Frequency Of Discontinuation Research Articles

Determination of corrective optimals for Chinese university learners of English

In the expectation of investigating the nature of corrective optimals of the sounds of English for Chinese EFL learners, a small selection of problematic English vowel sounds (i.e. /ɪ/, /i:/, /e/, /æ/, /ʊ/ and /u:/) was explored. The present study investigated the corrective optimals for these sounds. To this end, an experiment was conducted. Thirty-seven first-year non-English major university EFL learners participated. Each student went through two diagnostic steps. First, each student’s preferred center frequency (fcenter) was determined for a particular vowel sound, beginning with exposure to the fcenter of the traditional native-speaker optimal. Second, a combination of frequency bands that together form corrective optimals for each of the six vowels was determined for each individual student. Rather than consisting of single continuous 1-octave bands, corrective optimals for Chinese university EFL learners were found to be discontinuous multiple frequency bands that are both narrower and finer. The corrective optimals for Chinese university EFL learners were identified as discontinuous multiple band structures containing a bandpass filter narrower than one octave and, in addition, a significant low frequency component. In the light of this finding, it seems valuable to reorient the concept of corrective optimal away from a single octave frequency band and toward discontinuous multiband structures containing a significant low frequency component. Further research over a great number of vowels and consonants for various languages is desirable to confirm and extend this finding.

NCOG-29. O6-METHYLGUANINE DNA METHYLTRANSFERASE (MGMT) PROMOTER METHYLATION STATUS AND THE INCIDENCE OF TEMOZOLOMIDE-INDUCED HEMATOLOGIC TOXICITY: AN ASSOCIATION STUDY

Abstract BACKGROUND Despite the growing body of evidence demonstrating an increased clinical benefit of alkylating agents in glioblastoma patients with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, little is known regarding the effect of MGMT status on toxicity. The purpose of this investigation is to provide insight into the potential association between MGMT promoter methylation and the development of Grade 3/4 hematologic toxicities in patients receiving temozolomide. METHODS A total of 63 patients with documented glioblastoma or anaplastic astrocytoma diagnoses were evaluated retrospectively. A chi-square test of independence was utilized to evaluate the incidence of hematologic toxicities and patient overall survival was determined by univariate analysis estimated through use of Kaplan-Meier curves. Relative frequencies of treatment discontinuation secondary to myelosuppression were also compared. RESULTS At the time of study completion, 71.4% of patients with MGMT promoter hypermethylation had survived compared with 50% of patients with hypomethylation (HR 0.86; 95% CI 0.71 to 1.05; P>0.05). The percentage of patients who experienced Grade 3/4 hematologic toxicities during concurrent treatment was 20% and 5.1% within the hypermethylated and hypomethylated groups, respectively, and 26.7% and 17.9% throughout standard therapy. While a statistical difference was not found between the cumulative incidences of Grade 3/4 hematologic toxicity events throughout both phases of treatment, a statistical difference was noted in the incidence of Grade 4 occurrences with ten events occurring in the hypermethylated group and zero in those with hypomethylated promoter regions (P< 0.01). Furthermore, use of temozolomide in hypermethylated patients resulted in fewer completed cycles of standard therapy and higher rates of treatment delays and drug discontinuation. CONCLUSIONS This study showed marked differences in the frequency of temozolomide-induced hematologic toxicities and treatment discontinuation based on tumor MGMT promoter methylation status. Further research is warranted in larger patient populations to both validate and determine the clinical significance of these findings.

Real Life Treatment Alterations of Frontline Therapies in Classic Hodgkin's Lymphoma

Introduction Classic Hodgkin's lymphoma (cHL) is a highly curable lymphoid malignancy. Most of the patients receive either bleomycin or brentuximab vedotin (BV) based therapies as a frontline treatment. Treatment alterations are common and can be related to toxicity, patient's preference, and/or clinical evidence of response. The aim of our study is to explore the frequency and characteristics of treatment alterations, especially bleomycin and BV, in frontline therapies used in newly diagnosed cHL. Methods This single center study included patients with a diagnosis of cHL who were first seen at The University of Texas MD Anderson Cancer Center between January 1,2016 and May 28, 2020 for either newly diagnosed cHL or relapsed/refractory (R/R) cHL. Patients' charts were reviewed to assess frequency of treatment discontinuation at the time of frontline therapy and underlying reasons for any treatment alterations. The primary aims were to assess the frequency of treatment alterations and its effects on overall survival (OS), and progression-free survival (PFS). Descriptive statistics including mean, standard deviation, median, and range for continuous variables such as age, and lab measurements, and frequency counts and percentages for categorical variables such as race, gender, and response were analyzed. The Kaplan-Meier method was used for time-to-event analysis including PFS and OS. Median time to event in months with 95% confidence interval (CI) was calculated. The Log-rank test was used to evaluate the difference in time-to-event endpoints between patient groups. Statistical software SAS 9.4 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA) were used for statistical analyses. Results In the studied period, 644 patients met the inclusion criteria. The median age at diagnosis was 33 years (range:9-85) with 52% males. Advanced stage (stages III and IV) occurred in 45% of patients. Ninety-seven percent of patients had 0-1 Eastern Cooperative Oncology Group (ECOG) performance status. Histological subtype was predominately nodular sclerosis (83%). International prognostic index at the time of diagnosis was ≥4 in 13% of patients. Most of the patients received doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) based therapy (77%). Other therapies included brentuximab vedotin (BV)(13%) and checkpoint inhibitors (CPIs) (6%, as a part of clinical trial). Patient's demographics are outlined in Table.1. Treatment alteration, which included either addition or omission of drug/s, occurred in 26% of patients. The most common discontinued drugs were bleomycin (79%), and BV (15%). Of the patients who were started on ABVD based therapy, the frequency of bleomycin discontinuation was 26% (116 of 455 patients). The most common reasons for bleomycin discontinuation were: treatment response as per the RATHL study (49%), pulmonary toxicity (27%) and other treatment-related toxicity (9%). Of the patients who were started on frontline BV based therapy, the frequency of BV discontinuation was 26% (20 of 78 patients). The most common reasons for BV discontinuation were: peripheral neuropathy (65%), skin rash (10%) and other treatment-related toxicity (25%). Patients who discontinued bleomycin due to adverse events (AEs) had a higher chance of primary refractory disease at the end of frontline treatment (19% vs. 15%, p-value: 0.005) while patients who discontinued bleomycin due to treatment response had similar rates of primary refractory disease (13% vs. 15%, p-value: 0.57). The median cycles number of bleomycin based therapy were the same (6 cycles) among all the groups (those who continued bleomycin without AEs or discontinuation, patients who discontinued bleomycin for treatment response and patients who discontinued bleomycin for AEs) . Patients who discontinued BV due to AEs had similar outcome to the patients who continued the treatment without alterations. Conclusions Frontline treatment alterations in cHL are common. Positron emission tomography treatment response based bleomycin discontinuation was not associated with worse PFS or OS. However bleomycin discontinuation secondary to AEs was associated with a statistically significant higher rate of primary refractory disease and subsequent worse PFS and OS. BV discontinuation secondary to AEs didn't result in worse outcomes. Disclosures Parmar: Cellenkos Inc.:Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.Iyer:CRISPR:Research Funding;Spectrum:Research Funding;Merck:Research Funding;Afffimed:Research Funding;Rhizen:Research Funding;Seattle Genetics, Inc.:Research Funding;Legend Biotech:Consultancy;Daiichi Sankyo:Consultancy;Trillium:Research Funding;Curio Biosciences:Honoraria;Target Oncology:Honoraria.Nieto:Affimed:Consultancy, Other: Grant Support;Novartis:Other: Grant Support;Secura Bio:Other: Grant Support;Astra Zeneca:Other: Grant Support.Chuang:Sage-Evidence=Based Medicine & Practice:Consultancy.Wang:Lu Daopei Medical Group:Honoraria;Pulse Biosciences:Consultancy;Molecular Templates:Research Funding;BioInvent:Research Funding;VelosBio:Research Funding;Beijing Medical Award Foundation:Honoraria;Juno:Consultancy, Research Funding;Oncternal:Consultancy, Research Funding;AstraZeneca:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Celgene:Consultancy, Other: Travel, accommodation, expenses, Research Funding;InnoCare:Consultancy;Loxo Oncology:Consultancy, Research Funding;Verastem:Research Funding;Acerta Pharma:Research Funding;Pharmacyclics:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Janssen:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;MoreHealth:Consultancy;OncLive:Honoraria;Kite Pharma:Consultancy, Other: Travel, accommodation, expenses, Research Funding;Nobel Insights:Consultancy;Guidepoint Global:Consultancy;Dava Oncology:Honoraria;OMI:Honoraria, Other: Travel, accommodation, expenses;Targeted Oncology:Honoraria.Lee:Celgene:Research Funding;Guidepoint Blogal:Consultancy;Bristol-Myers Squibb:Consultancy, Research Funding;Aptitude Health:Speakers Bureau;Oncternal Therapeutics:Research Funding;Seattle Genetics:Research Funding;Takeda:Research Funding.

Selinexor in Combination with R-CHOP for Frontline Treatment of Non-Hodgkin Lymphoma: Results of a Phase 1b Study

Selinexor in Combination with R-CHOP for Frontline Treatment of Non-Hodgkin Lymphoma: Results of a Phase 1b Study

Impact of Invasive Quantitative Respiratory Cultures on Antimicrobial Therapy for Suspected Pneumonia in Trauma.

Invasive quantitative respiratory cultures are generally not recommended because of a lack of demonstrated benefit. There is insufficient literature regarding specific populations such as trauma. The objective of this study was to evaluate the effect of invasive quantitative respiratory sampling on de-escalation to targeted antimicrobial therapy for the management of pneumonia in a trauma population. This was a single-center retrospective cohort study conducted at an American College of Surgeons-verified Level II Trauma Center in Nashville, TN. Adult patients admitted to the trauma service and diagnosed with pneumonia from July 2013 to August 2018 were divided into 2 groups: invasive quantitative respiratory sampling versus noninvasive respiratory sampling. The primary endpoint was rate of targeted antimicrobial therapy. Secondary endpoints included in-hospital mortality, antibiotic days of therapy, and frequency of discontinuation of antibiotics when quantitative cultures were below the diagnostic threshold. A total of 88 patients were sampled, with 27 in the invasive quantitative group and 66 in the noninvasive group. There was no difference in rates of targeted therapy in patients with invasive quantitative sampling (17 [63%] vs. 35 [57%]; relative risk = 1.10; 95% confidence interval [0.76, 1.57]). No statistically significant differences were observed for in-hospital mortality (8 patients vs. 6 patients, p = .35) or antimicrobial days of therapy (10.3 ± 8.8 vs. 7.8 ± 3.6, p = .161). Only 2 patients (17%) had antibiotics withheld when below the diagnostic threshold. Invasive quantitative respiratory sampling did not result in significant changes in targeted antibiotic therapy in a trauma population.

Early Disease and Low Baseline Damage as Predictors of Response to Belimumab in Patients With Systemic Lupus Erythematosus in a Real-Life Setting.

To investigate predictors of response, remission, low disease activity, damage, and drug discontinuation in patients with systemic lupus erythematosus (SLE) who were treated with belimumab. In this retrospective study of a multicenter cohort of SLE patients who received intravenous belimumab, the proportion of patients who achieved remission, low disease activity, and treatment response according to the SLE Responder Index 4 (SRI-4) was determined, and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) was used to score disease damage yearly over the follow-up. Predictors of outcomes were analyzed by multivariate logistic regression with the results expressed as odds ratios (ORs) and 95% confidence intervals (95% CIs). The study included 466 patients with active SLE from 24 Italian centers, with a median follow-up period of 18 months (range 1-60 months). An SRI-4 response was achieved by 49.2%, 61.3%, 69.7%, 69.6%, and 66.7% of patients at 6, 12, 24, 36, and 48 months, respectively. Baseline predictors of response at 6 months included a score of ≥10 on the SLE Disease Activity Index 2000 (SLEDAI-2K) (OR 3.14 [95% CI 2.033-4.860]) and a disease duration of ≤2 years (OR 1.94 [95% CI 1.078-3.473). Baseline predictors of response at 12 months included a score of ≥10 on the SLEDAI-2K (OR 3.48 [95% CI 2.004-6.025]) and an SDI score of 0 (OR 1.74 [95% CI 1.036-2.923]). Baseline predictors of response at 24 months included a score of ≥10 on the SLEDAI-2K (OR 4.25 [95% CI 2.018-8.940]) and a disease duration of ≤2 years (OR 3.79 [95% CI 1.039-13.52]). Baseline predictors of response at 36 months included a score of ≥10 on the SLEDAI-2K (OR 14.59 [95% CI 3.54-59.79) and baseline status of current smoker (OR 0.19 [95% CI 0.039-0.69]). Patients who were in remission for ≥25% of the follow-up period (44.3%) or who had low disease activity for ≥50% of the follow-up period (66.1%) accrued significantly less damage (P = 0.046 and P = 0.007). A baseline SDI score of 0 was an independent predictor of achieving low disease activity in ≥50% of the follow-up period and remission in ≥25% of the follow-up period. Our findings suggest that the lower the baseline damage, the greater the probability of achieving remission over the course of ≥25% of the follow-up. Further, there was a negative association between the number of flares reported prior to belimumab initiation and the frequency of belimumab discontinuation due to inefficacy (P = 0.009). In patients with active SLE and low damage at baseline, treatment with belimumab early in the disease may lead to favorable outcomes in a real-life setting.

Response of lean premixed swirl tubular flame to acoustic perturbations

This study experimentally examined the response of a lean premixed methane/air swirl tubular flame to the longitudinal acoustic perturbations. Experiments were conducted by varying the acoustic frequency (f0), acoustic power (P0) and inlet air flow rate (QA) to systematically study the acoustic-excited flame dynamics, including the flame stability, flame structure, heat release rate and acoustic pressure fluctuations. The results demonstrated that the lean tubular flame was much sensitive to longitudinal perturbations below 210 Hz. Even at low power of P0, the flame was forced to oscillate intensively when the perturbation was operated in two discontinuous frequency ranges of f0 = 150–200 and f0 = 50–100 Hz, while a weakened oscillation regime was observed in the middle range of f0 = 100–150 Hz; a lower frequency (less than 50 Hz) would extinguish the flame. An increase in P0 intensified the flame oscillation under the perturbations of 50–100 Hz, and even resulted in flame lift-off and blow off with f0 between 150 and 200 Hz. In comparison to f0 and P0, the effects of air flow rate (QA) seemed to be weaker. The proper orthogonal decomposition (POD) analysis was performed to interpret the contributions from the mean mode and fluctuating axial and circumferential modes that led to combustion instability. It was found that as the energy fraction of the axial mode exceeded 5.0%, the flame lift-off appeared in the lean swirl tubular configuration.

Anterior–Posterior Patterning in Lepidopteran Wings

The color patterns on the wings of butterflies and moths are among the most complex manifestations of pattern formation in nature. The complexities of these patterns arise from the diversification of a conserved set of homologous elements known as the Nymphalid Ground Plan that can change color, shift position, expand, or disappear altogether. Recent work has shown that the anterior-posterior axis of the butterfly wing may also have an important role in the development and evolution of wing-pattern diversity. Here we characterize the anterior-posterior axis by mapping expression domains of key regulatory genes onto the wing. We show that the butterfly wing can be subdivided into four primary regions, with the boundaries of these domains arising at the positions of the M1, M3, and Cu2 wing-veins. We find that the correlation among variation in the border ocelli is strongest for those within the same domain. We show how these domains may be used to determine phenotypic outcomes by surveying the frequency of color boundaries, tail development, and wing shape discontinuities across five major butterfly families: Lycaenidae, Nymphalidae, Papilionidae, Pieridae, and Riodinidae. Of the more than 200 genera we surveyed in this study, color pattern discontinuities emerge most often at the boundary veins M1, M3, and Cu2, and shape discontinuities and tails at veins M3 and Cu2. These findings reveal a hitherto unrecognized mode of evolution of patterning in the Lepidoptera.

AB0273 PREDICTORS OF DRUG SURVIVAL OF bDMARDS IN BIO-NAIVE PATIENTS WITH RHEUMATOID ARTHRITIS (RA) DURING THE FIRST YEAR OF THERAPY.

Objectives:To investigate predictors of drug survival of bDMARDs in previously bio-naive patients (pts) with RA during the first year of therapy.Methods:204 adult bio-naive pts (173 women, 84.8%), with active RA, despite the concomitant DMARD therapy, were included into retrospective study. All of them initiated bDMARDs: infliximab (INF) - 65 pts (31.9%), rituximab (RTM) - 39 (19.1%), adalimumab (ADA) - 30 (14.7%), etanercept (ETA) - 28 (13.7%), abatacept (ABA) - 23 (11.3%), tocilizumab (TZ) - 15 (7.4%), certolizumab pegol - 4 (1.9%). The following indicators were used as survival predictors: sex, age and clinical form of RA. Pts were divided by age according to the classification adopted by the World Health Organization: 18-44 years (74 pts), 45-59 years (68 pts), 60-74 years (57 pts), 75 years or more (5 pts). Clinical forms of RA were presented: RA, seropositive by rheumatoid factor (RF), RA, seronegative by RF, RA with extra-articular manifestations, adult-oneset Still’s disease, juvenile RA. Predictors of therapy inefficiency or AE were investigated in Cox proportional risk model. Survival on drug was estimated using the Kaplan-Meier method and evaluation of difference significance using log-rank criterion.Results:A year later, 92 pts (45%) remained on bDMARDs and 112 pts had their treatment discontinued. The reasons of bDMARDs discontinuation during the first year of treatment were: lack of effectiveness (including primary inefficiency) - 50%, adverse events (AE) - 25%, administrative causes - 17%, remission - 6.25%, death due to reasons unrelated to the therapy - 1.75%. By the end of the observation period, the best survival was shown by RTM therapy (69.23% of patients continued treatment for a year), ETA (44.4% of patients) and ABA (43.48% of patients). Discontinuation of bDMARDs due to remission was achieved in 7 patients and proved to be significantly higher in the RTM group (10.26%, p < 0.05) compared to the ABA group (8.7%) and ADA group (3.45%). Although the number of women continued after a year was significantly higher than that of men (84.8% and 15.2% respectively), female sex was not a reliable predictor of drug survival. At the same time, the rate of discontinuation due to AE in women was higher (96.55%, p = 0.03). After a year, the number of pts continuing treatment in all age groups remained comparable, and the difference between them - statistically not significant: 1 group (18-44 years old, 29 pts) - 31.52% of pts, 2 group (45-59 years old, 36 pts) - 39.13%, 3 group (60-74 years old, 26 pts) - 28.26%, 4 group (75-90 years old, 1 pts). Discontinuation of bDMARDs due to inefficiency was noted in 1 group more often (46.43%, 26 pts, р =0.03), in other groups this indicator was 33.93% (19 pts) in the 2nd group, 19.64% (11 pts) in the 3rd group and 0% in the 4th group. Discontinuation therapy due to AE was also prevalent in 1 group (50%, 14 pts) than in 2 (14.3%, 4 pts), 3 (32.1%, 9 pts) and 4 (3.6%, 1 pts). Discontinuation of therapy due to inefficacy was more common in the group of seronegative RA - 59.1% (p < 0.05). In the seropositive RA group 24.8% of pts had interrupted bDMARDs for this reason, in the RA with extra-articular manifestations group it was 18.1%, in the adult-oneset Still’s disease group - 30% and in the juvenile RA group - 30%. Discontinuation of therapy due to remission was overwhelmingly observed in seropositive RA group (6 pts, 4%) and was significantly higher than in other groups (1 patient in RA with extra-articular manifestations group, 4.5%).Conclusion:Female sex, young age (18-44 years), RA, seronegative by RF were associated with less survival of bDMARDs due to lack of effectiveness and/or AE, and RTM and seropositive RA - with more frequency of discontinuation of therapy due to remission.Disclosure of Interests:Eugenia Aronova: None declared, Galina Lukina Speakers bureau: Novartis, Pfizer, UCB, Abbvie, Biocad, MSD, Roche, Galina Gridneva: None declared, Svetlana Glukhova: None declared, Anastasia Kudryavtseva: None declared

Prognostic model based on the geriatric nutritional risk index and sarcopenia in patients with diffuse large B-cell lymphoma

BackgroundSystemic inflammation and cachexia are associated with adverse clinical outcomes in diffuse large B-cell lymphoma (DLBCL). The Geriatric Nutritional Risk Index (GNRI) is one of the main parameters used to assess these conditions, but its efficacy in DLBCL is inconclusive.MethodsWe retrospectively reviewed 228 DLBCL patients who were treated with R-CHOP immunochemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). The patients were stratified according to GNRI score (> 98, 92 to 98, 82 to < 92, and < 82) as defined in previous studies. Additionally, the extent of sarcopenia was categorized as sarcopenia-both, sarcopenia-L3/PM alone, and non-sarcopenia-both according to skeletal muscle index.ResultsSurvival curves plotted against a combination of GNRI and sarcopenia scores revealed two clear groups as follows: high cachexia risk (HCR) group (GNRI < 82, sarcopenia-both, or GNRI 82–92 with sarcopenia-L3/PM alone) and low cachexia risk (LCR) group (others). The HCR group had a lower complete response rate (46.5% vs. 86.6%) and higher frequency of treatment-related mortality (19.7% vs. 3.8%) and early treatment discontinuation (43.7% vs. 8.3%) compared with the LCR group. The median progression-free survival (PFS) (not reached vs. 10.3 months, p < 0.001) and overall survival (OS) (not reached vs. 12.9 months, p < 0.001) were much shorter in the HCR group than in the LCR group. On multivariable analyses, the HCR group was shown to be an independent negative prognostic factor for PFS and OS after adjusting the National Comprehensive Cancer Network-International Prognostic Index (NCCN-IPI).ConclusionsA combined model of GNRI and sarcopenia may provide prognostic information independently of the NCCN-IPI in DLBCL.

Lipid microsphere bound oxycodone for pain management in patients receiving radiotherapy for head and neck cancer

Wax microsphere bound oxycodone was developed as an abuse-deterrent opioid and maintains a similar pharmacokinetic profile whether administered with or without an intact capsule. We hypothesized that microsphere oxycodone could be utilized for extended release analgesia in patients undergoing radiation (RT) for head-and-neck cancer (HNC) and would not need to be discontinued due to dysphagia or gastrostomy tube dependence. We performed a prospective trial that enrolled participants > 18years with histologically confirmed HNC who were scheduled to receive RT. Analgesia was prescribed in accordance with the WHO pain ladder. Microsphere oxycodone was initiated when total daily opioid dose exceeded 30mg of morphine sulfate equivalent and was titrated weekly during RT. Pain level and effect on quality of life were assessed using the Brief Pain Inventory. The primary feasibility endpoint was frequency of microsphere oxycodone discontinuation within 3months of RT for reasons other than pain resolution. Twenty-six eligible patients were enrolled. Microsphere oxycodone was initiated in 16 (61.5%) patients. Six (23.1%) patients utilized a gastrostomy tube to administer microsphere oxycodone during all or part of RT. Microsphere oxycodone was discontinued in 1 (7.6%) patient due to perceived inefficacy. No patients were discontinued due to toxicity or difficulty with administration. Ratings for average pain was 3.1 (± 3.4) at enrollment, 4.0 (± 2.4) at week 6 of RT, and 1.8 (± 2.2) at 3-month follow-up. These results support the feasibility and safety of microsphere oxycodone for extended release analgesia among patients with HNC undergoing RT.

How many chronic myeloid leukemia patients who started a frontline second-generation tyrosine kinase inhibitor have to switch to a second-line treatment? A retrospective analysis from the monitoring registries of the italian medicines agency (AIFA).

ABSTRACTThe frequency of patients who switch to a second‐line therapy from a frontline second‐generation (2gen) tyrosine kinase inhibitor (TKI) such as dasatinib and nilotinib, is still substantially unknown. We retrospectively investigated a large series of chronic phase chronic myeloid leukemia (CP‐CML) patients initially treated with 2gen TKIs monitored through the Italian Medicines Agency (AIFA Agenzia Italiana del farmaco) registries. Overall, 2420 patients were analyzed over a period of 6 years. One hundred and fifty‐seven patients (16.3%) treated with dasatinib and 164 treated with nilotinib (11.3%) have switched to another drug, with an overall frequency of 13.2%. In the dasatinib cohort, 39.4% of patients changed treatment for failure and 36.3% for intolerance as compared to 45.7% and 27.4% respectively in the nilotinib cohort. Overall, the median time to switch due to resistance was 293 days, whereas it was 317 days in case of intolerance. Resistance was observed mainly in younger male patients with high‐risk features, while intolerance was not related to any baseline parameter. After resistance/intolerance to nilotinib, the majority of patients switched to dasatinib (53.8%) whereas in case of frontline dasatinib to ponatinib (43.2%). To the best of our knowledge these data provide the first report on the frequency of discontinuation of frontline 2gen TKIs and on the main causes and pattern of choice to a second‐line therapy in the real‐life setting.

Thirty-day outcomes in patients with proximal deep vein thrombosis who discontinued anticoagulant therapy prematurely

IntroductionIn patients receiving anticoagulation for deep vein thrombosis (DVT), a variety of reasons (including active bleeding or high-risk for bleeding) may lead into premature discontinuation of therapy (prior to completing 90 days). The relative frequency and clinical consequences of premature discontinuation in contemporary patients remain unknown. MethodsWe used the data from RIETE, an international registry of patients with venous thromboembolism (VTE), to identify patients with proximal (above knee) lower limb DVT who prematurely discontinued anticoagulation. We assessed the incidence of the composite outcome: pulmonary embolism (PE)-related death, sudden death, or recurrent VTE within the subsequent 30 days after discontinuation and compared the risk of these events vs. the risk in patients without premature discontinuation, once adjusted for demographics and clinical factors. ResultsOf 26,335 patients with proximal DVT recruited from 2001 to 2018, 1322 (5.02%) prematurely discontinued anticoagulation. Thirty days after discontinuation, 12 (0.91%) patients suffered fatal PE (n = 8) or sudden death (n = 4) and 33 (2.50%) had non-fatal recurrent VTE (PE = 15; recurrent DVT = 18). In patients with premature discontinuation, the 30-day incidence of the composite outcome was 1.62 per 1000 patient-days (95%CI: 0.00–3.80). During the first week after discontinuation, the incidence rate was 4.09 per 1000 patient-days (95%CI: 0.65–7.52). The adjusted odds of the composite outcome was 7.88 times (95%CI: 6.39–9.72) higher in patients who discontinued prematurely than in those without premature discontinuation. ConclusionPremature discontinuation of anticoagulation occurred in 5% of patients with proximal DVT, and was associated an 8-fold increased odds for the composite outcome.

Neoadjuvant cisplatin-based chemotherapy in patients with ureteral obstruction secondary to muscle invasive bladder cancer.

523 Background: Neoadjuvant cisplatin-based chemotherapy (NAC) followed by cystectomy is the standard of care for muscle-invasive urothelial bladder cancer (MIBC). 15-35% of MIBC patients present with ureteral obstruction. Poor renal function increases cisplatin toxicity. It is unknown whether patients with ureteral obstruction which has been relieved (whether by nephrostomy tube or nephroureteral stent) have the same risk of toxicity as patients without ureteral obstruction. Methods: We retrospectively reviewed an institutional database of all patients undergoing NAC for MIBC with either dose dense MVAC (ddMVAC) or gemcitabine and cisplatin (GC) from January 2004 through May 2017. Patients without ureteral obstruction prior to initiation of NAC (Group A) were compared to those who had ureteral obstruction which was relieved prior to undergoing NAC (Group B). Continuous variables were compared using the Wilcoxon rank-sum test and categorical variables were compared using Fisher’s exact test. The primary outcome was premature discontinuation of NAC, which was defined as failure to complete all planned cycles. Logistic regression was used to test for differences between the groups in this outcome adjusting for age, ECOG performance status, and baseline glomerular filtration rate (GFR). Results: 160 patients in Group A and 59 patients in Group B were identified. Baseline age, Charlson Comorbidity Index, race, smoking status, and ECOG performance status were similar. Patients in Group B had lower GFR (99.2% vs 78.8% p &lt;0.001) and were more likely to be female (21.9% vs 27.3% p &lt;0.025) and to receive ddMVAC (65.0% vs. 83.1% p =0.012). There was no significant difference between groups in rates of premature NAC discontinuation (15.8% vs 22.0% p = 0.284) or grade ≥3 adverse events (23.4% vs 30.5% p = 0.285). Adjusted analysis showed no significant difference between the groups in frequency of premature NAC discontinuation (OR 1.96, 95% CI 0.84-4.57 p=0.12). Conclusions: We detected no difference in frequency of premature discontinuation of NAC in patients with relieved malignant ureteral obstruction relative to patients without obstruction. NAC for MIBC is likely safe in this population.

Similar Durability of Two Single Tablet Regimens, Dolutegravir/Abacavir/Lamivudine and Elvitegravir/Cobicistat/Tenofovir/Emtricitabine: Single Center Experience.

Integrase inhibitor is uniquely available as single tablet regimen (STR) in Korea. In this study, the durability until 96 weeks was compared between dolutegravir/abacavir/lamivudine (D/A/L) and elvitegravir/cobicistat/tenofovir/emtricitabine (E/T/E) in treatment naïve human immunodeficiency virus 1 (HIV-1) infected individuals. From 2014 to 2017, 153 and 234 subjects started D/A/L and E/T/E, respectively. During 96 weeks, 73 discontinued initial STR and the reason of discontinuation was typable in 44. The frequency of drug adverse event related discontinuation (AEDC) was higher in D/A/L (13.1% vs. 6.4%, P = 0.023) while most non-AE related discontinuations occurred in E/T/E (8/9), such as drug-drug interaction, meal requirement and virologic failure. AEDC occurred usually within 24 weeks (20/35) and D/A/L to E/T/E AEDC incidence rate ratio was 3.71 (95% confidence interval, 1.36–10.10) in this period. Regarding the durability, D/A/L and E/T/E revealed no significant difference at week 96 (P = 0.138) while durability of D/A/L was worse in the aspect of AEDC (P = 0.013).

Microsphere oxycodone for pain management in head and neck cancer (HNC) patients receiving radiotherapy.

123 Background: Pain is a common adverse effect of RT in patients with HNC, and extended release analgesic options are limited due to high rates of dysphagia. Wax microsphere bound oxycodone was developed as an abuse-deterrent opioid and maintains a similar pharmacokinetic profile whether administered with or without an intact capsule. We hypothesized that microsphere oxycodone could be used for extended release analgesia in patients undergoing RT for HNC and would not need to be discontinued due to dysphagia or gastrostomy tube dependence. Methods: We performed an open-label prospective clinical trial (NCT03317730) to assess the feasibility of microsphere oxycodone for extended release analgesia during RT for HNC. Participants were &gt; 18y, had histologically confirmed HNC, and were to receive &gt; 50 Gy of RT. Analgesia was prescribed in accordance with the World Health Organization pain ladder. Non-opioid and immediate release opioids were used at the discretion of the treating physicians. Microsphere oxycodone was initiated when total daily opioid dose exceeded 30mg morphine sulfate equivalent and was titrated weekly during RT. The primary feasibility endpoint was frequency of microsphere oxycodone discontinuation within 3 months of RT for reasons other than pain resolution. Secondary endpoints included pain level during RT. Results: Twenty-six eligible patients were enrolled between June and November, 2018. Microsphere oxycodone was initiated in 13 (50%) patients at a median of 5 weeks after beginning RT (range: 0 – 7 weeks). The mean Brief Pain Index Severity composite score at time of microsphere oxycodone initiation was 5.4 (SD ±2.0) and was 4.8 (SD ±1.5) during the final week of RT ( p= 0.21). Six patients utilized a gastrostomy tube to administer microsphere oxycodone for all or part of RT. Microsphere oxycodone was discontinued in 1 (7.6%) patient due to perceived inefficacy, 0 patients due to toxicity, and 0 patients due to difficulty with administration. Conclusions: These results support the feasibility and safety of microsphere oxycodone for extended release analgesia in patients with HNC undergoing RT. Future research should compare microsphere oxycodone and transdermal fentanyl in this population. Clinical trial information: NCT03317730.

Fast Induction Logging Modeling With Hierarchical Sudoku Meshes Based on DGFD

This letter extends the discontinuous Galerkin frequency domain (DGFD)-based domain decomposition method (DDM) to model the open borehole environment accurately with a newly developed hierarchical sudoku mesh. Both the borehole and mud invasion effects can be modeled by this framework efficiently. Furthermore, deep reading measurements can be modeled conveniently by inserting arbitrarily shaped objects into the hierarchical sudoku mesh; the capability to distinguish a cavity saturated with either oil or water with different borehole-object distances are then studied for a deep reading tool in an open borehole carbonate environment. The DGFD with the hierarchical sudoku mesh shows six times faster speed than the traditional finite-element method (FEM) for the deep reading case.

Energy-Efficient Group Paging Mechanism for QoS Constrained Mobile IoT Devices Over LTE-A Pro Networks Under 5G

The latest evolution of cellular technologies, i.e., 5G including long term evolution-advanced (LTE-A) Pro and 5G new radio promises enhancement to mobile technologies for the Internet of Things (IoT). Despite 5G’s vision to cater to IoT, yet some of the aspects are still optimized for human-to-human (H2H) communication. More specifically, the existing group paging mechanism in LTE-A Pro has not yet clearly defined approaches to group, mobile IoT devices (MIDs) having diverse characteristics, such as discontinuous reception (DRX) and data transmission frequency (DTF) with various mobility patterns. Inappropriate grouping of MIDs may lead to increased energy consumption and degraded quality of service, especially in terms of packet arrival delay (PAD) and packet loss rate (PLR). Therefore, in this paper, we devise novel models to estimate PAD, PLR, and energy consumption for MIDs, specifically for the group paging mechanism. Based on the proposed models, we formulate an optimization problem with the objective to minimize energy consumption of MIDs, while providing required PAD and PLR. The nonlinear convex optimization problem addressed herein is solved using the Lagrangian approach, and the Karush–Kuhn–Tucker conditions have been applied to derive optimal characteristics for MIDs to join the group, namely, DRX and DTF. The extensive numerical results presented verify the effectiveness of the proposed method, and the mathematical models demonstrate the superiority of our proposed approach over random grouping approach concerning significant energy consumption of MIDs.

Continuous vocoder applied in deep neural network based voice conversion

In this paper, a novel vocoder is proposed for a Statistical Voice Conversion (SVC) framework using deep neural network, where multiple features from the speech of two speakers (source and target) are converted acoustically. Traditional conversion methods focus on the prosodic feature represented by the discontinuous fundamental frequency (F0) and the spectral envelope. Studies have shown that speech analysis/synthesis solutions play an important role in the overall quality of the converted voice. Recently, we have proposed a new continuous vocoder, originally for statistical parametric speech synthesis, in which all parameters are continuous. Therefore, this work introduces a new method by using a continuous F0 (contF0) in SVC to avoid alignment errors that may happen in voiced and unvoiced segments and can degrade the converted speech. Our contribution includes the following. (1) We integrate into the SVC framework the continuous vocoder, which provides an advanced model of the excitation signal, by converting its contF0, maximum voiced frequency, and spectral features. (2) We show that the feed-forward deep neural network (FF-DNN) using our vocoder yields high quality conversion. (3) We apply a geometric approach to spectral subtraction (GA-SS) in the final stage of the proposed framework, to improve the signal-to-noise ratio of the converted speech. Our experimental results, using two male and one female speakers, have shown that the resulting converted speech with the proposed SVC technique is similar to the target speaker and gives state-of-the-art performance as measured by objective evaluation and subjective listening tests.

5D geostatistics for directional variables: Application in geotechnics to the simulation of the linear discontinuity frequency

In geotechnics and geomechanics, many rock mass properties are quantified by numerical variables defined by the observation or the testing of a borehole core sample. The value measured depends not only on the in-situ geographic coordinates of the sample, but also on the in-situ borehole direction. Interpolating such numerical variables in space without accounting for their directionality may produce misleading results, insofar as the interpolated values are representative of the rock mass properties in the sampling directions and not necessarily in other directions. A solution to this issue is to regionalize the geotechnical variables in a five-dimensional space, consisting of the Cartesian product of the three-dimensional Euclidean space and the unit 2-sphere, in order to account for both their geographic and directional variations. Spatial correlation analysis can be performed easily under an assumption of stationarity in the three-dimensional Euclidean space and isotropy on the sphere, so that the covariance or the variogram between two data only depends on their geographic and angular separations. The fitting of nested separable covariance functions eases the search for a valid spatial correlation model and for algorithms to simulate the geotechnical variables in the above-defined five-dimensional space. The concepts are applied to the modeling of the linear frequency of weak veins in a Chilean porphyry copper deposit, where the importance of accounting for directionality is demonstrated. Regionalized azimuthal projections are introduced as a visualization tool for structural geologists and geotechnicians to map the directional variations of the weak vein frequency at given locations in the geographic space.