Aplidin Cardiac Safety Analysis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4820-4820
Author(s):  
Arturo Soto-Matos ◽  
Sergio Szyldergemajn ◽  
Javier Gomez ◽  
Sonia Extremera ◽  
Bernardo Miguel-Lillo ◽  
...  
Keyword(s):  
Risk Factors ◽  
Clinical Trials ◽  
Multivariate Analysis ◽  
Drug Exposure ◽  
Single Agent ◽  
Fatal Outcome ◽  
Healthy Population ◽  
Qtc Interval ◽  
Cardiac Safety ◽  
Frequent Type

Abstract Abstract 4820 Background Aplidin (plitidepsin) is a cyclic depsipeptide of marine origin, with activity in relapsed/refractory multiple myeloma and T-cell NHL[1],[2]. Some depsipeptides have been linked to increased cardiac toxicity in the literature[3]. PharmaMar Pharmacovigilance and Clinical Trials Data Management databases were reviewed for cardiac adverse events (CAEs) occurring during clinical trials evaluating plitidepsin as single-agent as of November 2008. Data were analyzed for potential risk factors associations with the occurrence of CAE by univariate and multivariate logistic regression analyses. Results Forty-six of the 578 patients (8.0%) treated had at least one CAE. Eleven patients of 578 (1.9%) had CAE related to plitidepsin, none of them with fatal outcome. CAEs were retrospectively classified into 3 main groups after clinical review of all available data. The most frequent type of CAE were rhythm abnormalities (RA) (n=31; 5.4%), whereas atrial fibrillation (AF)/flutter accounted for most cases (n=15; 2.6%). Most events occurred randomly during plitidepsin treatment. Of note, no cases of life-threatening ventricular arrhythmias have been reported to date. The myocardial injury events (MI) (n=17; 3.0%) included possible ischemic related events as well as non-ischemic events. Finally, miscellaneous events (M) (n=6; 1.0%) included all other cardiac events that did not fit into the aforementioned categories. None of the M events was related to plitidepsin Demographic, clinical and pharmacological variables were explored by univariate and multivariate analysis. Significant association was found with prostate or pancreas cancer diagnosis (p=0.002), known baseline cardiac risk factors (p=0.002), myalgia at baseline (p=0.004), lower hemoglobin levels (p= 0.006) and ≥ grade 2 hypokalemia (p=0.006). Multivariate analysis confirmed all these associations. Importantly, treatment related variables, such as plitidepsin dose, number of cycles or schedule of administration did not result in any statistically significant association. Serial ECGs performed before and after plitidepsin administration (n=136) did not show any relevant effect on QTc interval. None of the PK parameters analyzed (Cmax and AUC from day 0 to day 28) had any significant impact on the probability of developing a CAE. Conclusions CAEs observed to date in plitidepsin trials fit into three clinical categories. The most frequent type observed was AF/atrial flutter, although its incidence was not different to what is reported in age-matched healthy population[4]. All other events were relatively infrequent. No dose-cumulative pattern was observed; moreover, neither plitidepsin dose nor schedule was associated with occurrence of CAEs. Relevant predisposing factors identified in univariate and multivariate analyses were related to patient's baseline and/or disease-related characteristics rather than to drug exposure or treatment-related variables. Data available on 578 adult patients with advanced cancer treated with singe-agent plitidepsin support a favorable cardiac safety profile. Disclosures: Soto-Matos: PharmaMar SAU: Employment. Szyldergemajn:PharmaMar SAU: Employment. Gomez:PharmaMar SAU: Employment. Extremera:PharmaMar SAU: Employment. Miguel-Lillo:PharmaMar SAU: Employment. Alfaro:PharmaMar SAU: Employment. Coronado:PharmaMar SAU: Employment. Lardelli:PharmaMar SAU: Employment. Roy:PharmaMar SAU: Employment. Corrado:PharmaMar SAU: Employment. Yovine:PharmaMar SAU: Employment. Kahatt:PharmaMar SAU: Employment.

Factors predictive of response to cisplatin-based chemotherapy in stage IVB persistent or recurrent cervical carcinoma: A multivariate analysis of three Gynecologic Oncology Group trials

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5534-5534
Author(s):  
D. H. Moore ◽  
C. Tian ◽  
B. J. Monk ◽  
H. J. Long ◽  
G. Omura
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
African American ◽  
High Risk ◽  
Predictive Model ◽  
Single Agent ◽  
Phase Iii ◽  
Gynecologic Oncology Group ◽  
Recurrent Cervical Cancer ◽  
Risk Of Death

5534 Purpose: A number of patients with advanced/recurrent cervical cancer do not respond to cisplatin-based chemotherapy. A pool analysis of three published phase III GOG studies was undertaken to identify the predictive factors and develop a model predictive of (non-) response to chemotherapy. Methods: The study population consisted of patients who received single-agent cisplatin or a cisplatin-containing combination in GOG protocols 110, 169 and 179. Prognostic variables (age, race, performance status, stage, histology, grade, disease site, prior chemotherapy—with primary radiation, time to recurrence, single-agent versus combination) were analyzed and multivariate analysis was conducted to identify factors independently predictive of response and survival. These analyses were used to establish a predictive model. Results: 816 patients were evaluable for response. In addition to single-agent treatment, multivariate analysis identified six factors (age, African-American, PS > 0, pelvic disease, prior radiosensitizer, recurrence ≤ one year) independently predictive of poor response. Those factors, but not age and African-American, were also independently associated with increased risk of death. 428 patients treated with a cisplatin- containing combination were classified into three risk groups based on the total number of risk factors (low risk: 0–1 factor; mid risk: 2–3 factors; high risk: 4–5 factors). Patients with 4–5 of risk factors were predicted to have a treatment response of only 13% (observed 10%), and median progression-free and overall survival of PFS of 2.8 months and 5.5 months, respectively. This subgroup of patients consist ∼14% of the target population in clinical practice. The predictive model was externally validated using GOG protocol 149 data that were not used for model development and further supported the predictive accuracy. Conclusions: High risk patients should be directed to non-cisplatin chemotherapy or investigational trials. No significant financial relationships to disclose.

Analysis of Parameters Predicting Treatment Efficacy and Outcome In Patients with Hairy Cell Leukemia (HCL) Receiving Subcutaneous Cladribine In the ICGHCL2004 Protocol (by the Italian Cooperative Group on HCL)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1369-1369
Author(s):  
Francesco Forconi ◽  
Emanuele Cencini ◽  
Francesco Zaja ◽  
Tamara Intermesoli ◽  
Francesca Fiore ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multivariate Analysis ◽  
Hairy Cell Leukemia ◽  
Single Agent ◽  
Rapid Progression ◽  
Costal Margin ◽  
Hairy Cell ◽  
Cell Leukemia ◽  
Independent Risk Factors ◽  
L 14

Abstract Abstract 1369 Introduction: Single-agent cladribine (2CdA) given intravenously or subcutaneously (sc) is highly effective in Hairy cell leukemia (HCL). However, HCL patients are projected to progress in their life-span or, in a minority, are refractory and may benefit from other treatment strategies. Parameters predicting efficacy of (sc)2CdA in HCL are scarcely known. Aims: In a national multicentre clinical trial (EudraCT code: ICGHCL2004) we prospectively sought parameters able to predict efficacy of sc2CdA in classic HCL requiring first treatment (1987 Consensus Criteria). Methods: Clinical data and samples were collected centrally for diagnostic revision according to the WHO criteria and for molecular analyses prior to treatment. Tumor IGH and TP53 analyses or Genome-wide DNA profiling was performed in the cases with >10% or >50% hairy cells (HC) in the test sample, respectively (Forconi, Blood 2009). Patients entering the study received 0.5–0.7 mg/kg sc2CdA as a single course. Efficacy endpoints were response to sc2CdA, treatment free interval (TFI), relapse free survival (RFS), and overall survival (OS). Responses were assessed on month 2 and 6 after treatment and defined according to the 1987 Consensus criteria. Complete Remissions (CR) and Partial Remissions (PR) were rated as beneficial responses (CR/PR), while minor Responses (mR) and No Responses (NR) were rated as failures (mR/NR). TFI was measured in all patients from sc2CdA initiation to time of new treatment requirement. RFS was measured in patients with CR/PR from sc2CdA initiation to relapse. OS was measured from sc2CdA initiation to death. Results: Of 148 patients, 116 were males (78,4%). Median values were: age 52 years (range 30–83), splenomegaly below costal margin 2 cm (0-16), hemoglobin 11,8 (5-17 g/dL), PLT 77×10e9/L (14-255), WBC 2,7×10e9/L (0,7-48), HC 0,2×10e9/L (0-38). Serum B2microglobulin was twice above upper limit (B2M>2X) in 9/122 patients (7,4%), IGH unmutated (UM) in 7/62 (11,3%) and TP53 mutated (mutTP53) in 2/62 (3,2%). Onehundred-forty patients (94,6%) had a CR/PR (101 CR, 68,2%; 39 PR, 26,4%) and 8 (5,4%) a mR/NR (5 mR, 3,4%; 3 NR, 2%). Risk factors of sc2CdA failure were splenomegaly (p=.001, best-cutoff> 3 cm bcm by ROC and Youden's Test), WBC (p<.001, best cut-off >10×10e9/L), HC counts (p<.001, best cut-off >5×10e9/L), and B2M>2X (p=.013). In 62 patients investigated for molecular features, UM-IGH and TP53 were confirmed as risk factors for mR/NR (p<.001 and p=.011). Conversely, age, performance status, 2CdA schedule, lymphadenopathy, neutrophil, haemoglobin and platelet counts, prior transfusions, time from diagnosis to treatment, Jansen score, LDH, marrow infiltration and hairy cell index failed to predict response. After a median follow-up of 37,5 months (range 12–67), 5 year TFI, RFS and OS were 67%, 71% and 94%, respectively. Causes of death were one infection in progressive refractory disease, 2 cardiac events and 3 second tumors. By Kaplan-Maier estimates, risk factors of shorter TFI at diagnosis were splenomegaly (p=.007), WBC>10×10e9/L (p<.001) or HC>5×10e9/L (p<.001), UM-IGH (p<.001), and TP53 disfunction (p=.002). By Cox multivariate analysis (covariates: HC>5×10e9/L, spleen>3cm, UM-IGH and mutTP53), UM-IGH (HR=8.1, 95%CI 1.7–38.1, p=.008, median TFI=8.5 months), high HC (HR=6.9, 95%CI 1.5–31.6, p=.012, TFI=27,4 months) and splenomegaly (HR=3.7, 95%CI 1.1–12.8, p=.039, TFI=49,3 months) scored as independent risk factors. Quality of response also predicted risk of short TFI (NR=mR>PR>CR, p<.001). In the patients with beneficial response, univariate analysis of clinical parameters identified WBC>5×10e9 (p=.016) and PR (p=.001)as risk factors of short RFS. Cox multivariate analysis revealed PR as the sole independent risk factor of relapse after a median of 46 months (HR=4.5, 95%CI 1,7-12,3, p=.003). 2CdA dose schedule was among other factors that did not associate with TFI or RFS. Conclusion: This data confirm that sc2CdA has potent activity in HCL. Tumor UM-IGH status, splenomegaly, high HC count (or leukocytosis) are confirmed as independent risk factors of treatment failure and rapid progression. RFS analysis identify PR as the sole independent factor of relapse risk in the patients initially responsive to sc2CdA. This analysis may have important implications for the selection of HCL patients that will require treatments alternative to single-agent 2CdA. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Determination of Risk Factors Associated With Walking Disorders After Anterior Cruciate Ligament Surgery With Hamstring Graft : A Controlled Multicenter Study

2020 ◽  
Author(s):  
Marine Gaignon ◽  
Jean Mazeas ◽  
Maude Traullé ◽  
Amaury Vandebrouck ◽  
Pascal Duffiet ◽  
...  
Keyword(s):  
Risk Factors ◽  
Anterior Cruciate Ligament ◽  
Multivariate Analysis ◽  
Cruciate Ligament ◽  
Univariate Analysis ◽  
Test Group ◽  
Healthy Population ◽  
Hamstring Graft ◽  
Factors Associated ◽  
Anterior Cruciate

Today, rupture of the anterior cruciate ligament is the most common heavy injury in athletes, but it can also occur in sedentary subjects. Its treatment, always adapted to the lifestyle, age and will of the patient, often remains surgical. However, despite its frequency and universality, there are still walking disorders following the operation. These disorders sometimes persist for several months, or even several years after surgery. The present study is therefore interested in determining the risk factors linked to walking disorders following reconstruction of the anterior cruciate ligament. The objective of this study is to determine what risk factors associated with walking disorders are after reconstruction of the anterior cruciate ligament by hamstring graft. This study focused on factors that may exist at 3 and 6 months postoperatively. Two populations participated in this study, a healthy population and a population having benefited from reconstruction of the anterior cruciate ligament. The operated test group is divided into two subgroups, one with a postoperative period of 3 months and the second at 6 months. All subjects were subjected to the same protocol, their gait on the treadmill was analyzed and evaluated with an Optogait&reg; analysis system. A univariate analysis was carried out first. Then, a multivariate analysis by adjustment method was carried out in order to eliminate the potential confounding factors. The comparison of the results between the populations in the univariate analysis shows an absence of significant results however there are trends. The statistical results of the multivariate analysis showed interactions in the two subgroups of the operated population.In fact, it turns out that at 3 months there is a tendency to worse gait disorders in subjects with a high BMI reflecting overweight, when an associated surgical procedure has taken place on the meniscus, in subjects over 35 years of age and males. On the other hand, at 6 months, the tendency to worsening is visible only in the strata represented by subjects with a BMI corresponding to overweight, as well as in subjects having benefited from a meniscal suture associated with ACL reconstruction. .The results of the present study show that there are certain factors which tend to increase the risk of these walking disorders after reconstruction of the anterior cruciate ligament by hamstring graft, these factors are different depending on the time postoperative.

scholarly journals How circadian variability of the heart rate and plasma electrolytes concentration influence the cardiac electrophysiology – model-based case study

2021 ◽  
Author(s):  
Barbara Wiśniowska ◽  
Zofia M. Bielecka ◽  
Sebastian Polak
Keyword(s):  
Heart Rate ◽  
Qt Interval ◽  
Cardiac Electrophysiology ◽  
Cardiac Activity ◽  
Diurnal Variations ◽  
Ion Concentration ◽  
Interval Length ◽  
Healthy Population ◽  
Qtc Interval ◽  
Cardiac Safety

AbstractThe circadian rhythm of cardiac electrophysiology is dependent on many physiological and biochemical factors. Provided, that models describing the circadian patterns of cardiac activity and/or electrophysiology which have been verified to the acceptable level, modeling and simulation can give answers to many of heart chronotherapy questions. The aim of the study was to assess the performance of the circadian models implemented in Cardiac Safety Simulator v 2.2 (Certara, Sheffield, UK) (CSS), as well as investigate the influence ofcircadian rhythms on the simulation results in terms of cardiac safety. The simulations which were run in CSS accounted for inter-individual and intra-individual variability. Firstly, the diurnal variations in QT interval length in a healthy population were simulated accounting for heart rate (HR) circadian changes alone, or with concomitant diurnal variations of plasma ion concentrations. Next, tolterodine was chosen as an exemplary drug for PKPD modelling exercise to assess the role of circadian rhythmicity in the prediction of drug effects on QT interval. The results of the simulations were in line with clinical observations, what can serve as a verification of the circadian models implemented in CSS. Moreover, the results have suggested that the circadian variability of the electrolytes balance is the main factor influencing QT circadian pattern. The fluctuation of ion concentration increases the intra-subject variability of predicted drug-triggered QT corrected for HR (QTc) prolongation effect and, in case of modest drug effect on QTc interval length, allows to capture this effect.

scholarly journals 199 Cardiac Safety and QTc Intervals With DM/Q Treatment for Pseudobulbar Affect: A Review of Clinical Trial Data

CNS Spectrums ◽  
2018 ◽  
Vol 23 (1) ◽  
pp. 112-112
Author(s):  
Jay W. Mason ◽  
Emmanuelle Hugentobler ◽  
Andrea E. Formella ◽  
Laura E. Pope
Keyword(s):  
Clinical Trials ◽  
Clinical Trial Data ◽  
Qtc Interval ◽  
Dependent Manner ◽  
Cardiac Safety ◽  
Open Label ◽  
Phase 3 ◽  
Post Dose ◽  
Pseudobulbar Affect ◽  
Q 30

AbstractOBJECTIVEDextromethorphan hydrobromide and quinidine sulfate (DM/Q) 20mg/10mg is FDA approved to treat pseudobulbar affect (PBA), a neurological condition characterized by sudden, frequent, involuntary crying or laughing. Although the total dose of quinidine (20 mg) from twice daily DM/Q for PBA is well below the antiarrhythmic dose (600-1600 mg/day), clinicians may be reticent to use DM/Q due to concerns for cardiac safety.METHODDM/Q cardiac safety was evaluated in two thorough QTc (TQT) studies and by ECG monitoring in DM/Q phase 3 clinical trials. In the TQT studies, twice daily DM/Q 30mg/10mg (Study 08-AVR-126; N=50 enrolled) and supratherapeutic doses 30mg/30mg and 60mg/60mg (Study 05-AVR-119; N=36 enrolled) were studied in healthy volunteers. In phase 3 controlled clinical trials, the effects of DM/Q on Fridericia’s corrected QT intervals (QTcF) were assessed, as was the incidence of ECG outliers. Adverse events (AEs) were monitored in all clinical trials.RESULTSOverall, 47/50 participants completed TQT study 08-AVR-126 and 36/36 completed TQT study 05-AVR-119. Time-matched, placebo-corrected mean maximal changes in QTcF for DM/Q 30mg/10mg and 30mg/30mg occurred 3h post-dose (10.3 and 10.1ms, respectively) vs moxifloxacin (12.2 and 14.4ms at 1.5 and 1.0h). For the supratherapeutic DM/Q 60/60 mg dose, mean maximal QTcF change was 18.8ms. No participant had a QTcF >480 ms or QTc increase >60 ms. In PBA phase 3 controlled trials, mean changes in QTcF were similar for DM/Q containing Q 10 mg (0.4 to 3.5 ms; n=217) andplacebo (0.4 to 3.1 ms; n=183), but greater for DM/Q with Q 30 mg (2.9 to 7.6 ms; n=146). In an outlier analysis, a similar percentage of DM/Q-treated participants (3.9%) had a QTcF shift from <450 ms at baseline to ≥450 ms during treatment vs placebo (2.9%). No participant with PBA had a QTc change from baseline >60 ms or an absolute QTc interval >480 ms. No dose- or time-related trends in cardiac arrhythmias or other cardiac-related AEs were observed.Of 2552 DM/Q-treated patients and healthy participants across all controlled and open-label trials for any indication, 11 deaths due to any cardiovascular AE have been reported; none were attributable to DM/Q treatment and none occurred in placebo-controlled PBA clinical trials in any treatment group. Overall 16 patients had a QTcF that exceeded 500 ms at any ECG measurement.CONCLUSIONSThe TQT studies demonstrated that DM/Q has the potential to prolong the QT interval in a dose-dependent manner, but that the risk for QTc prolongation and arrhythmias with Q 10 mg formulations is low. In clinical trials with PBA patients, the cardiac safety profile of DM/Q 20mg/10mg or 30/10 mg was indistinguishable from placebo.Funding AcknowledgementsAvanir Pharmaceuticals, Inc.

Prognostic factors for clinical benefit after epidermal growth factor receptor (EGFR) directed therapy in squamous cell carcinomas of the head and neck (SCCHN)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 6025-6025
Author(s):  
A. B. Halpern ◽  
K. Kasza ◽  
M. Kocherginsky ◽  
G. Clark ◽  
E. E. Vokes ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Clinical Benefit ◽  
Drug Exposure ◽  
Kinase Inhibitors ◽  
Performance Status ◽  
Single Agent ◽  
Progression Free Survival ◽  
Disease Status ◽  
Response Rates ◽  
Egfr Tki

6025 Background: Single agent EGFR tyrosine kinase inhibitors (TKI) have demonstrated reproducible response rates of 5–15% in treatment of SCCHN. The subset of patients that benefits most from these agents remains unknown. We undertook a review of data from 5 clinical trials administering EGFR TKI in order to determine if there are clinical characteristics that are associated with response or benefit. Methods: We reviewed individual patient data from 5 clinical trials of erlotinib, lapatinib, or gefitinib. The primary endpoint was association of clinical variables with clinical benefit, defined as response (CR or PR) and stable disease (SD) >4 months. Secondary correlative endpoints included progression-free survival (PFS) and overall survival (OS). Logistic regression and Cox proportional hazard models were used to conduct univariate and multivariate analysis. Results: 319 subjects were included in the analysis with a median age of 59 years, 79% male. Disease status at start of therapy was local only in 43%, metastatic only in 29%, and both in 27%. Performance status (PS) was 0 in 25%, 1 in 62%, and 2 in 13%. Observed responses were: 1% CR, 6% PR, 24% SD >4 mo, 18 % SD3 in 6%) and diarrhea (grade 1 in 30%, grade 2 in 10%, grade 3 in 5%). Lower PS (p=0.06, OR (0/2)=3.1), age 70+ (p=0.02, OR= 2.1), and development of rash (p<0.01, OR=3.6), and diarrhea (p=0.03, OR=1.8) were associated with higher response rates. These variables were also associated with longer OS and PFS. Conclusions: Clinical parameters that appear to predict response to EGFR TKI include PS and age. EGFR mechanistic toxicities that develop during therapy are highly associated with benefit and suggest a relationship between drug exposure and outcome. No significant financial relationships to disclose.

scholarly journals Energy Drink-Associated Electrophysiological and Ischemic Abnormalities: A Narrative Review

2021 ◽  
Vol 8 ◽  
Author(s):  
Diana X. Cao ◽  
Kimberly Maiton ◽  
Javed M. Nasir ◽  
N. A. Mark Estes ◽  
Sachin A. Shah
Keyword(s):  
Clinical Trials ◽  
Adverse Effects ◽  
Case Reports ◽  
Fatal Outcome ◽  
Energy Drink ◽  
Supraventricular Arrhythmia ◽  
Significant Finding ◽  
Qtc Interval ◽  
Available Energy ◽  
Energy Drink Consumption

An increasing number of cardiovascular adverse effects, emergency room visits, and deaths have been linked to energy drinks. In this review, we summarized available published literature assessing electrophysiological and ischemic adverse effects associated with energy drink consumption. Overall, 32 case reports and 19 clinical trials are included in this review. Ventricular arrhythmia, supraventricular arrhythmia, and myocardial ischemia were amongst the most commonly reported in case reports with 3 having a fatal outcome. Although serious ischemic changes, arrhythmias, or death were not observed in clinical trials, significant electrophysiological changes, such as PR/PQ interval shortening/prolongation, QT/QTc shortening/prolongation, and ST-T changes, were noted. QT/QTc interval prolongation appears to be the most significant finding in clinical trials, and there appears to be a dose-response relationship between energy drink consumption and QTc prolongation. The exact mechanisms and the particular combination of ingredients behind energy drink-induced cardiac abnormalities require further evaluation. Until more information is available, energy drink use should be considered as part of the differential diagnosis in appropriate patients presenting with electrocardiographic changes. Further, certain patient populations should exercise caution and limit their energy drink consumption.

A Multivariate Approach to Analyze Ordinal Data Collected in Clinical Trials of Analgesic Agents

1979 ◽  
Vol 18 (03) ◽  
pp. 175-179
Author(s):  
E. Mabubini ◽  
M. Rainisio ◽  
V. Mandelli
Keyword(s):  
Clinical Trials ◽  
Multivariate Analysis ◽  
Analgesic Effect ◽  
Ordinal Data ◽  
Ordinal Scale ◽  
Multivariate Approach ◽  
Controlled Clinical Trials ◽  
Second Stage ◽  
Analgesic Agents ◽  
Relevant Factors

After pointing out the drawbacks of the approach commonly used to analyze the data collected in controlled clinical trials carried out to evaluate the analgesic effect of potential agents, the authors suggest a procedure suitable for analyzing data coded according to an ordinal scale. In the first stage a multivariate analysis is carried out on the codec! data and the projection of each result in the space of the most relevant factors is obtained. In the second stage the whole set of these values is processed by distribution-free tests. The procedure has been applied to data previously published by VENTAITBIDDA et al. [18].

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