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1
Poyart, Claire, Marie Cécile Lamy, Claire Boumaila, Franz Fiedler, and Patrick Trieu-Cuot. "Regulation of d-Alanyl-Lipoteichoic Acid Biosynthesis in Streptococcus agalactiae Involves a Novel Two-Component Regulatory System." Journal of Bacteriology 183, no. 21 (November 1, 2001): 6324–34. http://dx.doi.org/10.1128/jb.183.21.6324-6334.2001.
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ABSTRACT The dlt operon of gram-positive bacteria comprises four genes (dltA, dltB, dltC, and dltD) that catalyze the incorporation of d-alanine residues into the lipoteichoic acids (LTAs). In this work, we characterized thedlt operon of Streptococcus agalactiae, which, in addition to the dltA to dltD genes, included two regulatory genes, designated dltR and dltS, located upstream of dltA. The dltR gene encodes a 224-amino-acid putative response regulator belonging to the OmpR family of regulatory proteins. The dltS gene codes for a 395-amino-acid putative histidine kinase thought to be involved in the sensing of environmental signals. The dlt operon ofS. agalactiae is mainly transcribed from the P dltR promoter, which directs synthesis of a 6.5-kb transcript encompassing dltR, dltS, dltA, dltB, dltC, and dltD, and from a weaker promoter, P dltA , which is located in the 3′ extremity ofdltS. We demonstrate that P dltR , but not P dlA , is activated by DltR in the presence of DltS in d-Ala-deficient LTA mutants resulting from insertional inactivation of the dltA gene, which encodes the cytoplasmic d-alanine-d-alanyl carrier ligase DltA. Expression of the dlt operon does not require DltR and DltS, since the basal activity of P dltR is high, being 20-fold that of the constitutive promoter P aphA-3 which directs synthesis of the kanamycin resistance gene aphA-3 in various gram-positive bacteria. We hypothesize that the role of DltR and DltS in the control of expression of the dlt operon is to maintain the level of d-Ala esters in LTAs at a constant and appropriate value whatever the environmental conditions. The DltA− mutant displayed the ability to form clumps in standing culture and exhibited an increased susceptibility to the cationic antimicrobial polypeptide colistin.
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Debabov, Dmitri V., Michael Y. Kiriukhin, and Francis C. Neuhaus. "Biosynthesis of Lipoteichoic Acid inLactobacillus rhamnosus: Role of DltD ind-Alanylation." Journal of Bacteriology 182, no. 10 (May 15, 2000): 2855–64. http://dx.doi.org/10.1128/jb.182.10.2855-2864.2000.
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ABSTRACT The dlt operon (dltA to dltD) of Lactobacillus rhamnosus 7469 encodes four proteins responsible for the esterification of lipoteichoic acid (LTA) byd-alanine. These esters play an important role in controlling the net anionic charge of the poly (GroP) moiety of LTA.dltA and dltC encode thed-alanine–d-alanyl carrier protein ligase (Dcl) and d-alanyl carrier protein (Dcp), respectively. Whereas the functions of DltA and DltC are defined, the functions of DltB and DltD are unknown. To define the role of DltD, the gene was cloned and sequenced and a mutant was constructed by insertional mutagenesis of dltD from Lactobacillus casei102S. Permeabilized cells of a dltD::erm mutant lacked the ability to incorporate d-alanine into LTA. This defect was complemented by the expression of DltD from pNZ123/dlt. In in vitro assays, DltD bound Dcp for ligation with d-alanine by Dcl in the presence of ATP. In contrast, the homologue of Dcp, the Escherichia coli acyl carrier protein (ACP), involved in fatty acid biosynthesis, was not bound to DltD and thus was not ligated with d-alanine. DltD also catalyzed the hydrolysis of the mischarged d-alanyl–ACP. The hydrophobic N-terminal sequence of DltD was required for anchoring the protein in the membrane. It is hypothesized that this membrane-associated DltD facilitates the binding of Dcp and Dcl for ligation of Dcp with d-alanine and that the resultingd-alanyl–Dcp is translocated to the primary site ofd-alanylation.
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Beeh, K. M., O. Kornmann, J. Lill, and R. Buhl. "Induced sputum cell profiles in lung transplant recipients with or without chronic rejection: correlation with lung function." Thorax 56, no. 7 (July 1, 2001): 557–60. http://dx.doi.org/10.1136/thx.56.7.557.
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BACKGROUNDSputum induction is a non-invasive procedure for measuring inflammatory processes of the lower respiratory tract. The aim of this study was to establish sputum cell counts and differentials in patients after lung transplantation (LTx), with or without chronic transplant rejection.METHODSSputum induction was performed in 41 LTx patients (25 single LTx (sLTx), 16 double LTx (dLTx) and 15 healthy non-smoking volunteers. Sputum was processed according to standard protocols. Total cell count was calculated as mean (SE) cells × 106/ml sputum and cell differential (%) was evaluated after staining. Cellular profiles were correlated with lung function.RESULTSTotal sputum cell counts were increased in sLTx (9 (1.9) cells × 106/ml, p=0.01) and dLTx patients (7.2 (1.5) × 106/ml, p=0.01) compared with healthy controls (2.6 (0.6) × 106/ml). There was also a marked sputum neutrophilia in both patient groups (59 (6)% and 62 (6)%, respectively, p<0.001v controls). Moreover, in both sLTx and dLTx patients with chronic transplant rejection there was an increased number of sputum neutrophils compared with patients with normal graft function (p<0.05 both comparisons), and neutrophils were inversely correlated with lung function (forced expiratory volume in one second (FEV1) % predicted): sLTx,r=–0.61, p=0.001; dLTx,r=–0.75, p=0.001, respectively). Sputum lymphocytes and eosinophils were similar in both groups. No relevant side effects occurred during sputum induction.CONCLUSIONSSputum induction is a safe and non-invasive tool for monitoring lower respiratory tract inflammation in LTx patients. Both sLTx and dLTx patients with chronic rejection had increased sputum neutrophils compared with patients with normal transplant function. These data support findings of other authors highlighting a possible role for neutrophils in the pathogenesis of chronic transplant rejection.
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Wood, B. McKay, John P. Santa Maria, Leigh M. Matano, Christopher R. Vickery, and Suzanne Walker. "A partial reconstitution implicates DltD in catalyzing lipoteichoic acid d-alanylation." Journal of Biological Chemistry 293, no. 46 (September 20, 2018): 17985–96. http://dx.doi.org/10.1074/jbc.ra118.004561.
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Modifications to the Gram-positive bacterial cell wall play important roles in antibiotic resistance and pathogenesis, but the pathway for the d-alanylation of teichoic acids (DLT pathway), a ubiquitous modification, is poorly understood. The d-alanylation machinery includes two membrane proteins of unclear function, DltB and DltD, which are somehow involved in transfer of d-alanine from a carrier protein inside the cell to teichoic acids on the cell surface. Here, we probed the role of DltD in the human pathogen Staphylococcus aureus using both cell-based and biochemical assays. We first exploited a known synthetic lethal interaction to establish the essentiality of each gene in the DLT pathway for d-alanylation of lipoteichoic acid (LTA) and confirmed this by directly detecting radiolabeled d-Ala-LTA both in cells and in vesicles prepared from mutant strains of S. aureus. We developed a partial reconstitution of the pathway by using cell-derived vesicles containing DltB, but no other components of the d-alanylation pathway, and showed that d-alanylation of previously formed lipoteichoic acid in the DltB vesicles requires the presence of purified and reconstituted DltA, DltC, and DltD, but not of the LTA synthase LtaS. Finally, based on the activity of DltD mutants in cells and in our reconstituted system, we determined that Ser-70 and His-361 are essential for d-alanylation activity, and we propose that DltD uses a catalytic dyad to transfer d-alanine to LTA. In summary, we have developed a suite of assays for investigating the bacterial DLT pathway and uncovered a role for DltD in LTA d-alanylation.
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Du, Liqin, and Yu Luo. "Thiolation-enhanced substrate recognition by D-alanyl carrier protein ligase DltA from Bacillus cereus." F1000Research 3 (May 13, 2014): 106. http://dx.doi.org/10.12688/f1000research.4097.1.
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D-alanylation of the lipoteichoic acid on Gram-positive cell wall is dependent on dlt gene-encoded proteins DltA, DltB, DltC and DltD. The D-alanyl carrier protein ligase DltA, as a remote homolog of acyl-(coenzyme A) (CoA) synthetase, cycles through two active conformations for the catalysis of adenylation and subsequent thiolation of D-alanine (D-Ala). The crystal structure of DltA in the absence of any substrate was observed to have a noticeably more disordered pocket for ATP which would explain why DltA has relatively low affinity for ATP in the absence of any D-alanyl carrier. We have previously enabled the thiolation of D-alanine in the presence of CoA as the mimic of D-alanyl carrier protein DltC which carries a 4’-phosphopantetheine group on a serine residue. Here we show that the resulting Michaelis constants in the presence of saturating CoA for both ATP and D-alanine were reduced more than 10 fold as compared to the values obtained in the absence of CoA. The presence of CoA also made DltA ~100-fold more selective on D-alanine over L-alanine. The CoA-enhanced substrate recognition further implies that the ATP and D-alanine substrates of the adenylation reaction are incorporated when the DltA enzyme cycles through its thiolation conformation.
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Davidsen, Jesper Rømhild, Hans Henrik Lawaetz Schultz, Daniel Pilsgaard Henriksen, Martin Iversen, Anna Kalhauge, Jørn Carlsen, Michael Perch, Ole Graumann, and Christian B. Laursen. "Lung Ultrasound in the Assessment of Pulmonary Complications After Lung Transplantation." Ultraschall in der Medizin - European Journal of Ultrasound 41, no. 02 (November 9, 2018): 148–56. http://dx.doi.org/10.1055/a-0783-2466.
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Abstract Introduction Lung ultrasound (LUS) has a high diagnostic accuracy for identifying frequent conditions in the post-operative phase after lung transplantation (LTx). This study aimed to investigate the feasibility and clinical ability of LUS to identify pulmonary complications such as pleural effusions and pneumonias in the early postoperative phase after LTx. Methods A prospective cohort study of lung transplant recipients who consecutively underwent single LTx (SLTx) or double LTx (DLTx) at the National Lung Transplantation Center in Denmark from May 1 to October 31, 2015 was conducted. LUS was performed at four time points corresponding to post-transplant day 3, and weeks 2, 6, and 12 (LUS #1–4) to detect and monitor variation in pathological LUS findings over time. Concurrent with LUS #4, a high-resolution computed tomography examination of the thorax (HRCT) was also performed. Results 14 patients (1 SLTx/13 DLTx, 7 (50 %) women, mean age: 50.4 years) who had undergone the four prespecified LUS examinations were included. Pleural effusion was the most common condition and most pronounced at post-LTx week 2. Findings consistent with pneumonia increased during week 2 and subsequently decreased. Corresponding to LUS #1, 2, 3, and 4, pleural effusion occurred in 85.7 %, 92.9 %, 85.7 %, and 78.6 %, and pneumonia in 21.4 %, 28.6 %, 14.3 %, and 14.3 %, respectively. HRCT findings at post-LTx week 12 were predominantly presented by unspecific ground glass opacities. Conclusion In a post-LTx setting, LUS represents a clinical novelty as a feasible diagnostic and monitoring tool to identify pathological pulmonary complications in the early post-operative phase.
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Lee, In-Gyun, Chiman Song, Seoyeong Yang, Hanul Jeon, Jingyeong Park, Hye-Jin Yoon, Hookang Im, Sung-Min Kang, Hyun-Jong Eun, and Bong-Jin Lee. "Structural and functional analysis of the D-alanyl carrier protein ligase DltA from Staphylococcus aureus Mu50." Acta Crystallographica Section D Structural Biology 78, no. 4 (March 16, 2022): 424–34. http://dx.doi.org/10.1107/s2059798322000547.
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D-Alanylation of the teichoic acids of the Gram-positive bacterial cell wall plays crucial roles in bacterial physiology and virulence. Deprivation of D-alanine from the teichoic acids of Staphylococcus aureus impairs biofilm and colony formation, induces autolysis and ultimately renders methicillin-resistant S. aureus highly susceptible to antimicrobial agents and host defense peptides. Hence, the D-alanylation pathway has emerged as a promising antibacterial target against drug-resistant S. aureus. D-Alanylation of teichoic acids is mediated via the action of four proteins encoded by the dlt operon, DltABCD, all four of which are essential for the process. In order to develop novel antimicrobial agents against S. aureus, the D-alanyl carrier protein ligase DltA, which is the first protein in the D-alanylation pathway, was focused on. Here, the crystal structure of DltA from the methicillin-resistant S. aureus strain Mu50 is presented, which reveals the unique molecular details of the catalytic center and the role of the P-loop. Kinetic analysis shows that the enantioselectivity of S. aureus DltA is much higher than that of DltA from other species. In the presence of DltC, the enzymatic activity of DltA is increased by an order of magnitude, suggesting a new exploitable binding pocket. This discovery may pave the way for a new generation of treatments for drug-resistant S. aureus.
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Koprivnjak, Tomaz, Vid Mlakar, Lindsey Swanson, Benedicte Fournier, Andreas Peschel, and Jerrold P. Weiss. "Cation-Induced Transcriptional Regulation of the dlt Operon of Staphylococcus aureus." Journal of Bacteriology 188, no. 10 (May 15, 2006): 3622–30. http://dx.doi.org/10.1128/jb.188.10.3622-3630.2006.
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ABSTRACT Lipoteichoic and wall teichoic acids (TA) are highly anionic cell envelope-associated polymers containing repeating polyglycerol/ribitol phosphate moieties. Substitution of TA with d-alanine is important for modulation of many cell envelope-dependent processes, such as activity of autolytic enzymes, binding of divalent cations, and susceptibility to innate host defenses. d-Alanylation of TA is diminished when bacteria are grown in medium containing increased NaCl concentrations, but the effects of increased salt concentration on expression of the dlt operon encoding proteins mediating d-alanylation of TA are unknown. We demonstrate that Staphylococcus aureus transcriptionally represses dlt expression in response to high concentrations of Na+ and moderate concentrations of Mg2+ and Ca2+ but not sucrose. Changes in dlt mRNA are induced within 15 min and sustained for several generations of growth. Mg2+-induced dlt repression depends on the ArlSR two-component system. Northern blotting, reverse transcription-PCR, and SMART-RACE analyses suggest that the dlt transcript begins 250 bp upstream of the dltA start codon and includes an open reading frame immediately upstream of dltA. Chloramphenicol transacetylase transcriptional fusions indicate that a region encompassing the 171 to 325 bp upstream of dltA is required for expression and Mg2+-induced repression of the dlt operon in S. aureus.
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Klein, Uwe, Waheedullah Karzai, Frank Bloos, Mathias Wohlfarth, Reiner Gottschall, Harald Fritz, Michael Gugel, and Albrecht Seifert. "Role of Fiberoptic Bronchoscopy in Conjunction with the Use of Double-lumen Tubes for Thoracic Anesthesia." Anesthesiology 88, no. 2 (February 1, 1998): 346–50. http://dx.doi.org/10.1097/00000542-199802000-00012.
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Background Fiberoptic bronchoscopy has been recommended to verify the position of double-lumen tubes (DLT), but this remains controversial. The authors studied the role of bronchoscopy for placing and monitoring right- and left-sided DLTs after blind intubation and after positioning the patient. Methods Two hundred patients having thoracic surgery requiring DLT insertion were prospectively studied. "Blind" tracheal intubations were done with 163 left-sided and 37 right-sided disposable polyvinyl chloride Robertshaw tubes. Bronchoscopy was performed by a different anesthesiologist after intubation and conventional clinical verification of correct placement and after patient positioning for thoracotomy. A DLT was considered malpositioned when it had to be moved >0.5 cm to correct its position. Critical malpositions were those that might have affected patient safety or influenced the surgical procedure if left uncorrected. Results After "blind" DLT intubation, clinical evidence of malpositioning was found in 28 patients. This was confirmed by fiberoptic assessment. In 172 patients in whom placement was judged correct by clinical assessment, malpositioning was detected by bronchoscopy in 79 cases, 25 of which were critical. After patient positioning, DLTs were found to be displaced in 93 patients, 48 of which were critical. Right-sided DLTs were significantly more likely to be malpositioned than were left-sided DLTs. Two complications were related to unsatisfactory lung separation in the 200 patients studied. Conclusions After blind intubation and patient positioning, more than one third of DLTs required repositioning. Routine bronchoscopy is therefore recommended after intubation and after patient positioning.
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Zhong, Wei, Roberto Bugarini, Ling Wang, Cynthia Basu, and Darrin M. Beaupre. "Rethinking about the dose limiting toxicities (DLTs): They can be equivocal!" Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 3064. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.3064.
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3064 Background: The primary goal of oncology phase I trials is to determine the maximum tolerated dose (MTD) in a small number of patients. Within the standard design methodology currently employed there remains many challenges and one pertains to the variability around defining dose limiting toxicities (DLTs). The pre-specified DLT criteria may not well reflect the clinician’s practical experience with some adverse events, while others may actually be related to the disease status more than the investigational drug and could be misclassified. DLT misclassification seen in testing a small sample size from each dose group could generate a large bias on dose finding and the MTD estimation. Methods: To mitigate the risk of dichotomizing and misclassifying DLTs, we proposed a strategy that introduced the new concept of “equivocal” DLT or AE. A novel dose escalation approach is applied to increase the variability associated with less interpretable AEs so that the model recommendations are more weighted towards the unequivocal AEs/DLTs. To evaluate this novel approach, we established a framework incorporating two types of systematic measurement errors on DLT misclassification, one for the misclassified DLT that is not related to the drug treatment while the other for the non-DLT AE that should be considered severe and relevant to dose finding. In our simulation studies, the Bayesian logistic regression model (BLRM) was used to guide dose escalation in simulated trials to compare the novel weighting approach with the traditional approach. A few numerical examples were also included for method illustration. Results: For different types of measurement errors, simulation studies showed that the weighting approach could successfully improve the trial performance, with higher chance of finding the correct MTD and treating more patients at the MTD level. Conclusions: The DLT weighting strategy provides a flexible but powerful tool that may incorporate the clinician’s valuable experience on some specific DLTs/AEs and improve MTD estimation in oncology phase I dose-escalation trials.
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Mthethwa, Sthembile, and Morne Pretorius. "Academic and Skills Credentialing Using Distributed Ledger Technology (DLT) and W3C Standards: Technology Assessment." International Conference on Intelligent and Innovative Computing Applications 2022 (December 31, 2022): 170–82. http://dx.doi.org/10.59200/iconic.2022.019.
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The ongoing push for the 4th industrial revolution is setting the stage to digitise, persist and verify identity along with credentials. Academic and skills credentials are currently verified manually and have much scope for automation using cryptographic techniques but requires standardisation to facilitate future systems interoperability. The Distributed Ledger Technology (DLT) and World Wide Web Consortium (W3C) Verifiable Credentials (VC) standards presents the possibility to achieve this credential verification automation. To accomplish this, an understanding of various DLTs and requirements for a viable skills tracking system is important. Therefore, this research aims to access the selected DLTs against the assessment criterion presented and an analysis has been completed to determine which DLT is suitable for the proposed system. The DLTs are assessed in terms of their ability to support the rapid prototyping of such a system and provide recommendations to guide a future development path from the perspective of standards compliance. We conclude that few DLTs possess the maturity to provide proper requirements coverage due to the emergent nature of the DLT space. Additionally, this paper presents the high-level requirements to achieve a minimally viable solution that can demonstrate such digital credential verification in the academic and skills tracking context.
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Kiriukhin, Michael Y., and Francis C. Neuhaus. "d-Alanylation of Lipoteichoic Acid: Role of the d-Alanyl Carrier Protein in Acylation." Journal of Bacteriology 183, no. 6 (March 15, 2001): 2051–58. http://dx.doi.org/10.1128/jb.183.6.2051-2058.2001.
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ABSTRACT The d-alanylation of membrane-associated lipoteichoic acid (LTA) in gram-positive organisms requires thed-alanine–d-alanyl carrier protein ligase (AMP) (Dcl) and the d-alanyl carrier protein (Dcp). Thedlt operon encoding these proteins (dltA anddltC) also includes dltB and dltD. dltB encodes a putative transport system, whiledltD encodes a protein which facilitates the binding of Dcp and Dcl for ligation with d-alanine and has thioesterase activity for mischarged d-alanyl-acyl carrier proteins (ACPs). In previous results it was shown that d-alanyl-Dcp donates its ester residue to membrane-associated LTA (M. P. Heaton and F. C. Neuhaus, J. Bacteriol. 176: 681–690, 1994). However, all efforts to identify an enzyme which catalyzes thisd-alanylation process were unsuccessful. It was discovered that incubation of d-alanyl-Dcp in the presence of LTA resulted in the time-dependent hydrolysis of this d-alanyl thioester. d-Alanyl-ACP in the presence of LTA was not hydrolyzed. When Dcp was incubated with membrane-associatedd-alanyl LTA, a time and concentration-dependent formation of d-alanyl-Dcp was found. The addition of NaCl to this reaction inhibited the formation of d-alanyl-Dcp and stimulated the hydrolysis of d-alanyl-Dcp. Since these reactions are specific for the carrier protein (Dcp), it is suggested that Dcp has a unique binding site which interacts with the poly(Gro-P) moiety of LTA. It is this specific interaction that provides the functional specificity for the d-alanylation process. The reversibility of this process provides a mechanism for the transacylation of the d-alanyl ester residues between LTA and wall teichoic acid.
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Spatafora, Grace A., Megan Sheets, Rebecca June, David Luyimbazi, Katherine Howard, Robin Hulbert, Daron Barnard, Mariam el Janne, and Michael C. Hudson. "Regulated Expression of the Streptococcus mutans dltGenes Correlates with Intracellular Polysaccharide Accumulation." Journal of Bacteriology 181, no. 8 (April 15, 1999): 2363–72. http://dx.doi.org/10.1128/jb.181.8.2363-2372.1999.
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ABSTRACT Intracellular polysaccharides (IPS) are glycogen-like storage polymers which contribute significantly to Streptococcus mutans-induced cariogenesis. We previously identified and cloned a locus from the S. mutans chromosome which is required for the accumulation of IPS. Sequencing of this locus revealed at least four contiguous open reading frames, all of which are preceded by a common promoter region and are transcribed in the same direction. Analysis of the amino acid sequence deduced from the first of these open reading frames (ORF1) revealed domains which are highly conserved among d-alanine-activating enzymes (DltA) inLactobacillus rhamnosus (formerlyLactobacillus casei) and Bacillus subtilis. The deduced amino acid sequences derived from ORF2, -3, and -4 also exhibit extensive similarity to DltB, -C, and -D, respectively, in these microorganisms. However, Southern hybridization experiments indicate that this operon maps to a locus on the S. mutanschromosome which is separate from the glgP,glgA, and glgD genes, whose products are known mediators of bacterial IPS accumulation. We therefore assigned a newdlt designation to the locus which we had formerly calledglg. We maintain that the dlt genes are involved in S. mutans IPS accumulation, however, since they complement a mutation in trans which otherwise rendersS. mutans IPS deficient. In this study, we found that expression of the S. mutans dlt genes is growth phase dependent and is modulated by carbohydrates internalized via the phosphoenolpyruvate phosphotransferase system (PTS). We demonstrated that the S. mutans dlt genes are expressed constitutively when non-PTS sugars are provided as the sole source of carbohydrate. Consistent with a role for the PTS in dltexpression is a similar constitutive expression of the dltgenes in an S. mutans PTS mutant grown in a chemically defined medium supplemented with glucose. In summary, these findings support a novel role for the dlt gene products inS. mutans IPS accumulation and suggest thatdlt expression in this oral pathogen is subject to complex mechanisms of control imposed by growth phase, dietary carbohydrate, and other factors present in the plaque environment.
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Soltani, Reza, Marzia Zaman, Rohit Joshi, and Srinivas Sampalli. "Distributed Ledger Technologies and Their Applications: A Review." Applied Sciences 12, no. 15 (August 6, 2022): 7898. http://dx.doi.org/10.3390/app12157898.
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With the success of Bitcoin and the introduction of different uses of Blockchain, such as smart contracts in Ethereum, many researchers and industries have turned their attention to applications that use this technology. In response to the advantages and disadvantages of Blockchain, similar technologies have emerged with alterations to the original structure. Distributed ledger technology (DLT) is a generalized distributed technology encompassing these new variants. Several studies have examined the challenges and applications of Blockchain technology. This article explores the possibilities of using different DLTs to solve traditional distributed computing problems based on their advantages and disadvantages. In this paper, we provide an overview and comparison of different DLTs, such as Hashgraph, Tangle, Blockchains, Side Chain and Holochain. The main objective of the article is to examine whether distributed ledger technologies can replace traditional computational methods in other areas instead of traditional methods. Based on the primary keywords, we conducted a systematic review of more than 200 articles. Based on the data extracted from articles related to the use of DLT, we conclude that that DLTs can complement other methods, but cannot completely replace them. Furthermore, several DLTs such as Sidechain, Holochain and Hashgraph are still in their infancy, and we foresee much research work in this area in the coming years.
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Costello, Brian Addis, Yingwei Qi, Mitesh J. Borad, George P. Kim, Donald W. Northfelt, Charles Erlichman, and Steven R. Alberts. "Phase I trial of everolimus, gemcitabine and cisplatin for patients with solid tumors refractory to standard therapy." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e13052-e13052. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e13052.
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e13052 Background: The combination of GEM and CDDP has shown activity in a variety of cancers, including biliary tract/gallbladder. Preclinical testing shows a potential benefit to the addition of EV. Methods: Using a standard 3+3 design, the MTDs of GEM + EV (Cohort I) and GEM + CDDP + EV (Cohort II) were determined as shown in the table. The MTD was defined as the dose level below the lowest dose that induces a DLT in at least one-third of pts. At the MTD of Cohort II, 10 patients were enrolled with biliary tract/gallbladder cancer (Cohort III). A weekly CBC was obtained. Assessments occurred every 3 weeks and imaging for response at every other cycle. Results: In Cohort I (N=12), no DLT occurred at dose level 0, and in dose level 1, grade 3 thrombocytopenia was found in 2 of 6 pts. The MTD for Cohort I was determined to be dose level 0. Responses were seen in 3 pts: 2 CRs (primary peritoneal, pancreatic) and 1 PR (breast). In Cohort II (N=15) DLTs at dose level 0 were neutropenia and thrombocytopenia in 2 of 3 pts and at dose level -1, thrombocytopenia in 2 of 6 pts. At dose level -2, 1 of 6 pts experienced a DLT (grade 3 thrombocytopenia), establishing this dose level as the MTD. Responses were seen in 2 pts, both PRs (ampullary, pheochromocytoma). All 10 pts have been enrolled in Cohort III with 2 DLTs (neutropenia and thrombocytopenia). Stable disease seen in 5 of 7 evaluable pts. Conclusions: Gem + EV was well tolerated at dose level 0, though dose escalation was limited by thrombocytopenia. GEM + CDDP + EV had DLTs of neutropenia and thrombocytopenia leading to the MTD of dose level of -2. Cohort III is fully accrued and the 2 DLTs are hematologic. [Table: see text]
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Jha, Sachin, and Jesse M. Ehrenfeld. "Double Lumen Tubes: Usage and Performance by Frequent and Infrequent Users." ISRN Anesthesiology 2011 (November 1, 2011): 1–4. http://dx.doi.org/10.5402/2011/586592.
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Double lumen tubes (DLT) are commonly used to achieve lung isolation (LI). Not all anesthesiologists are frequent DLT users. Our thoracic surgical service is covered by sub-specialty anesthesiologists who are frequent DLT users. Thus, we are in a position to evaluate the performance of infrequent DLT users relative to frequent DLT users. Using statistical methods, we examined the incidence, duration and severity of hypoxia, hypercapnea and high airway pressures for patients receiving LI via DLTs placed by infrequent versus frequent users. The incidence of low SpO2, high EtCO2, or high PIP was not different between frequent and infrequent DLT users. However, when these events do occur, they are more severe (elevated EtCO2 duration, lower SpO2, higher EtCO2, higher airway pressure) among infrequent than frequent DLT users. The practical significance of these differences, which are small, is unproven. However, when episodes of hypercapnea do occur, they last much longer among infrequent than frequent DLT users.
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Mehlis, Katja, Elena Bierwirth, Katsiaryna Laryionava, Friederike Mumm, Pia Heussner, and Eva C. Winkler. "Late decisions about treatment limitation in patients with cancer: empirical analysis of end-of-life practices in a haematology and oncology unit at a German university hospital." ESMO Open 5, no. 5 (October 2020): e000950. http://dx.doi.org/10.1136/esmoopen-2020-000950.
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BackgroundDecisions to limit treatment (DLTs) are important to protect patients from overtreatment but constitute one of the most ethically challenging situations in oncology practice. In the Ethics Policy for Advance Care Planning and Limiting Treatment study (EPAL), we examined how often DLT preceded a patient’s death and how early they were determined before (T1) and after (T2) the implementation of an intrainstitutional ethics policy on DLT.MethodsThis prospective quantitative study recruited 1.134 patients with haematological/oncological neoplasia in a period of 2×6 months at the University Hospital of Munich, Germany. Information on admissions, discharges, diagnosis, age, DLT, date and place of death, and time span between the initial determination of a DLT and the death of a patient was recorded using a standardised form.ResultsOverall, for 21% (n=236) of the 1.134 patients, a DLT was made. After implementation of the policy, the proportion decreased (26% T1/16% T2). However, the decisions were more comprehensive, including more often the combination of ‘Do not resuscitate’ and ‘no intense care unit’ (44% T1/64% T2). The median time between the determination of a DLT and the patient’s death was similarly short with 6 days at a regular ward (each T1/T2) and 10.5/9 (T1/T2) days at a palliative care unit. For patients with solid tumours, the DLTs were made earlier at both regular and palliative care units than for the deceased with haematological neoplasia.ConclusionOur results show that an ethics policy on DLT could sensitise for treatment limitations in terms of frequency and extension but had no significant impact on timing of DLT. Since patients with haematological malignancies tend to undergo intensive therapy more often during their last days than patients with solid tumours, special attention needs to be paid to this group. To support timely discussions, we recommend the concept of advance care planning.
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Shin, Hyejin, Jung-Eun Ha, Dae Young Zang, Sung-Hyun Kim, Young Rok Do, Won Sik Lee, Soo-Hyun Kim, et al. "Clinical Response Evaluation Toward Individualizing the Starting Dose of Dasatinib in Asian Patients with Chronic Myeloid Leukemia." Blood 136, Supplement 1 (November 5, 2020): 6. http://dx.doi.org/10.1182/blood-2020-140626.
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Introduction Dasatinib, a second-generation tyrosine kinase inhibitor (TKI), has been administered at a fixed starting dose of 100 mg once daily for patients with chronic myeloid leukemia in chronic phase (CP-CML). However, the relationships between TKI exposure, and safety and efficacy responses suggest that such fixed dosing may not be optimal for many Asian patients. In this study, the relationships between the starting dose of dasatinib adjusted for BW (Dose/BW), and dose limiting toxicities (DLTs) and molecular responses (MRs) were evaluated to develop an initial dosing strategy of dasatinib. Methods The safety and efficacy responses of dasatinib therapy were explored from the clinical data obtained in patients newly diagnosed with CP-CML at seventeen hospitals in South Korea. The safety response was assessed as the occurrence of first DLTs by 36 months that required an interruption in dasatinib therapy. The efficacy responses were evaluated as the achievement of MR at 3 months (MR1), 6 months (MR2), 12 months (major molecular response, MMR) and 24 months (deep molecular response, MR4.5). The rates and patterns of DLT occurrence and MR achievement by 36 months were examined using a Kaplan-Meier method. A logistic regression method was used to determine the effect of the Dose/BW of dasatinib on the occurrence of first DLTs or the achievement of MRs. A chi-square test for trend was used to assess the trend of DLT occurrence and MR achievement in patient subgroups divided into quartiles (Q1 to Q4) based on Dose/BW. Results The clinical data were obtained from a total of 102 Asian patients with CP-CML whose median BW was 64.0 kg (range, 37.8 to 106.0 kg) and Dose/BW 1.60 mg/kg (1.00 to 2.80 mg/kg). Safety. The most frequent DLTs were thrombocytopenia (46%), pericardial or pleural effusion (31%) and anemia (7%); the median time of occurrence for the DLTs were 29 days (range, 7 to 417 days), 336 days (7 to 681 days) and 35 days (10 to 140 days), respectively. The rate of DLT occurred first increased rapidly by four months of starting dasatinib therapy and then steadily by 28 months until reaching approximately 56% in the Kaplan-Meier curve. Patients with higher Dose/BW had a greater risk of DLT occurrence by 36 months as determined using a logistic regression (logit [P] = 1.58 × [Dose/BW] - 2.27, p = 0.03). As Dose/BW increases from Q1 to Q4 (median Dose/BW; 1.23, 1.45, 1.65 and 2.00 mg/kg, respectively), the rate of DLTs rises from 43.5% (Q1) to 66.7% (Q4) with a statistically significant trend of increment (p = 0.03). The median dose that would produce the lowest rate of DLTs is 78.7 mg as calculated by multiplying the median Dose/BW of Q1 (1.23 mg/kg) by the median BW of patients (64.0 kg). Efficacy. The achievement rates of MMR and MR4.5 increased continuously and reached 82% and 43%, respectively, by 36 months of starting dasatinib therapy. The Dose/BW of dasatinib did not affect the rates of MR achievements based on a logistic regression analysis. Even though Dose/BW increased, the achievement rates of MR1, MR2 and MMR demonstrated neither an increasing nor a decreasing trend from Q1 to Q4. Conclusion The higher the starting Dose/BW of dasatinib, the greater is the risk of DLT occurrence without improving the potential for MR achievement. Therefore, in order to minimize the risk of DLTs without compromising MRs, a lower starting dose of dasatinib 80 mg once daily is suggested for Asian patients with CP-CML especially with lighter BW. Disclosures Kim: ILYANG: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sun Pharma.: Research Funding.
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Hunaiti, Ziad. "Digital Learning Technologies." International Journal of Handheld Computing Research 8, no. 2 (April 2017): 41–50. http://dx.doi.org/10.4018/ijhcr.2017040103.
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Embedding Information and Communication Technology (ICT) within education is continually evolving research topic, because of the fast changes in information technology, software applications, and speed of internet. Therefore, many researchers around the globe are working in new projects of Digital Learning Technologies (DLTs). The success of new DLT is linked with the methods used during the evaluation process, which sometimes misunderstood. Hence, this article emphasises the importance of following the correct approach when selecting evaluation methods for DLT research and propose an approach, which can be followed by researchers, developers, students, educators, teaching & teaching specialists and other stakeholders to evaluate the effectiveness of new DLT.
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Zimmermann, Tanja. "End-of-Life: Patientinnen und Patienten rechtzeitig einbinden." Kompass Onkologie 8, no. 2 (2021): 84–85. http://dx.doi.org/10.1159/000516879.
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<b>Background:</b> Decisions to limit treatment (DLTs) are important to protect patients from overtreatment but constitute one of the most ethically challenging situations in oncology practice. In the Ethics Policy for Advance Care Planning and Limiting Treatment study (EPAL), we examined how often DLT preceded a patient’s death and how early they were determined before (T1) and after (T2) the implementation of an intrainstitutional ethics policy on DLT. <b>Methods:</b> This prospective quantitative study recruited 1.134 patients with haematological/oncological neoplasia in a period of 2×6 months at the University Hospital of Munich, Germany. Information on admissions, discharges, diagnosis, age, DLT, date and place of death, and time span between the initial determination of a DLT and the death of a patient was recorded using a standardised form. <b>Results:</b> Overall, for 21% (n = 236) of the 1.134 patients, a DLT was made. After implementation of the policy, the proportion decreased (26% T1/16% T2). However, the decisions were more comprehensive, including more often the combination of ‘Do not resuscitate’ and ‘no intense care unit’ (44% T1/64% T2). The median time between the determination of a DLT and the patient’s death was similarly short with 6 days at a regular ward (each T1/T2) and 10.5/9 (T1/T2) days at a palliative care unit. For patients with solid tumours, the DLTs were made earlier at both regular and palliative care units than for the deceased with haematological neoplasia. <b>Conclusion:</b> Our results show that an ethics policy on DLT could sensitise for treatment limitations in terms of frequency and extension but had no significant impact on timing of DLT. Since patients with haematological malignancies tend to undergo intensive therapy more often during their last days than patients with solid tumours, special attention needs to be paid to this group. To support timely discussions, we recommend the concept of advance care planning.
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Zimmermann, Tanja. "End-of-Life: Patientinnen und Patienten rechtzeitig einbinden." Kompass Pneumologie 9, no. 6 (2021): 308–9. http://dx.doi.org/10.1159/000519230.
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<b>Background:</b> Decisions to limit treatment (DLTs) are important to protect patients from overtreatment but constitute one of the most ethically challenging situations in oncology practice. In the Ethics Policy for Advance Care Planning and Limiting Treatment study (EPAL), we examined how often DLT preceded a patient’s death and how early they were determined before (T1) and after (T2) the implementation of an intrainstitutional ethics policy on DLT. <b>Methods:</b> This prospective quantitative study recruited 1.134 patients with haematological/oncological neoplasia in a period of 2×6 months at the University Hospital of Munich, Germany. Information on admissions, discharges, diagnosis, age, DLT, date and place of death, and time span between the initial determination of a DLT and the death of a patient was recorded using a standardised form. <b>Results</b>: Overall, for 21% (n = 236) of the 1.134 patients, a DLT was made. After implementation of the policy, the proportion decreased (26% T1/16% T2). However, the decisions were more comprehensive, including more often the combination of ‹Do not resuscitate› and ‹no intense care unit› (44% T1/64% T2). The median time between the determination of a DLT and the patient’s death was similarly short with 6 days at a regular ward (each T1/T2) and 10.5/9 (T1/T2) days at a palliative care unit. For patients with solid tumours, the DLTs were made earlier at both regular and palliative care units than for the deceased with haematological neoplasia. <b>Conclusion:</b> Our results show that an ethics policy on DLT could sensitise for treatment limitations in terms of frequency and extension but had no significant impact on timing of DLT. Since patients with haematological malignancies tend to undergo intensive therapy more often during their last days than patients with solid tumours, special attention needs to be paid to this group. To support timely discussions, we recommend the concept of advance care planning.
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Zimmermann, Tanja. "End-of-Life: Patientinnen und Patienten rechtzeitig einbinden." Kompass Dermatologie 9, no. 3 (2021): 134–35. http://dx.doi.org/10.1159/000517944.
Full textAbstract:
<b>Background:</b> Decisions to limit treatment (DLTs) are important to protect patients from overtreatment but constitute one of the most ethically challenging situations in oncology practice. In the Ethics Policy for Advance Care Planning and Limiting Treatment study (EPAL), we examined how often DLT preceded a patient’s death and how early they were determined before (T1) and after (T2) the implementation of an intrainstitutional ethics policy on DLT. <b>Methods:</b> This prospective quantitative study recruited 1.134 patients with haematological/oncological neoplasia in a period of 2×6 months at the University Hospital of Munich, Germany. Information on admissions, discharges, diagnosis, age, DLT, date and place of death, and time span between the initial determination of a DLT and the death of a patient was recorded using a standardised form. <b>Results</b>: Overall, for 21% (n = 236) of the 1.134 patients, a DLT was made. After implementation of the policy, the proportion decreased (26% T1/16% T2). However, the decisions were more comprehensive, including more often the combination of ‘Do not resuscitate’ and ‘no intense care unit’ (44% T1/64% T2). The median time between the determination of a DLT and the patient’s death was similarly short with 6 days at a regular ward (each T1/T2) and 10.5/9 (T1/T2) days at a palliative care unit. For patients with solid tumours, the DLTs were made earlier at both regular and palliative care units than for the deceased with haematological neoplasia. <b>Conclusion:</b> Our results show that an ethics policy on DLT could sensitise for treatment limitations in terms of frequency and extension but had no significant impact on timing of DLT. Since patients with haematological malignancies tend to undergo intensive therapy more often during their last days than patients with solid tumours, special attention needs to be paid to this group. To support timely discussions, we recommend the concept of advance care planning.
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Nurgazina, Jamilya, Udsanee Pakdeetrakulwong, Thomas Moser, and Gerald Reiner. "Distributed Ledger Technology Applications in Food Supply Chains: A Review of Challenges and Future Research Directions." Sustainability 13, no. 8 (April 9, 2021): 4206. http://dx.doi.org/10.3390/su13084206.
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The lack of transparency and traceability in food supply chains (FSCs) is raising concerns among consumers and stakeholders about food information credibility, food quality, and safety. Insufficient records, a lack of digitalization and standardization of processes, and information exchange are some of the most critical challenges, which can be tackled with disruptive technologies, such as the Internet of Things (IoT), blockchain, and distributed ledger technologies (DLTs). Studies provide evidence that novel technological and sustainable practices in FSCs are necessary. This paper aims to describe current practical applications of DLTs and IoT in FSCs, investigating the challenges of implementation, and potentials for future research directions, thus contributing to achievement of the United Nations’ Sustainable Development Goals (SDGs). Within a systematic literature review, the content of 69 academic publications was analyzed, describing aspects of implementation and measures to address the challenges of scalability, security, and privacy of DLT, and IoT solutions. The challenges of high costs, standardization, regulation, interoperability, and energy consumption of DLT solutions were also classified as highly relevant, but were not widely addressed in literature. The application of DLTs in FSCs can potentially contribute to 6 strategic SDGs, providing synergies and possibilities for more sustainable, traceable, and transparent FSCs.
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Matsuo, Miki, Yuichi Oogai, Fuminori Kato, Motoyuki Sugai, and Hitoshi Komatsuzawa. "Growth-phase dependence of susceptibility to antimicrobial peptides in Staphylococcus aureus." Microbiology 157, no. 6 (June 1, 2011): 1786–97. http://dx.doi.org/10.1099/mic.0.044727-0.
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Bacterial cell surface charge is responsible for susceptibility to cationic antimicrobial peptides. Previously, Staphylococcus aureus dlt and mprF were identified as factors conferring a positive charge upon cell surfaces. In this study, we investigated the regulation of cell surface charge during growth. Using a group of S. aureus MW2 mutants, which are gene-inactivated in 15 types of two-component systems (TCSs), we tested dltC and mprF expression and found that two TCSs, aps and agr, were associated with dltC and mprF expression in a growth phase-dependent manner. The first of these, aps, which had already been identified as a sensor of antimicrobial peptides and a positive regulator of dlt and mprF expression, was expressed strongly in the exponential phase, while its expression was significantly suppressed by agr in the stationary phase, resulting in higher expression of dltC and mprF in the exponential phase and lower expression in the stationary phase. Since both types of expression affected the cell surface charge, the susceptibility to antimicrobial peptides and cationic antibiotics was changed during growth. Furthermore, we found that the ability to sense antimicrobial peptides only functioned in the exponential phase. These results suggest that cell surface charge is tightly regulated during growth in S. aureus.
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Coupri, Delphine, Aurélie Budin-Verneuil, Axel Hartke, Abdellah Benachour, Loïc Léger, Thierry Lequeux, Emmanuel Pfund, and Nicolas Verneuil. "Genetic and pharmacological inactivation of d-alanylation of teichoic acids sensitizes pathogenic enterococci to β-lactams." Journal of Antimicrobial Chemotherapy 74, no. 11 (July 24, 2019): 3162–69. http://dx.doi.org/10.1093/jac/dkz322.
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AbstractBackgroundEnterococci intrinsically resistant to cephalosporins represent a major cause of healthcare-associated infections, and the emergence of MDR makes therapeutic approaches particularly challenging.ObjectivesTeichoic acids are cell wall glycopolymers present in Gram-positive bacteria. Teichoic acids can be modified by d-alanylation, which requires four proteins encoded by the dltABCD operon. Our objective was to evaluate the Dlt system as a druggable target to treat enterococcal infections.MethodsThe susceptibility of a d-alanylation-deficient strain of Enterococcus faecalis to β-lactam antibiotics individually and/or in combination was analysed. Moreover, a DltA inhibitor was synthesized to test pharmacological inhibition of d-alanylation in vivo and in host using the animal model Galleria mellonella with different clinical isolates of E. faecalis and Enterococcus faecium.ResultsMost cephalosporins used as mono treatment had no impact on survival of the parental strain, but were slightly lethal for the dltA mutant of E. faecalis. Addition of a very low concentration of amoxicillin significantly increased killing of the dltA mutant under these conditions. The most spectacular effect was obtained with a combination of cefotaxime (1 mg/L) and amoxicillin (0.03 mg/L). In the presence of the inhibitor, the WT strain was as susceptible to this combination treatment as the dltA mutant. This molecule associated with the antibiotics was also effective in killing other E. faecalis clinical isolates and successfully prevented death of Galleria infected with either E. faecalis or E. faecium.ConclusionsThe combined results support the potential usefulness of the Dlt system as a target to potentiate antibiotic combination therapies for the treatment of drug-resistant enterococci.
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Innocenti, Federico, Richard L. Schilsky, Jacqueline Ramírez, Linda Janisch, Samir Undevia, Larry K. House, Soma Das, et al. "Dose-Finding and Pharmacokinetic Study to Optimize the Dosing of Irinotecan According to the UGT1A1 Genotype of Patients With Cancer." Journal of Clinical Oncology 32, no. 22 (August 1, 2014): 2328–34. http://dx.doi.org/10.1200/jco.2014.55.2307.
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Purpose The risk of severe neutropenia from treatment with irinotecan is related in part to UGT1A1*28, a variant that reduces the elimination of SN-38, the active metabolite of irinotecan. We aimed to identify the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of irinotecan in patients with advanced solid tumors stratified by the *1/*1, *1/*28, and *28/*28 genotypes. Patients and Methods Sixty-eight patients received an intravenous flat dose of irinotecan every 3 weeks. Forty-six percent of the patients had the *1/*1 genotype, 41% had the *1/*28 genotype, and 13% had the *28/*28 genotype. The starting dose of irinotecan was 700 mg in patients with the *1/*1 and *1/*28 genotypes and 500 mg in patients with the *28/*28 genotype. Pharmacokinetic evaluation was performed at cycle 1. Results In patients with the *1/*1 genotype, the MTD was 850 mg (four DLTs per 16 patients), and 1,000 mg was not tolerated (two DLTs per six patients). In patients with the *1/*28 genotype, the MTD was 700 mg (five DLTs per 22 patients), and 850 mg was not tolerated (four DLTs per six patients). In patients with the *28/*28 genotype, the MTD was 400 mg (one DLT per six patients), and 500 mg was not tolerated (three DLTs per three patients). The DLTs were mainly myelosuppression and diarrhea. Irinotecan clearance followed linear kinetics. At the MTD for each genotype, dosing by genotype resulted in similar SN-38 areas under the curve (AUCs; r2 = 0.0003; P = .97), but the irinotecan AUC was correlated with the actual dose (r2 = 0.39; P < .001). Four of 48 patients with disease known to be responsive to irinotecan achieved partial response. Conclusion The UGT1A1*28 genotype can be used to individualize dosing of irinotecan. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in patients receiving irinotecan.
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Innocenti, Federico, Ravi Salgia, Jacqueline Ramirez, Linda A. Janisch, Samir D. Undevia, Larry House, Soma Das, et al. "A genotype-directed study to optimize dosing of irinotecan according to the UGT1A1 genotype." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 2570. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.2570.
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2570 Background: The risk of severe neutropenia from irinotecan (I) is in part related to UGT1A1*28, a polymorphism that reduces the elimination of SN-38, the active metabolite of I. We aimed to identify the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of I in advanced solid tumor patients (pts) stratified by*1/*1, *1/*28, and *28/*28 genotypes. We hypothesized that *1/*1 pts would tolerate a higher MTD than the standard 350 mg/m2 dose and that *28/*28 pts would require dose reduction. Methods: 68 pts (30 lung, 30 gastrointestinal, 8 other cancers) received q3w, flat-dose I. Genotype frequencies were 46% (*1/*1), 41% (*1/*28), and 13% (*28/*28). Pts (66% males, median age 68 years) had 0-1 PS (only one pt had PS 2). 82% were Caucasians, 13% African Americans, and 4% Hispanics. The I starting dose was 700 mg in *1/*1 and *1/*28 pts, and 500 mg in *28/*28 pts. Pharmacokinetics was obtained at cycle 1. DLT at cycle 1 was defined as grade (G) 4 neutropenia (N) for ≥4 days, G≥3N on a treatment day, G≥3 febrile N, G4 anemia or thrombocytopenia, or G≥3 non-hematological toxicity. Results: In *1/*1 pts, the MTD was 850 mg (4 DLTs/16 pts), and 1000 mg was not tolerated (2 DLTs/6). In *1/*28 pts, the MTD was 700 mg (5 DLTs/22) and 850 mg was not tolerated (4 DLTs/6). In *28/*28 pts, the MTD was 400 mg (1 DLT/6) and 500 mg was not tolerated (3 DLTs/3). DLTs were mainly G4N, G≥3 febrile N, and G3 diarrhea. I clearance followed linear kinetics. I and SN-38 AUCs were associated with decreased log10ANC nadir (r2 0.27 and 0.30, respectively, p<0.0001). At the MTD, I AUC in *28/*28 pts was 50% and 62% lower than that of *1/*28 and *1/*1 pts (16.8±4.4, 33.4±11.9, 44.2±11.3 h*ug/ml [mean±SD], respectively). At the MTD, SN-38 AUC in *28/*28 pts was 30% and 26% lower than that of *1/*28 and *1/*1 pts (620±407, 881±715, 841±888 h*ng/ml). 3 PRs were observed (NSCLC-700 mg-*1/*28, gastric-850 mg-*1/*1, small bowel-850 mg-*1/*28). Conclusions: In a heavily pretreated population, UGT1A1*28 information can be used to individualize dosing of I. Additional studies should evaluate the effect of genotype-guided dosing on efficacy in pts receiving I. Clinical trial information: NCT00708773.
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Rami, Avina, Steven G. DuBois, and Kevin M. Campbell. "Reporting and impact of subsequent cycle toxicities in oncology phase I clinical trials." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): 3149. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.3149.
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3149 Background: In recent years, the landscape of clinical trial development has evolved to include immunotherapy and targeted therapies, which have different lengths of administration and toxicity profiles compared to standard chemotherapy. As treatments have evolved, the classic assumptions of toxicity associated with cytotoxic agents may be less relevant, requiring new strategies for design of trials intended to inform dosing strategies for agents that may be administered beyond a set number of defined cycles. We aimed to describe the overall incidence of dose-limiting toxicities (DLTs) during and after cycle 1, the frequency of reporting subsequent cycle toxicities, and the impact of post-cycle 1 DLTs on conclusions drawn from oncology phase I clinical trials. Methods: We conducted a systematic review of subsequent cycle toxicities in oncology phase I clinical trials published in the Journal of Clinical Oncology from 2000 to 2020. Only trials that included more than one cycle of therapy were included. Data elements captured included: year of publication, study design, trial sponsor type, intervention type, number of anti-cancer therapies involved, primary diagnosis, incidence and type of cycle 1 DLT, incidence of dose modification in cycle 1, incidence and type of post-cycle 1 DLTs, incidence of dose modification in post-cycle 1, presence of a recommended phase 2 dose (RP2D) and impact of subsequent cycle toxicity on RP2D. Results: From 2000 to 2020, we identified 489 full-text articles reporting on therapeutic phase I clinical trials. Of these, 421 (86%) reported data regarding cycle 1 DLTs and 170 (35%) reported cycle 1 dose modifications. The overall median cycle 1 DLT rate was 8.89%. Only 47 (9.6%) publications reported whether or not there were post-cycle 1 DLTs and only 92 (19%) reported whether or not there were dose modifications beyond cycle 1. The overall median post-cycle 1 DLT rate among trials that reported post-cycle 1 data was 14.8%. A RP2D was reported in 76% (371 of 489) trials. Among these 371 studies, 89% did not report whether post-cycle 1 toxicities impacted the RP2D. Independent predictors of reporting toxicity data beyond cycle 1 included year of publication, investigational agent type, novelty, disease type, trial size, and sponsor. Conclusions: Reporting of subsequent cycle DLTs and dose modification is uncommon in oncology phase I clinical trial publications. As newer oncology treatments trend towards longer duration of treatment, there will be an increased need to understand toxicities occurring post-cycle 1. Guidelines for reporting of phase I clinical trials should expand to include toxicity data beyond the first cycle.
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Ledwaba, Lehlogonolo P. I., Gerhard P. Hancke, Sherrin J. Isaac, and Hein S. Venter. "Smart Microgrid Energy Market: Evaluating Distributed Ledger Technologies for Remote and Constrained Microgrid Deployments." Electronics 10, no. 6 (March 18, 2021): 714. http://dx.doi.org/10.3390/electronics10060714.
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The increasing strain on ageing generation infrastructure has seen more frequent instances of scheduled and unscheduled blackouts, rising reliability on fossil fuel based energy alternatives and a slow down in efforts towards achieving universal access to electrical energy in South Africa. To try and relieve the burden on the National Grid and still progress electrification activities, the smart microgrid model and secure energy trade paradigm is considered—enabled by the Industrial IoT (IIoT) and distributed ledger technologies (DLTs). Given the high availability requirements of microgrid operations, the limited resources available on IIoT devices and the high processing and energy requirements of DLT operations, this work aims to determine the effect of native DLT algorithms when implemented on IIoT edge devices to assess the suitability of DLTs as a mechanism to establish a secure, energy trading market for the Internet of Energy. Metrics such as the node transaction time, operating temperature, power consumption, processor and memory usage are considered towards determining possible interference on the edge node operation. In addition, the cost and time required for mining operations associated with the DLT-enabled node are determined in an effort to predict the cost to end users—in terms of fees payable and mobile data costs—as well as predicting the microgrid’s growth and potential blockchain network slowdown.
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Park, Jee Soo, Kyo Chul Koo, Doo Yong Chung, Sun Il Kim, Jeongho Kim, Cheol Kyu Oh, Tae Nam Kim, et al. "Visceral Adiposity as a Significant Predictor of Sunitinib-Induced Dose-Limiting Toxicities and Survival in Patients with Metastatic Clear Cell Renal Cell Carcinoma." Cancers 12, no. 12 (December 2, 2020): 3602. http://dx.doi.org/10.3390/cancers12123602.
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Sunitinib is a first-line treatment for metastatic renal cell carcinoma (mRCC). Little is known about the predictive factors of sunitinib-induced dose-limiting toxicity (DLT) in Asian populations. We investigated whether body composition predicts sunitinib-induced DLT. We retrospectively reviewed sunitinib-treated Korean patients with clear cell mRCC from eight institutions. Body composition was measured using computed tomography. DLT was defined as any adverse event leading to dose reduction or treatment discontinuation. Univariate analysis was used to compare body composition indices, and logistic regression analyses were performed for factors predicting early DLT. Overall, 111/311 (32.5%) of patients experienced DLT. Significant differences were observed in the subcutaneous adipose tissue index (SATI; p = 0.001) and visceral adipose tissue index (VATI; p < 0.001) between patients with and without DLT. Multivariate analyses revealed that VATI (odds ratio: 1.013; p = 0.029) was significantly associated with early DLT. Additionally, 20% of patients who had a body mass index (BMI) greater than 23 kg/m2 and a low VATI experienced DLT, whereas 34.3% of the remaining groups had DLT (p = 0.034). Significant differences were observed for median progression-free survival (13.0 vs. 26.0 months, respectively; p = 0.006) between patients with low and high VATI. Visceral adiposity was a significant predictor of sunitinib-associated DLT and survival. Patients with a low VATI and a BMI greater than 23 kg/m2 experienced lower DLTs.
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Rezaei, Mohsen, Rasoul Ajalloeian, and Mohammad Ghafoori. "Comparison between deformation modulus of rock mass measured by plate jacking and dilatometer tests." Przegląd Naukowy Inżynieria i Kształtowanie Środowiska 26, no. 3 (September 15, 2017): 317–25. http://dx.doi.org/10.22630/pniks.2017.26.3.31.
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For determination of the in-situ deformation modulus of rock mass at Bakhtiari Dam site, located in south-west of Iran, plate jacking tests (PJT) and dilatometer tests (DLT) carried out during the geotechnical investigations. In this study, the results of PJTs and DLTs were compared. This comparison involves 89 vertical and horizontal PJTs and 83 DLTs carried out in 6 rock units of Sarvak formation. Although, both PJTs and DLTs in the Bakhtiari Dam site were performed in same geological and geotechnical conditions, but there are not sufficient side by side data to make a paired two samples correlation. Therefore, the mean of in-situ data was compared at each rock unit. Besides Mann–Whitney U tests were performed to compare in-situ test results. The comparison shows that the deformation modulus measured by both methods has no significant differences. However, in low quality rock masses the moduli measured by the use of DLTs were greater than the modulus measured by PJTs. Conversely, in high quality rock masses the results of PJTs were greater than DLT’s.
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Burnett, Alan K., David Bowen, Nigel Russell, Steven Knapper, Donald Milligan, Ann E. Hunter, Asim Khwaja, et al. "AC220 (Quizartinib) Can Be Safely Combined With Conventional Chemotherapy In Older Patients With Newly Diagnosed Acute Myeloid Leukaemia: Experience From The AML18 Pilot Trial." Blood 122, no. 21 (November 15, 2013): 622. http://dx.doi.org/10.1182/blood.v122.21.622.622.
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Abstract Introduction AC220 (Quizartinib) is a novel FLT3 inhibitor that has shown a high level of activity as monotherapy in patients with advanced FLT3 +ve disease, and more modest activity in FLT3 -ve patients across Phase 1 and 2 studies. This is the first presentation of quizartinib use in combination with chemotherapy in newly diagnosed (FLT3 +ve and FLT3 -ve) older AML patients. Study Aim In preparation for a prospective Phase 3 trial (NCRI AML 18) in older patients with newly diagnosed AML, we tested the feasibility and dose of AC220 which could be sequentially given two days after each of two courses of ADE (Ara-C/ Daunorubicin/ Etoposide) followed by one course of DA (2+5) in patients over age 60 with FLT3 +ve or FLT3 –ve newly diagnosed AML. Six cohorts with escalating doses (60mg, 90mg or 135mg based on doses used in the Phase 2 ACE study with quizartinib) for 7 or 14 days were planned. If 60mg was not tolerated there was provision to de-escalate to 40mg for 7 or 14 days. The study was based on a 3+3 design whereby if 1 of 3 developed a DLT a cohort expansion was required but if >2 of 6 had a DLT, the cohort failed. A DLT was defined as any grade 4 non-haematological toxicity or failure of count recovery by day 42 in the absence of marrow blasts, or a grade 3 toxicity that did not recover to at least grade 2 within 7 days. Because of the increased sensitivity in females to QTc prolongation, each cohort required a minimum of 3 females. The day of safety evaluation was on completion of the chemotherapy in course 2. Results 55 patients with a median age of 69 years (62-87) entered of whom 48 were evaluable. 4 patients were FLT3 ITD +ve. 13 patients (4 males, 9 females) entered cohort 1 (AC220 60mg for 7days). No DLTs were seen in males but 3 DLTs occurred in females (all grade 4:1 cardiac (MI), 1 hypokalaemia; 1 mucositis) so this cohort exceeded tolerability for females. 8 patients (all males) entered cohort 2 (AC220 60mg for 14 days) where 4 DLTs (all grade 3; 3 QTC, 1 appetite loss) were seen, so this cohort exceeded tolerability for males. The de-escalation cohort (cohort 3) was activated (AC220 40mg for 7 days). 2 DLTs (1 grade 4 lung; 1 lung infection grade 3 >7days) in 7 evaluable females and 0 DLTs in 9 evaluable males were seen, so both males and females progressed to Cohort 4 (AC220 40mg for 14 days). There was 1 DLT (haematological) of 5 evaluable males and 0 of 8 evaluable females had a DLT. The DLTs were similarly distributed between males (5/25) and females (5/23). Induction death (death with 30 days) occurred in 3/46 (6.5%) evaluable patients. CR was achieved in 33/42 (79%; including all 4 FLT3 ITD +ve) of patients evaluable for CR or 60% of all 55 patients. Overall median time to neutrophil and platelet count recovery (neutrophils to 1.0x109/l; platelets to 100x109/l) was prompt (28 and 22 days post course 1; 22 and 19 days post course 2 respectively). No patients received SCT. The median OS is currently 15 months. Conclusion AC220 at 40mg for 14 days can safely be given sequentially after chemotherapy in older patients with newly diagnosed AML. The Phase 3 AML 18 study is planned to start in early 2014 and will incorporate AC220 into multiple courses of DA therapy as well as maintenance therapy. On behalf of the UK NCRI AML Working Group. We acknowledge the support from Ambit Biosciences for this study. Disclosures: Burnett: Ambit: Membership on an entity’s Board of Directors or advisory committees, Research Funding. Off Label Use: AC220 for newly diagnosed AML. Hills:Ambit: Consultancy.
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Ceponis, Tomas, Stanislau Lastovskii, Leonid Makarenko, Jevgenij Pavlov, Kornelijus Pukas, and Eugenijus Gaubas. "Study of Radiation-Induced Defects in p-Type Si1−xGex Diodes before and after Annealing." Materials 13, no. 24 (December 12, 2020): 5684. http://dx.doi.org/10.3390/ma13245684.
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In this work, electrically active defects of pristine and 5.5 MeV electron irradiated p-type silicon–germanium (Si1−xGex)-based diodes were examined by combining regular capacitance deep-level transient spectroscopy (C-DLTS) and Laplace DLTS (L-DLTS) techniques. The p-type SiGe alloys with slightly different Ge contents were examined. It was deduced from C-DLTS and L-DLTS spectra that the carbon/oxygen-associated complexes prevailed in the pristine Si0.949Ge0.051 alloys. Irradiation with 5.5 MeV electrons led to a considerable change in the DLT spectrum containing up to seven spectral peaks due to the introduction of radiation defects. These defects were identified using activation energy values reported in the literature. The double interstitial and oxygen complexes and the vacancy, di-vacancy and tri-vacancy ascribed traps were revealed in the irradiated samples. The interstitial carbon and the metastable as well as stable forms of carbon–oxygen (CiOi* and CiOi) complexes were also identified for the electron-irradiated SiGe alloys. It was found that the unstable form of the carbon–oxygen complex became a stable complex in the irradiated and the subsequently annealed (at 125 °C) SiGe samples. The activation energy shifts in the radiation-induced deep traps to lower values were defined when increasing Ge content in the SiGe alloy.
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Umemura, Yoshie, Wajd Al-Holou, Bernard Marini, Denise Leung, Michelle Kim, Sean Ferris, Larry Junck, et al. "CTNI-35. PHASE 0/1 TRIAL OF MYCOPHENOLATE MOFETIL COMBINED WITH CHEMORADIATION TO OVERCOME TREATMENT RESISTANCE IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA BY TARGETING PURINE METABOLISM." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii79. http://dx.doi.org/10.1093/neuonc/noac209.300.
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Abstract BACKGROUND Purine metabolism promotes glioblastoma growth, stemness, invasiveness, and treatment resistance. The purine synthesis inhibitor, mycophenolate mofetil (MMF), improves radiation and temozolomide efficacy in preclinical glioblastoma models. This phase 0/1 trial (NCT04477200) aims to determine the maximum-tolerated dose of MMF combined with chemoradiation in glioblastoma. It also aims to quantify the levels of the active metabolite of MMF and the extent of purine synthesis inhibition in enhancing and non-enhancing tumor tissue. METHODS Key eligibility criteria are age ≥ 18 and KPS ≥ 60%. TITE-CRM dose-escalation is used for MMF dosing starting at 1000mg PO BID (range 500-2000mg BID). Thirty recurrent glioblastoma patients receive MMF one-week prior to and concurrently with re-irradiation (40.5 Gy in 15 fractions), with 28 days of dose-limiting toxicity (DLT) period. Thirty newly diagnosed glioblastoma patients receive MMF one-week prior to and concurrently with standard radiation with concurrent temozolomide and followed for 28 days for DLT1-period, then MMF is given days 0-5 of each adjuvant cyclic temozolomide using a separate dose-escalation with the first two cycles as the DLT2-period. In phase 0, eight recurrent glioblastoma patients receive MMF 500-2000mg PO BID one-week pre-operatively and tissues are analyzed using mass spectrometry. RESULTS Eighteen phase 1 subjects (11 recurrent, 7 new) have received study treatment with no DLT to date up to MMF 2000mg BID. Main toxicities are mild nausea, fatigue, and elevated liver enzymes. No notable study-related hematotoxicity nor opportunistic infection have been observed. The active metabolite of MMF accumulated to active concentrations in enhancing and non-enhancing tumor tissue and appeared to inhibit purine synthesis. CONCLUSION MMF combined with chemoradiation has been reasonably well tolerated in glioblastoma patients with preliminary evidence of intracranial target engagement of its active metabolite. This study will yield a recommended phase 2 dose and preliminary efficacy estimate for future randomized phase 2/3 trial.
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Tillmanns, Todd D., Mark E. Reed, Melissa C. Privett, Amanda L. Johns, Mark S. Walker, and Arthur C. Houts. "Phase I trial of metronomic oral topotecan in combination with pazopanib utilizing a daily dosing schedule to treat recurrent or persistent gynecologic tumors." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 5014. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.5014.
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5014 Background: Metronomic oral topotecan has antiangiogenic properties. Oral pazopanib is also a potent inhibitor of VEGF angiogenesis with clinical benefit. This study investigated the safety and efficacy of daily topotecan and pazopanib. Methods: This phase I, single-center, open-label, dose ranging study comprised 28-day cycles of daily oral topotecan/pazopanib at dose levels of 0.50/400, 0.25/800, 0.25/600, and 0.25/400 mg. A standard 3+3 dose escalation design was used. Dose limiting toxicity (DLT) was defined as ≥ grade 3 adverse event (AE) occurring in cycle 1, noncompletion of cycle 1 at prescribed dose, or inability to start cycle 2 as scheduled due to toxicities. Imaging was conducted after every 2 cycles for response assessment. Confirmed responses were evaluated per RECIST 1.0. Results: 25 extensively pretreated patients (pts) with gynecologic tumors (6 cervical, 7 endometrial, 8 ovarian, 4 other) were enrolled. Mean age was 61 years; 19 Caucasian, 6 African American. Median number of cycles received was 4 (range 1-19). DLTs occurred ≥ 2 pts for A (2/6), B (2/7), C (3/7). For level D, 1/5 had a DLT, but one dose level C pt with a DLT received level D dosing due to unavailability of pazopanib. 9/25 pts had any serious adverse event (SAE), and respiratory SAEs were most common (4/16 SAEs). Nausea, fatigue, dysgeusia, diarrhea, and vomiting were the most common conditions reported as non-serious AEs. The Table shows best overall response (28%) by dose level. Conclusions: DLTs in dose levels C and D were effectively managed with minor dose and schedule adjustments. 4 pts with DLTs at these doses remained on treatment for 4, 5, and 6 months, with one pt still on treatment at 9 months. Given the initial biologically favorable signal in this heavily pretreated group and low toxicity, we recommend a randomized phase II trial to define efficacy using the 0.25/600 regimen allowing for dose reduction if needed. [Table: see text]
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Wright, Karen, Cassie Kline, Mohamed Abdelbaki, David Ebb, Elias Sayour, Jennifer Elster, Sarah Leary, et al. "CTNI-53. PNOC014: PHASE IB STUDY RESULTS OF DAY101(TOVORAFENIB) FOR CHILDREN WITH LOW-GRADE GLIOMAS (LGGS) AND OTHER RAS/RAF/MEK/ERK PATHWAY-ACTIVATED TUMORS." Neuro-Oncology 24, Supplement_7 (November 1, 2022): vii84. http://dx.doi.org/10.1093/neuonc/noac209.318.
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Abstract BACKGROUND Pharmacokinetic modeling for previously reported phase 1A data of pan-RAF inhibitor DAY101 in RAS/RAF/MEK/ERK pathway-altered tumors suggested a correlation between higher doses and improved efficacy without clear safety data. The protocol was amended to explore differential dosing across different body surface areas (BSA). METHODS Eligible patients were < 25 years old with radiographically recurrent/progressive RAS/RAF/MEK/ERK pathway-altered tumors. We applied a novel modification of a TITE-BOIN design to determine recommended phase 2 dosing of oral, weekly DAY101 in evaluable patients within two BSA subgroups: ≤ 1.5 m2 or > 1.5 m2. Target toxicity probability was closest to 20%. We tested 420 and 530 mg/m2. Dose limiting toxicities (DLTs) were determined within Cycle 1. Evaluable patients had either ‘complete’ or ‘partial’ information. Complete information meant patient had a DLT or received 3 of 4 planned doses with no DLT. Partial information meant patient received only 1 or 2 doses or did not complete the DLT observation period. Three patients with complete information at a given dose level were required before dose escalation. The primary endpoint driving dose escalation was time from start of Cycle 1 to first DLT or, if no DLT, time from start of Cycle 1 to minimum of date of last contact or end of Cycle 1. RESULTS We treated 35 eligible patients: 21 KIAA1549:BRAF-, 9 BRAFV600E-, 4 novel RAF- and one FGFR1-altered tumors. Histologically, cohort included 30 LGGs, 4 high grade gliomas and 1 soft tissue sarcoma. There were 6 DLTs: 3 in each BSA subgroup, all at 530 mg/m2/dose, all grade 3, and 5 known side effects ( 2 fatigue, 3 rash, 1 menorrhagia). CONCLUSIONS Oral weekly DAY101 is well tolerated. The TITE model recommends 530 mg/m2/dose PO weekly for patients with BSA < 1.5m2 and 420 mg/m2/dose PO weekly for patients with BSA >1.5m2.
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Waterhouse, David Michael, Jonathan Wade Goldman, Ben George, Peter J. O'Dwyer, Moncy Ye, Tianlei Chen, Nataliya Trunova, and Karen Kelly. "Nivolumab (nivo) + nab-paclitaxel (nab-P) + carboplatin (C) in patients (pts) with non-small cell lung cancer (NSCLC): Interim results from a multicenter phase I study." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 9095. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.9095.
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9095 Background: Despite success of single-agent immune checkpoint inhibitors, an unmet therapeutic need remains in pts with NSCLC. Chemotherapy and immunotherapy may have synergistic antitumor activity, but safety and efficacy need to be established. Here, we present interim results for pts with NSCLC (Arm C) from the phase I safety trial of nivo + nab-P in pancreatic cancer (± gemcitabine), NSCLC (+ C), and metastatic breast cancer. Methods: Part 1 evaluated potential dose-limiting toxicities (DLTs) before Part 2 expansion. Chemotherapy-naive pts with histologically/cytologically confirmed stage IIIB/IV NSCLC received 4 cycles of nab-P 100 mg/m2d 1, 8, 15 + C AUC 6 d 1 + nivo 5 mg/kg d 15 of each 21-d cycle; in cycles 5+, nivo was continued as maintenance monotherapy. Primary endpoints: number of pts with DLTs (Part 1) and percentage of pts with grade 3/4 treatment-emergent adverse events (TEAEs) or treatment discontinuation due to TEAEs (Parts 1 and 2). DLT-evaluable pts included those who received ≥ 2 complete nivo cycles and remained on study for 14 d after the last nivo dose in cycle 2, received ≥ 1 nivo dose and discontinued due to DLT before completing 2 nivo cycles, or experienced equivocal DLT after ≥ 1 nivo dose. Secondary endpoints included safety, PFS, OS, DCR, ORR, and DOR. Results: All pts (n = 22) received nab-P/C; results for nivo-treated pts (n = 20) are presented. Of the nivo-treated pts, the median age was 66 y (55% ≥ 65 y), 75% were female, 80% were white, and 70% had ECOG PS 1. More pts had adenocarcinoma (50%) than squamous cell carcinoma (35%; 10% other, 5% data pending). No DLTs reported (5 DLT-evaluable pts). Most common grade 3/4 TEAEs were neutropenia (45%) and anemia (35%). No grade 3/4 immune-related colitis or pneumonitis reported. Best ORR (RECIST v1.1) was 50% (1 CR [unconfirmed, 5%] and 9 PRs [45%]; 6 pts had SD [30%]; 4 pts had PD [20%]). Best ORR by histology: squamous, 71%; nonsquamous, 54%. Median PFS was 10.5 months (squamous, 10.5 months; nonsquamous, not evaluable). Conclusions: Results demonstrated safety of the nivo + nab-P/C combination in NSCLC with no unexpected safety signals. Preliminary efficacy results are promising. (NCT02309177) Clinical trial information: NCT02309177.
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Fury, M. G., J. Larkin, S. R. Gerst, P. Sabbatini, J. Konner, M. Orlando, D. F. Tai, T. Goss, C. Aghajanian, and M. L. Hensley. "Phase I study of pemetrexed (P) plus gemcitabine (G) in advanced solid tumors (ST)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 14055. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14055.
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14055 Background: P is active in multiple ST types, and preclinical data support P synergy with G. Methods: Eligible advanced ST patients (pts) with no prior P or G, no prior radiotherapy (RT) to ≡ 25% of the marrow, Karnofsky Performance Status ≡ 70%, and adequate organ function enrolled in cohorts (C) of 3, expanding to 6 if dose-limiting toxicity (DLT) occurred. P was given at 300 (C1), 400 (C2), 500 (C3) or 600 (C4) mg/m2 followed by G at 1500 mg/m2 q 14 days (d) without granulocyte-colony stimulating factor. Vitamin B12 and folate supplementation were given. Response was assessed by RECIST Results: 29 pts (median number prior regimens 2, range 1–5; 66% with prior RT) enrolled and are evaluable for safety; 23 are evaluable for response. There were no DLTs in C1. One pt in C2 was replaced after 1 cycle for progression of disease (PD). Among the next 6 pts, 2 had DLTs (1 G3 thrombocytopenia [TP] treatment delay; 1 neutropenic fever [NF]). C2-R (C2, Revised) re-opened after amendment permitting ≡ 2 prior cytotoxic regimens, no history of brain metastases/brain RT. C2-R enrolled 8 pts with 1 DLT (G3 TP with treatment delay) and 2 pts replaced (1 early PD, 1 no documented duration of neutropenia [NP]). C3 had 0/3 pts with DLT. C4 had 2/3 pts with DLTs (1 G4 hyponatremia; 1 herpes zoster-related treatment delay). C3 has been expanded to 5 of 6 planned patients, one with DLT (NF, G4 TP). Toxicities per cycle (n= 189 cycles, 29 patients): include NP-G3 (23%), G4 (14%); TP-G3 (2%); WBC-G3 (30%), G4 (4%); lymphopenia-G3 (11%), Hgb-G3 (4%); G3-NF (1%). 3/23 (13%) had objective partial responses (2 head and neck squamous cell cancer, HNSCC; 1 nasopharyngeal cancer, NPC), 4 stable disease (SD), 16 PD. (1 pt, no measurable disease at baseline; 5 pts, too early for response assesment). Conclusions: G + P is well-tolerated, and yields objective responses in HNSCC and NPC. C3 (P 500 mg/m2 + G 1500 mg/m2 q 14 d) was the phase II recommended dose in another phase I study of this regimen (Melemed ASCO 2005). Our final results will be available for ASCO 2007. No significant financial relationships to disclose.
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Vélez, Mónica Perea, Tine L. A. Verhoeven, Christian Draing, Sonja Von Aulock, Markus Pfitzenmaier, Armin Geyer, Ivo Lambrichts, et al. "Functional Analysis of d-Alanylation of Lipoteichoic Acid in the Probiotic Strain Lactobacillus rhamnosus GG." Applied and Environmental Microbiology 73, no. 11 (April 13, 2007): 3595–604. http://dx.doi.org/10.1128/aem.02083-06.
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ABSTRACT Lipoteichoic acid (LTA) is a macroamphiphile molecule which performs several functions in gram-positive bacteria, such as maintenance of cell wall homeostasis. d-Alanylation of LTA requires the proteins encoded by the dlt operon, and this process is directly related to the charge properties of this polymer strongly contributing to its function. The insertional inactivation of dltD of the probiotic strain Lactobacillus rhamnosus GG (ATCC 53103) resulted in the complete absence of d-alanyl esters in the LTA as confirmed by nuclear magnetic resonance analysis. This was reflected in modifications of the bacterial cell surface properties. The dltD strain showed 2.4-fold-increased cell length, a low survival capacity in response to gastric juice challenge, an increased sensitivity to human beta-defensin-2, an increased rate of autolysis, an increased capacity to initiate growth in the presence of an anionic detergent, and a decreased capacity to initiate growth in the presence of cationic peptides compared to wild-type results. However, in vitro experiments revealed no major differences for adhesion to human intestinal epithelial cells, biofilm formation, and immunomodulation. These properties are considered to be important for probiotics. The role of the dlt operon in lactobacilli is discussed in view of these results.
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Moehler, Markus H., Alexander Stein, Jorg Trojan, Jens Uwe Marquardt, Julia Quidde, Oliver Waidmann, Arndt Weinmann, et al. "Regorafenib with TAS-102 (REGOTAS) in metastatic colorectal cancer patients who progressed after at least two standard therapies: Efficacy and safety results of a multicenter phase I study (REMETY)." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 158. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.158.
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158 Background: The multi-kinase inhibitor regorafenib (REGO) and oral fluoropyrimidine TAS-102 (TAS) show efficacies as single agents in treatment of refractory metastatic CRC patients (pts). We conducted a conventional 3+3 dose finding to determine a recommended phase II dose (RP2D) of its combination REGOTAS and efficacy in 3-4.-line. Methods: Eligible patients with ECOG 0-1, measurable mCRC, not amenable to surgery had at least 3rd-line treatments. Prior fluoropyrimidine-based and anti-VEGF (R) combinations were mandatory, and anti-EGFR for RAS WT tumors. TAS was given on days 1-5 and 8-12 (28-days cycle); REGO on days 2-22 (dose levels see table below). The following major AE categories were used to define DLTs if they occurred during the first 2 treatment cycles: any grade ≥3 non-hematologic toxicity (except vomiting, nausea, non-significant lab abnormalities), grade ≥3 hematological toxicities, grade ≥3 bleeding. Tumor response was assessed Q8W as per RECIST1.1. EudraCT 2016-001968-11; NCT03305913. Results: All observed toxicities were consistent with safety profile of individual IMPs. 6 pts were enrolled into each DL1 and DL2 (n=12 in total). One DLT was observed in 1/6 pts in DL1; 2 DLTs in 2/6 pts in DL2. All DLTs were only grade 3 hypertension was well manageable, causality was attributed to REGO. No DLT resulted in treatment discontinuation. Results indicate a RP2D of 25mg/m² TAS-102 BID + 120mg REGO daily. No remissions were observed. Overall disease control rate (DCR) after 8 weeks was promising with 58.3% (DCR of 33.3% for DL1 and 83.3% in DL2) and remarkably better as historical data with 41/44% for REGO/TAS102 alone, respectively (Lancet 2013/NEJM 2015). Conclusions: Toxicities of REGOTAS were consistent with safety profiles of REGO and TAS alone. No additional DLTs were attributed to REGOTAS. Thus, the risk-benefit assessment of REGOTAS was positive. DCR was clinically quite meaningful. Mature PFS and OS will be presented at the meeting. Clinical trial information: NCT03305913. [Table: see text]
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Chakravarthy, A. B., F. Y. Wu, C. D. Blanke, J. D. Berlin, R. D. Beauchamp, H. Choy, and D. Delbeque. "A phase I study of neoadjuvant paclitaxel/radiation in patients with potentially resectable adenocarcinoma of the pancreas." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 15067. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.15067.
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15067 Background: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of weekly paclitaxel when given with concurrent radiation in the neoadjuvant setting to patients with potentially resectable adenocarcinoma of the pancreas. A secondary goal was to assess the value of 18-fluoro-deoxy-glucose positron emission tomography (FDG-PET) as an early marker of therapeutic response. Methods: Patients received weekly paclitaxel, given as a 3-hour infusion, during the course of radiation. The starting dose of paclitaxel was 30 mg/m2/week. Doses were escalated in increments of 15 mg/m2 in successive cohorts of 3–6 patients. Radiation therapy consisted of 45Gy in 25 fractions over 5 weeks. CT and PET scans were obtained prior to initiating treatment and one month following completion of chemoradiation. Results: Nine patients with resectable pancreatic cancer were enrolled through two dose levels. DLT was defined as grade 3 or greater. There were no DLTs at the first dose level of 30 mg/m2/ week. DLTs consisted of nausea, neutropenia and hepatic toxicity developed at the second dose level of 45 mg/m2/ week. Pre-treatment PET scans revealed uptake in all nine of the patients whereas pre-treatment CT scans detected disease in only 5 of 9 patients. Post-treatment PET scans correlated with pathologic findings in all 9 patients. Conclusions: The MTD for concurrent paclitaxel/radiation in the neoadjuvant setting was determined to be 30 mg/m2/week. DLTs were nausea, neutropenia and hepatic toxicity. FDG-PET may be superior to CT scans as a radiographic marker of treatment response. [Table: see text]
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Franklin, Anna, Marco Zecca, Franca Fagioli, Flavio Augusto Luisi, Gregory Song, Ajit Suri, E. Jane Leonard, and Franco Locatelli. "Phase 1 Results from a Phase 1/2 Study to Assess the Safety, Tolerability and Recommended Phase 2 Dose (RP2D) of Brentuximab Vedotin Plus Doxorubicin, Vinblastine and Dacarbazine (A+AVD) in Pediatric Patients (Pts) with Advanced Stage Newly Diagnosed Classical Hodgkin Lymphoma (cHL)." Blood 132, Supplement 1 (November 29, 2018): 1644. http://dx.doi.org/10.1182/blood-2018-99-112488.
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Abstract Background: Pediatric pts with cHL have better responses to therapy compared with adult pts; however, the combination regimens and radiotherapy used in treatment can result in significant morbidity. Including brentuximab vedotin as a component of multi-agent chemotherapy for pediatric pts with newly diagnosed HL may provide clinical benefit by decreasing the need for radiotherapy following chemotherapy, and reducing the risks of late effects associated with radiotherapy, including secondary malignancies, cardiac toxicity and thyroid dysfunction. The phase 1 portion of the study assessed the safety, tolerability, and RP2D of brentuximab vedotin when combined with doxorubicin, vinblastine, and dacarbazine (AVD) for frontline treatment of advanced stage cHL in pediatric pts. Methods: Eligible pts were aged 5 to <18 years, with treatment-naïve stage III/IV cHL, a Lansky Play/Karnofsky Performance Status of ≥50, and bidimensional measurable disease by radiography. Pts received up to six 28-day cycles of 48 mg/m2 brentuximab vedotin with AVD on days 1 and 15 of each cycle. RP2D was confirmed according to a modified 3+3 design; at least three pts were monitored for dose limiting toxicities (DLTs) during the evaluation period (cycle 1+28 days; from the first dose through study day 56), if 0/1 DLTs were observed, at least 3 additional pts were enrolled and monitored for DLTs. Toxicity was evaluated according to the NCI CTCAE, v4.03. The primary endpoints were to determine the RP2D of brentuximab vedotin in combination with AVD, and to assess treatment-emergent adverse events (AEs) and serious AEs (SAEs) from the first dose of treatment through 30 days after the last dose; pharmacokinetics (PK) was a secondary endpoint. G-CSF use was not permitted in the DLT-evaluation period. Results: Eight pts were enrolled (50% male), age range 6-17 years, with advanced stage cHL (stage III, n=5; IV, n=3) one of whom had bone marrow involvement. Four pts (50%) had two extra-nodal sites of involvement and four pts (50%) had no extranodal involvement. Two pts were not DLT-evaluable due to the administration of G-CSF under the original protocol. Of the six DLT-evaluable pts, all completed the 56-day DLT evaluation period with no DLTs reported. The RP2D of brentuximab vedotin was confirmed as 48 mg/m2. All pts reported at least one treatment-emergent, treatment-related AE during the DLT-evaluation period. During the DLT-evaluation period, 10 grade 4 AEs were reported, all treatment-related: neutrophil count decrease or neutropenia (n=7) and white blood cell (WBC) count decrease (n=3). One pt reported a treatment-related SAE of grade 3 febrile neutropenia for a duration of 2 days. Fifteen additional grade 3 AEs included: vomiting (n=3), WBC decreased (n=4), neutrophil count decreased or neutropenia (n=7), mucositis (n=1), and headache (n=1, not treatment related). Treatment-related AEs in pts who were not DLT-evaluable included: grade 4 neutropenia (n=3), grade 3 neutrophil count decrease (n=4), and grade 3 WBC decreased (n=1); non treatment-related AEs (1 each; grade 3) were leukopenia, anemia, and aspartate aminotransferase increase. Dose delays during the DLT-evaluation period were due to neutrophil count decrease/neutropenia (n=6) and mucositis (n=1). Currently, 5 of the Phase 1 patients continue on treatment while 3 patients have completed all 6 cycles. Full Phase 1 AE data will be provided. PK concentrations were within target range and consistent with two prior brentuximab vedotin studies: Phase 3 ECHELON-1 study (C25003; NCT01712490) and C25002 pediatric study (NCT01492088). Conclusions: The safety, tolerability, and PK profile of brentuximab vedotin were consistent with its expected profile, and a dose of 48mg/m2 was confirmed as the RP2D. Phase 2 is currently open for enrollment in the USA, Italy, Singapore, Taiwan, Hong Kong, Japan, and Brazil. Clinicaltrials.gov NCT02979522. Disclosures Zecca: Chimerix: Honoraria. Song:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Suri:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Leonard:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment; Takeda Pharmaceutical Company Limited: Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Honoraria.
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Glasspool, Rosalind Margaret, Sarah Patricia Blagden, Michelle Lockley, James Paul, Carol Hopkins, Fiona Thomson, Jennifer Brown, et al. "A phase I trial of the oral hedgehog inhibitor taladegib (LY2940680) in combination with weekly paclitaxel in patients with advanced, solid tumours." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 2594. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.2594.
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2594 Background: Aberrant Hedgehog (Hh) signaling is implicated in carcinogenesis and is associated with poor prognosis in multiple tumours types. Hh inhibitors increase sensitivity to paclitaxel in taxane-resistant cell lines. Taladegib is an orally bioavailable, potent inhibitor of Smoothened, a key Hh pathway component, with activity in basal cell carcinoma. The single agent recommended dose is 400mg od. We present the dose escalation phase of a phase I study of weekly paclitaxel with oral taladegib. Methods: Primary objective: determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of taladegib on a continuous oral daily dosing regimen in combination with paclitaxel (80mg/m2, iv, day 1, 8 and 15 q 28) in patients with advanced solid cancers. Secondary objectives: assess the safety and tolerability, determine the recommended phase II dose (RP2D), and evaluate the pharmacokinetics of taladegib and paclitaxel. Exploratory objective: assess preliminary efficacy. A standard 3 + 3 dose escalation design was used. All patients received up to 6 cycles of paclitaxel. In addition, successive cohorts received continuous oral taladegib continued until progression or unacceptable toxicity as follows: dose level 1: 100mg od; 2: 200mg od; 3: 400mg od. Results: No DLTs were seen at dose level 1 or in the first 3 patients at dose level 2. 3 DLTs of grade 2 neuropathy were seen at dose level 3 (400mg taladegib); therefore, dose level 2 was expanded to 6 patients. No DLT was seen in the fourth patient and 2 additional patients have started treatment. After the DLT period 2 patients developed G2 and 4 developed G1 neuropathy. Other non DLT, drug-related G3 toxicities: uncomplicated neutropenia x2, muscle cramp x1 and fatigue x1. To date, 3 patients have had partial responses. Conclusions: The combination of daily oral taladegib and weekly paclitaxel is feasible. DLT of G2 neuropathy was seen at 400mg. Promising activity has been seen in solid tumours. A dose expansion cohort is due to commence in high grade ovarian carcinoma. ISRCTN No:ISRCTN15903698 Eudract Ref:2014-004695-37 Funded by Cancer Research UK C8361/A18775 and Ignyta. Sponsored by NHS Greater Glasgow and Clyde. Clinical trial information: ISRCTN15903698.
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Lee, S. M., D. Hershman, P. Martin, J. Leonard, and K. Cheung. "Validation of toxicity burden score for use in phase I clinical trials." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 2514. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.2514.
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2514 Background: In phase I clinical trials, dose limiting toxicity (DLT) is defined as a binary outcome (DLT Yes/No). Concerns have been raised since this does not account for multiple non-DLTs that have a cumulative effect on drug tolerability and do not differentiate the severity of DLTs. Having a continuous toxicity burden score (TBS) as an outcome may provide more information regarding toxicity. We propose a new method for obtaining TBS. Methods: We illustrate the method using a phase I trial in lymphoma. The two main toxicities related to the experimental drug were low platelets and neuropathy with DLT defined as platelet count < 10,000/mm3 or grade 3 neuropathy. Three oncologists were asked to assign severity scores for the two main toxicities by assigning scores based on their impression of the impact of the toxicity on the patient and keeping in mind that DLT should be assigned a score of 1 and no toxicity should be assigned a score of 0. They were then given data from 25 patients along with their observed toxicities and the respective NCI toxicity grades and were asked to assign TBS to each patient. A mixed effects regression model was fit to the data. To validate the model, two of the oncologists assigned TBS to an additional list of 17 patients. Assuming the estimated TBS to be a rating, the three ratings (two oncologists and the estimated TBS) were compared using a mixed effects regression model. Results: The significant predictors of TBS are listed in the Table . Since no patient in the training data experienced grade 3 low- platelet and grade 4 neuropathy, model coefficients for these were not obtained. In the validation data, the TBS among the oncologists and the estimated TBS obtained using the fitted model were not different (P=0.18). Conclusions: A fitted model can be used to obtain TBS from maximal NCI toxicity grades suggesting the feasibility of using a continuous outcome such as TBS in dose finding studies. [Table: see text] No significant financial relationships to disclose.
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Fox, Elizabeth, Richard Aplenc, Rochelle Bagatell, Meredith K. Chuk, Eva Dombi, Wendy Goodspeed, Anne Goodwin, et al. "A Phase 1 Trial and Pharmacokinetic Study of Cediranib, an Orally Bioavailable Pan–Vascular Endothelial Growth Factor Receptor Inhibitor, in Children and Adolescents With Refractory Solid Tumors." Journal of Clinical Oncology 28, no. 35 (December 10, 2010): 5174–81. http://dx.doi.org/10.1200/jco.2010.30.9674.
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Purpose To determine the toxicity profile, dose-limiting toxicities (DLTs), maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of cediranib administered orally, once daily, continuously in children and adolescents with solid tumors. Patients and Methods Children and adolescents with refractory solid tumors, excluding primary brain tumors, were eligible. DLT at the starting dose of 12 mg/m2/d resulted in de-escalation to 8 mg/m2/d and subsequent re-escalation to 12 and 17 mg/m2/d. Pharmacokinetic and pharmacodynamic studies were performed during cycle 1. Response was evaluated using WHO criteria. Results Sixteen patients (median age, 15 years; range, 8 to 18 years) were evaluable for toxicity. DLTs (grade 3 nausea, vomiting, fatigue in one; hypertension and prolonged corrected QT interval in another) occurred in patients initially enrolled at 12 mg/m2/d. Subsequently, 8 mg/m2/d was well tolerated in three patients. An additional seven patients were enrolled at 12 mg/m2/d; one had DLT (grade 3 diarrhea). At 17 mg/m2/d, two of four patients had DLTs (grade 3 nausea; intolerable grade 2 fatigue). Non–dose-limiting toxicities included left ventricular dysfunction, elevated thyroid stimulating hormone, palmar-plantar erythrodysesthesia, weight loss, and headache. The MTD of cediranib was 12 mg/m2/d (adult fixed dose equivalent, 20 mg). At 12 mg/m2/d, the median area under the plasma concentration-time curve extrapolated to infinity (AUC0-∞) was 900 ng·h/mL, which is similar to adults receiving 20 mg. Objective responses were observed in patients with Ewing sarcoma, synovial sarcoma, and osteosarcoma. Conclusion The recommended monotherapy dose of cediranib for children with extracranial solid tumors is 12 mg/m2/d administered orally, once daily, continuously. A phase II study is in development.
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Skolnik, Jeffrey M., Jeffrey S. Barrett, Bhuvana Jayaraman, Dimple Patel, and Peter C. Adamson. "Shortening the Timeline of Pediatric Phase I Trials: The Rolling Six Design." Journal of Clinical Oncology 26, no. 2 (January 10, 2008): 190–95. http://dx.doi.org/10.1200/jco.2007.12.7712.
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Purpose To shorten the study conduct timeline of pediatric phase I oncology trials by employing a novel trial design. Methods A comparison of the traditional 3 + 3 patients per cohort, phase I trial design with a novel, rolling six design was performed by using discrete event simulation. The rolling six design allows for accrual of two to six patients concurrently onto a dose level based on the number of patients currently enrolled and evaluable, the number experiencing dose-limiting toxicity (DLT), and the number still at risk of developing a DLT. Clinical trial simulations (n = 1,000) were based on historical data and were performed using SAS 9.1.3 (SAS Institute, Cary, NC). Study timelines and patient numbers were determined for each design, and safety was assessed as a function of the number of DLTs observed. Results In twelve completed historical studies, the median time to study completion was 452 days (range, 220 to 606 days); number of evaluable participants enrolled was 22 (range, 11 to 33), and DLTs occurring per study was three (range, 0 to 5). In 1,000 study simulations, in which the average time to new patient accrual was 10 days, the average ± standard deviation (SD) time to study completion was 294 ± 75 days for the rolling six design versus 350 ± 84 days for the 3 + 3 design, whereas the number of DLTs per study was the same (average ± SD, 3.3 ± 1.1 v 3.2 ± 1.1 for the rolling six and 3 + 3 designs, respectively). Conclusion The rolling six design may significantly decrease the duration of pediatric phase I studies without increasing the risk of toxicity. The design will be tested prospectively in upcoming Children's Oncology Group phase I trials.
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Raymond, Eric, Valérie Boige, Sandrine Faivre, Ger-Jan Sanderink, Olivier Rixe, Laurent Vernillet, Christian Jacques, Michel Gatineau, Michel Ducreux, and Jean-Pierre Armand. "Dosage Adjustment and Pharmacokinetic Profile of Irinotecan in Cancer Patients With Hepatic Dysfunction." Journal of Clinical Oncology 20, no. 21 (November 1, 2002): 4303–12. http://dx.doi.org/10.1200/jco.2002.03.123.
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PURPOSE: To determine the recommended dose (RD) and the pharmacokinetic profile of irinotecan and its metabolites in cancer patients with hyperbilirubinemia. PATIENTS AND METHODS: Patients were assigned to four treatment groups according to their baseline total bilirubin level. Patients in group I (bilirubin within normal range) and group II (bilirubin 1.0 to 1.5 times upper limit of normal [ULN]) received a dose of 350 mg/m2 every 3 weeks. Patients in groups III (bilirubin 1.51 to 3.0 times ULN) and IV (bilirubin > 3.1 times ULN) received starting doses of 175 and 100 mg/m2, respectively. RDs were defined according to the dose-limiting toxicity (DLT) experienced at cycle 1. RESULTS: Thirty-three patients including 21 gastrointestinal cancers were included. Grade 4 febrile neutropenia and diarrhea were common DLTs in patients with hyperbilirubinemia. At a dose of irinotecan 350 mg/m2, DLTs were observed in two of seven and one of five patients in groups I and II, respectively. In group III, escalated doses of irinotecan 175, 200, and 240 mg/m2 were associated with DLTs in one of seven, one of five, and three of six patients, respectively. No DLT was observed in group IV. High bilirubin and alkaline phosphatase levels were associated with an exponential decrease in the clearance of irinotecan. Pharmacokinetic analysis showed that the relative increase in exposure was likely caused by reduced biliary excretion. CONCLUSION: We showed that baseline total bilirubin level could be used to determine the appropriate dose of irinotecan in cancer patients with hepatic dysfunction. Doses of 350 mg/m2 and 200 mg/m2 were considered RDs in patients with bilirubin values ≤ 1.5 times ULN and 1.51 to 3.0 times ULN, respectively.
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Sawyer, Michael B., Mark J. Ratain, Donna Bertucci, Robert P. Smith, Richard L. Schilsky, Nicholas J. Vogelzang, Keith Shulman, Edwin C. Douglass, and Gini F. Fleming. "Phase I Study of an Oral Formulation of ZD9331 Administered Daily for 28 Days." Journal of Clinical Oncology 21, no. 9 (May 1, 2003): 1859–65. http://dx.doi.org/10.1200/jco.2003.01.148.
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Purpose: To define the maximum-tolerated dose and dose-limiting toxicities (DLTs) of an oral formulation of ZD9331, a novel thymidylate synthase inhibitor that is not a substrate for folylpolyglutamate synthase. Patients and Methods: Patients had Cancer and Leukemia Group B performance status ≤ 2 and refractory solid tumors. Initially, patients received ZD9331 daily for 2 weeks, with the duration of treatment escalated to a maximum of 4 weeks, followed by a 2-week rest period. Once the maximum-tolerated duration of treatment was determined, the dose of ZD9331 was increased until DLT occurred. Results: Fifty-five patients were enrolled at eight dose levels. The DLTs were thrombocytopenia and neutropenia. At 3 mg/d, two of 19 patients developed DLT; one patient had grade 3 thrombocytopenia and grade 4 neutropenia, and the other patient had grade 3 thrombocytopenia only. Anemia was common, with a median hemoglobin nadir of 75% of baseline, before recovery or transfusion. The apparent oral clearance of ZD9931 was 11.6 ± 6.3 mL/min. Dose-limiting myelosuppression was associated with both an increased 24-hour ZD9931 concentration and blood urea nitrogen. Conclusion: The recommended phase II dose on this schedule is 3 mg/d for 4 weeks, followed by a 2-week rest period. ZD9331 seems to have a manageable toxicity profile, although it should be used with caution in patients with renal impairment.
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Long, Si, Yuhang Li, Junying Guo, and Rong Hu. "Effect of the VivaSight double-lumen tube on the incidence of hypoxaemia during one-lung ventilation in patients undergoing thoracoscopic surgery: a study protocol for a prospective randomised controlled trial." BMJ Open 13, no. 4 (April 2023): e068071. http://dx.doi.org/10.1136/bmjopen-2022-068071.
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IntroductionA double-lumen tube (DLT) is a traditional one-lung ventilation tool that needs to be positioned under the guidance of a fibreoptic bronchoscope or auscultation. The placement is complex, and poor positioning often causes hypoxaemia. In recent years, VivaSight double-lumen tubes (v-DLTs) have been widely used in thoracic surgery. Because the tubes can be continuously observed during intubation and the operation, malposition can be corrected at any time. However, the effect of v-DLT on perioperative hypoxaemia has been rarely reported. The aim of this study was to observe the incidence of hypoxaemia during one-lung ventilation with v-DLT and to compare the perioperative complications between v-DLT and conventional double-lumen tube (c-DLT).Methods and analysisOne hundred patients planning to undergo thoracoscopic surgery will be randomised into the c-DLT group and the v-DLT group. During one-lung ventilation, both groups of patients will receive low tidal volume for volume control ventilation. When the blood oxygen saturation falls below 95%, the DLT will be repositioned and the oxygen concentration will be increased to improve the respiratory parameters (5 cm H2O Positive end-expiratory pressure (PEEP) on the ventilation side and 5 cm H2O CPAP (continuous airway positive pressure) on the operation side), and double lung ventilation measures will be taken in sequence to prevent a further decline in blood oxygen saturation. The primary outcomes are the incidence and duration of hypoxaemia and the number of intraoperative hypoxaemia treatments, and the secondary outcomes will be postoperative complications and total hospitalisation expenses.Ethics and disseminationThe study protocol was approved by the Clinical Research Ethics Committee of The First Affiliated Hospital, Sun Yat-sen University (2020–418) and registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn). The results of the study will be analysed and reported.Trial registration numberChiCTR2100046484.
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BREITENSTEIN, O. "SCANNING-DLTS." Le Journal de Physique Colloques 50, no. C6 (June 1989): C6–101—C6–110. http://dx.doi.org/10.1051/jphyscol:1989609.
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