in the AURELIA trial.

PubMed

Trillsch, F; Mahner, S; Hilpert, F; Davies, L; García-Martínez, E; Kristensen, G; Savarese, A; Vuylsteke, P; Los, M; Zagouri, F; Gladieff, L; Sehouli, J; Khoon Lee, C; Gebski, V; Pujade-Lauraine, E

2016-09-01

Progression-free survival (PFS), objective response rate (ORR), and patient-reported outcomes (PROs) were significantly improved by adding bevacizumab to chemotherapy for platinum-resistant ovarian cancer (PROC) in the phase III AURELIA trial. We explored treatment outcomes according to primary platinum resistance (PPR) versus secondary platinum resistance (SPR). Patients were categorized as PPR (disease progression <6 months after completing first-line platinum therapy) or SPR (progression ≥6 months after first platinum but <6 months after second). The exploratory Cox and logistic regression analyses correlated PFS, ORR, overall survival (OS), and PROs with the time to development of platinum resistance. Baseline characteristics were similar in patients with PPR (n = 262; 73%) and SPR (n = 99; 27%), although ascites were more common in the PPR subgroup. In bevacizumab-treated patients (n = 179), SPR was associated with improved PFS (median 10.2 versus 5.6 months in PPR patients; P < 0.001) and OS (median 22.2 versus 13.7 months, respectively; P < 0.001) but not PROs (22% versus 22% with improved abdominal/gastrointestinal symptoms at week 8/9). In multivariate analyses, SPR remained an independent prognostic factor for better PFS [adjusted hazard ratio (HR) 0.41, 95% confidence interval (CI) 0.25-0.67; P < 0.001] and OS (HR 0.49, 95% CI 0.30-0.80; P = 0.005) in bevacizumab-treated patients, but was not statistically significant for either end point in the chemotherapy-alone subgroup. The magnitude of PFS benefit from bevacizumab appeared greater in SPR than PPR patients (HR 0.30 versus 0.55, respectively; interaction P = 0.07) with a similar direction of effect for OS (interaction P = 0.18). In bevacizumab-treated patients, PFS and OS were more favorable in SPR than PPR patients with equally improved PROs. The PFS and OS benefit from combining bevacizumab with chemotherapy was more pronounced in SPR than PPR PROC. PPR versus SPR should be a stratification factor in future trials evaluating anti-angiogenic therapy for PROC. © The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Clinical considerations of the role of palbociclib in the management of advanced breast cancer patients with and without visceral metastases.

PubMed

Turner, N C; Finn, R S; Martin, M; Im, S-A; DeMichele, A; Ettl, J; Diéras, V; Moulder, S; Lipatov, O; Colleoni, M; Cristofanilli, M; Lu, D R; Mori, A; Giorgetti, C; Iyer, S; Bartlett, C Huang; Gelmon, K A

2018-03-01

This report assesses the efficacy and safety of palbociclib plus endocrine therapy (ET) in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) with or without visceral metastases. Pre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N = 521) and postmenopausal women untreated for ABC (PALOMA-2; N = 666) were randomized 2 : 1 to ET (fulvestrant or letrozole, respectively) plus palbociclib or placebo. Progression-free survival (PFS), safety, and patient-reported quality of life (QoL) were evaluated by prior treatment and visceral involvement. Visceral metastases incidence was higher in patients with prior resistance to ET (58.3%, PALOMA-3) than in patients naive to ET in the ABC setting (48.6%, PALOMA-2). In patients with prior resistance to ET and visceral metastases, median PFS (mPFS) was 9.2 months with palbociclib plus fulvestrant versus 3.4 months with placebo plus fulvestrant [hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35-0.61], and objective response rate (ORR) was 28.0% versus 6.7%, respectively. In patients with nonvisceral metastases, mPFS was 16.6 versus 7.3 months, HR 0.53; 95% CI 0.36-0.77. In patients with visceral disease and naive to ET in the advanced disease setting, mPFS was 19.3 months with palbociclib plus letrozole versus 12.9 months with placebo plus letrozole (HR 0.63; 95% CI 0.47-0.85); ORR was 55.1% versus 40.0%; in patients with nonvisceral disease, mPFS was not reached with palbociclib plus letrozole versus 16.8 months with placebo plus letrozole (HR 0.50; 95% CI 0.36-0.70). In patients with prior resistance to ET with visceral metastases, palbociclib plus fulvestrant significantly delayed deterioration of QoL versus placebo plus fulvestrant, whereas patient-reported QoL was maintained with palbociclib plus letrozole in patients naive to endocrine-based therapy for ABC. Palbociclib plus ET prolonged mPFS in patients with visceral metastases, increased ORRs, and in patients previously treated for ABC, delayed QoL deterioration, presenting a standard treatment option among patients with visceral metastases amenable to endocrine-based therapy. NCT01942135, NCT01740427.

First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer.

PubMed

Vaccaro, Vanja; Bria, Emilio; Sperduti, Isabella; Gelibter, Alain; Moscetti, Luca; Mansueto, Giovanni; Ruggeri, Enzo Maria; Gamucci, Teresa; Cognetti, Francesco; Milella, Michele

2013-07-28

To investigate activity, toxicity, and prognostic factors for survival of erlotinib and fixed dose-rate gemcitabine (FDR-Gem) in advanced pancreatic cancer. We designed a single-arm prospective, multicentre, open-label phase II study to evaluate the combination of erlotinib (100 mg/d, orally) and weekly FDR-Gem (1000 mg/m(2), infused at 10 mg/m(2) per minute) in a population of previously untreated patients with locally advanced, inoperable, or metastatic pancreatic cancer. Primary endpoint was the rate of progression-free survival at 6 mo (PFS-6); secondary endpoints were overall response rate (ORR), response duration, tolerability, overall survival (OS), and clinical benefit. Treatment was not considered to be of further interest if the PFS-6 was < 20% (p0 = 20%), while a PFS-6 > 40% would be of considerable interest (p1 = 40%); with a 5% rejection error (α = 5%) and a power of 80%, 35 fully evaluable patients with metastatic disease were required to be enrolled in order to complete the study. Analysis of prognostic factors for survival was also carried out. From May 2007 to September 2009, 46 patients were enrolled (male/female: 25/21; median age: 64 years; median baseline carbohydrate antigen 19-9 (CA 19-9): 897 U/mL; locally advanced/metastatic disease: 5/41). PFS-6 and median PFS were 30.4% and 14 wk (95%CI: 10-19), respectively; 1-year and median OS were 20.2% and 26 wk (95%CI: 8-43). Five patients achieved an objective response (ORR: 10.9%, 95%CI: 1.9-19.9); disease control rate was 56.5% (95%CI: 42.2-70.8); clinical benefit rate was 43.5% (95%CI: 29.1-57.8). CA 19-9 serum levels were decreased by > 25% as compared to baseline in 14/23 evaluable patients (63.6%). Treatment was well-tolerated, with skin rash being the most powerful predictor of both longer PFS (P < 0.0001) and OS (P = 0.01) at multivariate analysis (median OS for patients with or without rash: 42 wk vs 15 wk, respectively, Log-rank P = 0.03). Additional predictors of better outcome were: CA 19-9 reduction, female sex (for PFS), and good performance status (for OS). Primary study endpoint was not met. However, skin rash strongly predicted erlotinib efficacy, suggesting that a pharmacodynamic-based strategy for patient selection deserves further investigation.

A novel microfluidic valve controlledby induced charge electro-osmotic flow

NASA Astrophysics Data System (ADS)

Wang, Chengfa; Song, Yongxin; Pan, Xinxiang; Li, Dongqing

2016-07-01

In this paper, a novel microfluidic valve by utilizing induced charge electro-osmotic flow (ICEOF) is proposed and analyzed. The key part of the microfluidic valve is a Y-shaped microchannel. A small metal plate is placed at each corner of the junction of the Y-shaped microchannel. When a DC electrical field is applied through the channels, electro-osmotic flows occur in the channels, and two vortices will be formed near each of the metal plates due to the ICEOF. The two vortices behave like virtual ‘blocking columns’ to restrain and direct the flow in the Y-channel. In this paper, effects of the length of the metal plates, the applied voltages, the width of the microchannel, the zeta potential of the non-metal microchannel wall, and the orientation of the branch channels on the flow switching between two outlet channels are numerically investigated. The results show that the flow switching between the two outlet channels can be flexibly achieved by adjusting the applied DC voltages. The critical switching voltage (CSV), under which one outlet channel is closed, decreases with the increase in the metal plate length and the orientation angle of the outlet channels. The CSV, however, increases with the increase in the inlet voltage, the width of the microchannel, and the absolute value of the zeta potential of the non-metal microchannel wall. Compared with other types of micro-valves, the proposed micro-valve is simple in structure without any moving parts. Only a DC power source is needed for its actuation, thus it can operate automatically by controlling the applied voltages.

Integral Battery Power Limiting Circuit for Intrinsically Safe Applications

NASA Technical Reports Server (NTRS)

Burns, Bradley M.; Blalock, Norman N.

2010-01-01

A circuit topology has been designed to guarantee the output of intrinsically safe power for the operation of electrical devices in a hazardous environment. This design uses a MOSFET (metal oxide semiconductor field-effect transistor) as a switch to connect and disconnect power to a load. A test current is provided through a separate path to the load for monitoring by a comparator against a preset threshold level. The circuit is configured so that the test current will detect a fault in the load and open the switch before the main current can respond. The main current passes through the switch and then an inductor. When a fault occurs in the load, the current through the inductor cannot change immediately, but the voltage drops immediately to safe levels. The comparator detects this drop and opens the switch before the current in the inductor has a chance to respond. This circuit protects both the current and voltage from exceeding safe levels. Typically, this type of protection is accomplished by a fuse or a circuit breaker, but in order for a fuse or a circuit breaker to blow or trip, the current must exceed the safe levels momentarily, which may be just enough time to ignite anything in a hazardous environment. To prevent this from happening, a fuse is typically current-limited by the addition of the resistor to keep the current within safe levels while the fuse reacts. The use of a resistor is acceptable for non-battery applications where the wasted energy and voltage drop across the resistor can be tolerated. The use of the switch and inductor minimizes the wasted energy. For example, a circuit runs from a 3.6-V battery that must be current-limited to 200 mA. If the circuit normally draws 10 mA, then an 18-ohm resistor would drop 180 mV during normal operation, while a typical switch (0.02 ohm) and inductor (0.97 ohm) would only drop 9.9 mV. From a power standpoint, the current-limiting resistor protection circuit wastes about 18 times more power than the switch and the inductor configuration. In the fault condition, both the resistor and the inductor react immediately. The resistor reacts by allowing more current to flow and dropping the voltage. Initially, the inductor reacts by dropping the voltage, and then by not allowing the current to change. When the comparator detects the drop in voltage, it opens the switch, thus preventing any further current flow. The inductor alone is not sufficient protection, because after the voltage drop has settled, the inductor would then allow the current to change, in this example, the current would be 3.7 A. In the fault condition, the resistor is flowing 200 mA until the fuse blows (anywhere from 1 ms to 100 s), while the switch and inductor combination is flowing about 2 A test current while monitoring for the fault to be corrected. Finally, as an additional safety feature, the circuit can be configured to hold the switch opened until both the load and source are disconnected.

Methods and compositions for rapid thermal cycling

DOEpatents

Beer, Neil Reginald; Benett, William J.; Frank, James M.; Deotte, Joshua R.; Spadaccini, Christopher

2015-10-27

The rapid thermal cycling of a material is targeted. A microfluidic heat exchanger with an internal porous medium is coupled to tanks containing cold fluid and hot fluid. Fluid flows alternately from the cold tank and the hot tank into the porous medium, cooling and heating samples contained in the microfluidic heat exchanger's sample wells. A valve may be coupled to the tanks and a pump, and switching the position of the valve may switch the source and direction of fluid flowing through the porous medium. A controller may control the switching of valve positions based on the temperature of the samples and determined temperature thresholds. A sample tray for containing samples to be thermally cycled may be used in conjunction with the thermal cycling system. A surface or internal electrical heater may aid in heating the samples, or may replace the necessity for the hot tank.

Methods and compositions for rapid thermal cycling

DOE Office of Scientific and Technical Information (OSTI.GOV)

Beer, Neil Reginald; Benett, William J.; Frank, James M.

The rapid thermal cycling of a material is targeted. A microfluidic heat exchanger with an internal porous medium is coupled to tanks containing cold fluid and hot fluid. Fluid flows alternately from the cold tank and the hot tank into the porous medium, cooling and heating samples contained in the microfluidic heat exchanger's sample wells. A valve may be coupled to the tanks and a pump, and switching the position of the valve may switch the source and direction of fluid flowing through the porous medium. A controller may control the switching of valve positions based on the temperature ofmore » the samples and determined temperature thresholds. A sample tray for containing samples to be thermally cycled may be used in conjunction with the thermal cycling system. A surface or internal electrical heater may aid in heating the samples, or may replace the necessity for the hot tank.« less

Nutrient removal by prairie filter strips in agricultural landscapes

Treesearch

X. Zhou; M.J. Helmers; H. Asbjornsen; R. Kolka; M.D. Tomer; R.M. Cruse

2014-01-01

Nitrogen (N) and phosphorus (P) from agricultural landscapes have been identified as primary sources of excess nutrients in aquatic systems. The main objective of this study was to evaluate the effectiveness of prairie filter strips (PFS) in removing nutrients from cropland runoff in 12 small watersheds in central Iowa. Four treatments with PFS of different spatial...

78 FR 76410 - Request for Information on Strategies To Accelerate the Testing and Adoption of Pay for Success...

Federal Register 2010, 2011, 2012, 2013, 2014

2013-12-17

... To Accelerate the Testing and Adoption of Pay for Success (PFS) Financing Models AGENCY: Office of... Strategies to Accelerate the Testing and Adoption of Pay for Success (PFS) Financing Models. The President's... Camacho, Attention: Pay for Success Incentive Fund RFI, U.S. Department of the Treasury, 1500 Pennsylvania...

Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer.

PubMed

Jänne, P A; Smith, I; McWalter, G; Mann, H; Dougherty, B; Walker, J; Orr, M C M; Hodgson, D R; Shaw, A T; Pereira, J R; Jeannin, G; Vansteenkiste, J; Barrios, C H; Franke, F A; Crinò, L; Smith, P

2015-07-14

Selumetinib (AZD6244, ARRY-142886)+docetaxel increases median overall survival (OS) and significantly improves progression-free survival (PFS) and objective response rate (ORR) compared with docetaxel alone in patients with KRAS mutant, stage IIIB/IV non-small-cell lung cancer (NSCLC; NCT00890825). Retrospective analysis of OS, PFS, ORR and change in tumour size at week 6 for different sub-populations of KRAS codon mutations. In patients receiving selumetinib+docetaxel and harbouring KRAS G12C or G12V mutations there were trends towards greater improvement in OS, PFS and ORR compared with other KRAS mutations. Different KRAS mutations in NSCLC may influence selumetinib/docetaxel sensitivity.

Push-pull switching power amplifier

NASA Technical Reports Server (NTRS)

Cuk, Slobodan M. (Inventor)

1980-01-01

A true push-pull switching power amplifier is disclosed utilizing two dc-to-dc converters. Each converter is comprised of two inductances, one inductance in series with a DC source and the other inductor in series with the output load, and an electrical energy transferring device with storage capability, namely storage capacitance, with suitable switching means between the inductances to obtain DC level conversion, where the switching means allows bidirectional current (and power) flow, and the switching means of one dc-to-dc converter is driven by the complement of a square-wave switching signal for the other dc-to-dc converter for true push-pull operation. For reduction of current ripple, the inductances in each of the two converters may be coupled, and with proper design of the coupling, the ripple can be reduced to zero at either the input or the output, but preferably the output.

Anthropogenic shift of planktonic food web structure in a coastal lagoon by freshwater flow regulation

NASA Astrophysics Data System (ADS)

Hemraj, Deevesh A.; Hossain, A.; Ye, Qifeng; Qin, Jian G.; Leterme, Sophie C.

2017-03-01

Anthropogenic modification of aquatic systems has diverse impacts on food web interactions and ecosystem states. To reverse the adverse effects of modified freshwater flow, adequate management of discharge is required, especially due to higher water requirements and abstractions for human use. Here, we look at the effects of anthropogenically controlled freshwater flow regimes on the planktonic food web of a Ramsar listed coastal lagoon that is under recovery from degradation. Our results show shifts in water quality and plankton community interactions associated to changes in water flow. These shifts in food web interactions represent modifications in habitat complexity and water quality. At high flow, phytoplankton-zooplankton interactions dominate the food web. Conversely, at low flow, bacteria, viruses and nano/picoplankton interactions are more dominant, with a substantial switch of the food web towards heterotrophy. This switch can be associated with excess organic matter loading, decomposition of dead organisms, and synergistic and antagonistic interactions. We suggest that a lower variability in flow amplitude could be beneficial for the long-term sustaining of water quality and food web interactions, while improving the ecosystem health of systems facing similar stresses as the Coorong.

Anthropogenic shift of planktonic food web structure in a coastal lagoon by freshwater flow regulation

PubMed Central

Hemraj, Deevesh A.; Hossain, A.; Ye, Qifeng; Qin, Jian G.; Leterme, Sophie C.

2017-01-01

Anthropogenic modification of aquatic systems has diverse impacts on food web interactions and ecosystem states. To reverse the adverse effects of modified freshwater flow, adequate management of discharge is required, especially due to higher water requirements and abstractions for human use. Here, we look at the effects of anthropogenically controlled freshwater flow regimes on the planktonic food web of a Ramsar listed coastal lagoon that is under recovery from degradation. Our results show shifts in water quality and plankton community interactions associated to changes in water flow. These shifts in food web interactions represent modifications in habitat complexity and water quality. At high flow, phytoplankton-zooplankton interactions dominate the food web. Conversely, at low flow, bacteria, viruses and nano/picoplankton interactions are more dominant, with a substantial switch of the food web towards heterotrophy. This switch can be associated with excess organic matter loading, decomposition of dead organisms, and synergistic and antagonistic interactions. We suggest that a lower variability in flow amplitude could be beneficial for the long-term sustaining of water quality and food web interactions, while improving the ecosystem health of systems facing similar stresses as the Coorong. PMID:28327643

Data Elevator

DOE Office of Scientific and Technical Information (OSTI.GOV)

BYNA, SUNRENDRA; DONG, BIN; WU, KESHENG

Data Elevator: Efficient Asynchronous Data Movement in Hierarchical Storage Systems Multi-layer storage subsystems, including SSD-based burst buffers and disk-based parallel file systems (PFS), are becoming part of HPC systems. However, software for this storage hierarchy is still in its infancy. Applications may have to explicitly move data among the storage layers. We propose Data Elevator for transparently and efficiently moving data between a burst buffer and a PFS. Users specify the final destination for their data, typically on PFS, Data Elevator intercepts the I/O calls, stages data on burst buffer, and then asynchronously transfers the data to their final destinationmore » in the background. This system allows extensive optimizations, such as overlapping read and write operations, choosing I/O modes, and aligning buffer boundaries. In tests with large-scale scientific applications, Data Elevator is as much as 4.2X faster than Cray DataWarp, the start-of-art software for burst buffer, and 4X faster than directly writing to PFS. The Data Elevator library uses HDF5's Virtual Object Layer (VOL) for intercepting parallel I/O calls that write data to PFS. The intercepted calls are redirected to the Data Elevator, which provides a handle to write the file in a faster and intermediate burst buffer system. Once the application finishes writing the data to the burst buffer, the Data Elevator job uses HDF5 to move the data to final destination in an asynchronous manner. Hence, using the Data Elevator library is currently useful for applications that call HDF5 for writing data files. Also, the Data Elevator depends on the HDF5 VOL functionality.« less

Circulating Tumor Cells as an Independent Predictor of Survival in Advanced Gastric Cancer.

PubMed

Okabe, H; Tsunoda, S; Hosogi, H; Hisamori, S; Tanaka, E; Tanaka, S; Sakai, Y

2015-11-01

When the indication for surgery of highly advanced gastric cancer is considered, careful selection of the patients is important. In addition to tumor-node-metastasis factors and peritoneal lavage cytology (CY), which are important predictors of prognosis, detection of circulating tumor cells (CTCs) could be another potential marker. This study prospectively evaluated CTCs using a semi-automated immunomagnetic separation system (CellSearch) for 136 patients with advanced gastric cancer to determine the frequency of CTC positivity. For 123 patients who also had their CY evaluated, the significance of both CTC and CY, was investigated as a potential biomarker to predict progression-free survival (PFS) or to monitor the therapeutic effect. In 25 patients (18.4 %), CTCs were positive. Positive CTC counts were more common for tumors with diffuse histologic type and distant metastasis. The PFS of CTC-positive patients was significantly shorter than that of CTC-negative patients (hazard ratio 2.03; P = 0.016). A multivariate analysis of 123 patients showed that CTC and CY as well as performance status and macroscopic distant metastasis were independent factors for PFS. When both CTC and CY were converted to negative values by therapeutic interventions, long-term PFS was achieved. Detection of CTCs was an independent predictor of a shorter PFS in advanced gastric cancer. For selecting patients who require intensive treatment, CTCs could be a valuable biomarker. The combined status of CTC and CY would be useful in selecting patients for radical surgery. Further investigation with a larger number of patients is necessary to establish the importance of CTCs.

Continued EGFR-TKI with concurrent radiotherapy to improve time to progression (TTP) in patients with locally progressive non-small cell lung cancer (NSCLC) after front-line EGFR-TKI treatment.

PubMed

Wang, Y; Li, Y; Xia, L; Niu, K; Chen, X; Lu, D; Kong, R; Chen, Z; Sun, J

2018-03-01

Epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) is the optimal treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, most patients developed systemic or local progression due to acquired EGFR-TKI resistance. This retrospective study aimed to evaluate the feasibility of continued EGFR-TKI with concurrent radiotherapy (CTCRT) in patients with local progression after front-line EGFR-TKI treatment. Advanced NSCLC patients with active EGFR mutation who received EGFR-TKI were treated with CTCRT after local progression. Medical data were analyzed for time to progression (TTP), progression-free survival (PFS), tumor response rate, overall survival (OS) and adverse events. A total of 50 irradiated lesions from 44 patients were included. Median TTP and PFS of measurable lesions (n = 31) were both significantly prolonged after local radiotherapy (TTP1 + TTP2 vs. TTP1: 21.7 vs. 16.0 months, P = 0.010; PFS1 + PFS2 vs. PFS1: 21.3 vs. 16.0 months, P = 0.027). For all lesions (n = 50), objective response rate (ORR) and local tumor control rate (LCR) were 54.0 and 84.0%, respectively. Median OS was 26.6 months. There were no serious adverse events before or after radiotherapy. The treatment modality of CTCRT is considerable and effective for EGFR-mutant NSCLC patients even with local failure from front-line EGFR-TKI treatment.

[La combinazione di gemcitabina e oxaliplatino (GEMOX) nel trattamento del carcinoma pancreatico in fase avanzata di malattia: le notizie sulla mia morte sono state esagerate?

PubMed

Giuliani, Jacopo; Bonetti, Andrea

2017-12-01

Riassunto. L'analisi è stata condotta al fine di valutare l'effetto sia sulla sopravvivenza globale (OS) sia sulla sopravvivenza libera da progressione di malattia (PFS) della chemioterapia di combinazione in prima linea per il carcinoma pancreatico in fase avanzata di malattia. La presente analisi è limitata agli studi randomizzati controllati (RCT) di fase III. Successivamente è stata applicata la European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) agli RCT di fase III analizzati per ricavare uno score relativo all'entità del beneficio clinico ottenuto per ciascun RCT. Sono state calcolate inoltre le differenze in termini di PFS tra i diversi bracci di trattamento rapportandole con i costi dei farmaci necessari per ottenere il beneficio di PFS. La nostra analisi ha valutato 11 RCT di fase III, per un totale di 4572 pazienti. Combinando i costi della terapia con la misura dell'efficacia espressa dalla PFS, è stato ottenuto un costo di 74,12 euro (€) per mese di vita guadagnato in termini di PFS con la combinazione di 5-fluorouracil, leucovorin, irinotecan e oxaliplatino (FOLFIRINOX), 90,14 € per la combinazione di gemcitabina e oxaliplatino (GEMOX) e 4708,7 € per la combinazione di nab-paclitaxel e gemcitabina. Da questo punto di vista riteniamo che l'utilizzo delle "vecche chemioterapie di combinazione" (per es., GEMOX) non dovrebbe essere completamente abbandonato, ma valutato sul singolo paziente, sulla base di diversi fattori (età, ECOG PS, comorbilità, carico di malattia), al fine di ottenere una reale "tailored therapy".

The effect of icotinib combined with chemotherapy in untreated non-small-cell lung cancer that harbored EGFR-sensitive mutations in a real-life setting: a retrospective analysis.

PubMed

Wang, Lulu; Li, Yan; Li, Luchun; Wu, Zhijuan; Yang, Dan; Ma, Huiwen; Wang, Donglin

2018-01-01

This study was conducted to compare the efficacy of a combination of icotinib and chemotherapy with icotinib or chemotherapy alone in untreated non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR)-sensitive mutations and to analyze the curative effect of different treatments on different genetic mutations (EGFR 19 exon deletion and L858R mutation) in a real-life setting. One hundred ninety-one patients were studied in this retrospective analysis from January 2013 to December 2015. The baseline characteristics, curative effects and adverse events of patients were analyzed. The primary endpoint was progression free survival (PFS). Longer PFS and overall survival (OS), and better objective response rate (ORR) were observed in the combination group compared to icotinib or chemotherapy along. For patients with an EGFR 19 exon deletion, the PFS, OS, and ORR in the combination group were superior to those in the icotinib or chemotherapy group. For the patients with the EGFR L858R mutation, better PFS and ORR were observed in the combination group, but OS was not obviously prolonged. Grade 3 or 4 adverse events were most commonly reported with combination therapy or chemotherapy alone. No possible drug-related interstitial lung disease or of drug related deaths occurred. The combination of icotinib and chemotherapy in patients with untreated NSCLC harboring sensitive EGFR mutations resulted in improved PFS and OS, especially in those who harbored the EGFR exon 19 deletion.

Efficacy of Exemestane in Korean Patients with Metastatic Breast Cancer after Failure of Nonsteroidal Aromatase Inhibitors

PubMed Central

Lee, June Koo; Lee, Daewon; Kim, Ji-Yeon; Lim, Yoojoo; Lee, Eunyoung; Moon, Hyeong-Gon; Kim, Tae-Yong; Han, Sae-Won; Oh, Do-Youn; Lee, Se-Hoon; Han, Wonshik; Kim, Dong-Wan; Kim, Tae-You; Noh, Dong-Young

2013-01-01

Purpose Exemestane has shown good efficacy and tolerability in postmenopausal women with hormone receptor-positive metastatic breast cancer. However, clinical outcomes in Korean patients have not yet been reported. Methods Data on 112 postmenopausal women with metastatic breast cancer were obtained retrospectively. Clinicopathological characteristics and treatment history were extracted from medical records. All patients received 25 mg exemestane daily until objective disease progression. Progression-free survival (PFS) was the primary endpoint, and secondary endpoints were overall survival (OS), objective response rate (ORR), and clinical benefit rate (CBR=complete response+partial response+stable disease for 6 months). Results The median age of the subjects was 55 years (range, 28-76 years). Exemestane treatment resulted in a median PFS of 5.7 months (95% confidence interval [CI], 4.4-7.0 months) and median OS of 21.9 months (95% CI, 13.6-30.3 months). ORR was 6.4% and CBR was 46.4% for the 110 patients with evaluable lesions. Symptomatic visceral disease was independently associated with shorter PFS (hazard ratio, 3.611; 95% CI, 1.904-6.848; p<0.001), compared with bone-dominant disease in a multivariate analysis of PFS after adjusting for age, hormone receptor, human epidermal growth factor receptor 2, Ki-67 status, dominant metastasis site, and sensitivity to nonsteroidal aromatase inhibitor (AI) treatment. Sensitivity to previous nonsteroidal AI treatment was not associated with PFS, suggesting no cross-resistance between exemestane and nonsteroidal AIs. Conclusion Exemestane was effective in postmenopausal Korean women with hormone receptor-positive metastatic breast cancer who failed previous nonsteroidal AI treatment. PMID:23593084

Determination and risk assessment of naturally occurring genotoxic and carcinogenic alkenylbenzenes in nutmeg-based plant food supplements.

PubMed

Al-Malahmeh, Amer J; Alajlouni, Abdalmajeed M; Ning, Jia; Wesseling, Sebastiaan; Vervoort, Jacques; Rietjens, Ivonne M C M

2017-10-01

A risk assessment of nutmeg-based plant food supplements (PFS) containing different alkenylbenzenes was performed based on the alkenylbenzene levels quantified in a series of PFS collected via the online market. The estimated daily intake (EDI) of the alkenylbenzenes amounted to 0.3 to 312 μg kg -1 body weight (bw) for individual alkenylbenzenes, to 1.5 to 631 μg kg -1 bw when adding up the alkenylbenzene levels assuming equal potency, and to 0.4 to 295 μg kg -1 bw when expressed in safrole equivalents using toxic equivalency factors (TEFs). The margin of exposure approach (MOE) was used to evaluate the potential risks. Independent of the method used for the intake estimate, the MOE values obtained were generally lower than 10000 indicating a priority for risk management. When taking into account that PFS may be used for shorter periods of time and using Haber's rule to correct for shorter than lifetime exposure it was shown that limiting exposure to only 1 or 2 weeks would result in MOE values that would be, with the presently determined levels of alkenylbenzenes and proposed uses of the PFS, of low priority for risk management (MOE > 10000). It is concluded that the results of the present paper reveal that nutmeg-based PFS consumption following recommendations for daily intake especially for longer periods of time raise a concern. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

Treatment of children with recurrent high grade gliomas with a bevacizumab containing regimen.

PubMed

Parekh, Chintan; Jubran, Rima; Erdreich-Epstein, Anat; Panigrahy, Ashok; Bluml, Stefan; Finlay, Jonathan; Dhall, Girish

2011-07-01

Children with recurrent high grade gliomas (HGG) have a dismal outcome with a median progression free survival (PFS) of 12 weeks. Adults with recurrent HGG treated with irinotecan and bevacizumab reportedly have a 63% response rate and a median PFS of 23 weeks. There is a paucity of corresponding published pediatric data. We retrospectively reviewed the records of patients less than 21 years of age with recurrent or progressive WHO grade 3-4 gliomas who were treated with bevacizumab containing regimens at our institution between January 2006 and September 2008. We identified eight patients. Six out of eight patients received irinotecan, temozolomide and bevacizumab, one patient received irinotecan and bevacizumab, and one patient received CCNU and bevacizumab. Three patients had stable disease for 30-93 weeks. The remaining five patients developed progressive disease within 17 weeks. The median PFS was 15 weeks and the 6-month PFS was 38%. Contrast enhancing disease responded or remained stable in five out of seven patients whereas non-enhancing disease progressed in three out of four patients. New distant non-enhancing lesions developed in three patients. The most common side effects included diarrhea, vomiting, thrombocytopenia and neutropenia. Bevacizumab was well tolerated when used in combination with conventional chemotherapy (irinotecan in most cases). PFS in our cohort was much shorter and the response rate was inferior in this small cohort of patients when compared with published adult data. However, bevacizumab containing regimens might be effective in a subset of pediatric patients, especially those with predominantly contrast-enhancing disease.

The effect of icotinib combined with chemotherapy in untreated non-small-cell lung cancer that harbored EGFR-sensitive mutations in a real-life setting: a retrospective analysis

PubMed Central

Wang, Lulu; Li, Yan; Li, Luchun; Wu, Zhijuan; Yang, Dan; Ma, Huiwen; Wang, Donglin

2018-01-01

Purpose This study was conducted to compare the efficacy of a combination of icotinib and chemotherapy with icotinib or chemotherapy alone in untreated non-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR)-sensitive mutations and to analyze the curative effect of different treatments on different genetic mutations (EGFR 19 exon deletion and L858R mutation) in a real-life setting. Patients and methods One hundred ninety-one patients were studied in this retrospective analysis from January 2013 to December 2015. The baseline characteristics, curative effects and adverse events of patients were analyzed. The primary endpoint was progression free survival (PFS). Results Longer PFS and overall survival (OS), and better objective response rate (ORR) were observed in the combination group compared to icotinib or chemotherapy along. For patients with an EGFR 19 exon deletion, the PFS, OS, and ORR in the combination group were superior to those in the icotinib or chemotherapy group. For the patients with the EGFR L858R mutation, better PFS and ORR were observed in the combination group, but OS was not obviously prolonged. Grade 3 or 4 adverse events were most commonly reported with combination therapy or chemotherapy alone. No possible drug-related interstitial lung disease or of drug related deaths occurred. Conclusion The combination of icotinib and chemotherapy in patients with untreated NSCLC harboring sensitive EGFR mutations resulted in improved PFS and OS, especially in those who harbored the EGFR exon 19 deletion. PMID:29731642

BIOMECHANICAL DIFFERENCES IN BRAZILIAN JIU-JITSU ATHLETES: THE ROLE OF COMBAT STYLE

PubMed Central

Lima, Alane Almeida; Coelho, Anita Camila Sampaio; Lima, Yuri Lopes; Almeida, Gabriel Peixoto Leão; Bezerra, Márcio Almeida; de Oliveira, Rodrigo Ribeiro

2017-01-01

Background Brazilian Jiu-Jitsu (BJJ) athletes can be divided into two combat styles: pass fighters (PFs) and guard fighters (GFs). Flexibility of the posterior chain muscles is highly necessary in these athletes, especially in GFs. On the other hand, isometric strength of the trunk extensors is required in PFs. Handgrip strength is important in holding the kimono of the opponent, and symmetrical lower-limb strength is important for the prevention of injuries due to the overload caused by training. Purpose The aim of this study was to compare the biomechanical profiles of BJJ athletes with different combat styles using the following outcome measures: flexibility, trunk extensor isometric endurance, postural balance, handgrip isometric endurance and lower-limb muscle strength. Methods A cross-sectional study was conducted using 19 GFs and 19 PFs. The sit-and-reach test was used to evaluate the flexibility of the posterior chain muscles. The Biodex Balance System® was used to evaluate balance. A handgrip dynamometer and a dorsal dynamometer were used to evaluate handgrip and trunk extensor endurance, respectively. Quadriceps and hamstring strength were evaluated with an isokinetic dynamometer at 60 °/s. Results No differences were observed between groups in terms of flexibility, balance, handgrip isometric endurance or quadriceps and hamstring strength; however, PFs (81.33) showed more isometric trunk extension endurance than GFs (68.85) (p = 0.02). Both groups had low values for hamstring/quadriceps ratio. Conclusion No significant biomechanical differences were observed between PFs and GFs. Level of Evidence 2b PMID:28217417

Adaptive Algorithm for Aircraft Configuration in Turbulent Flow

DTIC Science & Technology

1992-11-25

8217), + a2 (APO) (bUo)),2 + r4 (1 - APO) (bUO), (27) AP is the pressure switch chat is used to turn the shock smoothing and the background smoothing on at...the appropriate regions. For any node 0, the pressure switch is computed as (APo)= E𔃻=1 (PN()- PO) (28) zF:,’ + PO) the summation is over all the edges...that share the node 0. The pressure switch is normalized by the maximum value over the domain so that 0 < AP < 1. When evaluated as above, AP has a

Computational Modeling of Three-Dimensional Compressible Leading Edge Vortices

DTIC Science & Technology

1989-04-10

Ui_ .,, w (U,) = U,, +f - U,,_i. (10) The fourth-order damping is unweighted, and of the form D(U) = V4 [s:U + siU]. (11) The pressure switch in...edge. This was done by setting the pressure switch to 1 in a few cells in this region. Values of P2 = .05 and v4 = .01 were used for the calculations...effective numerical Reynolds number .- i which varies throughout the flow field due to mesh resolution, the magnitude of the pressure switch , and the value

Early Intervention for Preschoolers at Risk for Attention-Deficit/Hyperactivity Disorder: Preschool First Step to Success

ERIC Educational Resources Information Center

Feil, Edward G.; Small, Jason W.; Seeley, John R.; Walker, Hill M.; Golly, Annemieke; Frey, Andy; Forness, Steven R.

2016-01-01

This study evaluated the efficacy of the Preschool First Step (PFS) to Success early intervention for children at risk for attention deficit hyperactivity disorder (ADHD). PFS is a targeted intervention for children 3-5 years old with externalizing behavior problems and addresses secondary prevention goals and objectives. As part of a larger…

Accuracy of Person-Fit Statistics: A Monte Carlo Study of the Influence of Aberrance Rates

ERIC Educational Resources Information Center

St-Onge, Christina; Valois, Pierre; Abdous, Belkacem; Germain, Stephane

2011-01-01

Using a Monte Carlo experimental design, this research examined the relationship between answer patterns' aberrance rates and person-fit statistics (PFS) accuracy. It was observed that as the aberrance rate increased, the detection rates of PFS also increased until, in some situations, a peak was reached and then the detection rates of PFS…

Intake of selected bioactive compounds from plant food supplements containing fennel (Foeniculum vulgare) among Finnish consumers.

PubMed

Uusitalo, Liisa; Salmenhaara, Maija; Isoniemi, Merja; Garcia-Alvarez, Alicia; Serra-Majem, Lluís; Ribas-Barba, Lourdes; Finglas, Paul; Plumb, Jenny; Tuominen, Pirkko; Savela, Kirsti

2016-03-01

The purpose of this study was to estimate the intake of selected bioactive compounds from fennel-containing plant food supplements (PFS) among Finnish consumers. The estimated average intake of estragole was 0.20mg/d, of trans-anethole 1.15mg/d, of rosmarinic acid 0.09mg/d, of p-coumaric acid 0.0068mg/d, of kaempferol 0.0034mg/d, of luteolin 0.0525μg/d, of quercetin 0.0246mg/d, of matairesinol 0.0066μg/d and of lignans 0.0412μg/d. The intakes of kaempferol, quercetin, luteolin, matairesinol and lignans from PFS were low in comparison with their dietary supply. The intake of estragole was usually moderate, but a heavy consumption of PFS may lead to a high intake of estragole. The intake of trans-anethole did not exceed the acceptable daily intake, but PFS should be taken into account when assessing the total exposure. To our knowledge, this study provided the first intake estimates of trans-anethole, p-coumaric acid and rosmarinic acid in human populations. Copyright © 2015 Elsevier Ltd. All rights reserved.

Critical evaluation of methods to incorporate entropy loss upon binding in high-throughput docking.

PubMed

Salaniwal, Sumeet; Manas, Eric S; Alvarez, Juan C; Unwalla, Rayomand J

2007-02-01

Proper accounting of the positional/orientational/conformational entropy loss associated with protein-ligand binding is important to obtain reliable predictions of binding affinity. Herein, we critically examine two simplified statistical mechanics-based approaches, namely a constant penalty per rotor method, and a more rigorous method, referred to here as the partition function-based scoring (PFS) method, to account for such entropy losses in high-throughput docking calculations. Our results on the estrogen receptor beta and dihydrofolate reductase proteins demonstrate that, while the constant penalty method over-penalizes molecules for their conformational flexibility, the PFS method behaves in a more "DeltaG-like" manner by penalizing different rotors differently depending on their residual entropy in the bound state. Furthermore, in contrast to no entropic penalty or the constant penalty approximation, the PFS method does not exhibit any bias towards either rigid or flexible molecules in the hit list. Preliminary enrichment studies using a lead-like random molecular database suggest that an accurate representation of the "true" energy landscape of the protein-ligand complex is critical for reliable predictions of relative binding affinities by the PFS method. Copyright 2006 Wiley-Liss, Inc.

Plasma Torch for Plasma Ignition and Combustion of Coal

NASA Astrophysics Data System (ADS)

Ustimenko, Alexandr; Messerle, Vladimir

2015-09-01

Plasma-fuel systems (PFS) have been developed to improve coal combustion efficiency. PFS is a pulverized coal burner equipped with arc plasma torch producing high temperature air stream of 4000 - 6000 K. Plasma activation of coal at the PFS increases the coal reactivity and provides more effective ignition and ecologically friendly incineration of low-rank coal. The main and crucial element of PFS is plasma torch. Simplicity and reliability of the industrial arc plasma torches using cylindrical copper cathode and air as plasma forming gas predestined their application at heat and power engineering for plasma aided coal combustion. Life time of these plasma torches electrodes is critical and usually limited to 200 hours. Considered in this report direct current arc plasma torch has the cathode life significantly exceeded 1000 hours. To ensure the electrodes long life the process of hydrocarbon gas dissociation in the electric arc discharge is used. In accordance to this method atoms and ions of carbon from near-electrode plasma deposit on the active surface of the electrodes and form electrode carbon condensate which operates as ``actual'' electrode. Complex physicochemical investigation showed that deposit consists of nanocarbon material.

In vitro erythemal UV-A protection factors of inorganic sunscreens distributed in aqueous media using carnauba wax-decyl oleate nanoparticles.

PubMed

Villalobos-Hernández, J R; Müller-Goymann, C C

2007-01-01

This paper describes the in vitro photoprotection in the UV-A range, i.e. 320-400 nm obtained by the use of carnauba wax-decyl oleate nanoparticles either as encapsulation systems or as accompanying vehicles for inorganic sunscreens such as barium sulfate, strontium carbonate and titanium dioxide. Lipid-free inorganic sunscreen nanosuspensions, inorganic sunscreen-free wax-oil nanoparticle suspensions and wax-oil nanoparticle suspensions containing inorganic sunscreens dispersed either in their oil phase or their aqueous phase were prepared by high pressure homogenization. The in vitro erythemal UV-A protection factors (EUV-A PFs) of the nanosuspensions were calculated by means of a sun protection analyzer. EUV-A PFs being no higher than 4 were obtained by the encapsulation of barium sulfate and strontium carbonate, meanwhile by the distribution of titanium dioxide in presence of wax-oil nanoparticles, the EUV-A PFs varied between 2 and 19. The increase in the EUV-A PFs of the titanium dioxide obtained by the use of wax-oil nanoparticles demonstrated a better performance of the sun protection properties of this pigment in the UV-A region.

LMD Based Features for the Automatic Seizure Detection of EEG Signals Using SVM.

PubMed

Zhang, Tao; Chen, Wanzhong

2017-08-01

Achieving the goal of detecting seizure activity automatically using electroencephalogram (EEG) signals is of great importance and significance for the treatment of epileptic seizures. To realize this aim, a newly-developed time-frequency analytical algorithm, namely local mean decomposition (LMD), is employed in the presented study. LMD is able to decompose an arbitrary signal into a series of product functions (PFs). Primarily, the raw EEG signal is decomposed into several PFs, and then the temporal statistical and non-linear features of the first five PFs are calculated. The features of each PF are fed into five classifiers, including back propagation neural network (BPNN), K-nearest neighbor (KNN), linear discriminant analysis (LDA), un-optimized support vector machine (SVM) and SVM optimized by genetic algorithm (GA-SVM), for five classification cases, respectively. Confluent features of all PFs and raw EEG are further passed into the high-performance GA-SVM for the same classification tasks. Experimental results on the international public Bonn epilepsy EEG dataset show that the average classification accuracy of the presented approach are equal to or higher than 98.10% in all the five cases, and this indicates the effectiveness of the proposed approach for automated seizure detection.

B-IGEV (bortezomib plus IGEV) versus IGEV before high-dose chemotherapy followed by autologous stem cell transplantation in relapsed or refractory Hodgkin lymphoma: a randomized, phase II trial of the Fondazione Italiana Linfomi (FIL).

PubMed

Balzarotti, Monica; Brusamolino, Ercole; Angelucci, Emanuele; Carella, Angelo Michele; Vitolo, Umberto; Russo, Eleonora; Congiu, Angelagiovanna; Gotti, Manuel; Massidda, Stefania; Botto, Barbara; Annechini, Giorgia; Spina, Michele; Re, Alessandro; Zilioli, Vittorio Ruggero; Merli, Francesco; Salvi, Flavia; Stelitano, Caterina; Bonfichi, Maurizio; Rodari, Marcello; Murru, Roberta; Magagnoli, Massimo; Anastasia, Antonella; Mazza, Rita; Giordano, Laura; Santoro, Armando

2016-10-01

This randomized, multicenter study evaluates the addition of bortezomib (13 mg/m(2)) to IGEV (B-IGEV) in patients with relapsed/refractory Hodgkin Lymphoma (HL). Patients received either four courses of IGEV alone (n = 40) or B-IGEV (n = 40). The primary endpoint was the complete response (CR) proportion, evaluated by FDG-PET, after induction chemotherapy. CR proportion was 39% with B-IGEV and 53% with IGEV. PFS and OS were similar between the two groups (two-year PFS: 58% vs 56%; two-year OS: 93% vs 81%). The PET-negative status after treatment was the only variable favorably influencing both PFS (two-year PFS: 77% vs 40%; p = 0.002) and OS (two-year OS: 100% vs 76%; p < 0.001). Toxicity was overall similar with the two regimens. The addition of bortezomib to IGEV does not improve response in relapsed/refractory HL patients. However, its favorable therapeutic and safety profile, and the prognostic role of pre-transplant PET negativity in patients receiving IGEV-based regimens are confirmed.

A two-stage patient enrichment adaptive design in phase II oncology trials.

PubMed

Song, James X

2014-01-01

Illustrated is the use of a patient enrichment adaptive design in a randomized phase II trial which allows the evaluation of treatment benefits by the biomarker expression level and makes interim adjustment according to the pre-specified rules. The design was applied to an actual phase II metastatic hepatocellular carcinoma (HCC) trial in which progression-free survival (PFS) in two biomarker-defined populations is evaluated at both interim and final analyses. As an extension, a short-term biomarker is used to predict the long-term PFS in a Bayesian model in order to improve the precision of hazard ratio (HR) estimate at the interim analysis. The characteristics of the extended design are examined in a number of scenarios via simulations. The recommended adaptive design is shown to be useful in a phase II setting. When a short-term maker which correlates with the long-term PFS is available, the design can be applied in smaller early phase trials in which PFS requires longer follow-up. In summary, the adaptive design offers flexibility in randomized phase II patient enrichment trials and should be considered in an overall personalized healthcare (PHC) strategy. Copyright © 2013 Elsevier Inc. All rights reserved.

Prognostic Significance of Blood Transfusion in Elderly Patients with Primary Diffuse Large B-Cell Lymphoma

PubMed Central

Fan, Liping; Fu, Danhui; Hong, Jinquan; He, Wenqian; Zeng, Feng; Lin, Qiuyan; Xie, Qianling

2018-01-01

The current study sought to evaluate whether blood transfusions affect survival of elderly patients with primary diffuse large B-cell lymphoma (DLBCL). A total of 104 patients aged 60 years and over were enrolled and divided into two groups: 24 patients who received transfusions and 80 patients who did not. Statistical analyses showed significant differences in LDH levels, platelet (Plt) counts, and hemoglobin (Hb) and albumin (Alb) levels between the two groups. Univariate analyses showed that LDH level ≥ 245 IU/L, cell of origin (germinal center/nongerminal center), and blood transfusion were associated with both overall survival (OS) and progression-free survival (PFS). Higher IPI (3–5), Alb level < 35 g/L, and rituximab usage were associated with OS. Appearance of B symptoms was associated with PFS. Multivariate analyses showed that cell of origin and rituximab usage were independent factors for OS and LDH level was an independent factor for PFS. Blood transfusion was an independent factor for PFS, but not for OS. Our preliminary results suggested that elderly patients with primary DLBCL may benefit from a restrictive blood transfusion strategy. PMID:29750167

Lymphocyte-to-monocyte ratio is associated with survival in pembrolizumab-treated metastatic melanoma patients.

PubMed

Failing, Jarrett J; Yan, Yiyi; Porrata, Luis F; Markovic, Svetomir N

2017-12-01

The peripheral blood lymphocyte-to-monocyte ratio (LMR) has been associated with prognosis in many malignancies including metastatic melanoma. However, it has not been studied in patients treated with immune checkpoint inhibitors. In this study, we analyzed the baseline LMR with progression-free survival (PFS) and overall survival (OS) in metastatic melanoma patients treated with pembrolizumab. A total of 133 patients with metastatic melanoma treated with pembrolizumab were included in this retrospective study. LMR was calculated from pretherapy peripheral blood counts and the optimal cutoff value was determined by a receiver operator characteristic curve. PFS and OS were evaluated using the Kaplan-Meier method and multivariate Cox proportional hazard modeling. Patients with an LMR of at least 1.7 showed improved PFS (hazard ratio=0.55; 95% confidence interval: 0.34-0.92; P=0.024) and OS (hazard ratio=0.29; 95% confidence interval: 0.15-0.59; P=0.0007). The baseline LMR is associated with PFS and OS in metastatic melanoma patients treated with pembrolizumab, and could represent a convenient and cost-effective prognostic biomarker. Validation of these findings in an independent cohort is needed.

Epithermal Neutron Evidence for a Diurnal Surface Hydration Process in the Moon's High Latitudes

NASA Technical Reports Server (NTRS)

McClanahan, T. P.; Mitrofanov, I. G.; Boynton, W. V.; Chin, G.; Parsons, A.; Starr, R. D.; Evans, L. G.; Sanin, A.; Litvak, M.; Livengood, T.

2015-01-01

We report evidence from epithermal neutron flux observations that show that the Moon's high latitude surfaces are being actively hydrated, dehydrated and rehydrated in a diurnal cycle. The near-surface hydration is indicated by an enhanced suppression of the lunar epithermal neutron leakage flux on the dayside of the dawn terminator on poleward-facing slopes (PFS). At 0600 to 0800 local-time, hydrogen concentrations within the upper 1 meter of PFS are observed to be maximized relative to equivalent equator-facing slopes (EFS). During the lunar day surface hydrogen concentrations diminish towards dusk and then rebuild overnight. Surface hydration is determined by differential comparison of the averaged EFS to PFS epithermal neutron count rates above +/- 75 deg latitude. At dawn the contrast bias towards PFS is consistent with at least 15 to 25 parts-per-million (ppm) hydrogen that dissipates by dusk. We review several lines of evidence derived from temperature and epithermal neutron data by a correlated analysis of observations from the Lunar Reconnaissance Orbiter's (LRO) Lunar Exploration Neutron Detector (LEND) that were mapped as a function of lunar local-time, Lunar Observing Laser Altimeter (LOLA) topography and Diviner (DLRE) surface temperature.

Perceived family support and depression among people living with HIV/AIDS in the Kathmandu Valley, Nepal.

PubMed

Shrestha, Sadhana; Poudel, Krishna C; Poudel-Tandukar, Kalpana; Kobayashi, Jun; Pandey, Basu Dev; Yasuoka, Junko; Otsuka, Keiko; Jimba, Masamine

2014-01-01

Depression is emerging as a highly prevalent psychiatric condition among people living with HIV/AIDS (PLWHA). Perceived family support (PFS) buffers depression among chronic disease patients. However, a similar relationship among PLWHA is unexplored. To examine the relationship between PFS and depression among PLWHA in the Kathmandu Valley, Nepal. In this cross-sectional study, depression was measured by Beck Depression Inventory Ia. Perceived family support was measured by Nepali Family Support and Difficulties Scale. The status of depression was compared between 208 PLWHA and 208 HIV-negative participants. The relationship between PFS and depression was examined only among PLWHA. Among each of the 208 participants, the number of depressed PLWHA (n = 61,29.3%) was higher than that of HIV-negative participants (n = 13,6.2%; P < .001). Perceived family support had a negative association with depression in PLWHA (adjusted odds ratio [AOR] = 0.20, 95% confidence interval [CI] = 0.08-0.53). In Nepal, PLWHA display a higher level of depression than HIV-negative people, and a lower level of PFS is associated with depression among PLWHA. Improved family support might be helpful in reducing depression among Nepalese PLWHA.

Methods and Apparatus for Pulsed-DC Dielectric Barrier Discharge Plasma Actuator and Circuit

NASA Technical Reports Server (NTRS)

Corke, Thomas C. (Inventor); Gold, Calman (Inventor); Kaszeta, Richard (Inventor)

2017-01-01

A plasma generating device intended to induce a flow in a fluid via plasma generation includes a dielectric separating two electrodes and a power supply. The first electrode is exposed to a fluid flow while the second electrode is positioned under the dielectric. The power supply is electrically coupled to a switch and the first and second electrodes. When the power supply is energized by repeated action of the switch, it causes a pulsed DC current between the electrodes which causes the fluid to ionize generating a plasma. The generation of the plasma induces a force with a velocity component in the fluid.

Light-weight DC to very high voltage DC converter

DOEpatents

Druce, R.L.; Kirbie, H.C.; Newton, M.A.

1998-06-30

A DC-DC converter capable of generating outputs of 100 KV without a transformer comprises a silicon opening switch (SOS) diode connected to allow a charging current from a capacitor to flow into an inductor. When a specified amount of charge has flowed through the SOS diode, it opens up abruptly; and the consequential collapsing field of the inductor causes a voltage and current reversal that is steered into a load capacitor by an output diode. A switch across the series combination of the capacitor, inductor, and SOS diode closes to periodically reset the SOS diode by inducing a forward-biased current. 1 fig.

Inventions Utilizing Microfluidics and Colloidal Particles

NASA Technical Reports Server (NTRS)

Marr, David W.; Gong, Tieying; Oakey, John; Terray, Alexander V.; Wu, David T.

2009-01-01

Several related inventions pertain to families of devices that utilize microfluidics and/or colloidal particles to obtain useful physical effects. The families of devices can be summarized as follows: (1) Microfluidic pumps and/or valves wherein colloidal-size particles driven by electrical, magnetic, or optical fields serve as the principal moving parts that propel and/or direct the affected flows. (2) Devices that are similar to the aforementioned pumps and/or valves except that they are used to manipulate light instead of fluids. The colloidal particles in these devices are substantially constrained to move in a plane and are driven to spatially order them into arrays that function, variously, as waveguides, filters, or switches for optical signals. (3) Devices wherein the ultra-laminar nature of microfluidic flows is exploited to effect separation, sorting, or filtering of colloidal particles or biological cells in suspension. (4) Devices wherein a combination of confinement and applied electrical and/or optical fields forces the colloidal particles to become arranged into three-dimensional crystal lattices. Control of the colloidal crystalline structures could be exploited to control diffraction of light. (5) Microfluidic devices, incorporating fluid waveguides, wherein switching of flows among different paths would be accompanied by switching of optical signals.

Pressure-Aware Control Layer Optimization for Flow-Based Microfluidic Biochips.

PubMed

Wang, Qin; Xu, Yue; Zuo, Shiliang; Yao, Hailong; Ho, Tsung-Yi; Li, Bing; Schlichtmann, Ulf; Cai, Yici

2017-12-01

Flow-based microfluidic biochips are attracting increasing attention with successful biomedical applications. One critical issue with flow-based microfluidic biochips is the large number of microvalves that require peripheral control pins. Even using the broadcasting addressing scheme, i.e., one control pin controls multiple microvalves simultaneously, thousands of microvalves would still require hundreds of control prins, which is unrealistic. To address this critical challenge in control scalability, the control-layer multiplexer is introduced to effectively reduce the number of control pins into log scale of the number of microvalves. There are two practical design issues with the control-layer multiplexer: (1) the reliability issue caused by the frequent control-valve switching, and (2) the pressure degradation problem caused by the control-valve switching without pressure refreshing from the pressure source. This paper addresses these two design issues by the proposed Hamming-distance-based switching sequence optimization method and the XOR-based pressure refreshing method. Simulation results demonstrate the effectiveness and efficiency of the proposed methods with an average 77.2% (maximum 89.6%) improvement in total pressure refreshing cost, and an average 88.5% (maximum 90.0%) improvement in pressure deviation.

The Additional Costs per Month of Progression-Free Survival and Overall Survival: An Economic Model Comparing Everolimus with Cabozantinib, Nivolumab, and Axitinib for Second-Line Treatment of Metastatic Renal Cell Carcinoma.

PubMed

Swallow, Elyse; Messali, Andrew; Ghate, Sameer; McDonald, Evangeline; Duchesneau, Emilie; Perez, Jose Ricardo

2018-04-01

When considering optimal second-line treatments for metastatic renal cell carcinoma (mRCC), clinicians and payers seek to understand the relative clinical benefits and costs of treatment. To use an economic model to compare the additional cost per month of overall survival (OS) and of progression-free survival (PFS) for cabozantinib, nivolumab, and axitinib with everolimus for the second-line treatment of mRCC from a third-party U.S. payer perspective. The model evaluated mean OS and PFS and costs associated with drug acquisition/administration; adverse event (AE) treatment; monitoring; and postprogression (third-line treatment, monitoring, and end-of-life costs) over 1- and 2-year horizons. Efficacy, safety, and treatment duration inputs were estimated from regimens' pivotal clinical trials; for everolimus, results were weighted across trials. Mean 1- and 2-year OS and mean 1-year PFS were estimated using regimens' reported OS and PFS Kaplan-Meier curves. Dosing and administration inputs were consistent with approved prescribing information and the clinical trials used to estimate efficacy and safety inputs. Cost inputs came from published literature and public data. Additional cost per additional month of OS or PFS was calculated using the ratio of the cost difference per treated patient and the corresponding difference in mean OS or PFS between everolimus and each comparator. One-way sensitivity analyses were conducted by varying efficacy and cost inputs. Compared with everolimus, cabozantinib, nivolumab, and axitinib were associated with 1.6, 0.3, and 0.5 additional months of PFS, respectively, over 1 year. Cabozantinib and nivolumab were associated with additional months of OS compared with everolimus (1 year: 0.7 and 0.8 months; 2 years: 1.6 and 2.3 months; respectively); axitinib was associated with fewer months (1 year: -0.2 months; 2 years: -0.7 months). The additional costs of treatment with cabozantinib, nivolumab, or axitinib versus everolimus over 1 year were $34,141, $19,371, and $17,506 higher, respectively. Everolimus had similar OS and lower costs compared with axitinib. The additional cost per month of OS was $48,773 for cabozantinib and $24,214 for nivolumab versus everolimus. The additional treatment cost with cabozantinib, nivolumab, or axitinib versus everolimus for each additional month of PFS was estimated at $21,338, $64,570, and $35,012, respectively. Over 2 years, the additional costs per additional month of OS for nivolumab and axitinib versus everolimus were similar to the 1-year analysis; for cabozantinib, the cost was lower. Results were sensitive to changes in mean OS, mean PFS, therapy duration, and drug costs estimates. Everolimus for second-line mRCC was associated with similar OS and lower costs compared with axitinib over 1- and 2-year horizons. The additional cost per additional month of OS and PFS associated with cabozantinib or nivolumab versus everolimus creates a metric for evaluating the cost of second-line therapies in relation to their respective treatment effects. Funding for this research was provided by Novartis, which was involved in all stages of study research and manuscript preparation. Ghate and Perez are employees of Novartis and own stock/stock options. Swallow, Messali, McDonald, and Duchesneau are employees of Analysis Group, which has received consultancy fees from Novartis. Study concept and design were contributed by Swallow, Messali, Ghate, and Perez, along with McDonald and Duchesneau. Swallow, Messali, McDonald, and Duchesneau collected the data, and all authors participated in data interpretation. The manuscript was written by Swallow, Messali, and Ghate, along with the other authors, and revised by Swallow, Messali, Ghate, and Perez. A synopsis of the current research was presented in poster format at the 15th International Kidney Cancer Symposium on November 4-5, 2016, in Miami, Florida.

[Value of surgery for stage IIIa non-small cell lung cancer].

PubMed

Liu, Huihui; Wang, Mengzhao; Hu, Ke; Xu, Yan; Ma, Manjiao; Zhong, Wei; Zhao, Jing; Li, Longyun; Wang, Huazhu

2013-12-01

Nowadays, comprehensive treatment, including surgery, chemotherapy and radiotherapy is advocated for stage III non-small cell lung cancer (NSCLC). However, many researchers have questioned the effectiveness of surgery. The aim of this study is to evaluate the effect of surgery for stage III NSCLC. Between March 2002 and October 2012, 310 cases that have completed followed-up data with stage III NSCLC were received in the Peking Union Medical College Hospital. They were divided into surgical and non-surgical groups according to whether received surgery when diagnosed. In TNM staging, stage III NSCLC includes stage IIIa and IIIb, and stage IIIa NSCLC can be grouped into stage T4N0/T3-4N1M0 and T1-3N2M0 according to different N stages. Analyzed the enumeration data by Chi-Square test. Kaplan-Meier survival method was used to calculate the overall survival (OS) and progression-free survival (PFS), and to draw the survival curves. A P value less than 0.05 was evaluated as statistically significant. Three hundred and ten stage III NSCLC patients include surgical group 189 cases and non-surgical group 121 cases. One hundred and eighty-eight stage IIIa NSCLC patients include surgical group 152 cases and non-surgical group 36 cases. In stage IIIa, stage T4N0/T3-4N1M0 had 57 patients with 44 surgical and 13 non-surgical patients, and stage T1-3N2M0 had 131 patients with 108 surgical and 23 non-surgical patients. Thirty-seven out of 121 stage IIIb NSCLC patients received surgery. They had 22 stage T4N2M0 cases and 15 stage T1-4N3M0 cases. The patient whose performance status was 0 and staging was stage IIIa was more inclined to undergo surgery. For stage IIIa NSCLC patients, the median OS of surgical and non-surgical groups were 38.9 and 21.8 months, and the median PFS of them were 19.2 and 11.9 months respectively. The difference of OS between the two groups was significant (P=0.041), but the PFS of them had no significant difference (P=0.209). For stage T4N0/T3-4N1M0 which belongs to stage IIIa, the median OS of surgical and non-surgical groups were 48.7 and 20.1 months, and the median PFS of them were 14.6 and 10.5 months respectively. There were no significant differences of OS and PFS between the two groups (P>0.05). For stage T1-3N2M0 which also belongs to stage IIIa, the median OS of surgical and non-surgical groups were 38.9 and 30.8 months, and the median PFS of them were 19.8 and 12.7 months respectively. There were also no significant differences of OS and PFS between the two groups (P>0.05). The maximum diameter of tumor and auxillary chemotherapy had significant influences on OS and PFS of stage IIIa-N2 NSCLC patients, while the histology of tumor only influenced the OS of them (P<0.05). The patient whose performance status is 0 and staging is stage IIIa is more inclined to undergo surgery. Surgery can prolong OS of patients with stage IIIa, especially for stage T4N0/T3-4N1M0. However, it has no benefit on PFS. The maximum diameter of tumor and auxillary chemotherapy have significant influences on OS and PFS of stage IIIa-N2 NSCLC patients, while the histology of tumor only influence the OS of them.

A graphene-based non-volatile memory

NASA Astrophysics Data System (ADS)

Loisel, Loïc.; Maurice, Ange; Lebental, Bérengère; Vezzoli, Stefano; Cojocaru, Costel-Sorin; Tay, Beng Kang

2015-09-01

We report on the development and characterization of a simple two-terminal non-volatile graphene switch. After an initial electroforming step during which Joule heating leads to the formation of a nano-gap impeding the current flow, the devices can be switched reversibly between two well-separated resistance states. To do so, either voltage sweeps or pulses can be used, with the condition that VSET < VRESET , where SET is the process decreasing the resistance and RESET the process increasing the resistance. We achieve reversible switching on more than 100 cycles with resistance ratio values of 104. This approach of graphene memory is competitive as compared to other graphene approaches such as redox of graphene oxide, or electro-mechanical switches with suspended graphene. We suggest a switching model based on a planar electro-mechanical switch, whereby electrostatic, elastic and friction forces are competing to switch devices ON and OFF, and the stability in the ON state is achieved by the formation of covalent bonds between the two stretched sides of the graphene, hence bridging the nano-gap. Developing a planar electro-mechanical switch enables to obtain the advantages of electro-mechanical switches while avoiding most of their drawbacks.

Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer

PubMed Central

Jänne, P A; Smith, I; McWalter, G; Mann, H; Dougherty, B; Walker, J; Orr, M C M; Hodgson, D R; Shaw, A T; Pereira, J R; Jeannin, G; Vansteenkiste, J; Barrios, C H; Franke, F A; Crinò, L; Smith, P

2015-01-01

Background: Selumetinib (AZD6244, ARRY-142886)+docetaxel increases median overall survival (OS) and significantly improves progression-free survival (PFS) and objective response rate (ORR) compared with docetaxel alone in patients with KRAS mutant, stage IIIB/IV non-small-cell lung cancer (NSCLC; NCT00890825). Methods: Retrospective analysis of OS, PFS, ORR and change in tumour size at week 6 for different sub-populations of KRAS codon mutations. Results: In patients receiving selumetinib+docetaxel and harbouring KRAS G12C or G12V mutations there were trends towards greater improvement in OS, PFS and ORR compared with other KRAS mutations. Conclusion: Different KRAS mutations in NSCLC may influence selumetinib/docetaxel sensitivity. PMID:26125448

Switching to a 10-day Mediterranean-style diet improves mood and cardiovascular function in a controlled crossover study.

PubMed

Lee, Jaime; Pase, Matthew; Pipingas, Andrew; Raubenheimer, Jessica; Thurgood, Madeline; Villalon, Lorena; Macpherson, Helen; Gibbs, Amy; Scholey, Andrew

2015-05-01

Even short-term adherence to a Mediterranean-style diet may benefit aspects of psychological functioning. The aim of the present study was to assess the effects of switching to a 10-d Mediterranean-style diet on mood, cognition, and cardiovascular measures. Using a crossover design, 24 women were randomly assigned to either the diet change (where they switched to a Mediterranean-style diet) or no diet change (normal diet) condition for 10 days before switching to the other condition for the same duration. Mood, cognition, and cardiovascular measures of blood pressure, blood flow velocity, and arterial stiffness were assessed at baseline and at the completion of the two diets (days 11 and 22). Independent of whether the Mediterranean-style diet was undertaken before or after the crossover, it was associated with significantly elevated contentment and alertness, and significantly reduced confusion. Additionally, aspects of cognition, such as memory recall, improved significantly as a result of switching to the Mediterranean-style diet. Regarding cardiovascular measures, there was a significant reduction in augmentation pressure associated with the Mediterranean-style diet intervention, but blood flow velocity through the common carotid artery did not change. This Mediterranean-style diet has the potential to enhance aspects of mood, cognition, and cardiovascular function in a young, healthy adult sample. Copyright © 2015 Elsevier Inc. All rights reserved.

Prime Focus Spectrograph: A very wide-field, massively multiplexed, optical & near-infrared spectrograph for Subaru Telescope

NASA Astrophysics Data System (ADS)

Tamura, Naoyuki

This short article is about Prime Focus Spectrograph (PFS), a very wide-field, massively-multiplexed, and optical & near-infrared (NIR) spectrograph as a next generation facility instrument on Subaru Telescope. More details and updates are available on the PFS official website (http://pfs.ipmu.jp), blog (http://pfs.ipmu.jp/blog/), and references therein. The project, instrument, & timeline PFS will position 2400 fibers to science targets or blank sky in the 1.3 degree field on the Subaru prime focus. These fibers will be quickly (~60sec) reconfigurable and feed the photons during exposures to the Spectrograph System (SpS). SpS consists of 4 modules each of which accommodate ~600 fibers and deliver spectral images ranging from 380nm to 1260nm simultaneously at one exposure via the 3 arms of blue, red, and NIR cameras. The instrument development has been undertaken by the international collaboration at the initiative of Kavli IPMU. The project is now going into the construction phase aiming at system integration and on-sky engineering observations in 2017-2018, and science operation in 2019. The survey design has also been under development envisioning a survey spanning ~300 nights over ~5 years in the framework of Subaru Strategic Program (SSP). The key science areas are: Cosmology, galaxy/AGN evolution, and Galactic Archaeology (GA) (Takada et al. 2014). The cosmology program will be to constrain the nature of dark energy via a survey of emission line galaxies over a comoving volume of 10 Gpc3 at z=0.8-2.4. In the galaxy/AGN program, the wide wavelength coverage of PFS as well as the large field of view will be exploited to characterize the galaxy populations and its clustering properties over a wide redshift range. A survey of color-selected galaxies/AGN at z = 1-2 will be conducted over 20 square degrees yielding a fair sample of galaxies with stellar masses down to ~1010 M ⊙. In the GA program, radial velocities and chemical abundances of stars in the Milky Way, dwarf spheroids, and M31 will be used to understand the past assembly histories of those galaxies and the structures of their dark matter halos. Spectra will be taken for 1 million stars as faint as V = 22 mag therefore out to large distances from the Sun. PFS will provide powerful spectroscopic capabilities even in the era of Euclid, LSST, WFIRST and TMT, and the effective synergies are expected for further unique science outputs.

Correlation between TS, MTHFR, and ERCC1 gene polymorphisms and the efficacy of platinum in combination with pemetrexed first-line chemotherapy in mesothelioma patients.

PubMed

Powrózek, Tomasz; Kowalski, Dariusz M; Krawczyk, Paweł; Ramlau, Rodryg; Kucharczyk, Tomasz; Kalinka-Warzocha, Ewa; Knetki-Wróblewska, Magdalena; Winiarczyk, Kinga; Dyszkiewicz, Wojciech; Krzakowski, Maciej; Milanowski, Janusz

2014-11-01

The combination of pemetrexed and platinum compound represents the standard regimen for first-line chemotherapy in malignant pleural mesothelioma patients. Pemetrexed is a multitarget antifolate agent that inhibits folate-dependent enzymes (eg, thymidylate synthase [TS]) and thus synthesis of nucleotides and DNA. Expression of TS and folate availability, regulated by gene polymorphisms, have implications for effectiveness of chemotherapy and the outcome of mesothelioma patients. The aim of this retrospective multicenter study was to assess the correlation between TS, 5,10-methylenetetrahydrofolate reductase (MTHFR) and excision repair cross-complementing group 1 (ERCC1) gene polymorphisms and the efficacy of pemetrexed-based first-line chemotherapy of mesothelioma patients. Fifty-nine mesothelioma patients (31 men with a median age of 62 years) treated in first-line chemotherapy with platinum in combination with pemetrexed or pemetrexed monotherapy were enrolled. Genomic DNA was isolated from peripheral blood. Using polymerase chain reaction and high resolution melt methods, the variable number of tandem repeat, the G>C single nucleotide polymorphism (SNP) in these repeats, and 6-base pair (bp) insertion/deletion polymorphism of the TS gene, the SNP of 677C>T in MTHFR, and 19007C>T in the ERCC1 gene were analyzed and correlated with disease control rate, progression-free survival (PFS), and overall survival (OS) of mesothelioma patients. Greater risk of early disease progression (PD), and shortening of PFS and OS were associated with several clinical factors (eg, anemia for early PD and OS), weight loss (for PFS and OS), and previous surgical treatment (for early PD, PFS, and OS). Insertion of 6-bp in both alleles of the TS gene (1494del6) was the only genetic factor that increased the incidence of early progression (P = .028) and shortening of median PFS (P = .06) in patients treated with pemetrexed-based chemotherapy. In multivariate analysis, the 1494del6 in the 3' untranslated region (UTR) of the TS gene also had a predictive role for PFS (P = .0185; hazard ratio, 2.3258 for +6/+6 homozygotes) in analyzed mesothelioma patients. Most analyzed polymorphisms in TS, MTHFR, and ERCC1 genes failed to predict outcome in mesothelioma patients treated with pemetrexed-based chemotherapy. However, different variants of 1494del6 in the 3' UTR of the TS gene were associated with differences in disease control rate and PFS of our patients. Copyright © 2014 Elsevier Inc. All rights reserved.

Pazopanib in Metastatic Renal Cancer: A "Real-World" Experience at National Cancer Institute "Fondazione G. Pascale".

PubMed

Cecere, Sabrina C; Rossetti, Sabrina; Cavaliere, Carla; Della Pepa, Chiara; Di Napoli, Marilena; Crispo, Anna; Iovane, Gelsomina; Piscitelli, Raffaele; Sorrentino, Domenico; Ciliberto, Gennaro; Maiolino, Piera; Muto, Paolo; Perdonà, Sisto; Berretta, Massimiliano; Pignata, Sandro; Facchini, Gaetano; D'Aniello, Carmine

2016-01-01

Pazopanib is an oral angiogenesis inhibitor, currently approved for treatment of metastatic renal cell carcinoma (mRCC) and soft tissue sarcoma. The present study analyzed the outcomes of pazopanib in first-line treatment of mRCC, in a single Italian cancer center. In the light of the retrospective, observational nature and the unselected population, our experience can be defined a "real-world" study. The medical records of 38 mRCC patients treated with front-line pazopanib were retrospectively reviewed and analyzed. The progression free survival (PFS) and the overall survival (OS) were the primary endpoints, while secondary objectives included objective response rate (ORR), disease control rate (DCR), and treatment tolerability. Pazopanib achieved a median PFS (mPFS) of 12.7 months (95% CI, 6.9-18.5 months). The median OS (mOS) was 26.2 months (95% CI, 12.6-39.9 months); the observed ORR and DCR were 30.3 and 72.7%, respectively, with a median duration of response of 11 weeks. mPFS appeared not to be influenced by number of co-morbidities (< 3 vs. ≥3), gender, Fuhrman grade and age. Conversely, the ORR and the DCR positively affect the mPFS (HR = 0.05 [95% CI, 0.05-0.55], p = 0.01; HR = 0.10 [95% CI, 0.02-0.43], p = 0.002, respectively). A worse outcome was associated with a lower mPFS in patients with liver metastases (p = 0.2) and with a high tumor burden (number of metastatic sites < 6 vs. ≥6) (p = 0.08). Worst OS was observed in patients aged ≥70 years old (HR = 6.91 [95% CI, 1.49-31.91], p = 0.01). The treatment was well-tolerated: no grade 4 adverse events, nor discontinuation due to toxicities was reported. Grade 3 hypertension affected positively the OS reaching the statistical significance (HR = 0.22 [95% CI, 0.05-0.8], p = 0.03). Thyroid dysfunction (hypo and hyperthyroidism) seems to correlate with better outcome in terms of a longer mPFS (HR = 0.12 [95% CI, 0.02-0.78], p = 0.02). Our results are consistent with those reported in prospective phase III trials and the published retrospective "real world" experiences. This analysis confirms the safety and efficacy of pazopanib in first-line setting, both in frail patients with multiple co-morbidities and Karnofsky PS < 80% and in younger, healthier patients with a number of metastatic sites < 6.

Pazopanib in Metastatic Renal Cancer: A “Real-World” Experience at National Cancer Institute “Fondazione G. Pascale”

PubMed Central

Cecere, Sabrina C.; Rossetti, Sabrina; Cavaliere, Carla; Della Pepa, Chiara; Di Napoli, Marilena; Crispo, Anna; Iovane, Gelsomina; Piscitelli, Raffaele; Sorrentino, Domenico; Ciliberto, Gennaro; Maiolino, Piera; Muto, Paolo; Perdonà, Sisto; Berretta, Massimiliano; Pignata, Sandro; Facchini, Gaetano; D'Aniello, Carmine

2016-01-01

Pazopanib is an oral angiogenesis inhibitor, currently approved for treatment of metastatic renal cell carcinoma (mRCC) and soft tissue sarcoma. The present study analyzed the outcomes of pazopanib in first-line treatment of mRCC, in a single Italian cancer center. In the light of the retrospective, observational nature and the unselected population, our experience can be defined a “real-world” study. The medical records of 38 mRCC patients treated with front-line pazopanib were retrospectively reviewed and analyzed. The progression free survival (PFS) and the overall survival (OS) were the primary endpoints, while secondary objectives included objective response rate (ORR), disease control rate (DCR), and treatment tolerability. Pazopanib achieved a median PFS (mPFS) of 12.7 months (95% CI, 6.9–18.5 months). The median OS (mOS) was 26.2 months (95% CI, 12.6–39.9 months); the observed ORR and DCR were 30.3 and 72.7%, respectively, with a median duration of response of 11 weeks. mPFS appeared not to be influenced by number of co-morbidities (< 3 vs. ≥3), gender, Fuhrman grade and age. Conversely, the ORR and the DCR positively affect the mPFS (HR = 0.05 [95% CI, 0.05–0.55], p = 0.01; HR = 0.10 [95% CI, 0.02–0.43], p = 0.002, respectively). A worse outcome was associated with a lower mPFS in patients with liver metastases (p = 0.2) and with a high tumor burden (number of metastatic sites < 6 vs. ≥6) (p = 0.08). Worst OS was observed in patients aged ≥70 years old (HR = 6.91 [95% CI, 1.49–31.91], p = 0.01). The treatment was well-tolerated: no grade 4 adverse events, nor discontinuation due to toxicities was reported. Grade 3 hypertension affected positively the OS reaching the statistical significance (HR = 0.22 [95% CI, 0.05–0.8], p = 0.03). Thyroid dysfunction (hypo and hyperthyroidism) seems to correlate with better outcome in terms of a longer mPFS (HR = 0.12 [95% CI, 0.02–0.78], p = 0.02). Our results are consistent with those reported in prospective phase III trials and the published retrospective “real world” experiences. This analysis confirms the safety and efficacy of pazopanib in first-line setting, both in frail patients with multiple co-morbidities and Karnofsky PS < 80% and in younger, healthier patients with a number of metastatic sites < 6. PMID:27630568

Phase III, Randomized Study of Dual Human Epidermal Growth Factor Receptor 2 (HER2) Blockade With Lapatinib Plus Trastuzumab in Combination With an Aromatase Inhibitor in Postmenopausal Women With HER2-Positive, Hormone Receptor-Positive Metastatic Breast Cancer: ALTERNATIVE.

PubMed

Johnston, Stephen R D; Hegg, Roberto; Im, Seock-Ah; Park, In Hae; Burdaeva, Olga; Kurteva, Galina; Press, Michael F; Tjulandin, Sergei; Iwata, Hiroji; Simon, Sergio D; Kenny, Sarah; Sarp, Severine; Izquierdo, Miguel A; Williams, Lisa S; Gradishar, William J

2018-03-10

Purpose Human epidermal growth factor receptor 2 (HER2) targeting plus endocrine therapy (ET) improved clinical benefit in HER2-positive, hormone receptor (HR)-positive metastatic breast cancer (MBC) versus ET alone. Dual HER2 blockade enhances clinical benefit versus single HER2 blockade. The ALTERNATIVE study evaluated the efficacy and safety of dual HER2 blockade plus aromatase inhibitor (AI) in postmenopausal women with HER2-positive/HR-positive MBC who received prior ET and prior neo(adjuvant)/first-line trastuzumab (TRAS) plus chemotherapy. Methods Patients were randomly assigned (1:1:1) to receive lapatinib (LAP) + TRAS + AI, TRAS + AI, or LAP + AI. Patients for whom chemotherapy was intended were excluded. The primary end point was progression-free survival (PFS; investigator assessed) with LAP + TRAS + AI versus TRAS + AI. Secondary end points were PFS (comparison of other arms), overall survival, overall response rate, clinical benefit rate, and safety. Results Three hundred fifty-five patients were included in this analysis: LAP + TRAS + AI (n = 120), TRAS + AI (n = 117), and LAP + AI (n = 118). Baseline characteristics were balanced. The study met its primary end point; superior PFS was observed with LAP + TRAS + AI versus TRAS + AI (median PFS, 11 v 5.7 months; hazard ratio, 0.62; 95% CI, 0.45 to 0.88; P = .0064). Consistent PFS benefit was observed in predefined subgroups. Overall response rate, clinical benefit rate, and overall survival also favored LAP + TRAS + AI. The median PFS with LAP + AI versus TRAS + AI was 8.3 versus 5.7 months (hazard ratio, 0.71; 95% CI, 0.51 to 0.98; P = .0361). Common adverse events (AEs; ≥ 15%) with LAP + TRAS + AI, TRAS + AI, and LAP + AI were diarrhea (69%, 9%, and 51%, respectively), rash (36%, 2%, and 28%, respectively), nausea (22%, 9%, and 22%, respectively), and paronychia (30%, 0%, and 15%, respectively), mostly grade 1 or 2. Serious AEs were reported similarly across the three groups, and AEs leading to discontinuation were lower with LAP + TRAS + AI. Conclusion Dual HER2 blockade with LAP + TRAS + AI showed superior PFS benefit versus TRAS + AI in patients with HER2-positive/HR-positive MBC. This combination offers an effective and safe chemotherapy-sparing alternative treatment regimen for this patient population.

Activation or suppression of the immune response mediators in biliary tract cancer (BTC) patients: a systematic review and meta-analysis

PubMed Central

Wang, Ying; Ding, Min; Zhang, Qian; Wang, Jinghan; Yang, Xijing; Zhou, Fuping; Li, Linfang; Yuan, Zhengang; Jin, Huajun; Qian, Qijun

2017-01-01

Background: Infiltration of immune cells and immune microenvironment determine the proliferative activity of the tumor and metastasis. The aim of this study was to analyze the influence of activation or suppression of the immune response mediators on the prognosis of biliary tract cancer (BTC). Methods: We searched Pubmed, Web of Science, Embase and The Cochrane Library for relevant literatures until June 2016. The quality of studies was assessed by QUADAS-2 and NOS tools. Forest and funnel plots and all statistical analyses were generated by using Review Manager 5.3. The bias of included studies was estimated by Egger's test using Meta R package. Results: A total of 2339 patients from 12 studies were finally enrolled in this meta-analysis. Patients with high expression of immune active factors, intraepithelial tumor-infiltrating CD4+ , CD8+, and Foxp3+ T lymphocytes, MHC I, NKG2D, showed a better overall survival (OS) than those with low expression (HR=0.52, 95% CI=0.41-0.67, P<0.00001). On the contrary, the high expression of immune suppressive factors (CD66b+ neutrophils, Neutrophil-lymphocyte ratio, Intratumoral IL-17+ cells and PD-1+/CD8+ TILs) was significantly associated with poor OS (HR=1.79, 95% CI=1.44-2.22, P<0.00001). A further analysis of therapies targeting tumor microenvironment modulation showed that the median progression free survival (PFS) for BTC patients who received adjuvant immunotherapy was longer than those who received surgery or chemotherapy alone, and the estimated pooled mean difference demonstrated a highly significant improvement (MD =2.33; 95% CI: 0.63-4.02, P=0.007). The total effect of PFS and OS was statistically longer in experimental group, compared to patients in control groups, respectively (PFS: RR=1.25; 95% CI: 1.08-1.46, P=0.004; OS: RR=1.16; 95% CI: 1.07-1.27, P=0.0006). In subgroup meta-analysis of studies on 6-, 12- and 18-month PFS and OS, it showed that adjuvant immunotherapy could improve the 6-month PFS (RR=1.23; 95% CI: 1.05-1.44, P=0.009), and 6-month OS (RR=1.17; 95% CI: 1.06-1.30, P=0.002). Conclusions: So given the above issue, our meta-analysis confirmed that the level of immune mediators could be a predicative factor for prognosis of BTC patients, and immunotherapy regimens by modulating the tumor microenvironment was superior for enhancing median PFS, 6-month PFS and OS. PMID:28123600

Activation or suppression of the immune response mediators in biliary tract cancer (BTC) patients: a systematic review and meta-analysis.

PubMed

Wang, Ying; Ding, Min; Zhang, Qian; Wang, Jinghan; Yang, Xijing; Zhou, Fuping; Li, Linfang; Yuan, Zhengang; Jin, Huajun; Qian, Qijun

2017-01-01

Background: Infiltration of immune cells and immune microenvironment determine the proliferative activity of the tumor and metastasis. The aim of this study was to analyze the influence of activation or suppression of the immune response mediators on the prognosis of biliary tract cancer (BTC). Methods: We searched Pubmed, Web of Science, Embase and The Cochrane Library for relevant literatures until June 2016. The quality of studies was assessed by QUADAS-2 and NOS tools. Forest and funnel plots and all statistical analyses were generated by using Review Manager 5.3. The bias of included studies was estimated by Egger's test using Meta R package. Results: A total of 2339 patients from 12 studies were finally enrolled in this meta-analysis. Patients with high expression of immune active factors, intraepithelial tumor-infiltrating CD4+ , CD8+, and Foxp3+ T lymphocytes, MHC I, NKG2D, showed a better overall survival (OS) than those with low expression (HR=0.52, 95% CI=0.41-0.67, P<0.00001). On the contrary, the high expression of immune suppressive factors (CD66b+ neutrophils, Neutrophil-lymphocyte ratio, Intratumoral IL-17+ cells and PD-1+/CD8+ TILs) was significantly associated with poor OS (HR=1.79, 95% CI=1.44-2.22, P<0.00001). A further analysis of therapies targeting tumor microenvironment modulation showed that the median progression free survival (PFS) for BTC patients who received adjuvant immunotherapy was longer than those who received surgery or chemotherapy alone, and the estimated pooled mean difference demonstrated a highly significant improvement (MD =2.33; 95% CI: 0.63-4.02, P=0.007). The total effect of PFS and OS was statistically longer in experimental group, compared to patients in control groups, respectively (PFS: RR=1.25; 95% CI: 1.08-1.46, P=0.004; OS: RR=1.16; 95% CI: 1.07-1.27, P=0.0006). In subgroup meta-analysis of studies on 6-, 12- and 18-month PFS and OS, it showed that adjuvant immunotherapy could improve the 6-month PFS (RR=1.23; 95% CI: 1.05-1.44, P=0.009), and 6-month OS (RR=1.17; 95% CI: 1.06-1.30, P=0.002). Conclusions: So given the above issue, our meta-analysis confirmed that the level of immune mediators could be a predicative factor for prognosis of BTC patients, and immunotherapy regimens by modulating the tumor microenvironment was superior for enhancing median PFS, 6-month PFS and OS.

Clinical considerations of the role of palbociclib in the management of advanced breast cancer patients with and without visceral metastases

PubMed Central

Turner, N C; Finn, R S; Martin, M; Im, S -A; DeMichele, A; Ettl, J; Diéras, V; Moulder, S; Lipatov, O; Colleoni, M; Cristofanilli, M; Lu, D R; Mori, A; Giorgetti, C; Iyer, S; Bartlett, C Huang; Gelmon, K A

2018-01-01

Abstract Background This report assesses the efficacy and safety of palbociclib plus endocrine therapy (ET) in women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC) with or without visceral metastases. Patients and methods Pre- and postmenopausal women with disease progression following prior ET (PALOMA-3; N = 521) and postmenopausal women untreated for ABC (PALOMA-2; N = 666) were randomized 2 : 1 to ET (fulvestrant or letrozole, respectively) plus palbociclib or placebo. Progression-free survival (PFS), safety, and patient-reported quality of life (QoL) were evaluated by prior treatment and visceral involvement. Results Visceral metastases incidence was higher in patients with prior resistance to ET (58.3%, PALOMA-3) than in patients naive to ET in the ABC setting (48.6%, PALOMA-2). In patients with prior resistance to ET and visceral metastases, median PFS (mPFS) was 9.2 months with palbociclib plus fulvestrant versus 3.4 months with placebo plus fulvestrant [hazard ratio (HR), 0.47; 95% confidence interval (CI), 0.35–0.61], and objective response rate (ORR) was 28.0% versus 6.7%, respectively. In patients with nonvisceral metastases, mPFS was 16.6 versus 7.3 months, HR 0.53; 95% CI 0.36–0.77. In patients with visceral disease and naive to ET in the advanced disease setting, mPFS was 19.3 months with palbociclib plus letrozole versus 12.9 months with placebo plus letrozole (HR 0.63; 95% CI 0.47–0.85); ORR was 55.1% versus 40.0%; in patients with nonvisceral disease, mPFS was not reached with palbociclib plus letrozole versus 16.8 months with placebo plus letrozole (HR 0.50; 95% CI 0.36–0.70). In patients with prior resistance to ET with visceral metastases, palbociclib plus fulvestrant significantly delayed deterioration of QoL versus placebo plus fulvestrant, whereas patient-reported QoL was maintained with palbociclib plus letrozole in patients naive to endocrine-based therapy for ABC. Conclusions Palbociclib plus ET prolonged mPFS in patients with visceral metastases, increased ORRs, and in patients previously treated for ABC, delayed QoL deterioration, presenting a standard treatment option among patients with visceral metastases amenable to endocrine-based therapy. Clinical trial registration NCT01942135, NCT01740427 PMID:29342248

First-line erlotinib and fixed dose-rate gemcitabine for advanced pancreatic cancer

PubMed Central

Vaccaro, Vanja; Bria, Emilio; Sperduti, Isabella; Gelibter, Alain; Moscetti, Luca; Mansueto, Giovanni; Ruggeri, Enzo Maria; Gamucci, Teresa; Cognetti, Francesco; Milella, Michele

2013-01-01

AIM: To investigate activity, toxicity, and prognostic factors for survival of erlotinib and fixed dose-rate gemcitabine (FDR-Gem) in advanced pancreatic cancer. METHODS: We designed a single-arm prospective, multicentre, open-label phase II study to evaluate the combination of erlotinib (100 mg/d, orally) and weekly FDR-Gem (1000 mg/m2, infused at 10 mg/m2 per minute) in a population of previously untreated patients with locally advanced, inoperable, or metastatic pancreatic cancer. Primary endpoint was the rate of progression-free survival at 6 mo (PFS-6); secondary endpoints were overall response rate (ORR), response duration, tolerability, overall survival (OS), and clinical benefit. Treatment was not considered to be of further interest if the PFS-6 was < 20% (p0 = 20%), while a PFS-6 > 40% would be of considerable interest (p1 = 40%); with a 5% rejection error (α = 5%) and a power of 80%, 35 fully evaluable patients with metastatic disease were required to be enrolled in order to complete the study. Analysis of prognostic factors for survival was also carried out. RESULTS: From May 2007 to September 2009, 46 patients were enrolled (male/female: 25/21; median age: 64 years; median baseline carbohydrate antigen 19-9 (CA 19-9): 897 U/mL; locally advanced/metastatic disease: 5/41). PFS-6 and median PFS were 30.4% and 14 wk (95%CI: 10-19), respectively; 1-year and median OS were 20.2% and 26 wk (95%CI: 8-43). Five patients achieved an objective response (ORR: 10.9%, 95%CI: 1.9-19.9); disease control rate was 56.5% (95%CI: 42.2-70.8); clinical benefit rate was 43.5% (95%CI: 29.1-57.8). CA 19-9 serum levels were decreased by > 25% as compared to baseline in 14/23 evaluable patients (63.6%). Treatment was well-tolerated, with skin rash being the most powerful predictor of both longer PFS (P < 0.0001) and OS (P = 0.01) at multivariate analysis (median OS for patients with or without rash: 42 wk vs 15 wk, respectively, Log-rank P = 0.03). Additional predictors of better outcome were: CA 19-9 reduction, female sex (for PFS), and good performance status (for OS). CONCLUSION: Primary study endpoint was not met. However, skin rash strongly predicted erlotinib efficacy, suggesting that a pharmacodynamic-based strategy for patient selection deserves further investigation. PMID:23901226

An extreme vertices mixture design approach to the optimisation of 1,2,3-trichlorobenzene specific molecularly imprinted polymers.

PubMed

Cleland, Dougal; McCluskey, Adam

2013-07-28

Traditional approaches to molecularly imprinted polymer (MIP) design and optimisation typically afford a template (T) : functional monomer (FM) : crosslinker (CL) ratio of 1 : 2 : 20 to 1 : 4 : 20. This approach for 1,2,3-trichlorobenzene (7) as template gave a styrene based MIP (MIP(STY)) with an imprinting factor (IF) = 1.3. An extreme vertices mixture design (EVMD) approach was applied, and in two design cycles, 15 total experimental points, the optimum composition for MIP(STY) was determined as 0.40 : 0.05 : 0.55 (T : FM : CL) with IF = 2.8. Refinements gave optimum T : FM : CL ratios for the functional monomers: 4-vinylpyridine (4VP, 0.40 : 0.02 : 0.58); 2,4,6-trimethylstyrene (TMS, 0.40 : 0.02 : 0.58) and 2,3,4,5,6-pentafluorostyrene (PFS, 0.30 : 0.12 : 0.58) with IF = 2.8, 2.8 and 3.7 respectively. These ratios deviated significantly from the traditional MIP synthesis ratio. The low levels of FM for all MIPs, except for MIP(PFS), suggest that imprinting was more consistent with T-CL, than FM-T, interactions. Analysis of the specific interactions and removal (SR) of 7 with these MIPs revealed that the SR with MIP(STY) increased from 36% at 0.02 STY to 48% at 0.13 STY; with MIP(TMS) SR increased from 38% at 0.02 TMS to 42% at 0.10 TMS; and with MIP(PFS) SR increased from 34% at 0.02 PFS to 56% at 0.14 PFS. MIP(4VP) saw a decline in SR with increasing FM, with the highest SR was 35% at 0.02 4VP. This is consistent with changes in the non-specific interactions between 7 and the MIPs. Increasing the proportion of PFS produced the largest increase in imprinting of 7 demonstrated by the highest SR (56%) and highest IF (3.7). The application of an EVMD approach resulted in the IF of MIP(STY) increased from 1.3 to 2.8. The highest IF achieved by this study was 3.7 for MIP(PFS) in proportions of 0.30 : 0.12 : 0.48 (T : FM : CL).

A Monte Carlo Study of the Effect of Item Characteristic Curve Estimation on the Accuracy of Three Person-Fit Statistics

ERIC Educational Resources Information Center

St-Onge, Christina; Valois, Pierre; Abdous, Belkacem; Germain, Stephane

2009-01-01

To date, there have been no studies comparing parametric and nonparametric Item Characteristic Curve (ICC) estimation methods on the effectiveness of Person-Fit Statistics (PFS). The primary aim of this study was to determine if the use of ICCs estimated by nonparametric methods would increase the accuracy of item response theory-based PFS for…

78 FR 60998 - Strategies To Accelerate the Testing and Adoption of Pay for Success (PFS) Financing Models

Federal Register 2010, 2011, 2012, 2013, 2014

2013-10-02

.... What is the purpose of the new PFS Incentive Fund? Over the past three years, multiple states and local...\\ THE BUDGET FOR FISCAL YEAR 2014--See page 978 of the President's FY 2014 Budget Appendix (see http... and social impact bonds. \\3\\ THE BUDGET FOR FISCAL YEAR 2014--See page 978 of the President's FY 2014...

Principal Attrition and Mobility: Results from the 2012-13 Principal Follow-Up Survey. First Look. NCES 2014-064

ERIC Educational Resources Information Center

Goldring, Rebecca; Taie, Soheyla

2014-01-01

This report presents selected findings from the Public School Principal Status and Private School Principal Status Data Files of the 2012-13 Principal Follow-up Survey (PFS). The PFS is a nationally representative sample survey of public and private K-12 schools in the 50 states and District of Columbia and was initiated to inform discussions and…

Prevalence of Plasmodium falciparum transmission reducing immunity among primary school children in a malaria moderate transmission region in Zimbabwe.

PubMed

Paul, Noah H; Vengesai, Arthur; Mduluza, Takafira; Chipeta, James; Midzi, Nicholas; Bansal, Geetha P; Kumar, Nirbhay

2016-11-01

Malaria continues to cause alarming morbidity and mortality in more than 100 countries worldwide. Antigens in the various life cycle stages of malaria parasites are presented to the immune system during natural infection and it is widely recognized that after repeated malaria exposure, adults develop partially protective immunity. Specific antigens of natural immunity represent among the most important targets for the development of malaria vaccines. Immunity against the transmission stages of the malaria parasite represents an important approach to reduce malaria transmission and is believed to become an important tool for gradual elimination of malaria. Development of immunity against Plasmodium falciparum sexual stages was evaluated in primary school children aged 6-16 years in Makoni district of Zimbabwe, an area of low to modest malaria transmission. Malaria infection was screened by microscopy, rapid diagnostic tests and finally using nested PCR. Plasma samples were tested for antibodies against recombinant Pfs48/45 and Pfs47 by ELISA. Corresponding serum samples were used to test for P. falciparum transmission reducing activity in Anopheles stephensi and An. gambiae mosquitoes using the membrane feeding assay. The prevalence of malaria diagnosed by rapid diagnostic test kit (Paracheck)™ was 1.7%. However, of the randomly tested blood samples, 66% were positive by nested PCR. ELISA revealed prevalence (64% positivity at 1:500 dilution, in randomly selected 66 plasma samples) of antibodies against recombinant Pfs48/45 (mean A 405nm=0.53, CI=0.46-0.60) and Pfs47 (mean A405nm=0.91, CI=0.80-1.02); antigens specific to the sexual stages. The mosquito membrane feeding assay demonstrated measurable transmission reducing ability of the samples that were positive for Pfs48/45 antibodies by ELISA. Interestingly, 3 plasma samples revealed enhancement of infectivity of P. falciparum in An. stephensi mosquitoes. These studies revealed the presence of antibodies with transmission reducing immunity in school age children from a moderate transmission area of malaria, and provide further support to exploit target antigens such as Pfs48/45 for further development of a malaria transmission blocking vaccine. Copyright © 2016 Elsevier B.V. All rights reserved.

Identifying Conventionally Sub-Seismic Faults in Polygonal Fault Systems

NASA Astrophysics Data System (ADS)

Fry, C.; Dix, J.

2017-12-01

Polygonal Fault Systems (PFS) are prevalent in hydrocarbon basins globally and represent potential fluid pathways. However the characterization of these pathways is subject to the limitations of conventional 3D seismic imaging; only capable of resolving features on a decametre scale horizontally and metres scale vertically. While outcrop and core examples can identify smaller features, they are limited by the extent of the exposures. The disparity between these scales can allow for smaller faults to be lost in a resolution gap which could mean potential pathways are left unseen. Here the focus is upon PFS from within the London Clay, a common bedrock that is tunnelled into and bears construction foundations for much of London. It is a continuation of the Ieper Clay where PFS were first identified and is found to approach the seafloor within the Outer Thames Estuary. This allows for the direct analysis of PFS surface expressions, via the use of high resolution 1m bathymetric imaging in combination with high resolution seismic imaging. Through use of these datasets surface expressions of over 1500 faults within the London Clay have been identified, with the smallest fault measuring 12m and the largest at 612m in length. The displacements over these faults established from both bathymetric and seismic imaging ranges from 30cm to a couple of metres, scales that would typically be sub-seismic for conventional basin seismic imaging. The orientations and dimensions of the faults within this network have been directly compared to 3D seismic data of the Ieper Clay from the offshore Dutch sector where it exists approximately 1km below the seafloor. These have typical PFS attributes with lengths of hundreds of metres to kilometres and throws of tens of metres, a magnitude larger than those identified in the Outer Thames Estuary. The similar orientations and polygonal patterns within both locations indicates that the smaller faults exist within typical PFS structure but are sub-seismic in conventional imaging techniques. These unseen faults could create additional unseen pathways that impact construction in London via water ingress and influence fluid migration within hydrocarbon basins.

Double-Blind, Placebo-Controlled, Randomized Phase III Trial Evaluating Pertuzumab Combined With Chemotherapy for Low Tumor Human Epidermal Growth Factor Receptor 3 mRNA-Expressing Platinum-Resistant Ovarian Cancer (PENELOPE).

PubMed

Kurzeder, Christian; Bover, Isabel; Marmé, Frederik; Rau, Joern; Pautier, Patricia; Colombo, Nicoletta; Lorusso, Domenica; Ottevanger, Petronella; Bjurberg, Maria; Marth, Christian; Barretina-Ginesta, Pilar; Vergote, Ignace; Floquet, Anne; Del Campo, Josep M; Mahner, Sven; Bastière-Truchot, Lydie; Martin, Nicolas; Oestergaard, Mikkel Z; Kiermaier, Astrid; Schade-Brittinger, Carmen; Polleis, Sandra; du Bois, Andreas; Gonzalez-Martin, Antonio

2016-07-20

The AGO-OVAR 2.29/ENGOT-ov14/PENELOPE prospectively randomized phase III trial evaluated the addition of pertuzumab to chemotherapy in patients with platinum-resistant ovarian carcinoma with low tumor human epidermal growth factor receptor 3 (HER3) mRNA expression. We report the results of the primary efficacy analysis. Eligible patients had ovarian carcinoma that progressed during or within 6 months of completing four or more platinum cycles, centrally tested low tumor HER3 mRNA expression (concentration ratio ≤ 2.81 by quantitative reverse transcriptase polymerase chain reaction on cobas z480 [Roche Molecular Diagnostics, Pleasanton, CA]), and no more than two prior lines of chemotherapy. After investigators' selection of the chemotherapy backbone (single-agent topotecan, weekly paclitaxel, or gemcitabine), patients were randomly assigned to also receive either placebo or pertuzumab (840-mg loading dose followed by 420 mg every 3 weeks). Stratification factors were selected chemotherapy, prior antiangiogenic therapy, and platinum-free interval. The primary end point was independent review committee-assessed progression-free survival (PFS). Additional end points included overall survival, investigator-assessed PFS, objective response rate, safety, patient-reported outcomes, and translational research. Overall, 156 patients were randomly assigned. Adding pertuzumab to chemotherapy did not significantly improve independent review committee-assessed PFS for the primary analysis (stratified hazard ratio, 0.74; 95% CI, 0.50 to 1.11; P = .14; median PFS, 4.3 months for pertuzumab plus chemotherapy v 2.6 months for placebo plus chemotherapy). Sensitivity analyses and secondary efficacy end point results were consistent with the primary analysis. The effect on PFS favoring pertuzumab was more pronounced in the gemcitabine and paclitaxel cohorts. No new safety signals were seen. Although the primary objective was not met, subgroup analyses showed trends in PFS favoring pertuzumab in the gemcitabine and paclitaxel cohorts, meriting further exploration of pertuzumab in ovarian cancer. © 2016 by American Society of Clinical Oncology.

A systematic review and meta-analysis of individual patient data on the impact of the BIM deletion polymorphism on treatment outcomes in epidermal growth factor receptor mutant lung cancer

PubMed Central

Allen, John C.; Kim, Go Woon; Lee, Jae Cheol; Yatabe, Yasushi; Soda, Manabu; Mano, Hiroyuki; Soo, Ross A.; Chin, Tan-Min; Ebi, Hiromichi; Yano, Seiji; Matsuo, Keitaro; Niu, Xiaomin; Lu, Shun; Isobe, Kazutoshi; Lee, Jih-Hsiang; Yang, James C.; Zhao, Mingchuan; Zhou, Caicun; Lee, June-Koo; Lee, Se-Hoon; Lee, Ji Yun; Ahn, Myung-Ju; Tan, Tira J.; Tan, Daniel S.; Tan, Eng-Huat; Ong, S. Tiong; Lim, Wan-Teck

2017-01-01

Background A germline deletion in the BIM (BCL2L11) gene has been shown to impair the apoptotic response to tyrosine kinase inhibitors (TKIs) in vitro but its association with poor outcomes in TKI-treated non-small cell lung cancer (NSCLC) patients remains unclear. We conducted a systematic review and meta-analysis on both aggregate and individual patient data to address this issue. Results In an aggregate data meta-analysis (n = 1429), the BIM deletion was associated with inferior PFS (HR = 1.51, 95%CI = 1.06–2.13, P = 0.02). Using individual patient data (n = 1200), we found a significant interaction between the deletion and ethnicity. Amongst non-Koreans, the deletion was an independent predictor of shorter PFS (Chinese: HR = 1.607, 95%CI = 1.251–2.065, P = 0.0002; Japanese: HR = 2.636, 95%CI = 1.603–4.335, P = 0.0001), and OS (HR = 1.457, 95% CI = 1.063–1.997, P = 0.019). In Kaplan-Meier analyses, the BIM deletion was associated with shorter survival in non-Koreans (PFS: 8.0 months v 11.1 months, P < 0.0005; OS: 25.7 v 30.0 months, P = 0.042). In Koreans, the BIM deletion was not predictive of PFS or OS. Materials and Methods 10 published and 3 unpublished studies that reported survival outcomes in NSCLC patients stratified according to BIM deletion were identified from PubMed and Embase. Summary risk estimates were calculated from aggregate patient data using a random-effects model. For individual patient data, Kaplan-Meier analyses were supported by multivariate Cox regression to estimate hazard ratios (HRs) for PFS and OS. Conclusions In selected populations, the BIM deletion is a significant predictor of shorter PFS and OS on EGFR-TKIs. Further studies to determine its effect on response to other BIM-dependent therapeutic agents are needed, so that alternative treatment strategies may be devised. PMID:28467813

Prognostic Value of Quantitative Metabolic Metrics on Baseline Pre-Sunitinib FDG PET/CT in Advanced Renal Cell Carcinoma

PubMed Central

Minamimoto, Ryogo; Barkhodari, Amir; Harshman, Lauren; Srinivas, Sandy; Quon, Andrew

2016-01-01

Purpose The objective of this study was to prospectively evaluate various quantitative metrics on FDG PET/CT for monitoring sunitinib therapy and predicting prognosis in patients with metastatic renal cell cancer (mRCC). Methods Seventeen patients (mean age: 59.0 ± 11.6) prospectively underwent a baseline FDG PET/CT and interim PET/CT after 2 cycles (12 weeks) of sunitinib therapy. We measured the highest maximum standardized uptake value (SUVmax) of all identified lesions (highest SUVmax), sum of SUVmax with maximum six lesions (sum of SUVmax), total lesion glycolysis (TLG) and metabolic tumor volume (MTV) from baseline PET/CT and interim PET/CT, and the % decrease in highest SUVmax of lesion (%Δ highest SUVmax), the % decrease in sum of SUVmax, the % decrease in TLG (%ΔTLG) and the % decrease in MTV (%ΔMTV) between baseline and interim PET/CT, and the imaging results were validated by clinical follow-up at 12 months after completion of therapy for progression free survival (PFS). Results At 12 month follow-up, 6/17 (35.3%) patients achieved PFS, while 11/17 (64.7%) patients were deemed to have progression of disease or recurrence within the previous 12 months. At baseline, PET/CT demonstrated metabolically active cancer in all cases. Using baseline PET/CT alone, all of the quantitative imaging metrics were predictive of PFS. Using interim PET/CT, the %Δ highest SUVmax, %Δ sum of SUVmax, and %ΔTLG were also predictive of PFS. Otherwise, interim PET/CT showed no significant difference between the two survival groups regardless of the quantitative metric utilized including MTV and TLG. Conclusions Quantitative metabolic measurements on baseline PET/CT appears to be predictive of PFS at 12 months post-therapy in patients scheduled to undergo sunitinib therapy for mRCC. Change between baseline and interim PET/CT also appeared to have prognostic value but otherwise interim PET/CT after 12 weeks of sunitinib did not appear to be predictive of PFS. PMID:27123976

Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T-DM1) vs. treatment of physician's choice in previously treated HER2-positive advanced breast cancer.

PubMed

Kim, Sung-Bae; Wildiers, Hans; Krop, Ian E; Smitt, Melanie; Yu, Ron; Lysbet de Haas, Sanne; Gonzalez-Martin, Antonio

2016-11-15

In the phase III TH3RESA study (NCT01419197), 602 patients with HER2-positive advanced breast cancer who received prior taxane therapy and ≥2 HER2-directed regimens, including trastuzumab and lapatinib (advanced setting), were randomized to trastuzumab emtansine (T-DM1) or treatment of physician's choice (TPC). A statistically significant progression-free survival (PFS) benefit favoring T-DM1 was demonstrated. Here, we examine the relationship between HER2-related biomarkers and PFS in an exploratory analysis. Biomarkers assessed included HER2 (n = 505) and HER3 (n = 505) mRNA expression, PIK3CA mutation status (n = 410) and PTEN protein expression (n = 358). For biomarkers with continuous data (HER2, HER3, PTEN), subgroups were defined using median values (>median and ≤median). For all biomarker subgroups, median PFS was longer with T-DM1 vs. TPC. The PFS benefit favoring T-DM1 vs. TPC was numerically greater in the HER2 mRNA >median subgroup (7.2 vs. 3.4 months; unstratified hazard ratio [HR], 0.40; 95% CI, 0.28-0.59; p < 0.0001) vs. ≤median subgroup (5.5 vs. 3.9 months; HR, 0.68; 95% CI, 0.49-0.92; p = 0.0131). The PFS benefit with T-DM1 was similar among HER3, PIK3CA and PTEN subgroups. Consistent with other reports, benefit was seen with T-DM1 regardless of PIK3CA mutation status. In a multivariate analysis including an interaction term (treatment group by log2-transformed HER2 mRNA), patients with higher HER2 mRNA levels benefited more from receiving T-DM1 (HR, 0.84; 95% CI, 0.75-0.94; interaction p value = 0.0027). In summary, T-DM1 prolonged median PFS in all biomarker subgroups analyzed, including activating PIK3CA mutations, with numerically greater benefit in patients with tumors expressing HER2 mRNA >median vs. ≤median. © 2016 UICC.

Randomized Phase II Trial of Gemcitabine Plus TH-302 Versus Gemcitabine in Patients With Advanced Pancreatic Cancer.

PubMed

Borad, Mitesh J; Reddy, Shantan G; Bahary, Nathan; Uronis, Hope E; Sigal, Darren; Cohn, Allen L; Schelman, William R; Stephenson, Joe; Chiorean, E Gabriela; Rosen, Peter J; Ulrich, Brian; Dragovich, Tomislav; Del Prete, Salvatore A; Rarick, Mark; Eng, Clarence; Kroll, Stew; Ryan, David P

2015-05-01

TH-302 is an investigational hypoxia-activated prodrug that releases the DNA alkylator bromo-isophosphoramide mustard in hypoxic settings. This phase II study (NCT01144455) evaluated gemcitabine plus TH-302 in patients with previously untreated, locally advanced or metastatic pancreatic cancer. Patients were randomly assigned 1:1:1 to gemcitabine (1,000 mg/m(2)), gemcitabine plus TH-302 240 mg/m(2) (G+T240), or gemcitabine plus TH-302 340 mg/m(2) (G+T340). Randomized crossover after progression on gemcitabine was allowed. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), tumor response, CA 19-9 response, and safety. Two hundred fourteen patients (77% with metastatic disease) were enrolled between June 2010 and July 2011. PFS was significantly longer with gemcitabine plus TH-302 (pooled combination arms) compared with gemcitabine alone (median PFS, 5.6 v 3.6 months, respectively; hazard ratio, 0.61; 95% CI, 0.43 to 0.87; P = .005; median PFS for metastatic disease, 5.1 v 3.4 months, respectively). Median PFS times for G+T240 and G+T340 were 5.6 and 6.0 months, respectively. Tumor response was 12%, 17%, and 26% in the gemcitabine, G+T240, and G+T340 arms, respectively (G+T340 v gemcitabine, P = .04). CA 19-9 decrease was greater with G+T340 versus gemcitabine (-5,398 v -549 U/mL, respectively; P = .008). Median OS times for gemcitabine, G+T240, and G+T340 were 6.9, 8.7, and 9.2 months, respectively (P = not significant). The most common adverse events (AEs) were fatigue, nausea, and peripheral edema (frequencies similar across arms). Skin and mucosal toxicities (2% grade 3) and myelosuppression (55% grade 3 or 4) were the most common TH-302-related AEs but were not associated with treatment discontinuation. PFS, tumor response, and CA 19-9 response were significantly improved with G+TH-302. G+T340 is being investigated further in the phase III MAESTRO study (NCT01746979). © 2014 by American Society of Clinical Oncology.

Whole-Pelvis Radiotherapy in Combination With Interstitial Brachytherapy: Does Coverage of the Pelvic Lymph Nodes Improve Treatment Outcome in High-Risk Prostate Cancer?

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bittner, Nathan; Merrick, Gregory S., E-mail: gmerrick@UrologicResearchInstitute.or; Wallner, Kent E.

2010-03-15

Purpose: To compare biochemical progression-free survival (bPFS), cause-specific survival (CSS), and overall survival (OS) rates among high-risk prostate cancer patients treated with brachytherapy and supplemental external beam radiation (EBRT) using either a mini-pelvis (MP) or a whole-pelvis (WP) field. Methods and Materials: From May 1995 to October 2005, 186 high-risk prostate cancer patients were treated with brachytherapy and EBRT with or without androgen-deprivation therapy (ADT). High-risk prostate cancer was defined as a Gleason score of >=8 and/or a prostate-specific antigen (PSA) concentration of >=20 ng/ml. Results: With a median follow-up of 6.7 years, the 10-year bPFS, CSS, and OS ratesmore » for the WP vs. the MP arms were 91.7% vs. 84.4% (p = 0.126), 95.5% vs. 92.6% (p = 0.515), and 79.5% vs. 67.1% (p = 0.721), respectively. Among those patients who received ADT, the 10-year bPFS, CSS, and OS rates for the WP vs. the MP arms were 93.6% vs. 90.1% (p = 0.413), 94.2% vs. 96.0% (p = 0.927), and 73.7% vs. 70.2% (p = 0.030), respectively. Among those patients who did not receive ADT, the 10-year bPFS, CSS, and OS rates for the WP vs. the MP arms were 82.4% vs. 75.0% (p = 0.639), 100% vs. 88% (p = 0.198), and 87.5% vs. 58.8% (p = 0.030), respectively. Based on multivariate analysis, none of the evaluated parameters predicted for CSS, while bPFS was best predicted by ADT and percent positive biopsy results. OS was best predicted by age and percent positive biopsy results. Conclusions: For high-risk prostate cancer patients receiving brachytherapy, there is a nonsignificant trend toward improved bPFS, CSS, and OS rates when brachytherapy is given with WPRT. This trend is most apparent among ADT-naive patients, for whom a significant improvement in OS was observed.« less

Effect of visceral metastases on the efficacy and safety of everolimus in postmenopausal women with advanced breast cancer: subgroup analysis from the BOLERO-2 study.

PubMed

Campone, Mario; Bachelot, Thomas; Gnant, Michael; Deleu, Ines; Rugo, Hope S; Pistilli, Barbara; Noguchi, Shinzaburo; Shtivelband, Mikhail; Pritchard, Kathleen I; Provencher, Louise; Burris, Howard A; Hart, Lowell; Melichar, Bohuslav; Hortobagyi, Gabriel N; Arena, Francis; Baselga, José; Panneerselvam, Ashok; Héniquez, Aurelia; El-Hashimyt, Mona; Taran, Tetiana; Sahmoud, Tarek; Piccart, Martine

2013-08-01

Everolimus (EVE; an inhibitor of mammalian target of rapamycin [mTOR]) enhances treatment options for postmenopausal women with hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)) advanced breast cancer (ABC) who progress on a non-steroidal aromatase inhibitor (NSAI). This is especially true for patients with visceral disease, which is associated with poor prognosis. The BOLERO-2 (Breast cancer trial of OraLEveROlimus-2) trial showed that combination treatment with EVE and exemestane (EXE) versus placebo (PBO)+EXE prolonged progression-free survival (PFS) by both investigator (7.8 versus 3.2 months, respectively) and independent (11.0 versus 4.1 months, respectively) central assessment in postmenopausal women with HR(+), HER2(-) ABC recurring/progressing during/after NSAI therapy. The BOLERO-2 trial included a substantial proportion of patients with visceral metastases (56%). Prespecified exploratory subgroup analysis conducted to evaluate the efficacy and safety of EVE+EXE versus PBO+EXE in a prospectively defined subgroup of patients with visceral metastases. At a median follow-up of 18 months, EVE+EXE significantly prolonged median PFS compared with PBO+EXE both in patients with visceral metastases (N=406; 6.8 versus 2.8 months) and in those without visceral metastases (N=318; 9.9 versus 4.2 months). Improvements in PFS with EVE+EXE versus PBO+EXE were also observed in patients with visceral metastases regardless of Eastern Cooperative Oncology Group performance status (ECOG PS). Patients with visceral metastases and ECOG PS 0 had a median PFS of 6.8 months with EVE+EXE versus 2.8 months with PBO+EXE. Among patients with visceral metastases and ECOG PS ≥1, EVE+EXE treatment more than tripled median PFS compared with PBO+EXE (6.8 versus 1.5 months). Adding EVE to EXE markedly extended PFS by ≥4 months among patients with HR(+) HER2(-) ABC regardless of the presence of visceral metastases. Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

Effects of supervised exercise on progression-free survival in lymphoma patients: an exploratory follow-up of the HELP Trial.

PubMed

Courneya, Kerry S; Friedenreich, Christine M; Franco-Villalobos, Conrado; Crawford, Jennifer J; Chua, Neil; Basi, Sanraj; Norris, Mary K; Reiman, Tony

2015-02-01

Few randomized controlled trials in exercise oncology have examined survival outcomes. Here, we report an exploratory follow-up of progression-free survival (PFS) from the Healthy Exercise for Lymphoma Patients (HELP) Trial. The HELP Trial randomized 122 lymphoma patients between 2005 and 2008 to either control (n = 62) or 12 weeks of supervised aerobic exercise (n = 60). PFS events were abstracted from medical records in 2013. In addition to the randomized comparison, we explored the effects of exercise adherence (<80 % vs. ≥80 %) and control group crossover (no vs. yes). After a median follow-up of 61 months (interquartile range 36-67), the adjusted 5-year PFS was 64.8 % for the exercise group compared with 65.0 % for the control group (Hazard ratio [HR] 1.01, 95 % CI 0.51-2.01, p = 0.98). In the secondary analysis, the adjusted 5-year PFS was 59.0 % in the control group without crossover compared with 69.2 % for the control group with crossover (HR 0.68, 95 % CI 0.22-2.06, p = 0.49), 67.7 % for the exercise group with <80 % adherence (HR 0.72, 95 % CI 0.28-1.85, p = 0.50), and 68.4 % for the exercise group with ≥80 % adherence (HR 0.70, 95 % CI 0.32-1.56, p = 0.39). In a post hoc analysis combining the three groups that received supervised exercise, the adjusted 5-year PFS for the supervised exercise groups was 68.5 % compared with 59.0 % for the group that received no supervised exercise (HR 0.70, 95 % CI 0.35-1.39, p = 0.31). This exploratory follow-up of the HELP Trial suggests that supervised aerobic exercise may be associated with improved PFS in lymphoma patients. Larger trials designed to answer this question are needed.

Impact of SPARC expression on outcome in patients with advanced pancreatic cancer not receiving nab-paclitaxel: a pooled analysis from prospective clinical and translational trials

PubMed Central

Ormanns, Steffen; Haas, Michael; Baechmann, Sibylle; Altendorf-Hofmann, Annelore; Remold, Anna; Quietzsch, Detlef; Clemens, Michael R; Bentz, Martin; Geissler, Michael; Lambertz, Helmut; Kruger, Stephan; Kirchner, Thomas; Heinemann, Volker; Boeck, Stefan

2016-01-01

Background: Conflicting results on the role of secreted protein acidic and rich in cysteins (SPARC) expression have been reported in resected pancreatic ductal adenocarcinoma (PDAC), and its prognostic and/or predictive role in advanced PDAC (aPDAC) has not been extensively investigated yet. This study was designed to evaluate SPARC expression as a biomarker in aPDAC patients (pts) not receiving nab-paclitaxel. Methods: Using immunohistochemistry, we examined the stromal as well as the tumoral (i.e., cytoplasmic) SPARC expression in tumour tissue (primary tumours and metastases) of 134 aPDAC pts participating in completed prospective clinical and biomarker trials. The SPARC expression levels were correlated to the pts' clinicopathological parameters and survival times. Results: Sixty-seven per cent of the analysed tumours showed high stromal SPARC expression, which was not associated with overall survival (OS, median 9.1 vs 7.6 months, P=0.316). A positive cytoplasmic SPARC expression was detected in 55% of the tumours and correlated significantly with inferior progression-free survival (PFS, 6.2 vs 8.6 months, P=0.004) and OS (7.8 vs 8.4 months, P=0.032). This association was strongest for pts, where primary tumour tissue was examined (PFS: 6.7 vs 10.8 months, P=0.004; OS: 7.9 vs 11.9 months, P=0.030), whereas no significant correlation was detected for pts, where only metastatic tissue was available (PFS: 5.8 vs 6.6 months, P=0.502; OS: 7.0 vs 7.8 months, P=0.452). In pts receiving gemcitabine-based chemotherapy cytoplasmic SPARC expression was significantly associated with an inferior PFS and OS (PFS: 6.2 vs 9.2 months, P=0.002; OS 7.3 vs 9.9 months, P=0.012), whereas no such association was detected for stromal SPARC expression or for pts receiving fluoropyrimidine-based chemotherapy. Conclusion: We identified cytoplasmic SPARC expression in the primary tumour as a biomarker associated with inferior PFS and OS in aPDAC. Cytoplasmic SPARC expression may furthermore act as a negative predictive biomarker in pts treated with gemcitabine-based chemotherapy. PMID:27802454

Sunitinib-induced hypertension, neutropaenia and thrombocytopaenia as predictors of good prognosis in patients with metastatic renal cell carcinoma.

PubMed

Rautiola, Juhana; Donskov, Frede; Peltola, Katriina; Joensuu, Heikki; Bono, Petri

2016-01-01

To evaluate the clinical significance of hypertension (HTN), neutropaenia and thrombocytopaenia as possible new biomarkers of sunitinib efficacy in non-trial patients with metastatic renal cell carcinoma (mRCC). In all, 181 consecutive patients with mRCC were treated with sunitinib; 39 (22%) received sunitinib 50 mg/day 4 weeks on/2 weeks off, 80 (44%) received 37.5 mg/day continuously and 62 (34%) received 25 mg/day continuously as their starting dose. Treatment-induced adverse events (AEs) and their impact on outcome were analysed on multiple sunitinib doses. During sunitinib treatment 60 patients (33%) developed ≥grade 2 HTN, 88 (49%) ≥grade 2 neutropaenia and 135 (75%) ≥grade 1 thrombocytopaenia. These AEs were associated significantly with longer progression-free survival (PFS; 15.7 vs 6.7; 14.6 vs 6.9; 10.4 vs 4.2 months, respectively; P < 0.001) and overall survival (OS; 37.5 vs 16.2; 33.7 vs 13.2; 22.3 vs 13.2 months, respectively, P ≤ 0.008). Although only neutropaenia was associated with a significantly improved PFS and OS in all sunitinib doses, a similar trend was also seen with HTN and thrombocytopaenia in all sunitinib doses. In multivariate analysis, HTN and neutropaenia were significantly associated with PFS and OS and thrombocytopaenia was significantly associated with PFS. In a 12-week landmark analysis, HTN and thrombocytopaenia were significantly associated with PFS and OS. Patients who developed all three AEs (a favourable biomarker profile) had significantly better outcome than patients without these AEs (a poor biomarker profile); response rate 47% vs 4%, median PFS 27.1 vs 3.5 months and OS not reached vs 5.3 months (all P < 0.001). HTN, neutropaenia and thrombocytopaenia were all biomarkers of sunitinib efficacy in patients with mRCC. Our results may help to individualise sunitinib dosing during therapy based on these common sunitinib-related AEs. © 2014 The Authors BJU International © 2014 BJU International Published by John Wiley & Sons Ltd.

Phase II Study of Paclitaxel Given Once per Week Along With Trastuzumab and Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2–Positive Metastatic Breast Cancer

PubMed Central

Dang, Chau; Iyengar, Neil; Datko, Farrah; D'Andrea, Gabriella; Theodoulou, Maria; Dickler, Maura; Goldfarb, Shari; Lake, Diana; Fasano, Julie; Fornier, Monica; Gilewski, Theresa; Modi, Shanu; Gajria, Devika; Moynahan, Mary Ellen; Hamilton, Nicola; Patil, Sujata; Jochelson, Maxine; Norton, Larry; Baselga, Jose; Hudis, Clifford

2015-01-01

Purpose The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. Patients and Methods Patients with metastatic human epidermal growth factor receptor 2–positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m2 once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. Results From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. Conclusion Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy. PMID:25547504

A network flow model for load balancing in circuit-switched multicomputers

NASA Technical Reports Server (NTRS)

Bokhari, Shahid H.

1990-01-01

In multicomputers that utilize circuit switching or wormhole routing, communication overhead depends largely on link contention - the variation due to distance between nodes is negligible. This has a major impact on the load balancing problem. In this case, there are some nodes with excess load (sources) and others with deficit load (sinks) and it is required to find a matching of sources to sinks that avoids contention. The problem is made complex by the hardwired routing on currently available machines: the user can control only which nodes communicate but not how the messages are routed. Network flow models of message flow in the mesh and the hypercube were developed to solve this problem. The crucial property of these models is the correspondence between minimum cost flows and correctly routed messages. To solve a given load balancing problem, a minimum cost flow algorithm is applied to the network. This permits one to determine efficiently a maximum contention free matching of sources to sinks which, in turn, tells one how much of the given imbalance can be eliminated without contention.

RISK FACTORS FOR NONREMISSION AND PROGRESSION-FREE SURVIVAL AFTER I-131 THERAPY IN PATIENTS WITH LUNG METASTASIS FROM DIFFERENTIATED THYROID CANCER: A SINGLE-INSTITUTE, RETROSPECTIVE ANALYSIS IN SOUTHERN CHINA.

PubMed

Chen, Pan; Feng, Hui-Juan; Ouyang, Wei; Wu, Ju-Qing; Wang, Jing; Sun, Yun-Gang; Xian, Jia-Lang; Huang, Liu-Hua

2016-09-01

Prognostic factors related to progression-free survival (PFS) have not received much attention in the literature regarding iodine-131 ((131)I) therapy for patients with differentiated thyroid cancer and lung metastases. We sought to explore the factors associated with PFS and nonremission in a group of patients with differentiated thyroid cancer and pulmonary metastases at initial diagnosis and to investigate the impact of (131)I therapy on pulmonary function and peripheral blood counts in the same cohort of patients. The medical records of 1,050 patients with differentiated thyroid cancer treated at the Zhujiang Hospital of Southern Medical University from January 2006 to January 2015 were retrospectively reviewed. Among them, 107 patients fulfilled the inclusion criteria. Multivariate Cox regression analysis indicated that age ≥45 years and (131)I nonavidity were independent risk factors for disease progression. Multivariate logistic regression analysis revealed that pulmonary nodule size ≥1 cm and (131)I nonavidity were the strongest risk factors predicting nonremission. Varying cumulative (131)I dosage had no association with posttreatment pulmonary function or peripheral blood cell counts. Similar to earlier studies, our results confirm that (131)I nonavidity was associated with an increased risk of disease progression and greater odds of nonremission. In addition, patients with differentiated thyroid cancer and lung metastases with pulmonary nodules ≥1 cm had a reduced likelihood of achieving remission. Furthermore, special attention is needed when monitoring patients over 45 years at a higher risk of disease progression. CI = confidence interval DTC = differentiated thyroid cancer (18)F-FDG = fluoro-18 fluorodeoxyglucose FEF = forced expiratory flow FTC = follicular thyroid cancer FVC = forced vital capacity GR = granulocytes Hb = hemoglobin HR = hazard ratio (131)I = iodine-131 LN = lymph node OR = odds ratio OS = overall survival PET/CT = positive positron emission tomography/computed tomography PFS = progression-free survival PT = partial thyroidectomy PTC = papillary thyroid cancer RAI = radioactive iodine RBC = red blood cell Tg = thyroglobulin TgAb = thyroglobulin antibody TSH = thyroid-stimulating hormone TT = total thyroidectomy WBC = white blood cells WBS = whole body scan.

A flow-based synthesis of imatinib: the API of Gleevec.

PubMed

Hopkin, Mark D; Baxendale, Ian R; Ley, Steven V

2010-04-14

A concise, flow-based synthesis of Imatinib, a compound used for the treatment of chronic myeloid leukaemia, is described whereby all steps are conducted in tubular flow coils or cartridges packed with reagents or scavengers to effect clean product formation. An in-line solvent switching procedure was developed enabling the procedure to be performed with limited manual handling of intermediates.

Positron emission tomography–computed tomography predictors of progression after DA-R-EPOCH for PMBCL

PubMed Central

Ng, Andrea K.; Dabaja, Bouthaina S.; Milgrom, Sarah A.; Gunther, Jillian R.; Fuller, C. David; Smith, Grace L.; Abou Yehia, Zeinab; Qiao, Wei; Wogan, Christine F.; Akhtari, Mani; Mawlawi, Osama; Medeiros, L. Jeffrey; Chuang, Hubert H.; Martin-Doyle, William; Armand, Philippe; LaCasce, Ann S.; Oki, Yasuhiro; Fanale, Michelle; Westin, Jason; Neelapu, Sattva; Nastoupil, Loretta

2018-01-01

Dose-adjusted rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) has produced good outcomes in primary mediastinal B-cell lymphoma (PMBCL), but predictors of resistance to this treatment are unclear. We investigated whether [18F]fluorodeoxyglucose positron emission tomography–computed tomography (PET-CT) findings could identify patients with PMBCL who would not respond completely to DA-R-EPOCH. We performed a retrospective analysis of 65 patients with newly diagnosed stage I to IV PMBCL treated at 2 tertiary cancer centers who had PET-CT scans available before and after frontline therapy with DA-R-EPOCH. Pretreatment variables assessed included metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Optimal cutoff points for progression-free survival (PFS) were determined by a machine learning approach. Univariate and multivariable models were constructed to assess associations between radiographic variables and PFS. At a median follow-up of 36.6 months (95% confidence interval, 28.1-45.1), 2-year PFS and overall survival rates for the 65 patients were 81.4% and 98.4%, respectively. Machine learning–derived thresholds for baseline MTV and TLG were associated with inferior PFS (elevated MTV: hazard ratio [HR], 11.5; P = .019; elevated TLG: HR, 8.99; P = .005); other pretreatment clinical factors, including International Prognostic Index and bulky (>10 cm) disease, were not. On multivariable analysis, only TLG retained statistical significance (P = .049). Univariate analysis of posttreatment variables revealed that residual CT tumor volume, maximum standardized uptake value, and Deauville score were associated with PFS; a Deauville score of 5 remained significant on multivariable analysis (P = .006). A model combining baseline TLG and end-of-therapy Deauville score identified patients at increased risk of progression. PMID:29895624

Prognostic value of (18)F-FDG PET/CT volumetric parameters in recurrent epithelial ovarian cancer.

PubMed

Mayoral, M; Fernandez-Martinez, A; Vidal, L; Fuster, D; Aya, F; Pavia, J; Pons, F; Lomeña, F; Paredes, P

2016-01-01

Metabolic tumour volume (MTV) and total lesion glycolysis (TLG) from (18)F-FDG PET/CT are emerging prognostic biomarkers in various solid neoplasms. These volumetric parameters and the SUVmax have shown to be useful criteria for disease prognostication in preoperative and post-treatment epithelial ovarian cancer (EOC) patients. The purpose of this study was to evaluate the utility of (18)F-FDG PET/CT measurements to predict survival in patients with recurrent EOC. Twenty-six patients with EOC who underwent a total of 31 (18)F-FDG PET/CT studies for suspected recurrence were retrospectively included. SUVmax and volumetric parameters whole-body MTV (wbMTV) and whole-body TLG (wbTLG) with a threshold of 40% and 50% of the SUVmax were obtained. Correlation between PET parameters and progression-free survival (PFS) and the survival analysis of prognostic factors were calculated. Serous cancer was the most common histological subtype (76.9%). The median PFS was 12.5 months (range 10.7-20.6 months). Volumetric parameters showed moderate inverse correlation with PFS but there was no significant correlation in the case of SUVmax. The correlation was stronger for first recurrences. By Kaplan-Meier analysis and log-rank test, wbMTV 40%, wbMTV 50% and wbTLG 50% correlated with PFS. However, SUVmax and wbTLG 40% were not statistically significant predictors for PFS. Volumetric parameters wbMTV and wbTLG 50% measured by (18)F-FDG PET/CT appear to be useful prognostic predictors of outcome and may provide valuable information to individualize treatment strategies in patients with recurrent EOC. Copyright © 2015 Elsevier España, S.L.U. and SEMNIM. All rights reserved.

Systemic Therapy in Advanced Cutaneous Squamous Cell Carcinoma (CSCC): The Roswell Park Experience and a Review of the Literature.

PubMed

Jarkowski, Anthony; Hare, Ryan; Loud, Peter; Skitzki, Joseph J; Kane, John M; May, Kilian S; Zeitouni, Nathalie C; Nestico, Jill; Vona, Karen L; Groman, Adrienne; Khushalani, Nikhil I

2016-12-01

Treatment of locally advanced unresectable or metastatic cutaneous squamous cell carcinoma (mCSCC) is suboptimal with a paucity of robust data on systemic therapy. This retrospective study aimed to evaluate the efficacy and outcomes of patients with locally advanced unresectable or mCSCC treated with systemic therapy. Records of patients with CSCC treated with systemic therapy from January 2001 to January 2011 were reviewed. Response was assessed using WHO criteria. Descriptive results were assessed using Wilcoxon rank-sum test for ordinal responses and Pearson χ test for categorical responses. Survival was calculated by the Kaplan-Meier method. Of 28 patients identified, 25 patients (M:F=18:7), median age 66 years (range, 39 to 85 y), had the required data for final analysis. Partial response was 44% and stable disease (SD) was 24%. The median progression-free survival (PFS) and overall survival (OS) were 5.5 months (2.3, 13.2) and 10.9 months (5.3, 21.3) respectively; 3-year OS was 22%. Patients with WHO response had improved PFS (20.8 mo; 4.4, NR) and OS (37.5 mo; 10.3, NR) compared with patients with SD/PD (PFS 2.7 mo; OS 5.9 mo). Use of platinum-based therapy significantly improved PFS and OS, whereas taxanes and cetuximab had no impact in this small cohort. There was no difference in PFS or OS with multiagent versus single-agent therapy. Platinum-based therapy remains as one of the standard options in advanced CSCC management. Agents to improve response rates are needed and future trials should address the use of novel targeted and new chemotherapy combinations in CSCC.

Concurrent Androgen Deprivation Therapy During Salvage Prostate Radiotherapy Improves Treatment Outcomes in High-Risk Patients

DOE Office of Scientific and Technical Information (OSTI.GOV)

Soto, Daniel E., E-mail: dsoto2@partners.org; Passarelli, Michael N.; Daignault, Stephanie

2012-03-01

Purpose: To determine whether concurrent androgen deprivation therapy (ADT) during salvage radiotherapy (RT) improves prostate cancer treatment outcomes. Methods and Materials: A total of 630 postprostatectomy patients were retrospectively identified who were treated with three-dimensional conformal RT. Of these, 441 were found to be treated for salvage indications. Biochemical failure was defined as prostate-specific antigen (PSA) of 0.2 ng/mL or greater above nadir with another PSA increase or the initiation of salvage ADT. Progression-free survival (PFS) was defined as the absence of biochemical failure, continued PSA rise despite salvage therapy, initiation of systemic therapy, clinical progression, or distant failure. Multivariate-adjustedmore » Cox proportional hazards modeling was performed to determine which factors predict PFS. Results: Low-, intermediate-, and high-risk patients made up 10%, 24%, and 66% of patients, respectively. The mean RT dose was 68 Gy. Twenty-four percent of patients received concurrent ADT (cADT). Regional pelvic nodes were treated in 16% of patients. With a median follow-up of 3 years, the 3-year PFS was 4.0 years for cADT vs. 3.4 years for cADT patients (p = 0.22). Multivariate analysis showed that concurrent ADT (p = 0.05), Gleason score (p < 0.001), and pre-RT PSA (p = 0.03) were independent predictors of PFS. When patients were stratified by risk group, the benefits of cADT (hazard ratio, 0.65; p = 0.046) were significant only for high-risk patients. Conclusions: This retrospective study showed a PFS benefit of concurrent ADT during salvage prostate RT. This benefit was observed only in high-risk patients.« less

Prognostic Factors in Patients with Primary Hemangiopericytomas of the Central Nervous System: A Series of 103 Cases at a Single Institution.

PubMed

Zhu, Hongda; Duran, Daniel; Hua, Lingyang; Tang, Hailiang; Chen, Hong; Zhong, Ping; Zheng, Kang; Wang, Yongfei; Che, Xiaoming; Bao, Weimin; Wang, Yin; Xie, Qing; Gong, Ye

2016-06-01

Hemangiopericytoma (HPC) is a rare mesenchymal tumor that tends to affect the central nervous system and is associated with distant metastasis and a high recurrence rate. The purpose of this study was to analyze the prognostic factors in patients with primary HPC who received surgical treatment. This retrospective study reviewed all adult patients with primary HPC of the central nervous system treated from 2001 to 2009 at our institution. Clinical information, adjuvant radiation, and expression levels of Ki-67 and p53 were correlated with patient outcomes. The final analysis included 103 patients. The mean follow-up period was 75.9 months ± 36.5 (range, 1-165 months). There was a significant difference in progression-free survival (PFS) (P < 0.001) and overall survival (P = 0.014) between patients who underwent gross total resection versus subtotal resection. Expression of p53 was found in 48.5% of patients and showed utility as an independent unfavorable prognostic factor for PFS (P = 0.006). Multivariate analysis revealed that only extent of tumor resection (P = 0.004) and p53 expression (P = 0.024) were independent prognostic factors for PFS. Adjuvant radiation was found to extend PFS only in the p53-negative expression group (P = 0.044). Gross total resection significantly improves the outcome of patients with primary HPCs, whereas adjuvant radiation contributes significantly to PFS only in patients with negative p53 expression and in patients with incomplete resections. Extent of resection and p53 expression may serve as prognostic markers for the outcome of patients with primary HPC. Copyright © 2016 Elsevier Inc. All rights reserved.

The association of fatigue with depression and insomnia in HIV-seropositive patients: a pilot study.

PubMed

Low, Yinghui; Preud'homme, Xavier; Goforth, Harold W; Omonuwa, Toma; Krystal, Andrew D

2011-12-01

Fatigue is a pervasive symptom associated with HIV, resulting in significant functioning impairment; but little is known about its etiology or treatment. In patients with primary insomnia, data have shown improvement in fatigue following successful treatment of insomnia. However, little is known about the role of insomnia in patients with fatigue in HIV. This manuscript seeks to test the hypothesis that insomnia severity is correlated with increased fatigue in HIV-seropositive patients. Fifty-seven ambulatory HIV-seropositive patients, aged 18-60 years, with a DSM-IV-TR diagnosis of insomnia, were administered the Insomnia Severity Index (ISI), Piper Fatigue Scale (PFS), Hospital Anxiety and Depression scale, and Hamilton Depression Rating Scale (HAM-D). Their most recent CD4 count and time since diagnosis of HIV were recorded. Regression analysis was carried out with PFS as the dependent variable. A higher ISI score correlated with higher PFS score, (R2 = 0.1713, P = 0.0042). Overall depression severity was not significantly correlated with PFS score, except in the most severely depressed subgroup, in which the HADS depression score was the strongest predictor of PFS (R2 = 0.182, P = 0.0009). In participants without depression, ISI accounted for most of the variance in fatigue (R2 = 0.6035, P = 0.0011). Greater insomnia severity is associated with greater fatigue severity in HIV seropositive patients. Depression may contribute to both fatigue and insomnia. In the absence of depression, the treatment of insomnia may emerge as a treatment strategy to help alleviate fatigue. Further studies are needed to confirm these data. Clinical Trials.Gov: The Treatment of Insomnia in Patients with HIV Disease. Registry Number: NCT00465972. URL: http://www.clinicaltrials.gov/ct2/show/NCT00465972?term = HIV+insomnia&rank = 1.

Clinical characteristics and prognostic indicators for metastatic melanoma: data from 446 patients in north China.

PubMed

Hao, Mengze; Zhao, Gang; Du, Xiaoling; Yang, Yun; Yang, Jilong

2016-08-01

Melanoma is an extremely rare tumor in Asia. This retrospective study aimed to identify the clinical characteristics and prognostic factors of metastatic melanoma patients at Tianjin Medical University Cancer Hospital over the last 30 years. Survival analysis was performed with Kaplan-Meier, log-rank test, and multivariate Cox regression method using SPSS 19.0 software. The 1-, 2-, and 5-year survival rates of metastatic melanoma patients were 52, 32, and 16 %, respectively. Median overall survival (OS) was 13.5 months, median progression-free survival (PFS) 9.0 months, and median disease-free survival 20.3 months. Furthermore, patients with a single metastatic site achieved better OS and PFS than those with two or more metastatic lesions (OS 21.6 vs. 8.9 months, P < 0.001; PFS 11.3 vs. 7.1 months, P < 0.001). Survival times of patients with visceral metastases were the shortest (OS 8.5 months; PFS 7.5 months). Specifically, patients with primary mucosal lesions had a worse OS (9.7 months) and PFS (6.8 months) than those with acral (19.2 and 15.6 months, respectively) or non-acral primary lesions (11.8 and 11.1 months, respectively). The treatment of advanced melanoma was unitary, and prognoses of patients with metastatic melanoma in China were poor. Visceral metastasis, multiple metastatic sites, and primary mucosal lesions were significant predictors of survival of patients with metastatic melanoma. Those with primary mucosal lesions had significantly worse survivals than those with primary cutaneous lesions. More active involvement in clinical studies and more feedback on various treatment options are required.

Clinical outcomes of TS-1 chemotherapy for advanced and recurrent gastric cancer.

PubMed

Lee, Sung Ryol; Kim, Hyung Ook; Yoo, Chang Hak

2011-09-01

Titanium silicate (TS)-1 chemotherapy has been widely used against gastric cancer in Japan. The aim of the present study was to assess the efficacy and hematological safety of TS-1 as treatment for advanced and recurrent gastric cancer. From September 2006 to February 2011, 51 advanced or recurrent gastric cancers were treated with TS-1. One course of treatment consisted of 40, 50, or 60 mg/m(2) of TS-1 twice a day for 28 days, followed by withdrawal for two weeks. The primary end point was progression-free survival (PFS), and the secondary end point was overall survival (OS). The disease control rate was 39.2% (complete response, 0/51; partial response, 6/51; stable disease, 14/51; progressive disease, 23/51; not evaluable, 8/51). The median PFS was 4.0 months (95% confidence interval [CI], 2.2 to 5.7); the median PFS of the advanced group was 6.0 months (95% CI, 2.8 to 9.1), and the median PFS of the recurrent group was 3.0 months (95% CI, 1.8 to 4.1). The median OS was 11.0 months (95% CI, 6.3 to 15.6); the median OS of the advanced group was 10.0 months (95% CI, 4.9 to 15.0), and the median OS of the recurrent group was 14.0 months (95% CI, 4.1 to 23.8). Grade 3 or 4 hematological toxicity occurred in three patients (5.9%), anemia occurred in two patients (3.9%), and thrombocytopenia occurred in one patient (2%). TS-1 chemotherapy was safe and effective, with relatively long PFS and OS in patients with advanced and recurrent gastric cancers.

EZH2 expression is a prognostic biomarker in patients with colorectal cancer treated with anti-EGFR therapeutics.

PubMed

Yamamoto, Itaru; Nosho, Katsuhiko; Kanno, Shinichi; Igarashi, Hisayoshi; Kurihara, Hiroyoshi; Ishigami, Keisuke; Ishiguro, Kazuya; Mitsuhashi, Kei; Maruyama, Reo; Koide, Hideyuki; Okuda, Hiroyuki; Hasegawa, Tadashi; Sukawa, Yasutaka; Okita, Kenji; Takemasa, Ichiro; Yamamoto, Hiroyuki; Shinomura, Yasuhisa; Nakase, Hiroshi

2017-03-14

The polycomb group protein enhancer of zeste homolog 2 (EZH2) is a methyltransferase that suppresses microRNA-31 (miR-31) in various human malignancies including colorectal cancer. We recently suggested that miR-31 regulates the signaling pathway downstream of epidermal growth factor receptor (EGFR) in colorectal cancer. Therefore, we conducted this study for assessing the relationship between EZH2 expression and clinical outcomes in patients with colorectal cancer treated with anti-EGFR therapeutics. We immunohistochemically evaluated EZH2 expression and assessed miR-31 and gene mutations [KRAS (codon 61/146), NRAS (codon 12/13/61), and BRAF (codon 600)] in 109 patients with colorectal cancer harboring KRAS (codon 12/13) wild-type. We also evaluated the progression-free survival (PFS) and overall survival (OS). In the result, low EZH2 expression was significantly associated with shorter PFS (log-rank test: P = 0.023) and OS (P = 0.036) in patients with colorectal cancer. In the low-miR-31-expression group and the KRAS (codon 61/146), NRAS, and BRAF wild-type groups, a significantly shorter PFS (P = 0.022, P = 0.039, P = 0.021, and P = 0.036, respectively) was observed in the EZH2 low-expression groups than in the high-expression groups. In the multivariate analysis, low EZH2 expression was associated with a shorter PFS (P = 0.046), independent of the mutational status and miR-31. In conclusion, EZH2 expression was associated with survival in patients with colorectal cancer who were treated with anti-EGFR therapeutics. Moreover, low EZH2 expression was independently associated with shorter PFS in patients with cancer, suggesting that EZH2 expression is a useful additional prognostic biomarker for anti-EGFR therapy.

Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial.

PubMed

Pujade-Lauraine, Eric; Hilpert, Felix; Weber, Béatrice; Reuss, Alexander; Poveda, Andres; Kristensen, Gunnar; Sorio, Roberto; Vergote, Ignace; Witteveen, Petronella; Bamias, Aristotelis; Pereira, Deolinda; Wimberger, Pauline; Oaknin, Ana; Mirza, Mansoor Raza; Follana, Philippe; Bollag, David; Ray-Coquard, Isabelle

2014-05-01

In platinum-resistant ovarian cancer (OC), single-agent chemotherapy is standard. Bevacizumab is active alone and in combination. AURELIA is the first randomized phase III trial to our knowledge combining bevacizumab with chemotherapy in platinum-resistant OC. Eligible patients had measurable/assessable OC that had progressed < 6 months after completing platinum-based therapy. Patients with refractory disease, history of bowel obstruction, or > two prior anticancer regimens were ineligible. After investigators selected chemotherapy (pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan), patients were randomly assigned to single-agent chemotherapy alone or with bevacizumab (10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks) until progression, unacceptable toxicity, or consent withdrawal. Crossover to single-agent bevacizumab was permitted after progression with chemotherapy alone. The primary end point was progression-free survival (PFS) by RECIST. Secondary end points included objective response rate (ORR), overall survival (OS), safety, and patient-reported outcomes. The PFS hazard ratio (HR) after PFS events in 301 of 361 patients was 0.48 (95% CI, 0.38 to 0.60; unstratified log-rank P < .001). Median PFS was 3.4 months with chemotherapy alone versus 6.7 months with bevacizumab-containing therapy. RECIST ORR was 11.8% versus 27.3%, respectively (P = .001). The OS HR was 0.85 (95% CI, 0.66 to 1.08; P < .174; median OS, 13.3 v 16.6 months, respectively). Grade ≥ 2 hypertension and proteinuria were more common with bevacizumab. GI perforation occurred in 2.2% of bevacizumab-treated patients. Adding bevacizumab to chemotherapy statistically significantly improved PFS and ORR; the OS trend was not significant. No new safety signals were observed.

Phenotype-dependent Ca(2+) dynamics in single boutons of various anatomically identified GABAergic interneurons in the rat hippocampus.

PubMed

Lőrincz, Tibor; Kisfali, Máté; Lendvai, Balázs; Sylvester Vizi, Elek

2016-02-01

Interneurons (INs) of the hippocampus exert versatile inhibition on pyramidal cells by silencing the network at different oscillation frequencies. Although IN discharge can phase-lock to various rhythms in the hippocampus, under high-frequency axon firing, the boutons may not be able to follow the fast activity. Here, we studied Ca(2+) responses to action potentials (APs) in single boutons using combined two-photon microscopy and patch clamp electrophysiology in three types of INs: non-fast-spiking (NFS) neurons showing cannabinoid 1 receptor labelling and dendrite targeting, fast-spiking partially parvalbumin-positive cells synapsing with dendrites (DFS), and parvalbumin-positive cells with perisomatic innervation (PFS). The increase in [Ca(2+) ]i from AP trains was substantially higher in NFS boutons than in DFS or PFS boutons. The decay of bouton Ca(2+) responses was markedly faster in DFS and PFS cells compared with NFS neurons. The bouton-to-bouton variability of AP-evoked Ca(2+) transients in the same axon was surprisingly low in each cell type. Importantly, local responses were saturated after shorter trains of APs in NFS cells than in PFS cells. This feature of fast-spiking neurons might allow them to follow higher-frequency gamma oscillations for a longer time than NFS cells. The function of NFS boutons may better support asynchronous GABA release. In conclusion, we demonstrate several neuron-specific Ca(2+) transients in boutons of NFS, PFS and DFS neurons, which may serve differential functions in hippocampal networks. © 2015 The Authors. European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Impact of oligodendroglial component in glioblastoma (GBM-O): Is the outcome favourable than glioblastoma?

PubMed

Goda, Jayant S; Lewis, Shirley; Agarwal, Aditi; Epari, Sridhar; Churi, Shraddha; Padmavati, A; Gupta, Tejpal; Shetty, Prakash; Moiyadi, Aliasgar; Jalali, Rakesh

2015-08-01

Prognosis of patients with glioblastoma with oligodendroglial component (GBM-O) is not well defined. We report our experience of patients of GBM-O treated at our center. Between January 2007 and August 2013, out of 817 consecutive patients with glioblastoma (GBM), 74 patients with GBM-O were identified in our prospectively maintained database. An experienced neuropathologist revaluated the histopathology of all these 74 patients and the diagnosis of GBM-O was eventually confirmed in 57 patients. Patients were uniformly treated with maximal safe resection followed by focal radiotherapy with concurrent and adjuvant temozolamide (TMZ). At a median follow up of 16 months, median overall survival (OS) and progression free survival (PFS) of the entire cohort was 23 months and 13 months respectively. Near total excision was performed in 30/57 (52.6%). On univariate analysis, age < 50 years was a significant favourable prognostic factor for OS (p = 0.009) and PFS (p = 0.017), while patients with near total resection had a significantly better PFS (p = 0.017), patients who completed a minimum of 6 cycles of adjuvant TMZ had significantly better OS (p = 0.000) and PFS (p = 0.003). On multivariate analysis, none of the above factors were significant except for patient who had completed a minimum of 6 cycles of TMZ (OS; p = 0.000 & PFS; p = 0.015). A comparative analysis of GBM-O patients with a similarly treated cohort of 105 GBM patients during the same period revealed significantly better median OS in favour of GBM-O (p = 0.01). Our experience suggests patients with GBM-O have a more favourable clinical outcome as compared to GBM. Copyright © 2015 Elsevier B.V. All rights reserved.

Automated Transfer Vehicle Proximity Flight Safety Overview

NASA Astrophysics Data System (ADS)

Cornier, Dominique; Berthelier, David; Requiston, Helene; Zekri, Eric; Chase, Richard

2005-12-01

The European Automated Transfer Vehicle (ATV) is an unmanned transportation spacecraft designed to contribute to the logistic servicing of the ISS. The ATV will be launched by ARIANE 5 and, after phasing and rendezvous maneuvers, it autonomously docks to the International Space Station (ISS).The ATV control is nominally handled by the Guidance, Navigation and Control (GNC) function using computers, software, sensors and actuators. During rendezvous operations, in order to cover the extreme situations where the GNC function fails to ensure a safe trajectory with respect to the ISS, a segregated Proximity Flight Safety (PFS) function is activated : this function will initiate a collision avoidance maneuver which will place the ATV on a trajectory ensuring safety with respect to the ISS. The PFS function relies on segregated computers, the Monitoring and Safing Units (MSUs) running specific software, on four dedicated thrusters, on dedicated batteries and on specific interfaces with ATV gyrometers.The PFS function being the ultimate protection to ensure ISS safety in case of ATV malfunction, specific rules have been applied to its implementation, in particular for the development of the MSU software, which is critical since any failure of this software may result in catastrophic consequences.This paper provides an overview of the ATV Proximity Flight Safety function. After a short description of the overall ATV avionics architecture and its rationale, the second part of the paper presents more details on the PFS function both in terms of hardware and software implementation. The third part of the paper is dedicated to the MSU software validation method that is specific considering its criticality. The last part of the paper provides information on the different operations related to the use of the PFS function during an ATV flight.

Prevalence of fatigue in Parkinson disease and its clinical correlates.

PubMed

Stocchi, Fabrizio; Abbruzzese, Giovanni; Ceravolo, Roberto; Cortelli, Pietro; D'Amelio, Marco; De Pandis, Maria F; Fabbrini, Giovanni; Pacchetti, Claudio; Pezzoli, Gianni; Tessitore, Alessandro; Canesi, Margherita; Iannacone, Claudio; Zappia, Mario

2014-07-15

To assess in a noninterventional setting the prevalence and severity of fatigue in patients with Parkinson disease (PD). This was a cross-sectional study conducted in Italian patients with PD. Objectives included the evaluation of the current prevalence and severity of fatigue in patients with PD measured using the 16-item Parkinson Fatigue Scale (PFS-16), distressing fatigue (defined as a PFS-16 mean score ≥3.3), and assessment of its clinical correlates. A total of 402 patients were enrolled and 394 patients completed the PFS-16 questionnaire with a PFS-16 mean (±SD) score of 2.87 ± 0.99. Of these, 136 patients (33.8%) reported distressing fatigue (PFS-16 mean score ≥3.3). Patients with distressing fatigue were older (p = 0.044) and had a longer duration of PD (p < 0.0001) than those without distressing fatigue. The presence of distressing fatigue was associated with higher total Unified Parkinson's Disease Rating Scale (UPDRS) scores, poorer quality of life (39-item Parkinson's Disease Questionnaire [PDQ-39]), worse social and psychological behaviors, a higher severity of depressive symptoms, and a higher prevalence of sleep disorders (all p < 0.001). Logistic regression analyses revealed that higher total UPDRS scores, female sex, depression, sleep disorders, as well as higher UPDRS activities of daily living scores and PDQ-39 mobility scores increase the likelihood of distressing fatigue in patients with PD. Approximately one-third of patients with PD have distressing fatigue, which is significantly associated with depression and sleep disorders. The fact that the presence of fatigue worsens patient quality of life supports the need to better diagnose and treat this debilitating symptom. © 2014 American Academy of Neurology.

Disease Extent at Secondary Cytoreductive Surgery is Predictive of Progression-free and Overall Survival in Advanced Stage Ovarian Cancer: an NRG Oncology/Gynecologic Oncology Group study

PubMed Central

Rose, Peter G.; Java, James J.; Morgan, Mark A.; Secord, Angeles Alvarez; Kesterson, Joshua P.; Stehman, Frederick B.; Warshal, David P.; Creasman, William T.; Hanjani, Parviz; Morris, Robert T.; Copeland, Larry J.

2017-01-01

Purpose GOG 152 was a randomized trial of secondary cytoreductive surgery (SCS) in patients with suboptimal residual disease (residual tumor nodule >1 cm in greatest diameter) following primary cytoreductive surgery for advanced stage ovarian cancer. The current analysis was undertaken to evaluate the impact of disease findings at SCS on progression-free survival (PFS) and overall survival (OS). Methods Among the 550 patients enrolled on GOG-152, two-hundred-sixteen patients were randomly assigned following 3 cycles of cisplatin and paclitaxel to receive SCS. In 15 patients (7%) surgery was declined or contraindicated. In the remaining 201 patients the operative and pathology reports were utilized to classify their disease status at the beginning of SCS as; no gross disease/microscopically negative N= 40 (19.9%), no gross disease/microscopically positive N= 8 (4.0%), and gross disease N=153 (76.1%). Results The median PFS for patients with no gross disease/microscopically negative was 16.1 months, no gross disease/microscopically positive was 13.5 months and for gross disease was 11.7 months, p=0.002. The median OS for patients with no gross disease/microscopically negative was 51.5 months, no gross disease/microscopically positive was 42.6 months and for gross disease was 34.9 months, p=0.018. Conclusion Although as previously reported SCS did not change PFS or OS, for those who underwent the procedure, their operative and pathologic findings were predictive of PFS and OS. Surgical/pathological residual disease is a biomarker of response to chemotherapy and predictive of PFS and OS. PMID:27692669

Does time interval between surgery and intraperitoneal chemotherapy administration in advanced ovarian cancer carry a prognostic impact? An NRG Oncology/Gynecologic Oncology Group study ancillary study

PubMed Central

Garcia-Soto, Arlene E; Java, James J; Neira, Wilberto Nieves; Pearson, J Matthew; Cohn, David E.; Lele, Shashikant B; Tewari, Krishnansu S; Walker, Joan L; Secord, Angeles Alvarez; Armstrong, Deborah K; Copeland, Larry J

2016-01-01

Objectives To determine the relationship of the time from surgery to intraperitoneal (IP) chemotherapy (TSIC) initiation with survival of patients with stage III epithelial ovarian cancer (EOC) patients using ancillary data from cooperative group clinical trials. Methods Data from 420 patients with stage III EOC treated with IP chemotherapy under GOG-0114 and 172 were reviewed. The Cox proportional hazards model was used to evaluate independent prognostic factors and estimate their covariate-adjusted effects on PFS and OS. Results The median TSIC was 62.5 days (interquartile range 28-83). The median TSIC was longer for patients in GOG-0114 vs those in GOG-172 (83 vs 26 days, p <0.001). TSIC was significantly associated (P = 0.049) with PFS: each 10% increase in TSIC (days) decreases the risk of progression by 3%. TSIC was not significantly associated with OS in this model. In a linear regression model, gross residual disease was significantly associated with shorter TSIC (R2 -0.141, 95%CI -0.217, -0.064, p < 0.001). When only data from GOG-172 were considered, no statistical significant association was found between TSIC and PFS or OS. Conclusions In this ancillary data study, TSIC was not associated with improved OS in patients with stage III epithelial ovarian cancer. TSIC was significantly associated with PFS for the entire cohort, suggesting increase in PFS with longer TSIC. However, this was not found when only data from GOG 172 or GOG 114 were analyzed separately. Hence, the relationship between IP chemotherapy initiation and time from surgery needs to be studied further. PMID:27726923

Research outcomes and recommendations for the assessment of progression in cancer clinical trials from a PhRMA working group.

PubMed

Stone, A M; Bushnell, W; Denne, J; Sargent, D J; Amit, O; Chen, C; Bailey-Iacona, R; Helterbrand, J; Williams, G

2011-08-01

Progression free survival (PFS) is increasingly used as a primary end-point in oncology clinical trials. This paper provides recommendations for optimal trial design, conduct and analysis in situations where PFS has the potential to be an acceptable end-point for regulatory approval. These recommendations are based on research performed by the Pharmaceutical Research and Manufacturers Association (PhRMA) sponsored PFS Working Group, including the re-analysis of 28 randomised Phase III trials from 12 companies/institutions. (1) In the assessment of PFS, there is a critical distinction between measurement error that results from random variation, which by itself tends to attenuate treatment effect, versus bias which increases the probability of a false negative or false positive finding. Investigator bias can be detected by auditing a random sample of patients by blinded, independent, central review (BICR). (2) ITT analyses generally resulted in smaller treatment effects (HRs closer to 1) than analyses that censor patients for potentially informative events (such as starting other anti-cancer therapy). (3) Interval censored analyses (ICA) are more robust to time-evaluation bias than the log-rank test. A sample based BICR audit may be employed in open or partially blinded trials and should not be required in true double-blind trials. Patients should be followed until progression even if they have discontinued treatment to be consistent with the ITT principle. ICAs should be a standard sensitivity analysis to assess time-evaluation bias. Implementation of these recommendations would standardize and in many cases simplify phase III oncology clinical trials that use a PFS primary end-point. Copyright © 2011 Elsevier Ltd. All rights reserved.

Body weight changes in patients undergoing chemotherapy for ovarian cancer influence progression-free and overall survival.

PubMed

Mardas, Marcin; Stelmach-Mardas, Marta; Madry, Radosław

2017-03-01

The aim of this study was to evaluate whether body weight changes in patients undergoing chemotherapy for epithelial ovarian cancer (EOC) influence progression-free survival (PFS) and overall survival (OS). An analysis of 190 patients diagnosed with ovarian cancer after first-line chemotherapy was conducted. Changes in body weight were assessed by comparing measurements at baseline to those of the third and sixth cycles of chemotherapy. PFS and OS were calculated with the Kaplan-Meier method and multivariate Cox model. Significant reduction in body weight in advanced EOC was observed with no changes in early EOC. Significant differences in PFS were observed in advanced EOC patients that lost more than 5 % of their body weight (6 months), maintained weight (13 months), or gained more than 5 % of their body weight (15 months). Similarly, significant differences in OS were noted in advanced EOC at the following time points: 24.3, 42.4, and 66.2 months. No effect was reported for early EOC patients. The multivariate Cox analysis showed significant body weight changes from the first to the sixth chemotherapy cycle for PFS (HR = 0.97; 95 % CI 0.95-0.99) and OS (HR = 0.94; 95 % CI 0.91-0.97) as well as from the first to the third chemotherapy cycle for OS (HR = 0.93; 95 % CI 0.88-0.98). Body weight changes can be recognized as a prognostic factor for PFS and OS in advanced EOC patients undergoing chemotherapy. Weight loss is associated with poorer survival while weight gain improved outcomes.

Randomized, phase II study of the thrombospondin-1-mimetic angiogenesis inhibitor ABT-510 in patients with advanced soft tissue sarcoma.

PubMed

Baker, Laurence H; Rowinsky, Eric K; Mendelson, David; Humerickhouse, Rod A; Knight, Raymond A; Qian, Jiang; Carr, Robert A; Gordon, Gary B; Demetri, George D

2008-12-01

Sarcomas are among the most proangiogenic malignancies in preclinical models. Phase I study results for ABT-510, which inhibits angiogenesis via a novel thrombospondin-mimetic mechanism, suggested activity in soft tissue sarcoma (STS) patients. This phase II study further evaluated the safety and efficacy of ABT-510 in advanced STS patients. Patients with metastatic or unresectable STS were randomly assigned to treatment with one of two ABT-510 dose schedules (20 mg once a day [20 mg], n = 42; or 100 mg twice a day [200 mg], n = 46), which were self-administered subcutaneously in 28-day treatment periods. End points included progression-free survival (PFS), objective response rate (ORR), overall survival (OS), and safety. Median PFS for the 20-mg arm was 94 days, with 4- and 6-month PFS rate estimates of 42% and 24%, respectively. Median PFS for the 200-mg arm was 64 days, with 4- and 6-month PFS rate estimates of 41% and 32%, respectively. Although only one objective response was noted, stable disease was observed in 52% (20 mg) and 48% (200 mg) of patients. Median OS was 431 days (20 mg) and 295 days (200 mg). ABT-510 was well tolerated. Rare treatment-related grade 3 or 4 adverse events were one event each of hypotension, deep vein thrombosis, and hypophosphatemia. ABT-510 pharmacokinetics were dose proportional, time independent, and consistent with those in previous studies. ABT-510 had a favorable safety profile, and the rate of disease control and OS times were encouraging. However, with low ORR and lack of dose response, the study failed to yield compelling evidence of strong single-agent activity in STS.

Spatial Distribution of Seismic Anisotropy in the Crust in the Northeast Front Zone of Tibetan Plateau

NASA Astrophysics Data System (ADS)

Gao, Y.; Wang, Q.; SHI, Y.

2017-12-01

There are orogenic belts and strong deformation in northeastern zone of Tibetan Plateau. The media in crust and in the upper mantle are seismic anisotropic there. This study uses seismic records by permanent seismic stations and portable seismic arrays, and adopts analysis techniques on body waves to obtain spatial anisotropic distribution in northeastern front zone of Tibetan Plateau. With seismic records of small local earthquakes, we study shear-wave splitting in the upper crust. The polarization of fast shear wave (PFS) can be obtained, and PFS is considered parallel to the strike of the cracks, as well as the direction of maximum horizontal compressive stress. However, the result shows the strong influence from tectonics, such as faults. It suggests multiple-influence including stress and fault. Spatial distribution of seismic anisotropy in study zone presents the effect in short range. PFS at the station on the strike-slip fault is quite different to PFS at station just hundreds of meters away from the fault. With seismic records of teleseismic waveforms, we obtained seismic anisotropy in the whole crust by receiver functions. The PFS directions from Pms receiver functions show consistency, generally in WNW. The time-delay of slow S phases is significant. With seismic records of SKS, PKS and SKKS phases, we can detect seismic anisotropy in the upper mantle by splitting analysis. The fast directions of these phases also show consistency, generally in WNW, similar to those of receiver functions, but larger time-delays. It suggests significant seismic anisotropy in the crust and crustal deformation is coherent to that in the upper mantle.Seismic anisotropy in the upper crust, in the whole crust and in the upper mantle are discussed both in difference and tectonic implications [Grateful to the support by NSFC Project 41474032].

Double-Blind, Randomized Trial of Docetaxel Plus Vandetanib Versus Docetaxel Plus Placebo in Platinum-Pretreated Metastatic Urothelial Cancer

PubMed Central

Choueiri, Toni K.; Ross, Robert W.; Jacobus, Susanna; Vaishampayan, Ulka; Yu, Evan Y.; Quinn, David I.; Hahn, Noah M.; Hutson, Thomas E.; Sonpavde, Guru; Morrissey, Stephanie C.; Buckle, Geoffrey C.; Kim, William Y.; Petrylak, Daniel P.; Ryan, Christopher W.; Eisenberger, Mario A.; Mortazavi, Amir; Bubley, Glenn J.; Taplin, Mary-Ellen; Rosenberg, Jonathan E.; Kantoff, Philip W.

2012-01-01

Purpose Vandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with docetaxel was assessed in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy. Patients and Methods The primary objective was to determine whether vandetanib 100 mg plus docetaxel 75 mg/m2 intravenously every 21 days prolonged progression-free survival (PFS) versus placebo plus docetaxel. The study was designed to detect a 60% improvement in median PFS with 80% power and one-sided α at 5%. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Overall survival (OS), overall response rate (ORR), and safety were secondary objectives. Results In all, 142 patients were randomly assigned and received at least one dose of therapy. Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = .9). ORR and OS were not different between both arms. Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhea (7% v 0%). Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months. Conclusion In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR, or OS. The toxicity of vandetanib plus docetaxel was greater than that for vendetanib plus placebo. Single-agent vandetanib activity was minimal. PMID:22184381

A Phase 2 Randomized Study of Ramucirumab (IMC-1121B) with or without Dacarbazine in Patients with Metastatic Melanoma

PubMed Central

Carvajal, Richard D.; Wong, Michael K.; Thompson, John A.; Gordon, Michael S.; Lewis, Karl D.; Pavlick, Anna C.; Wolchok, Jedd D.; Rojas, Patrick B.; Schwartz, Jonathan D.; Bedikian, Agop Y.

2017-01-01

SUMMARY Background To evaluate the efficacy and safety of ramucirumab (IMC-1121B; LY3009806), a fully human monoclonal antibody targeting the vascular endothelial growth factor receptor-2, alone and in combination with dacarbazine in chemotherapy-naïve patients with metastatic melanoma (MM). Methods Eligible patients received ramucirumab (10 mg/kg) + dacarbazine (1000 mg/m2) (Arm A) or ramucirumab only (10 mg/kg) (Arm B) every 3 weeks. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), overall response, and safety. Findings Of 106 randomized patients, 102 received study treatment (Arm A, N = 52; Arm B, N = 50). Baseline characteristics were similar in both arms. Median PFS was 2·6 months (Arm A) and 1·7 months (Arm B); median 6-month PFS rates were 30·7% and 17·9% and 12-month PFS rates were 23·7% and 15·6%, respectively. In Arm A, 9 (17·3%) patients had partial response (PR) and 19 (36·5%), stable disease (SD); PR and SD in Arm B were 2 (4·0%) and 21 (42·0%), respectively. Median OS was 8·7 months in Arm A and 11·1 months in Arm B. Patients in both arms tolerated the treatment with limited grade 3/4 toxicities. Interpretation Ramucirumab alone or in combination with dacarbazine was associated with an acceptable safety profile in patients with MM. Although the study was not powered for comparison between treatment arms, PFS appeared greater with combination therapy. Sustained disease control was observed on both study arm Funding Funded by ImClone Systems LLC, a wholly-owned subsidiary of Eli Lilly and Company, Bridgewater, NJ PMID:24930625

Combination immunohistochemistry for SMAD4 and Runt-related transcription factor 3 may identify a favorable prognostic subgroup of pancreatic ductal adenocarcinomas.

PubMed

Lee, Yangkyu; Lee, Hyejung; Park, Hyunjin; Kim, Jin-Won; Hwang, Jin-Hyeok; Kim, Jaihwan; Yoon, Yoo-Seok; Han, Ho-Seong; Kim, Haeryoung

2017-09-29

SMAD4/DPC4 mutations have been associated with aggressive behavior in pancreatic ductal adenocarcinomas (PDAC), and it has recently been suggested that RUNX3 expression combined with SMAD4 status may predict the metastatic potential of PDACs. We evaluated the prognostic utility of SMAD4/RUNX3 status in human PDACs by immunohistochemistry. Immunohistochemical stains were performed for SMAD4 and RUNX3 on 210 surgically resected PDACs, and the results were correlated with the clinicopathological features. Loss of SMAD4 expression was associated with poor overall survival (OS) ( p = 0.015) and progression-free survival (PFS) ( p = 0.044). Nuclear RUNX3 expression was associated with decreased OS ( p = 0.010) and PFS ( p = 0.009), and more frequent in poorly differentiated PDACs ( p = 0.037). On combining RUNX3/SMAD4 status, RUNX3-/SMAD4+ PDACs demonstrated longer OS ( p = 0.008, median time; RUNX3-/SMAD4+ 34 months, others 17 months) and PFS ( p = 0.009, median time; RUNX3-/SMAD4+ 29 months, others 8 months) compared to RUNX3+/SMAD4+ and SMAD4- groups; RUNX3-/SMAD4+ was a significant independent predictive factor for both OS [ p = 0.025, HR 1.842 (95% CI 1.079-3.143)] and PFS [ p = 0.020, HR 1.850 (95% CI 1.100-3.113)]. SMAD4-positivity with RUNX3-negativity was a significant independent predictive factor for favorable OS and PFS in PDAC. This is the first and large clinicopathological study of RUNX3/SMAD4 expression status in human PDAC. Combination immunohistochemistry for SMAD4 and RUNX3 may help identify a favorable prognostic subgroup of PDAC.

Combination immunohistochemistry for SMAD4 and Runt-related transcription factor 3 may identify a favorable prognostic subgroup of pancreatic ductal adenocarcinomas

PubMed Central

Lee, Yangkyu; Lee, Hyejung; Park, Hyunjin; Kim, Jin-Won; Hwang, Jin-Hyeok; Kim, Jaihwan; Yoon, Yoo-Seok; Han, Ho-Seong; Kim, Haeryoung

2017-01-01

Purposes SMAD4/DPC4 mutations have been associated with aggressive behavior in pancreatic ductal adenocarcinomas (PDAC), and it has recently been suggested that RUNX3 expression combined with SMAD4 status may predict the metastatic potential of PDACs. We evaluated the prognostic utility of SMAD4/RUNX3 status in human PDACs by immunohistochemistry. Materials and Methods Immunohistochemical stains were performed for SMAD4 and RUNX3 on 210 surgically resected PDACs, and the results were correlated with the clinicopathological features. Results Loss of SMAD4 expression was associated with poor overall survival (OS) (p = 0.015) and progression-free survival (PFS) (p = 0.044). Nuclear RUNX3 expression was associated with decreased OS (p = 0.010) and PFS (p = 0.009), and more frequent in poorly differentiated PDACs (p = 0.037). On combining RUNX3/SMAD4 status, RUNX3-/SMAD4+ PDACs demonstrated longer OS (p = 0.008, median time; RUNX3-/SMAD4+ 34 months, others 17 months) and PFS (p = 0.009, median time; RUNX3-/SMAD4+ 29 months, others 8 months) compared to RUNX3+/SMAD4+ and SMAD4- groups; RUNX3-/SMAD4+ was a significant independent predictive factor for both OS [p = 0.025, HR 1.842 (95% CI 1.079-3.143)] and PFS [p = 0.020, HR 1.850 (95% CI 1.100-3.113)]. Conclusions SMAD4-positivity with RUNX3-negativity was a significant independent predictive factor for favorable OS and PFS in PDAC. This is the first and large clinicopathological study of RUNX3/SMAD4 expression status in human PDAC. Combination immunohistochemistry for SMAD4 and RUNX3 may help identify a favorable prognostic subgroup of PDAC. PMID:29100342

Retrospective audit of clinico-pathologic features and treatment outcomes in a cohort of elderly non-Hodgkin's lymphoma patients in a tertiary cancer center.

PubMed

Nair, C K; Patil, V M; Raghavan, V; Babu, S; Nayanar, S

2015-01-01

There is limited data from India regarding elderly non-Hodgkin's lymphomas (NHL) patients. Hence, this audit was planned to study the clinic-pathological features and treatment outcomes in elderly NHL patients. Retrospective analysis of all NHL patients above age of 59 years treated at the author's institute, between December 2010 and December 2013 was done. Case records were reviewed for baseline details, staging details, prognostic factors, treatment delivered, response, toxicity and efficacy. SPSS version 16 (IBM, Newyork) was used for analysis. Descriptive statistics was performed. Kaplan-Meir survival analysis was done for estimation of progression-free survival (PFS) and overall survival (OS). Univariate analysis was done for identifying factors affecting PFS and OS. Out of 141 NHL patients, 67 patients were identified subjected to the inclusion criteria. The median age was 68 years (60-92). Majority were B-cell NHL (86.6%). The commonest subtype in B-cell was diffuse large B-cell lymphoma (55.2%). Fifty-four patients took treatment. The treatment intent was curative in 41 patients (61.2%). Among the patients receiving curative treatment, 16 patients couldn't receive treatment in accordance with NCCN guidelines due to financial issues. Two years PFS was 55%. Two years PFS for B-cell NHL and T-cell NHL were 55% and 50% respectively (P = 0.982). Two years PFS for standard Rx and nonstandard Rx were 62% and 50% respectively, but it didn't reach statistical significance (P = 0.537). Two years OS for the entire cohort was 84%. Standard treatment in accordance with guidelines can be delivered in elderly patients irrespective of age. There is a need for creating financial assistance for patients, so that potentially curative treatments are not denied.

Positron Emission Tomography/Computed Tomography Findings During Therapy Predict Outcome in Patients With Diffuse Large B-Cell Lymphoma Treated With Chemotherapy Alone but Not in Those Who Receive Consolidation Radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dabaja, Bouthaina S., E-mail: bdabaja@mdanderson.org; Hess, Kenneth; Shihadeh, Ferial

2014-06-01

Purpose: To assess the value of mid-therapy positron emission tomography (PET) findings for predicting survival and disease progression in patients with diffuse large B-cell lymphoma, considering type of therapy (chemotherapy with or without radiation therapy). Methods and Materials: We retrospectively evaluated 294 patients with histologically confirmed diffuse large B-cell lymphoma with respect to age, sex, disease stage, International Prognostic Index score, mid-therapy PET findings (positive or negative), and disease status after therapy and at last follow-up. Overall survival (OS) and progression-free survival (PFS) were compared according to mid-therapy PET findings. Results: Of the 294 patients, 163 (55%) were male, 144more » (49%) were age >61 years, 110 (37%) had stage I or II disease, 219 (74%) had International Prognostic Index score ≤2, 216 (73%) received ≥6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, and 88 (30%) received consolidation radiation therapy. Five-year PFS and OS rates were associated with mid-therapy PET status: PFS was 78% for those with PET-negative (PET−) disease versus 63% for PET-positive (PET+) disease (P=.024), and OS was 82% for PET− versus 62% for PET+ (P<.002). These associations held true for patients who received chemotherapy only (PFS 71% for PET− vs 52% PET+ [P=.012], OS 78% for PET− and 51% for PET+ [P=.0055]) but not for those who received consolidation radiation therapy (PFS 84% PET− vs 81% PET+ [P=.88]; OS 90% PET− vs 81% PET+ [P=.39]). Conclusion: Mid-therapy PET can predict patient outcome, but the use of consolidation radiation therapy may negate the significance of mid-therapy findings.« less

Positron emission tomography-computed tomography predictors of progression after DA-R-EPOCH for PMBCL.

PubMed

Pinnix, Chelsea C; Ng, Andrea K; Dabaja, Bouthaina S; Milgrom, Sarah A; Gunther, Jillian R; Fuller, C David; Smith, Grace L; Abou Yehia, Zeinab; Qiao, Wei; Wogan, Christine F; Akhtari, Mani; Mawlawi, Osama; Medeiros, L Jeffrey; Chuang, Hubert H; Martin-Doyle, William; Armand, Philippe; LaCasce, Ann S; Oki, Yasuhiro; Fanale, Michelle; Westin, Jason; Neelapu, Sattva; Nastoupil, Loretta

2018-06-12

Dose-adjusted rituximab plus etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (DA-R-EPOCH) has produced good outcomes in primary mediastinal B-cell lymphoma (PMBCL), but predictors of resistance to this treatment are unclear. We investigated whether [ 18 F]fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) findings could identify patients with PMBCL who would not respond completely to DA-R-EPOCH. We performed a retrospective analysis of 65 patients with newly diagnosed stage I to IV PMBCL treated at 2 tertiary cancer centers who had PET-CT scans available before and after frontline therapy with DA-R-EPOCH. Pretreatment variables assessed included metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Optimal cutoff points for progression-free survival (PFS) were determined by a machine learning approach. Univariate and multivariable models were constructed to assess associations between radiographic variables and PFS. At a median follow-up of 36.6 months (95% confidence interval, 28.1-45.1), 2-year PFS and overall survival rates for the 65 patients were 81.4% and 98.4%, respectively. Machine learning-derived thresholds for baseline MTV and TLG were associated with inferior PFS (elevated MTV: hazard ratio [HR], 11.5; P = .019; elevated TLG: HR, 8.99; P = .005); other pretreatment clinical factors, including International Prognostic Index and bulky (>10 cm) disease, were not. On multivariable analysis, only TLG retained statistical significance ( P = .049). Univariate analysis of posttreatment variables revealed that residual CT tumor volume, maximum standardized uptake value, and Deauville score were associated with PFS; a Deauville score of 5 remained significant on multivariable analysis ( P = .006). A model combining baseline TLG and end-of-therapy Deauville score identified patients at increased risk of progression. © 2018 by The American Society of Hematology.

Phase II trial of temozolomide and sorafenib in advanced melanoma patients with or without brain metastases

PubMed Central

Amaravadi, Ravi K.; Schuchter, Lynn M.; McDermott, David F.; Kramer, Amy; Giles, Lydia; Gramlich, Kristi; Carberry, Mary; Troxel, Andrea B.; Letrero, Richard; Nathanson, Katherine L.; Atkins, Michael B.; O’Dwyer, Peter J.; Flaherty, Keith T.

2009-01-01

Purpose The combination of the oral alkylating agent temozolomide and the oral multi-kinase inhibitor sorafenib was evaluated in advanced melanoma patients. Patients and Methods Patients with metastatic melanoma (N=167) were treated on four arms. All patients received sorafenib at 400 mg orally twice daily without interruption. Patients without brain metastases or prior temozolomide were randomized between Arm A: extended dosing of temozolomide (EDT; 75 mg/m2 temozolomide daily for 6/8 weeks) and Arm B: standard dosing (SDT; 150 mg/m2 temozolomide daily for 5/28 days). Patients previously treated with temozolomide were enrolled on Arm C: EDT. Patients with brain metastases and no prior temozolomide were assigned to Arm D: SDT. The primary endpoint was 6-month progression-free survival (PFS) rate. Secondary endpoints included response rate, toxicity rates, and the rates of BRAF or NRAS mutations. Results The 6-month PFS rate for arms A, B, C, and D were 50%, 40%, 11%, and 23%. The median PFS for patients on arm A, B, C, and D was 5.9, 4.2, 2.2, and 3.5 months, respectively. No significant differences were observed between Arms A and B in 6-month PFS rate, median PFS, or response rates. Treatment was well tolerated in all arms. No significant differences in toxicity were observed between arms A and B except for more grade 3–4 lymphopenia in arm A. Conclusion Temozolomide plus sorafenib was well tolerated and demonstrated activity in melanoma patients without prior history of temozolomide. The activity of this combination regimen warrants further investigation. PMID:19996224

Regulation of intrapleural fibrinolysis by urokinase-α-macroglobulin complexes in tetracycline-induced pleural injury in rabbits

PubMed Central

Mazar, Andrew P.; Koenig, Kathy; Kurdowska, Anna K.; Idell, Steven

2009-01-01

The proenzyme single-chain urokinase plasminogen activator (scuPA) more effectively resolved intrapleural loculations in rabbits with tetracycline (TCN)-induced loculation than a range of clinical doses of two-chain uPA (Abbokinase) and demonstrated a trend toward greater efficacy than single-chain tPA (Activase) (Idell S et al., Exp Lung Res 33: 419, 2007.). scuPA more slowly generates durable intrapleural fibrinolytic activity than Abbokinase or Activase, but the interactions of these agents with inhibitors in pleural fluids (PFs) have been poorly understood. PFs from rabbits with TCN-induced pleural injury treated with intrapleural scuPA, its inactive Ser195Ala mutant, Abbokinase, Activase, or vehicle, were analyzed to define the mechanism by which scuPA induces durable fibrinolysis. uPA activity was elevated in PFs of animals treated with scuPA, correlated with the ability to clear pleural loculations, and resisted (70–80%) inhibition by PAI-1. α-macroglobulin (αM) but not urokinase receptor complexes immunoprecipitated from PFs of scuPA-treated rabbits retained uPA activity that resists PAI-1 and activates plasminogen. Conversely, little plasminogen activating or enzymatic activity resistant to PAI-1 was detectable in PFs of rabbits treated with Abbokinase or Activase. Consistent with these findings, PAI-1 interacts with scuPA much slower than with Activase or Abbokinase in vitro. An equilibrium between active and inactive scuPA (kon = 4.3 h−1) limits the rate of its inactivation by PAI-1, favoring formation of complexes with αM. These observations define a newly recognized mechanism that promotes durable intrapleural fibrinolysis via formation of αM/uPA complexes. These complexes promote uPA-mediated plasminogen activation in scuPA-treated rabbits with TCN-induced pleural injury. PMID:19666776

A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcoma of the uterus, an NRG Oncology/Gynecologic Oncology Group study.

PubMed

McCourt, Carolyn K; Deng, Wei; Dizon, Don S; Lankes, Heather A; Birrer, Michael J; Lomme, Michele M; Powell, Matthew A; Kendrick, James E; Saltzman, Joel N; Warshal, David; Tenney, Meaghan E; Kushner, David M; Aghajanian, Carol

2017-01-01

The primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. Patients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40mg/m 2 as a 3hour IV infusion on day 1 of a 21daycycle. Treatment was continued until disease progression or unacceptable toxicity occurred. Forty-two women were enrolled, with 34 eligible and evaluable. Median age was 68years. ECOG performance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8% (4/34, 90% CI 4.2-25.1%); all were partial responses. Stable disease for at least 8weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7mo and 7.7mo, respectively, with a median follow-up of 37mo. Six month PFS was 20.6%. Major grade≥3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. In this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity. Copyright © 2016. Published by Elsevier Inc.

A phase II evaluation of ixabepilone in the treatment of recurrent/persistent carcinosarcom a of the uterus, an NRG Oncology/Gynecologic Oncology Group study☆

PubMed Central

McCourt, Carolyn K.; Deng, Wei; Dizon, Don S.; Lankes, Heather A.; Birrer, Michael J.; Lomme, Michele M.; Powell, Matthew A.; Kendrick, James E.; Saltzman, Joel N.; Warshal, David; Tenney, Meaghan E.; Kushner, David M.; Aghajanian, Carol

2017-01-01

Background The primary objectives were to determine the objective response rate (ORR) and safety profile of ixabepilone in women with recurrent or persistent uterine carcinosarcoma (UCS). Secondary objectives included progression-free survival (PFS) and overall survival (OS). Exploratory translational objectives included characterization of class III beta tubulin expression and its association with response, PFS, and OS. Methods Patients had measurable disease; up to two prior chemotherapeutic regimens were allowed, but must have included a taxane. Women received ixabepilone 40 mg/m2 as a 3 hour IV infusion on day 1 of a 21 day cycle. Treatment was continued until disease progression or unacceptable toxicity occurred. Results Forty-two women were enrolled, with 34 eligible and evaluable. Median age was 68 years. ECOGperformance status was 0 in 56% of women, 38% had received radiation, and 15% had received 2 lines of chemotherapy. Overall ORR was 11.8%(4/34, 90%CI 4.2–25.1%); all were partial responses. Stable disease for at least 8 weeks was achieved in 8 patients (23.5%). Median PFS and OS were 1.7 mo and 7.7 mo, respectively, with a median follow-up of 37 mo. Six month PFS was 20.6%. Major grade ≥ 3 toxicities were neutropenia (47%), fatigue (15%), dehydration (15%), hypertension (15%), and hyponatremia (15%); grade 2 peripheral neuropathy was reported in 18%. In this small sample size, class III beta tubulin expression in the primary tumor was not associated with the response to ixabepilone, PFS, or OS. Conclusion In this cohort of women, single agent ixabepilone showed modest but insufficient clinical activity. PMID:28029447

Bisphosphonates enhance EGFR-TKIs efficacy in advanced NSCLC patients with EGFR activating mutation: A retrospective study

PubMed Central

Cai, Xiao-Hong; Yao, Wen-Xiu; Xu, Yong; Liu, Xiao-Ke; Zhu, Wen-Jiang; Wang, Yan; Zhou, Jin; Lu, You; Wang, Yong-Sheng

2016-01-01

Background Bisphosphonates have exhibited anti-tumor activity in non-small cell lung cancer (NSCLC). We aimed to evaluate whether the combination of bisphosphonates with tyrosine kinase inhibitors of EGFR (EGFR-TKIs) could obtain a synergistic effect on advanced NSCLC patients with EGFR mutations. Methods Between January 2008 and October 2013, 114 advanced EGFR mutations NSCLC patients who received EGFR-TKIs as first-line therapy were recruited from two cancer centers. Patients were separated into EGFR-TKIs alone or EGFR-TKIs plus bisphosphonates (combination) group. Median progression free survival (mPFS), median overall survival (mOS) distributions and survival curves were analyzed. Results Among the 114 patients, 62 had bone metastases (19 patients treated with EGFR-TKIs, 43 patients treated with EGFR-TKIs + bisphosphonates). Median PFS and OS were significantly improved in combination group compared with EGFR-TKIs group (mPFS: 15.0 vs 7.3 months, P = 0.0017; mOS: 25.2 vs 10.4 months, P = 0.0015) in patients with bone metastases. Among the 71 patients (19 patients with bone metastases) treated with EGFR-TKIs alone, patients with bone metastases had poor survival prognosis (mPFS:7.3 vs 12.1 months, P = 0.0434; mOS:10.4 vs 22.0 months, P = 0.0036). The survival of patients with bone metastases who received EGFR-TKIs plus bisphosphonates therapy was non-inferior to patients without bone metastases treated with EGFR-TKIs alone (mPFS: 15.0 vs 12.1 months, p = 0.1871; mOS: 25.2 vs 22.0 months, p = 0.9798). Conclusions Concomitant use of bisphosphonates and EGFR-TKIs improves therapeutic efficacy and brings survival benefits to NSCLC patients with EGFR mutation and bone metastases. PMID:26624882

Cytotoxic chemotherapy may overcome the development of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) therapy.

PubMed

Kanda, Shintaro; Horinouchi, Hidehito; Fujiwara, Yutaka; Nokihara, Hiroshi; Yamamoto, Noboru; Sekine, Ikuo; Kunitoh, Hideo; Kubota, Kaoru; Tamura, Tomohide; Ohe, Yuichiro

2015-09-01

In the first-line treatment of non-small cell lung cancer (NSCLC) harboring EGFR mutations, epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has been shown to yield a longer progression-free survival (PFS) rate than platinum-doublet chemotherapy; however, after the initial response, most patients develop resistance to the EGFR-TKIs. We hypothesized that the insertion of platinum-doublet chemotherapy after the initial response to EGFR-TKIs might prevent the emergence of acquired resistance to EGFR-TKIs and prolong survival. We carried out a phase II study of the following first-line treatment for patients with advanced NSCLC harboring EGFR mutations. Gefitinib (250 mg) was administered on days 1-56. Then, after a two-week drug-free period, three cycles of cisplatin (80 mg/m2) and docetaxel (60 mg/m2) were administered on days 71, 92, and 113. Thereafter, gefitinib was re-started on day 134 and continued until disease progression. The primary endpoint was the two-year PFS rate. A total of 34 patients were enrolled. Of the 33 eligible patients and 12 achieved a two-year PFS. Thus, this therapeutic strategy met the criterion for usefulness. The 1-, 2-, 3-, and 5-year PFS rates were 67.0%, 40.2%, 36.9%, and 22.0%, respectively, and the median PFS was 19.5 months. The 1-, 2-, 3- and 5-year survival rates were 90.6%, 71.9%, 64.8%, and 36.5% respectively, and the median survival time was 48.0 months. These results indicate that the insertion of platinum-doublet chemotherapy might prevent the development of acquired resistance to EGFR-TKIs in patients with advanced NSCLC harboring EGFR mutations. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Endometrial Carcinomas with POLE Exonuclease Domain Mutations Have a Favorable Prognosis.

PubMed

McConechy, Melissa K; Talhouk, Aline; Leung, Samuel; Chiu, Derek; Yang, Winnie; Senz, Janine; Reha-Krantz, Linda J; Lee, Cheng-Han; Huntsman, David G; Gilks, C Blake; McAlpine, Jessica N

2016-06-15

The aim of this study was to confirm the prognostic significance of POLE exonuclease domain mutations (EDM) in endometrial carcinoma patients. In addition, the effect of treatment on POLE-mutated tumors was assessed. A retrospective patient cohort of 496 endometrial carcinoma patients was identified for targeted sequencing of the POLE exonuclease domain, yielding 406 evaluable tumors. Univariable and multivariable analyses were performed to determine the effect of POLE mutation status on progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS). Combining results from eight studies in a meta-analysis, we computed pooled HR for PFS, DSS, and OS. POLE EDMs were identified in 39 of 406 (9.6%) endometrial carcinomas. Women with POLE-mutated endometrial carcinomas were younger, with stage I (92%) tumors, grade 3 (62%), endometrioid histology (82%), and frequent (49%) lymphovascular invasion. In univariable analysis, POLE-mutated endometrial carcinomas had significantly improved outcomes compared with patients with no EDMs for PFS, DSS, and OS. In multivariable analysis, POLE EDMs were only significantly associated with improved PFS. The effect of adjuvant treatment on POLE-mutated cases could not be determined conclusively; however, both treated and untreated patients with POLE EDMs had good outcomes. Meta-analysis revealed an association between POLE EDMs and improved PFS and DSS with pooled HRs 0.34 [95% confidence interval (CI), 0.15-0.73] and 0.35 (95% CI, 0.13-0.92), respectively. POLE EDMs are prognostic markers associated with excellent outcomes for endometrial carcinoma patients. Further investigation is needed to conclusively determine if treatment is necessary for this group of women. Clin Cancer Res; 22(12); 2865-73. ©2016 AACR. ©2016 American Association for Cancer Research.

Moderate hypofractionated radiotherapy with volumetric modulated arc therapy and simultaneous integrated boost for pelvic irradiation in prostate cancer.

PubMed

Franzese, C; Fogliata, A; D'Agostino, G R; Di Brina, L; Comito, T; Navarria, P; Cozzi, L; Scorsetti, M

2017-07-01

The optimal treatment for unfavourable intermediate/high-risk prostate cancer is still debated. In the present study, the pattern of toxicity and early clinical outcome of patients with localized prostate cancer was analyzed. A cohort of 90 patients treated on pelvic lymph nodes from 2010 to 2015 was selected. All patients were treated with Volumetric Modulated Arc Therapy (VMAT), and Simultaneous integrated boost (SIB) in 28 fractions; the prostate, the seminal vesicle and the pelvic lymph node received total doses of 74.2, 65.5, and 51.8 Gy, respectively. End points were the detection of acute and late toxicities graded according to the Common Toxicity Criteria CTCAE version 3, evaluating the rectal, genito-urinary and gastro-intestinal toxicity. Correlation of OARs dose parameters and related toxicities was explored. Preliminary overall survival and Progression-free survival (PFS) were evaluated. With a median follow-up of 25 months, no interruptions for treatment-related toxicity were recorded. Univariate analysis among dosimetric data and acute toxicities showed no correlations. Regarding late toxicity: the dose received by a rectal volume of 90 cm 3 was found to be significant for toxicity prediction (p = 0.024). PFS was 90.6% and 60.2% at 2 and 4 years, respectively. PFS correlates with age (p = 0.011) and Gleason score (p = 0.011). Stratifying the PSA nadir in quartiles, its value was significant (p = 0.016) in predicting PFS, showing a reduction of PFS of 2 months for each PSA-nadir increase of 0.1 ng/ml. HRT with VMAT and SIB on the whole pelvis in unfavourable prostate cancer patients is effective with a mild pattern of toxicity.

Gene signatures and expression of miRNAs associated with efficacy of panitumumab in a head and neck cancer phase II trial.

PubMed

Siano, Marco; Espeli, Vittoria; Mach, Nicolas; Bossi, Paolo; Licitra, Lisa; Ghielmini, Michele; Frattini, Milo; Canevari, Silvana; De Cecco, Loris

2018-07-01

Platinum-based chemotherapy plus the anti-EGFR monoclonal antibody (mAb) cetuximab is used to treat recurrent/metastatic (RM) head-neck squamous cell carcinoma (HNSCC). Recently, we defined Cluster3 gene-expression signature as a potential predictor of favorable progression-free survival (PFS) in cetuximab-treated RM-HNSCC patients and predictor of partial metabolic FDG-PET response in an afatinib window-of-opportunity trial. Another anti-EGFR-mAb (panitumumab) was used as the treatment agent in RM-HNSCC patients in the phase II PANI01trial. PANI01 tumor samples were analyzed using functional genomics to explore response predictors to anti-EGFR therapy. Whole-gene expression and real-time PCR analyses were applied to pre-treatment samples from 25 PANI01 patients. Three gene signatures (Cluster3 score, RAS onco-signature, microenvironment score) and seven selected miRNAs were separately analyzed for association with panitumumab efficacy. Cluster3 expression levels had a profile with a significant bimodal separation of samples (P =  3.08 E-13). Higher RAS activation, microenvironment score, and miRNA expression were associated with low-Cluster3 patients. The same biomarkers were separately associated with PFS. Patients with high-Cluster3 had significantly longer PFS than patients with low-Cluster3 (median PFS: 174 versus 51 days; log-rank P = 0.0021). ROC analysis demonstrated accuracy in predicting PFS (AUC = 0.877). Despite differences in clinical settings and anti-EGFR inhibitors used for treatment, response prediction by the Cluster3 signature and selected miRNAs was essentially the same. Translation into a useful clinical assay requires validation in a broader setting. Copyright © 2018 Elsevier Ltd. All rights reserved.

A Phase II Study of Cixutumumab (IMC-A12, NSC742460) in Advanced Hepatocellular Carcinoma

PubMed Central

Abou-Alfa, Ghassan K.; Capanu, Marinela; O’Reilly, Eileen M.; Ma, Jennifer; Chou, Joanne F.; Gansukh, Bolorsukh; Shia, Jinru; Kalin, Marcia; Katz, Seth; Abad, Leslie; Reidy-Lagunes, Diane L.; Kelsen, David P.; Chen, Helen X.; Saltz, Leonard B.

2014-01-01

Background and Aims IGF-IR is implicated in hepatic carcinogenesis. This and preliminary evidence of biological activity of anti-IGF-1R monoclonal antibody cixutumumab in phase I trials prompted this phase II study. Methods Patients with advanced HCC, Child-Pugh A-B8, received cixutumumab 6 mg/kg weekly, in a Simon two-stage design study, with the primary endpoints being 4-month PFS and RECIST-defined response rate. Tissue and circulating markers plus different HCC scoring systems were evaluated for correlation with PFS and OS. Results As a result of pre-specified futility criteria, only stage 1 was accrued: N= 24: median age 67.5 years (range 49–83), KPS 80% (70–90%), 20 males (83%), 9 stage III (37%)/15 stage IV (63%), 18 Child-Pugh A (75%), 11 HBV (46%) /10 HCV (42%)/11 alcoholic cirrhosis (46%)/2 NASH (8%), 11 (46%) diabetic. Median number of doses: 7 (range 1–140). Grade 3/4 toxicities > 10% included: diabetes, elevated liver function tests, hyponatremia, and lymphopenia. Four-month PFS was 30% (95% CI 13–48), and there were no objective responses. Median overall survival was 8 months (95%CI 5.8– 14). IGF-R1 staining did not correlate with outcome. Elevated IGFBP-1 correlated with improved PFS (1.2 [95%CI 1–1.4]; p 0.009) and OS (1.2 [95%CI 1.1–1.4]; p 0.003). Conclusions Cixutumumab monotherapy did not have clinically meaningful activity in this unselected HCC population. Grade 3–4 hyperglycemia occurred in 46% of patients. Elevated IGFBP-1 correlated with improved PFS and OS. PMID:24045151

Improving the Energy Market: Algorithms, Market Implications, and Transmission Switching

NASA Astrophysics Data System (ADS)

Lipka, Paula Ann

This dissertation aims to improve ISO operations through a better real-time market solution algorithm that directly considers both real and reactive power, finds a feasible Alternating Current Optimal Power Flow solution, and allows for solving transmission switching problems in an AC setting. Most of the IEEE systems do not contain any thermal limits on lines, and the ones that do are often not binding. Chapter 3 modifies the thermal limits for the IEEE systems to create new, interesting test cases. Algorithms created to better solve the power flow problem often solve the IEEE cases without line limits. However, one of the factors that makes the power flow problem hard is thermal limits on the lines. The transmission networks in practice often have transmission lines that become congested, and it is unrealistic to ignore line limits. Modifying the IEEE test cases makes it possible for other researchers to be able to test their algorithms on a setup that is closer to the actual ISO setup. This thesis also examines how to convert limits given on apparent power---as is in the case in the Polish test systems---to limits on current. The main consideration in setting line limits is temperature, which linearly relates to current. Setting limits on real or apparent power is actually a proxy for using the limits on current. Therefore, Chapter 3 shows how to convert back to the best physical representation of line limits. A sequential linearization of the current-voltage formulation of the Alternating Current Optimal Power Flow (ACOPF) problem is used to find an AC-feasible generator dispatch. In this sequential linearization, there are parameters that are set to the previous optimal solution. Additionally, to improve accuracy of the Taylor series approximations that are used, the movement of the voltage is restricted. The movement of the voltage is allowed to be very large at the first iteration and is restricted further on each subsequent iteration, with the restriction corresponding to the accuracy and AC-feasiblity of the solution. This linearization was tested on the IEEE and Polish systems, which range from 14 to 3375 buses and 20 to 4161 transmission lines. It had an accuracy of 0.5% or less for all but the 30-bus system. It also solved in linear time with CPLEX, while the non-linear version solved in O(n1.11) to O(n1.39). The sequential linearization is slower than the nonlinear formulation for smaller problems, but faster for larger problems, and its linear computational time means it would continue solving faster for larger problems. A major consideration to implementing algorithms to solve the optimal generator dispatch is ensuring that the resulting prices from the algorithm will support the market. Since the sequential linearization is linear, it is convex, its marginal values are well-defined, and there is no duality gap. The prices and settlements obtained from the sequential linearization therefore can be used to run a market. This market will include extra prices and settlements for reactive power and voltage, compared to the present-day market, which is based on real power. An advantage of this is that there is a very clear pool that can be used for reactive power/voltage support payments, while presently there is not a clear pool to take them out of. This method also reveals how valuable reactive power and voltage are at different locations, which can enable better planning of reactive resource construction. Transmission switching increases the feasible region of the generator dispatch, which means there may be a better solution than without transmission switching. Power flows on transmission lines are not directly controllable; rather, the power flows according to how it is injected and the physical characteristics of the lines. Changing the network topology changes the physical characteristics, which changes the flows. This means that sets of generator dispatch that may have previously been infeasible due to the flow exceeding line constraints may be feasible, since the flows will be different and may meet line constraints. However, transmission switching is a mixed integer problem, which may have a very slow solution time. For economic switching, we examine a series of heuristics. We examine the congestion rent heuristic in detail and then examine many other heuristics at a higher level. Post-contingency corrective switching aims to fix issues in the power network after a line or generator outage. In Chapter 7, we show that using the sequential linear program with corrective switching helps solve voltage and excessive flow issues. (Abstract shortened by UMI.).

Reconfigurable optofluidic switch for generation of optical pulse width modulation based on tunable reflective interface.

PubMed

Mansuori, M; Zareei, G H; Hashemi, H

2015-10-01

We present a numerical method for generation of optical pulse width modulation (PWM) based on tunable reflective interface by using a microfluidic droplet. We demonstrate a single layer, planar, optofluidic PWM switch that is driven by excited alternating microbubbles. The main parameters of generation of this PWM such as frequency and speed of switching can be controlled by the mass flow rates of input fluids, and the shape of plug or droplet. Advantages of this design are the reconfigurability in design and the easy control of the switching parameters. The validation of the proposed design is carried out by employing the finite element method (FEM) for the mechanical simulation and the finite-difference time-domain (FDTD) for the optical simulation.

Spin–orbit torque-assisted switching in magnetic insulator thin films with perpendicular magnetic anisotropy

DOE PAGES

Li, Peng; Liu, Tao; Chang, Houchen; ...

2016-09-01

As an in-plane charge current flows in a heavy metal film with spin-orbit coupling, it produces a torque on and thereby switches the magnetization in a neighbouring ferromagnetic metal film. Such spin-orbit torque (SOT)-induced switching has been studied extensively in recent years and has shown higher efficiency than switching using conventional spin-transfer torque. Here we report the SOT-assisted switching in heavy metal/magnetic insulator systems. The experiments used a Pt/BaFe 12O 19 bilayer where the BaFe 12O 19 layer exhibits perpendicular magnetic anisotropy. As a charge current is passed through the Pt film, it produces a SOT that can control themore » up and down states of the remnant magnetization in the BaFe 12O 19 film when the film is magnetized by an in-plane magnetic field. Furthermore, it can reduce or increase the switching field of the BaFe 12O 19 film by as much as about 500 Oe when the film is switched with an out-of-plane field.« less

Spin-orbit torque-assisted switching in magnetic insulator thin films with perpendicular magnetic anisotropy

NASA Astrophysics Data System (ADS)

Li, Peng; Liu, Tao; Chang, Houchen; Kalitsov, Alan; Zhang, Wei; Csaba, Gyorgy; Li, Wei; Richardson, Daniel; Demann, August; Rimal, Gaurab; Dey, Himadri; Jiang, J. S.; Porod, Wolfgang; Field, Stuart B.; Tang, Jinke; Marconi, Mario C.; Hoffmann, Axel; Mryasov, Oleg; Wu, Mingzhong

2016-09-01

As an in-plane charge current flows in a heavy metal film with spin-orbit coupling, it produces a torque on and thereby switches the magnetization in a neighbouring ferromagnetic metal film. Such spin-orbit torque (SOT)-induced switching has been studied extensively in recent years and has shown higher efficiency than switching using conventional spin-transfer torque. Here we report the SOT-assisted switching in heavy metal/magnetic insulator systems. The experiments used a Pt/BaFe12O19 bilayer where the BaFe12O19 layer exhibits perpendicular magnetic anisotropy. As a charge current is passed through the Pt film, it produces a SOT that can control the up and down states of the remnant magnetization in the BaFe12O19 film when the film is magnetized by an in-plane magnetic field. It can reduce or increase the switching field of the BaFe12O19 film by as much as about 500 Oe when the film is switched with an out-of-plane field.

Micro optical fiber display switch based on the magnetohydrodynamic (MHD) principle

NASA Astrophysics Data System (ADS)

Lian, Kun; Heng, Khee-Hang

2001-09-01

This paper reports on a research effort to design, microfabricate and test an optical fiber display switch based on magneto hydrodynamic (MHD) principal. The switch is driven by the Lorentz force and can be used to turn on/off the light. The SU-8 photoresist and UV light source were used for prototype fabrication in order to lower the cost. With a magnetic field supplied by an external permanent magnet, and a plus electrical current supplied across the two inert sidewall electrodes, the distributed body force generated will produce a pressure difference on the fluid mercury in the switch chamber. By change the direction of current flow, the mercury can turn on or cut off the light pass in less than 10 ms. The major advantages of a MHD-based micro-switch are that it does not contain any solid moving parts and power consumption is much smaller comparing to the relay type switches. This switch can be manufactured by molding gin batch production and may have potential applications in extremely bright traffic control,, high intensity advertising display, and communication.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Peng; Liu, Tao; Chang, Houchen

As an in-plane charge current flows in a heavy metal film with spin-orbit coupling, it produces a torque on and thereby switches the magnetization in a neighbouring ferromagnetic metal film. Such spin-orbit torque (SOT)-induced switching has been studied extensively in recent years and has shown higher efficiency than switching using conventional spin-transfer torque. Here we report the SOT-assisted switching in heavy metal/magnetic insulator systems. The experiments used a Pt/BaFe 12O 19 bilayer where the BaFe 12O 19 layer exhibits perpendicular magnetic anisotropy. As a charge current is passed through the Pt film, it produces a SOT that can control themore » up and down states of the remnant magnetization in the BaFe 12O 19 film when the film is magnetized by an in-plane magnetic field. Furthermore, it can reduce or increase the switching field of the BaFe 12O 19 film by as much as about 500 Oe when the film is switched with an out-of-plane field.« less

Doxorubicin chemotherapy for presumptive cardiac hemangiosarcoma in dogs†.

PubMed

Mullin, C M; Arkans, M A; Sammarco, C D; Vail, D M; Britton, B M; Vickery, K R; Risbon, R E; Lachowicz, J; Burgess, K E; Manley, C A; Clifford, C A

2016-12-01

Sixty-four dogs were treated with single-agent doxorubicin (DOX) for presumptive cardiac hemangiosarcoma (cHSA). The objective response rate (CR + PR) was 41%, and the biologic response rate (CR + PR + SD), or clinical benefit, was 68%. The median progression-free survival (PFS) for treated dogs was 66 days. The median survival time (MST) for this group was 116 days and was significantly improved compared to a MST of 12 days for untreated control dogs (P = 0.0001). Biologic response was significantly associated with improved PFS (P < 0.0001) and OS (P < 0.0001). Univariate analysis identified larger tumour size as a variable negatively associated with PFS. The high rate of clinical benefit and improved MST suggest that DOX has activity in canine cHSA. © 2014 John Wiley & Sons Ltd.

Real-world effectiveness of everolimus-based therapy versus fulvestrant monotherapy in HR(+)/HER2(-) metastatic breast cancer.

PubMed

Hao, Yanni; Lin, Peggy L; Xie, Jipan; Li, Nanxin; Koo, Valerie; Ohashi, Erika; Wu, Eric Q; Rogerio, Jaqueline

2015-08-01

Assessing real-world effectiveness of everolimus-based therapy (EVE) versus fulvestrant monotherapy (FUL) among postmenopausal women with hormone receptor-positive (HR(+))/HER2(-) metastatic breast cancer (mBC) after progression on nonsteroidal aromatase inhibitor (NSAI). Medical charts of community-based patients who received EVE or FUL for mBC after NSAI were examined. Progression-free survival (PFS), time on treatment and time to chemotherapy were compared using Kaplan-Meier curves and Cox proportional hazards models adjusting for line of therapy and patient characteristics. 192 patients received EVE and 156 FUL. After adjusting for patient characteristics, EVE was associated with significantly longer PFS than FUL (hazard ratio: 0.71; p = 0.045). EVE was associated with better PFS than FUL among NSAI-refractory postmenopausal HR(+)/HER2(-) mBC patients.

Visible camera cryostat design and performance for the SuMIRe Prime Focus Spectrograph (PFS)

NASA Astrophysics Data System (ADS)

Smee, Stephen A.; Gunn, James E.; Golebiowski, Mirek; Hope, Stephen C.; Madec, Fabrice; Gabriel, Jean-Francois; Loomis, Craig; Le fur, Arnaud; Dohlen, Kjetil; Le Mignant, David; Barkhouser, Robert; Carr, Michael; Hart, Murdock; Tamura, Naoyuki; Shimono, Atsushi; Takato, Naruhisa

2016-08-01

We describe the design and performance of the SuMIRe Prime Focus Spectrograph (PFS) visible camera cryostats. SuMIRe PFS is a massively multi-plexed ground-based spectrograph consisting of four identical spectrograph modules, each receiving roughly 600 fibers from a 2394 fiber robotic positioner at the prime focus. Each spectrograph module has three channels covering wavelength ranges 380 nm - 640 nm, 640 nm - 955 nm, and 955 nm - 1.26 um, with the dispersed light being imaged in each channel by a f/1.07 vacuum Schmidt camera. The cameras are very large, having a clear aperture of 300 mm at the entrance window, and a mass of 280 kg. In this paper we describe the design of the visible camera cryostats and discuss various aspects of cryostat performance.

Exploration of MEMS G-Switches at 100-10,000 G-Levels with Redundancy

DTIC Science & Technology

2014-04-01

Muntz, A.D. Ketsdever, “Kinetic Modeling of Temperature -Driven Flows in Short Microchannels,” International Journal of Thermal Sciences, Vol. 45, No...switches silicon DRIE Unclassified Unclassified Unclassified UU 59 Suhithi Peiris 703-767-4732 CONVERSION...designed. The devices were fabricated on low resistivity (ɘ.01 Ω-cm) silicon on insulator wafers (SOI) using standard micromachining techniques. Fixed

Electrically operated magnetic switch designed to display reduced leakage inductance

DOEpatents

Cook, Edward G.

1994-01-01

An electrically operated magnetic switch is disclosed herein for use in opening and closing a circuit between two terminals depending upon the voltage across these terminals. The switch so disclosed is comprised of a ferrite core in the shape of a toroid having opposing ends and opposite inner and outer sides and an arrangement of electrically conductive components defining at least one current flow path which makes a number of turns around the core. This arrangement of components includes a first plurality of electrically conducive rigid rods parallel with and located outside the outer side of the core and a second plurality of electrically conductive rigid rods parallel with and located inside the inner side of the core. The arrangement also includes means for electrically connecting these rods together so that the define the current flow path. In one embodiment, this latter means uses rigid cross-tab means. In another, preferred embodiment, printed circuits on rigid dielectric substrates located on opposite ends of the core are utilized to interconnect the rods together.

Simultaneous dynamic characterization of charge and structural motion during ferroelectric switching

NASA Astrophysics Data System (ADS)

Kwamen, C.; Rössle, M.; Reinhardt, M.; Leitenberger, W.; Zamponi, F.; Alexe, M.; Bargheer, M.

2017-10-01

Monitoring structural changes in ferroelectric thin films during electric field induced polarization switching is important for a full microscopic understanding of the coupled motion of charges, atoms, and domain walls in ferroelectric nanostructures. We combine standard ferroelectric test sequences of switching and nonswitching electrical pulses with time-resolved x-ray diffraction to investigate the structural response of a nanoscale Pb (Zr0.2Ti0.8) O3 ferroelectric oxide capacitor upon charging, discharging, and polarization reversal. We observe that a nonlinear piezoelectric response of the ferroelectric layer develops on a much longer time scale than the R C time constant of the device. The complex atomic motion during the ferroelectric polarization reversal starts with a contraction of the lattice, whereas the expansive piezoelectric response sets in after considerable charge flow due to the applied voltage pulses on the electrodes of the capacitor. Our simultaneous measurements on a working device elucidate and visualize the complex interplay of charge flow and structural motion and challenges theoretical modeling.

Flow rate logging seepage meter

NASA Technical Reports Server (NTRS)

Reay, William G. (Inventor); Walthall, Harry G. (Inventor)

1996-01-01

An apparatus for remotely measuring and logging the flow rate of groundwater seepage into surface water bodies. As groundwater seeps into a cavity created by a bottomless housing, it displaces water through an inlet and into a waterproof sealed upper compartment, at which point, the water is collected by a collection bag, which is contained in a bag chamber. A magnet on the collection bag approaches a proximity switch as the collection bag fills, and eventually enables the proximity switch to activate a control circuit. The control circuit then rotates a three-way valve from the collection path to a discharge path, enables a data logger to record the time, and enables a pump, which discharges the water from the collection bag, through the three-way valve and pump, and into the sea. As the collection bag empties, the magnet leaves the proximity of the proximity switch, and the control circuit turns off the pump, resets the valve to provide a collection path, and restarts the collection cycle.

Magnetic switching in granular FePt layers promoted by near-field laser enhancement

DOE PAGES

Granitzka, Patrick W.; Jal, Emmanuelle; Le Guyader, Loic; ...

2017-03-08

Light-matter interaction at the nanoscale in magnetic materials is a topic of intense research in view of potential applications in next-generation high-density magnetic recording. Laser-assisted switching provides a pathway for overcoming the material constraints of high-anisotropy and high-packing density media, though much about the dynamics of the switching process remains unexplored. We use ultrafast small-angle X-ray scattering at an X-ray free-electron laser to probe the magnetic switching dynamics of FePt nanoparticles embedded in a carbon matrix following excitation by an optical femtosecond laser pulse. We observe that the combination of laser excitation and applied static magnetic field, 1 order ofmore » magnitude smaller than the coercive field, can overcome the magnetic anisotropy barrier between “up” and “down” magnetization, enabling magnetization switching. This magnetic switching is found to be inhomogeneous throughout the material with some individual FePt nanoparticles neither switching nor demagnetizing. The origin of this behavior is identified as the near-field modification of the incident laser radiation around FePt nanoparticles. Furthermore, the fraction of not-switching nanoparticles is influenced by the heat flow between FePt and a heat-sink layer.« less

Superconducting flux flow digital circuits

DOEpatents

Hietala, Vincent M.; Martens, Jon S.; Zipperian, Thomas E.

1995-01-01

A NOR/inverter logic gate circuit and a flip flop circuit implemented with superconducting flux flow transistors (SFFTs). Both circuits comprise two SFFTs with feedback lines. They have extremely low power dissipation, very high switching speeds, and the ability to interface between Josephson junction superconductor circuits and conventional microelectronics.

Evolution of low-aspect-ratio rectangular synthetic jets in a quiescent environment

NASA Astrophysics Data System (ADS)

Wang, Lei; Feng, Li-Hao; Wang, Jin-Jun; Li, Tian

2018-06-01

An experimental study was conducted on the evolution of low-aspect-ratio (AR) rectangular synthetic jets using time-resolved two-dimensional particle image velocimetry and stereoscopic particle image velocimetry. Five orifice ARs ranging from 1 to 5 were found to have an obvious effect on the axis switching of vortex rings and the near-field flow physics at a uniform Reynolds number of 166 and non-dimensional stroke length of 4.5. Compared with conventional continuous jets, rectangular synthetic jets displayed more times of axis switching and the first axis-switching location was closer to the jet exit. Two types of different streamwise vortices, SV-I and SV-II, were detected in the near field as the characteristic products of axis switching. Influenced by the axis switching and streamwise vortices, significant entrainment and mixing enhancement was demonstrated for low-AR rectangular synthetic jets.

Behavioral plasticity through the modulation of switch neurons.

PubMed

Vassiliades, Vassilis; Christodoulou, Chris

2016-02-01

A central question in artificial intelligence is how to design agents capable of switching between different behaviors in response to environmental changes. Taking inspiration from neuroscience, we address this problem by utilizing artificial neural networks (NNs) as agent controllers, and mechanisms such as neuromodulation and synaptic gating. The novel aspect of this work is the introduction of a type of artificial neuron we call "switch neuron". A switch neuron regulates the flow of information in NNs by selectively gating all but one of its incoming synaptic connections, effectively allowing only one signal to propagate forward. The allowed connection is determined by the switch neuron's level of modulatory activation which is affected by modulatory signals, such as signals that encode some information about the reward received by the agent. An important aspect of the switch neuron is that it can be used in appropriate "switch modules" in order to modulate other switch neurons. As we show, the introduction of the switch modules enables the creation of sequences of gating events. This is achieved through the design of a modulatory pathway capable of exploring in a principled manner all permutations of the connections arriving on the switch neurons. We test the model by presenting appropriate architectures in nonstationary binary association problems and T-maze tasks. The results show that for all tasks, the switch neuron architectures generate optimal adaptive behaviors, providing evidence that the switch neuron model could be a valuable tool in simulations where behavioral plasticity is required. Copyright © 2015 Elsevier Ltd. All rights reserved.

A novel boundary layer sensor utilizing domain switching in ferroelectric liquid crystals

NASA Technical Reports Server (NTRS)

Parmar, D. S.

1991-01-01

This paper describes the design and the principles of operation of a novel sensor for the optical detection of a shear stress field induced by air or gas flow on a rigid surface. The detection relies on the effects of shear-induced optical switching in ferroelectric liquid crystals. It is shown that the method overcomes many of the limitations of similar measuring techniques including those using cholesteric liquid crystals. The present method offers a preferred alternative for flow visualization and skin friction measurements in wind-tunnel experiments on laminar boundary layer transition investigations. A theoretical model for the optical response to shear stress is presented together with a schematic diagram of the experimental setup.

Low pressure spark gap triggered by an ion diode

DOEpatents

Prono, Daniel S.

1985-01-01

Spark gap apparatus for use as an electric switch operating at high voltage, high current and high repetition rate. Mounted inside a housing are an anode, cathode and ion plate. An ionizable fluid is pumped through the chamber of the housing. A pulse of current to the ion plate causes ions to be emitted by the ion plate, which ions move into and ionize the fluid. Electric current supplied to the anode discharges through the ionized fluid and flows to the cathode. Current stops flowing when the current source has been drained. The ionized fluid recombines into its initial dielectric ionizable state. The switch is now open and ready for another cycle.

Low-pressure spark gap triggered by an ion diode

DOEpatents

Prono, D.S.

1982-08-31

Spark gap apparatus for use as an electric switch operating at high voltage, high current and high repetition rate. Mounted inside a housing are an anode, cathode and ion plate. An ionizable fluid is pumped through the chamber of the housing. A pulse of current to the ion plate causes ions to be emitted by the ion plate, which ions move into and ionize the fluid. Electric current supplied to the anode discharges through the ionized fluid and flows to the cathode. Current stops flowing when the current source has been drained. The ionized fluid recombines into its initial dielectric ionizable state. The switch is now open and ready for another cycle.

Container Closure Integrity Testing of Prefilled Syringes.

PubMed

Peláez, Sarah S; Mahler, Hanns-Christian; Matter, Anja; Koulov, Atanas; Singh, Satish K; Germershaus, Oliver; Mathaes, Roman

2018-04-05

Prefilled syringes (PFSs) are increasingly preferred over vials as container closure systems (CCSs) for injectable drug products when facilitated or self-administration is required. However, PFSs are more complex compared to CCSs consisting of vial, rubber stopper, and crimp cap. Container closure integrity (CCI) assurance and verification has been a specific challenge for PFSs as they feature several sealing areas. A comprehensive understanding of the CCS is necessary for an appropriate CCI assessment as well as for packaging development and qualification. A comprehensive CCI assessment of 6 different PFSs from 3 different manufacturers (including 1 polymeric PFS) was conducted using helium leak testing. PFS components were manipulated to systematically assess the contribution of the different sealing areas to CCI, namely rigid needle shield (RNS)/needle, RNS/tip cone, and the individual ribs of a syringe plunger. The polymeric PFS required an equilibrium measurement for accurate container closure integrity testing. The different sealing areas and a single plunger rib were shown to provide adequate CCI. Acceptable tip cap movement until the point of CCI failure was estimated. The assessment of acceptable tip cap movement demonstrated the importance of considering the RNS/tip cone seal design to ensure CCI of the PFS upon post assembly possesses and shipment. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

The relation of hedonic hunger and restrained eating to lateralized frontal activation.

PubMed

Winter, S R; Feig, E H; Kounios, J; Erickson, B; Berkowitz, S; Lowe, M R

2016-09-01

Asymmetrical alpha activation in the prefrontal cortex (frontal asymmetry) in electroencephalography (EEG) has been related to eating behavior. Prior studies linked dietary restraint with right frontal asymmetry [1] and disinhibition with left frontal asymmetry [2]. The current study simultaneously assessed restrained eating and hedonic hunger (drive for food reward in the absence of hunger) in relation to frontal asymmetry. Resting-state EEG and measures of restrained eating (Revised Restraint Scale; RRS) and hedonic hunger (Power of Food Scale; PFS) were assessed in 61 non-obese adults. Individually, hedonic hunger predicted left asymmetry. However, PFS and RRS were correlated (r=0.48, p<0.05) and there was a significant interaction between PFS and RRS on frontal asymmetry, p<0.01. Results indicated that those high in hedonic hunger exhibited left asymmetry irrespective of RRS scores; among those low in PFS, only those high in RRS showed right asymmetry. Results were consistent with literature linking avoidant behaviors (restraint) with right-frontal asymmetry and approach behaviors (binge eating) with left-frontal asymmetry. It appears that a strong drive toward palatable foods predominates at a neural level even when restraint is high. Findings suggest that lateralized frontal activity is an indicator of motivation both to consume and to avoid consuming highly palatable foods. Copyright © 2016 Elsevier Inc. All rights reserved.

Surrogate endpoints for overall survival in lung cancer trials: a review.

PubMed

Fiteni, Frédéric; Westeel, Virginie; Bonnetain, Franck

2017-05-01

Intermediate endpoints are often used as primary endpoints instead of overall survival (OS) in lung cancer trials but they are not systematically validated as surrogate endpoints for OS. Areas covered: The aim of the study was to review the studies which assessed potential surrogate endpoints for OS in lung cancer trials. Expert commentary: Twenty studies were identified. In operable non-small cell lung cancer (NSCLC) (adjuvant trials) and locally advanced NSCLC (radiotherapy trials), one individual-patient data meta-analysis found a high correlation of disease-free survival (DFS) and progression-free survival (PFS) with OS at patient and trial level. In trials of adjuvant chemotherapy, correlation between disease-free survival DFS and OS were 0.83 at the individual level (95% CI 0.83-0.83) and 0.92 at trial level (95% CI 0.88-0.95). In locally advanced disease, correlation between PFS and OS was 0.77 to 0.85 at the individual level, and 0.89 to 0.97 at trial level. This study provides a 'proof' of the surrogacy of PFS and DFS on OS according to the IQWiG framework and the surrogacy of PFS and DFS on OS was classified level 2 according to Fleming hierarchy. In all the other setting, no endpoint was judged to be valid surrogate for OS.

[Subgroup Analysis of the Non-interventional REASON Study: PFS and OS According to Age, Smoking History, Gender, and Histology in NSCLC Patients Treated with Gefitinib or Chemotherapy].

PubMed

Schuette, W; Eberhardt, W E E; Waller, C; Schirmacher, P; Dietel, M; Zirrgiebel, U; Radke, S; Thomas, M

2016-09-01

Assessment of several clinical factors on progression-free (PFS) and overall survival (OS) in NSCLC patients (pts.) (stage IV) with mutated epidermal growth factor receptor (EGFRm+) treated with gefitinib (gef) or with chemotherapy (CT) under real-world conditions. 285 EGFRm+ pts. of the non-interventional REASON study treated with gef (n = 206) or CT (n = 79) as first-line therapy or with gef (n = 213) or CT (n = 61) in any line throughout the course of therapy were analyzed according to age, gender, smoking history and histology. Compared with CT, patients treated with gef showed prolongation of PFS and OS in all subgroups. PFS was significantly increased in women and non-smokers. OS was significantly increased in women, non-smokers, (ex)-smokers, patients with adenocarcinoma and elderly patients when treated with gef compared to CT. Female gender turned out to be an independent positive predictive factor for OS in patients treated with gef (HRmale: 1.74, p = 0.0009). A clinical benefit of gef was shown for all analyzed clinical subgroups of EGFRm+ pts. This was confirmed for the female gender in a multivariate analysis. © Georg Thieme Verlag KG Stuttgart · New York.

Statistical Mechanics Provides Novel Insights into Microtubule Stability and Mechanism of Shrinkage

PubMed Central

Jain, Ishutesh; Inamdar, Mandar M.; Padinhateeri, Ranjith

2015-01-01

Microtubules are nano-machines that grow and shrink stochastically, making use of the coupling between chemical kinetics and mechanics of its constituent protofilaments (PFs). We investigate the stability and shrinkage of microtubules taking into account inter-protofilament interactions and bending interactions of intrinsically curved PFs. Computing the free energy as a function of PF tip position, we show that the competition between curvature energy, inter-PF interaction energy and entropy leads to a rich landscape with a series of minima that repeat over a length-scale determined by the intrinsic curvature. Computing Langevin dynamics of the tip through the landscape and accounting for depolymerization, we calculate the average unzippering and shrinkage velocities of GDP protofilaments and compare them with the experimentally known results. Our analysis predicts that the strength of the inter-PF interaction (Ems) has to be comparable to the strength of the curvature energy (Emb) such that Ems−Emb≈1kBT, and questions the prevalent notion that unzippering results from the domination of bending energy of curved GDP PFs. Our work demonstrates how the shape of the free energy landscape is crucial in explaining the mechanism of MT shrinkage where the unzippered PFs will fluctuate in a set of partially peeled off states and subunit dissociation will reduce the length. PMID:25692909

Well-Defined Peapod-like Magnetic Nanoparticles and Their Controlled Modification for Effective Imaging Guided Gene Therapy.

PubMed

Wang, Ranran; Hu, Yang; Zhao, Nana; Xu, Fu-Jian

2016-05-11

Due to their unique properties, one-dimensional (1D) magnetic nanostructures are of great significance for biorelated applications. A facile and straightforward strategy to fabricate 1D magnetic structure with special shapes is highly desirable. In this work, well-defined peapod-like 1D magnetic nanoparticles (Fe3O4@SiO2, p-FS) are readily synthesized by a facile method without assistance of any templates, magnetic string or magnetic field. There are few reports on 1D gene carriers based on Fe3O4 nanoparticles. BUCT-PGEA (ethanolamine-functionalized poly(glycidyl methacrylate) is subsequently grafted from the surface of p-FS nanoparticles by atom transfer radical polymerization to construct highly efficient gene vectors (p-FS-PGEA) for effective biomedical applications. Peapod-like p-FS nanoparticles were proven to largely improve gene transfection performance compared with ordinary spherical Fe3O4@SiO2 nanoparticles (s-FS). External magnetic field was also utilized to further enhance the transfection efficiency. Moreover, the as-prepared p-FS-PGEA gene carriers could combine the magnetic characteristics of p-FS to well achieve noninvasive magnetic resonance imaging (MRI). We show here novel and multifunctional magnetic nanostructures fabricated for biomedical applications that realized efficient gene delivery and real-time imaging at the same time.

Adverse Effects of Plant Food Supplements and Plants Consumed as Food: Results from the Poisons Centres-Based PlantLIBRA Study.

PubMed

Lüde, Saskia; Vecchio, Sarah; Sinno-Tellier, Sandra; Dopter, Aymeric; Mustonen, Harriet; Vucinic, Slavica; Jonsson, Birgitta; Müller, Dieter; Veras Gimenez Fruchtengarten, Ligia; Hruby, Karl; De Souza Nascimento, Elizabeth; Di Lorenzo, Chiara; Restani, Patrizia; Kupferschmidt, Hugo; Ceschi, Alessandro

2016-06-01

Plant food supplements (PFS) are products of increasing popularity and wide-spread distribution. Nevertheless, information about their risks is limited. To fill this gap, a poisons centres-based study was performed as part of the EU project PlantLIBRA. Multicentre retrospective review of data from selected European and Brazilian poisons centres, involving human cases of adverse effects due to plants consumed as food or as ingredients of food supplements recorded between 2006 and 2010. Ten poisons centres provided a total of 75 cases. In 57 cases (76%) a PFS was involved; in 18 (24%) a plant was ingested as food. The 10 most frequently reported plants were Valeriana officinalis, Camellia sinensis, Paullinia cupana, Melissa officinalis, Passiflora incarnata, Mentha piperita, Glycyrrhiza glabra, Ilex paraguariensis, Panax ginseng, and Citrus aurantium. The most frequently observed clinical effects were neurotoxicity and gastro-intestinal symptoms. Most cases showed a benign clinical course; however, five cases were severe. PFS-related adverse effects seem to be relatively infrequent issues for poisons centres. Most cases showed mild symptoms. Nevertheless, the occurrence of some severe adverse effects and the increasing popularity of PFS require continuous active surveillance, and further research is warranted. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Splenic marginal zone lymphoma: excellent outcomes in 64 patients treated in the rituximab era.

PubMed

Starr, Adam G; Caimi, Paolo F; Fu, PingFu; Massoud, Mira R; Meyerson, Howard; Hsi, Eric D; Mansur, David B; Cherian, Sheen; Cooper, Brenda W; De Lima, Marcos J G; Lazarus, Hillard M; Gerson, Stanton L; Jagadeesh, Deepa; Smith, Mitchell R; Dean, Robert M; Pohlman, Brad L; Hill, Brian T; William, Basem M

2017-08-01

Splenic marginal zone lymphoma (SMZL) is a rare non-Hodgkin lymphoma. We sought to identify prognostic factors and define outcomes in a cohort of 64 patients with SMZL who were treated at two large academic medical centers in North America in the rituximab era. Over a median follow-up of 37.8 (range 6-167.1) months, Kaplan-Meier estimate of median OS was 156.3 months and median PFS was 52.9 months. On univariate analysis, baseline hemoglobin <12 g/dl was associated with inferior OS (p = 0.045). High-risk FLIPI score was associated with inferior PFS when compared with intermediate/low risk (p = 0.05) and marginally significant with regard to OS (p = 0.056). Splenectomy was not predictive of OS or PFS (p = 0.563 and 0.937, respectively). Transformation to diffuse large B-cell lymphoma occurred in four (6.3%) patients during the observation period. OS was comparable to contemporaneous cohorts of patients with extranodal and nodal marginal lymphomas and FLIPI score was highly predictive for inferior PFS and OS when all three cohorts were analyzed together. Outcomes of SMZL, in our series, were excellent, with a median OS of >13 years. Low hemoglobin and high-risk FLIPI were associated with inferior outcomes.

A Mission Planning Approach for Precision Farming Systems Based on Multi-Objective Optimization.

PubMed

Zhai, Zhaoyu; Martínez Ortega, José-Fernán; Lucas Martínez, Néstor; Rodríguez-Molina, Jesús

2018-06-02

As the demand for food grows continuously, intelligent agriculture has drawn much attention due to its capability of producing great quantities of food efficiently. The main purpose of intelligent agriculture is to plan agricultural missions properly and use limited resources reasonably with minor human intervention. This paper proposes a Precision Farming System (PFS) as a Multi-Agent System (MAS). Components of PFS are treated as agents with different functionalities. These agents could form several coalitions to complete the complex agricultural missions cooperatively. In PFS, mission planning should consider several criteria, like expected benefit, energy consumption or equipment loss. Hence, mission planning could be treated as a Multi-objective Optimization Problem (MOP). In order to solve MOP, an improved algorithm, MP-PSOGA, is proposed, taking advantages of the Genetic Algorithms and Particle Swarm Optimization. A simulation, called precise pesticide spraying mission, is performed to verify the feasibility of the proposed approach. Simulation results illustrate that the proposed approach works properly. This approach enables the PFS to plan missions and allocate scarce resources efficiently. The theoretical analysis and simulation is a good foundation for the future study. Once the proposed approach is applied to a real scenario, it is expected to bring significant economic improvement.

Association of programmed death ligand-1 (PD-L1) expression with treatment outcomes in patients with BRAF mutation-positive melanoma treated with vemurafenib or cobimetinib combined with vemurafenib.

PubMed

Wongchenko, Matthew J; Ribas, Antoni; Dréno, Brigitte; Ascierto, Paolo A; McArthur, Grant A; Gallo, Jorge D; Rooney, Isabelle A; Hsu, Jessie; Koeppen, Hartmut; Yan, Yibing; Larkin, James

2017-11-20

The prognostic significance of programmed death ligand-1 (PD-L1) on treatment outcomes in patients receiving BRAF with or without MEK inhibitors is not well understood. This retrospective exploratory analysis evaluated the association of tumour PD-L1 expression with progression-free survival (PFS) and overall survival (OS) among 210 patients in the coBRIM trial treated with cobimetinib plus vemurafenib or placebo plus vemurafenib. In the vemurafenib cohort, there was a trend of increased PFS and OS in those with PD-L1 + melanoma, with hazard ratios (HRs; PD-L1 + vs. PD-L1 - ) of 0.70 (95% CI, 0.46-1.07) and 0.69 (95% CI, 0.42-1.13) for PFS and OS, respectively. However, in patients treated with cobimetinib plus vemurafenib, a similar trend was not observed with HRs (PD-L1 + versus PD-L1 - ) of 1.04 (95% CI, 0.66-1.68) and 0.94 (95% CI, 0.57-1.57) for PFS and OS, respectively. The combination cobimetinib plus vemurafenib appears to overcome the poor prognosis associated with low PD-L1 expression. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Should Animals Navigating Over Short Distances Switch to a Magnetic Compass Sense?

PubMed Central

Wyeth, Russell C.

2010-01-01

Magnetoreception can play a substantial role in long distance navigation by animals. I hypothesize that locomotion guided by a magnetic compass sense could also play a role in short distance navigation. Animals identify mates, prey, or other short distance navigational goals using different sensory modalities (olfaction, vision, audition, etc.) to detect sensory cues associated with those goals. In conditions where these cues become unreliable for navigation (due to flow changes, obstructions, noise interference, etc.), switching to a magnetic compass sense to guide locomotion toward the navigational goals could be beneficial. Using simulations based on known locomotory and flow parameters, I show this strategy has strong theoretical benefits for the nudibranch mollusk Tritonia diomedea navigating toward odor sources in variable flow. A number of other animals may garner similar benefits, particularly slow-moving species in environments with rapidly changing cues relevant for navigation. Faster animals might also benefit from switching to a magnetic compass sense, provided the initial cues used for navigation (acoustic signals, odors, etc.) are intermittent or change rapidly enough that the entire navigation behavior cannot be guided by a continuously detectable cue. Examination of the relative durations of navigational tasks, the persistence of navigational cues, and the stability of both navigators and navigational targets will identify candidates with the appropriate combination of unreliable initial cues and relatively immobile navigational goals for which this hypothetical behavior could be beneficial. Magnetic manipulations can then test whether a switch to a magnetic compass sense occurs. This hypothesis thus provides an alternative when considering the behavioral significance of a magnetic compass sense in animals. PMID:20740070

Switching moving boundary models for two-phase flow evaporators and condensers

NASA Astrophysics Data System (ADS)

Bonilla, Javier; Dormido, Sebastián; Cellier, François E.

2015-03-01

The moving boundary method is an appealing approach for the design, testing and validation of advanced control schemes for evaporators and condensers. When it comes to advanced control strategies, not only accurate but fast dynamic models are required. Moving boundary models are fast low-order dynamic models, and they can describe the dynamic behavior with high accuracy. This paper presents a mathematical formulation based on physical principles for two-phase flow moving boundary evaporator and condenser models which support dynamic switching between all possible flow configurations. The models were implemented in a library using the equation-based object-oriented Modelica language. Several integrity tests in steady-state and transient predictions together with stability tests verified the models. Experimental data from a direct steam generation parabolic-trough solar thermal power plant is used to validate and compare the developed moving boundary models against finite volume models.

Automated Postattack Damage Assessment System (APUDAS) for Sewage and Mission-Critical HVAC Systems

DTIC Science & Technology

1990-10-01

immediately thickened and processed for disposal. Common methods of sludge processing include: digestion, vacuum filtration, and centrifugation . The most...Paddle TYDe Switches for ’Flow-No Flow’ DAetection f r PEiino Systems " and Up catalog. 20. Newark (Potter and Brumfield) Relays, Buzzers, Contactors

Specialist Osmia bees forage indiscriminately among hybridizing Balsamorhiza floral hosts

Treesearch

James H. Cane

2011-01-01

Pollinators, even floral generalists (=polyleges), typically specialize during individual foraging bouts, infrequently switching between floral hosts. Such transient floral constancy restricts pollen flow, and thereby gene flow, to conspecific flowers in mixed plant communities. Where incipient flowering species meet, however, weak cross-fertility and often similar...

Superconducting flux flow digital circuits

DOEpatents

Hietala, V.M.; Martens, J.S.; Zipperian, T.E.

1995-02-14

A NOR/inverter logic gate circuit and a flip flop circuit implemented with superconducting flux flow transistors (SFFTs) are disclosed. Both circuits comprise two SFFTs with feedback lines. They have extremely low power dissipation, very high switching speeds, and the ability to interface between Josephson junction superconductor circuits and conventional microelectronics. 8 figs.

Fringe Field Superconducting Switch

DTIC Science & Technology

1997-10-31

However, it is not believed that any known superconducting switch has all of these desirable 3 properties . 4 Many known superconducting devices rely on...will recognize, a weak link is a structure that does not in itself have superconducting properties , but 7 will allow a relatively small flow of tunnel... properties of the junction. 12 Thus, the operating parameters of conventional Josephson junctions tend to drift over time. This 13 shortcoming of

Exposure-response evaluations of venetoclax efficacy and safety in patients with non-Hodgkin lymphoma.

PubMed

Parikh, Apurvasena; Gopalakrishnan, Sathej; Freise, Kevin J; Verdugo, Maria E; Menon, Rajeev M; Mensing, Sven; Salem, Ahmed Hamed

2018-04-01

Exposure-response analyses were performed for a venetoclax monotherapy study in 106 patients with varying subtypes of non-Hodgkin lymphoma (NHL) (NCT01328626). Logistic regression, time-to-event, and progression-free survival (PFS) analyses were used to evaluate the relationship between venetoclax exposure, NHL subtype and response, PFS, or occurrence of serious adverse events. Trends for small increases in the probability of response with increasing venetoclax exposures were identified, and became more evident when assessed by NHL subtype. Trends in exposure-PFS were shown for the mantle cell lymphoma (MCL) subtype, but not other subtypes. There was no increase in the probability of experiencing a serious adverse event with increasing exposure. Overall, the results indicate that venetoclax doses of 800-1200 mg as a single agent may be appropriate to maximize efficacy in MCL, follicular lymphoma, and diffuse large B-cell lymphoma subtypes with no expected negative impact on safety.

Dust observations by PFS on Mars Express

NASA Astrophysics Data System (ADS)

Zasova, L. V.; Formisano, V.; Moroz, V. I.; Grassi, D.; Ignatiev, N. I.; Blecka, M. I.; Maturilli, A.; Palomba, E.; Piccioni, G.; Pfs Team

Dust is always present in the Martian atmosphere with opacity, which changes from values below 0.1 (at 9 μ m) up to several units during the dust storms. From the thermal IR (LW channel of PFS) the dust opacity is retrieved in a self consistent way together with the temperature profile from the same spectrum A preliminary investigation along the orbit, which comes through Hellas, shows that the value of dust opacity anticorrelates with surface altitude. From -70 to +25 of latitude the vertical dust distribution follows the exponential low with the scale of 12 km, which corresponds to the gaseous scale height near noon and indicates for well mixed condition. The dust opacity, corresponding to the zero surface altitude, is found of 0.25+-0.05. More detailed investigations of all available data will be presented, including analysis of both short- and long- wavelength spectra of PFS.

First results of the observations of trace gases in the Martian atmosphere by the Planetary Fourier Spectrometer onboard the Mars Express

NASA Astrophysics Data System (ADS)

Titov, D. V.; Ignatiev, N.; Formisano, V.; Grassi, D.; Giuranna, M.; Maturilli, A.; Piccioni, G.; Moroz, V. I.; Lellouch, E.; Encrenaz, T.; Pfs Team

High spectral resolution observations of Mars by the PFS/Mars Express provide new insight into the atmospheric composition. Spectral features of atmospheric CO2 and its isotopes at 15, 4.3, 2.7, 1.4 μ m, CO at 4.7 and 2.35 μ m, and H2O at 40, 2.56, and 1.38 μ m as well as solar spectral features are clearly identified in the PFS spectra. HDO spectral details at 3.7 μ m were also tentatively detected. The paper will present qualitative and quantitative analysis of the PFS spectra in the regions of spectral bands of trace gases. Abundance of minor constituents will be determined using complete radiative transfer modeling including possible non-LTE effects. We will also present results of search for other minor species with emphasis on the limb observations that provide higher air mass factor.

Finger vein recognition with personalized feature selection.

PubMed

Xi, Xiaoming; Yang, Gongping; Yin, Yilong; Meng, Xianjing

2013-08-22

Finger veins are a promising biometric pattern for personalized identification in terms of their advantages over existing biometrics. Based on the spatial pyramid representation and the combination of more effective information such as gray, texture and shape, this paper proposes a simple but powerful feature, called Pyramid Histograms of Gray, Texture and Orientation Gradients (PHGTOG). For a finger vein image, PHGTOG can reflect the global spatial layout and local details of gray, texture and shape. To further improve the recognition performance and reduce the computational complexity, we select a personalized subset of features from PHGTOG for each subject by using the sparse weight vector, which is trained by using LASSO and called PFS-PHGTOG. We conduct extensive experiments to demonstrate the promise of the PHGTOG and PFS-PHGTOG, experimental results on our databases show that PHGTOG outperforms the other existing features. Moreover, PFS-PHGTOG can further boost the performance in comparison with PHGTOG.

Finger Vein Recognition with Personalized Feature Selection

PubMed Central

Xi, Xiaoming; Yang, Gongping; Yin, Yilong; Meng, Xianjing

2013-01-01

Finger veins are a promising biometric pattern for personalized identification in terms of their advantages over existing biometrics. Based on the spatial pyramid representation and the combination of more effective information such as gray, texture and shape, this paper proposes a simple but powerful feature, called Pyramid Histograms of Gray, Texture and Orientation Gradients (PHGTOG). For a finger vein image, PHGTOG can reflect the global spatial layout and local details of gray, texture and shape. To further improve the recognition performance and reduce the computational complexity, we select a personalized subset of features from PHGTOG for each subject by using the sparse weight vector, which is trained by using LASSO and called PFS-PHGTOG. We conduct extensive experiments to demonstrate the promise of the PHGTOG and PFS-PHGTOG, experimental results on our databases show that PHGTOG outperforms the other existing features. Moreover, PFS-PHGTOG can further boost the performance in comparison with PHGTOG. PMID:23974154

Study of Electromagnetic Repulsion Switch to High Speed Reclosing and Recover Time Characteristics of Superconductor

NASA Astrophysics Data System (ADS)

Koyama, Tomonori; Kaiho, Katsuyuki; Yamaguchi, Iwao; Yanabu, Satoru

Using a high-temperature superconductor, we constructed and tested a model superconducting fault current limiter (SFCL). The superconductor and vacuum interrupter as the commutation switch were connected in parallel using a bypass coil. When the fault current flows in this equipment, the superconductor is quenched and the current is then transferred to the parallel coil due to the voltage drop in the superconductor. This large current in the parallel coil actuates the magnetic repulsion mechanism of the vacuum interrupter and the current in the superconductor is broken. Using this equipment, the current flow time in the superconductor can be easily minimized. On the other hand, the fault current is also easily limited by large reactance of the parallel coil. This system has many merits. So, we introduced to electromagnetic repulsion switch. There is duty of high speed re-closing after interrupting fault current in the electrical power system. So the SFCL should be recovered to superconducting state before high speed re-closing. But, superconductor generated heat at the time of quench. It takes time to recover superconducting state. Therefore it is a matter of recovery time. In this paper, we studied recovery time of superconductor. Also, we proposed electromagnetic repulsion switch with reclosing system.

Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study.

PubMed

Conteduca, V; Wetterskog, D; Sharabiani, M T A; Grande, E; Fernandez-Perez, M P; Jayaram, A; Salvi, S; Castellano, D; Romanel, A; Lolli, C; Casadio, V; Gurioli, G; Amadori, D; Font, A; Vazquez-Estevez, S; González Del Alba, A; Mellado, B; Fernandez-Calvo, O; Méndez-Vidal, M J; Climent, M A; Duran, I; Gallardo, E; Rodriguez, A; Santander, C; Sáez, M I; Puente, J; Gasi Tandefelt, D; Wingate, A; Dearnaley, D; Demichelis, F; De Giorgi, U; Gonzalez-Billalabeitia, E; Attard, G

2017-07-01

There is an urgent need to identify biomarkers to guide personalized therapy in castration-resistant prostate cancer (CRPC). We aimed to clinically qualify androgen receptor (AR) gene status measurement in plasma DNA using multiplex droplet digital PCR (ddPCR) in pre- and post-chemotherapy CRPC. We optimized ddPCR assays for AR copy number and mutations and retrospectively analyzed plasma DNA from patients recruited to one of the three biomarker protocols with prospectively collected clinical data. We evaluated associations between plasma AR and overall survival (OS) and progression-free survival (PFS) in 73 chemotherapy-naïve and 98 post-docetaxel CRPC patients treated with enzalutamide or abiraterone (Primary cohort) and 94 chemotherapy-naïve patients treated with enzalutamide (Secondary cohort; PREMIERE trial). In the primary cohort, AR gain was observed in 10 (14%) chemotherapy-naïve and 33 (34%) post-docetaxel patients and associated with worse OS [hazard ratio (HR), 3.98; 95% CI 1.74-9.10; P < 0.001 and HR 3.81; 95% CI 2.28-6.37; P < 0.001, respectively], PFS (HR 2.18; 95% CI 1.08-4.39; P = 0.03, and HR 1.95; 95% CI 1.23-3.11; P = 0.01, respectively) and rate of PSA decline ≥50% [odds ratio (OR), 4.7; 95% CI 1.17-19.17; P = 0.035 and OR, 5.0; 95% CI 1.70-14.91; P = 0.003, respectively]. AR mutations [2105T>A (p.L702H) and 2632A>G (p.T878A)] were observed in eight (11%) post-docetaxel but no chemotherapy-naïve abiraterone-treated patients and were also associated with worse OS (HR 3.26; 95% CI 1.47-not reached; P = 0.004). There was no interaction between AR and docetaxel status (P = 0.83 for OS, P = 0.99 for PFS). In the PREMIERE trial, 11 patients (12%) with AR gain had worse PSA-PFS (sPFS) (HR 4.33; 95% CI 1.94-9.68; P < 0.001), radiographic-PFS (rPFS) (HR 8.06; 95% CI 3.26-19.93; P < 0.001) and OS (HR 11.08; 95% CI 2.16-56.95; P = 0.004). Plasma AR was an independent predictor of outcome on multivariable analyses in both cohorts. Plasma AR status assessment using ddPCR identifies CRPC with worse outcome to enzalutamide or abiraterone. Prospective evaluation of treatment decisions based on plasma AR is now required. NCT02288936 (PREMIERE trial). © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.

Prognostic Value and Grading of MRI-Based T Category in Patients With Nasopharyngeal Carcinoma Without Lymph Node Metastasis Undergoing Intensity-Modulated Radiation Therapy

PubMed Central

Chen, Yu-Pei; Tang, Ling-Long; Zhang, Wen-Na; Mao, Yan-Ping; Chen, Lei; Sun, Ying; Liu, Li-Zhi; Li, Wen-Fei; Liu, Xu; Zhou, Guan-Qun; Guo, Rui; Mai, Hai-Qiang; Shao, Jian-Yong; Lin, Ai-Hua; Li, Li; Ma, Jun

2015-01-01

Abstract We investigated the prognostic value and gradation of the T category in N0 nasopharyngeal carcinoma (NPC) patients undergoing magnetic resonance imaging (MRI) and intensity-modulated radiotherapy (IMRT). A total of 749 patients were retrospectively reviewed, and a total of 181 N0 NPC patients were included in this retrospective study. All patients were restaged according to the 7th edition of the American Joint Committee on Cancer staging system. The following endpoints were estimated: overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS). The 5-year survival rates for T1 to T4 were: OS (97.3%, 100.0%, 86.1%, and 82.8%; P = 0.007), PFS (94.6%, 96.9%, 76.5%, and 76.7%; P = 0.002), LRFS (98.5%, 100.0%, 92.2%, and 86.7%; P < 0.001), and DMFS (97.3%, 96.9%, 85.5%, and 85.7%; P = 0.042), respectively. Pairwise comparisons showed that the OS, PFS, and LRFS rates were significantly poorer in the advanced T categories (T3 and T4) than the early ones (T1 and T2), and no significant differences between T1 and T2, and T3 and T4 were found. In Cox's proportional hazard analysis, T category was found to be an independent prognostic factor only for PFS (P = 0.003). According to the primary tumor extent, we then graded all 181 N0 patients into 3 groups: group 1, early T category (n = 107); group 2, low-risk advanced T category (n = 35); and group 3, high-risk advanced T category (n = 39). The 5-year survival rates for the 3 groups were: OS (98.1%, 94.1%, and 76.3%; P < 0.001), PFS (95.3%, 88.2%, and 66.2%; P < 0.001), LRFS (99.0%, 97.0%, and 83.4%; P < 0.001), and DMFS (97.2%, 91.1%, and 80.4%; P = 0.002). The 5-year OS, PFS, and LRFS rates of group 3 differed significantly from those of groups 1 and 2, and a significant difference was observed in the DMFS rate only between groups 3 and 1. In Cox's proportional hazard analysis, the 3-grade T category was an independent prognostic factor for OS (P = 0.002), PFS (P < 0.001), and LRFS (P = 0.002). The 3-grade T category, using MRI according to the site of invasion, has prognostic value for the outcome of IMRT treatment in N0 NPC, and could aid in developing individualized treatment strategies. PMID:26512556

Protocol for “Seal or Varnish?” (SoV) trial: a randomised controlled trial to measure the relative cost and effectiveness of pit and fissure sealants and fluoride varnish in preventing dental decay

PubMed Central

2012-01-01

Background Dental caries remains a significant public health problem, prevalence being linked to social and economic deprivation. Occlusal surfaces of first permanent molars are the most susceptible site in the developing permanent dentition. Cochrane reviews have shown pit and fissure sealants (PFS) and fluoride varnish (FV) to be effective over no intervention in preventing caries. However, the comparative cost and effectiveness of these treatments is uncertain. The primary aim of the trial described in this protocol is to compare the clinical effectiveness of PFS and FV in preventing dental caries in first permanent molars in 6-7 year-olds. Secondary aims include: establishing the costs and the relative cost-effectiveness of PFS and FV delivered in a community/school setting; examining the impact of PFS and FV on children and their parents/carers in terms of quality of life/treatment acceptability measures; and examining the implementation of treatment in a community setting. Methods/design The trial design comprises a randomised, assessor-blinded, two-arm, parallel group trial in 6–7 year old schoolchildren. Clinical procedures and assessments will be performed at 66 primary schools, in deprived areas in South Wales. Treatments will be delivered via a mobile dental clinic. In total, 920 children will be recruited (460 per trial arm). At baseline and annually for 36 months dental caries will be recorded using the International Caries Detection and Assessment System (ICDAS) by trained and calibrated dentists. PFS and FV will be applied by trained dental hygienists. The FV will be applied at baseline, 6, 12, 18, 24 and 30 months. The PFS will be applied at baseline and re-examined at 6, 12, 18, 24, and 30 months, and will be re-applied if the existing sealant has become detached/is insufficient. The economic analysis will estimate the costs of providing the PFS versus FV. The process evaluation will assess implementation and acceptability through acceptability scales, a schools questionnaire and interviews with children, parents, dentists, dental nurses and school staff. The primary outcome measure will be the proportion of children developing new caries on any one of up to four treated first permanent molars. Discussion The objectives of this study have been identified by the National Institute for Health Research as one of importance to the National Health Service in the UK. The results of this trial will provide guidance on which of these technologies should be adopted for the prevention of dental decay in the most susceptible tooth-surface in the most at risk children. Trial registrations ISRCTN ref: ISRCTN17029222 EudraCT: 2010-023476-23 UKCRN ref: 9273 PMID:23167481

LASER APPLICATIONS AND OTHER TOPICS IN QUANTUM ELECTRONICS: Optoelectronic switching in diamond and optical surface breakdown

NASA Astrophysics Data System (ADS)

Lipatov, E. I.; Tarasenko, V. F.

2008-03-01

The optoelectronic switching in two natural diamond samples of type 2-A is studied at voltages up to 1000 V and the energy density of control 60-ns, 308-nm laser pulses up to 0.6 J cm-2. It is shown that the design of a diamond switch affects the switching efficiency. When the energy density exceeds 0.2 J cm-2 and the interelectrode surface is completely illuminated, the surface breakdown is initiated by UV radiation, which shunts the current flow through the diamond crystal. When the illumination of the interelectrode surface is excluded, the surface breakdown does not occur. The threshold radiation densities sufficient for initiating the surface breakdown are determined for electric field strengths up to 10 kV cm-1.

Modeling and Density Estimation of an Urban Freeway Network Based on Dynamic Graph Hybrid Automata

PubMed Central

Chen, Yangzhou; Guo, Yuqi; Wang, Ying

2017-01-01

In this paper, in order to describe complex network systems, we firstly propose a general modeling framework by combining a dynamic graph with hybrid automata and thus name it Dynamic Graph Hybrid Automata (DGHA). Then we apply this framework to model traffic flow over an urban freeway network by embedding the Cell Transmission Model (CTM) into the DGHA. With a modeling procedure, we adopt a dual digraph of road network structure to describe the road topology, use linear hybrid automata to describe multi-modes of dynamic densities in road segments and transform the nonlinear expressions of the transmitted traffic flow between two road segments into piecewise linear functions in terms of multi-mode switchings. This modeling procedure is modularized and rule-based, and thus is easily-extensible with the help of a combination algorithm for the dynamics of traffic flow. It can describe the dynamics of traffic flow over an urban freeway network with arbitrary topology structures and sizes. Next we analyze mode types and number in the model of the whole freeway network, and deduce a Piecewise Affine Linear System (PWALS) model. Furthermore, based on the PWALS model, a multi-mode switched state observer is designed to estimate the traffic densities of the freeway network, where a set of observer gain matrices are computed by using the Lyapunov function approach. As an example, we utilize the PWALS model and the corresponding switched state observer to traffic flow over Beijing third ring road. In order to clearly interpret the principle of the proposed method and avoid computational complexity, we adopt a simplified version of Beijing third ring road. Practical application for a large-scale road network will be implemented by decentralized modeling approach and distributed observer designing in the future research. PMID:28353664