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Blood Feb 2024Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma...
Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by the phase 2, multicenter, single-arm ZUMA-5 study of axi-cel for patients with R/R indolent non-Hodgkin lymphoma (iNHL; N = 104), including FL and marginal zone lymphoma (MZL). In the primary analysis (median follow-up, 17.5 months), the overall response rate (ORR) was 92% (complete response rate, 74%). Here, we report long-term outcomes from ZUMA-5. Eligible patients with R/R iNHL after ≥2 lines of therapy underwent leukapheresis, followed by lymphodepleting chemotherapy and axi-cel infusion (2 × 106 CAR T cells per kg). The primary end point was ORR, assessed in this analysis by investigators in all enrolled patients (intent-to-treat). After median follow-up of 41.7 months in FL (n = 127) and 31.8 months in MZL (n = 31), ORR was comparable with that of the primary analysis (FL, 94%; MZL, 77%). Median progression-free survival was 40.2 months in FL and not reached in MZL. Medians of overall survival were not reached in either disease type. Grade ≥3 adverse events of interest that occurred after the prior analyses were largely in recently treated patients. Clinical and pharmacokinetic outcomes correlated negatively with recent exposure to bendamustine and high metabolic tumor volume. After 3 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable responses, with very few relapses beyond 2 years, and manageable safety in patients with R/R iNHL. The ZUMA-5 study was registered at www.clinicaltrials.gov as #NCT03105336.
Topics: Humans; Follow-Up Studies; Neoplasm Recurrence, Local; Biological Products; Immunotherapy, Adoptive; Lymphoma, Follicular; Lymphoma, B-Cell, Marginal Zone; Lymphoma, Large B-Cell, Diffuse; Antigens, CD19
PubMed: 37879047
DOI: 10.1182/blood.2023021243 -
Diabetes Care Sep 2023To study the relationships between artificial sweeteners, accounting for all dietary sources (total and by type of artificial sweetener) and risk of type 2 diabetes...
OBJECTIVE
To study the relationships between artificial sweeteners, accounting for all dietary sources (total and by type of artificial sweetener) and risk of type 2 diabetes (T2D), in a large-scale prospective cohort.
RESEARCH DESIGN AND METHODS
The analyses included 105,588 participants from the web-based NutriNet-Santé study (France, 2009-2022; mean age 42.5 ± 14.6 years, 79.2% women). Repeated 24-h dietary records, including brands and commercial names of industrial products, merged with qualitative and quantitative food additive composition data, enabled artificial sweetener intakes to be accurately assessed from all dietary sources. Associations between artificial sweeteners (total, aspartame, acesulfame potassium [K], and sucralose) and T2D were investigated using Cox proportional hazard models adjusted for potential confounders, including weight variation during follow-up.
RESULTS
During a median follow-up of 9.1 years (946,650 person-years, 972 incident T2D), compared with nonconsumers, higher consumers of artificial sweeteners (i.e., above the sex-specific medians of 16.4 mg/day in men and 18.5 mg/day in women) had higher risks of developing T2D (hazard ratio [HR] 1.69; 95% CI 1.45-1.97; P-trend <0.001). Positive associations were also observed for individual artificial sweeteners: aspartame (HR 1.63 [95% CI 1.38-1.93], P-trend <0.001), acesulfame-K (HR 1.70 [1.42-2.04], P-trend <0.001), and sucralose (HR 1.34 [1.07-1.69], P-trend = 0.013).
CONCLUSIONS
Potential for reverse causality cannot be eliminated; however, many sensitivity analyses were computed to limit this and other potential biases. These findings of positive associations between artificial sweetener intakes and increased T2D risk strengthen the evidence that these additives may not be safe sugar alternatives. This study provides important insights in the context of on-going reevaluation of artificial sweeteners by health authorities worldwide.
Topics: Male; Humans; Female; Adult; Middle Aged; Sweetening Agents; Diabetes Mellitus, Type 2; Aspartame; Prospective Studies; Diet
PubMed: 37490630
DOI: 10.2337/dc23-0206 -
JAMA Oncology Nov 2023Inhibition of the T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor pathway may amplify the antitumor immune response of atezolizumab in...
IMPORTANCE
Inhibition of the T-cell immunoreceptor with Ig and ITIM domains (TIGIT)/poliovirus receptor pathway may amplify the antitumor immune response of atezolizumab in programmed death ligand 1-selected tumors.
OBJECTIVE
To evaluate the safety and antitumor activity of the anti-TIGIT antibody tiragolumab and its combination with atezolizumab in patients with advanced solid tumors.
DESIGN, SETTING, AND PARTICIPANTS
The GO30103 open-label, first-in-human phase 1a/1b dose-escalation and dose-expansion nonrandomized controlled trial was conducted at 13 sites in 6 countries (Australia, Canada, France, Korea, Spain, and the US). The start dates were May 23, 2016, for phase 1a and October 11, 2016, for phase 1b. Patients were aged 18 years or older with measurable disease at baseline. The clinical cutoff date was October 1, 2021. Data analysis was performed on January 24, 2022.
INTERVENTIONS
Patients received fixed-dose intravenous tiragolumab on day 1 of each 21-day cycle (2 mg escalating to 1200 mg) in phase 1a, plus fixed-dose intravenous atezolizumab (1200 mg every 3 weeks) in phase 1b. Patients were treated until disease progression, loss of clinical benefit, or development of unacceptable toxicity.
MAIN OUTCOMES AND MEASURES
The primary end points included the safety, tolerability, and recommended phase 2 dose (RP2D) of tiragolumab or combination tiragolumab plus atezolizumab. The secondary end point included the investigator-assessed objective response rate (ORR). Counts and percentages are used for categorical variables, and medians and ranges are used for continuous variables.
RESULTS
Among the phase 1a (n = 24) and 1b (n = 49) dose-escalation cohorts, the median age was 60 (range, 40-77) and 54 (range, 25-81) years, respectively. More than half of patients were women (14 of 24 [58%] and 25 of 49 [51%]), and more than a third (10 [42%] and 18 [37%]) had received 4 or more prior cancer therapies. No dose-limiting toxicities occurred, and the maximum tolerated dose of tiragolumab was not reached (NR). The most frequent treatment-related adverse events (AEs) were fatigue (5 of 24 [21%]) in phase 1a and pruritus (5 of 49 [10%]) in phase 1b; the majority of AEs were grade 1 or 2. Immune-mediated AEs occurred in 4 of 24 (17%) and 29 of 49 (59%) patients during phases 1a and 1b, respectively (primarily grade 1 or 2). The RP2D of tiragolumab was 600 mg intravenously every 3 weeks, which was tested in phase 1b dose expansion. The confirmed ORR was 0% during phase 1a, with evidence of antitumor activity in 6% of patients (n = 3) during phase 1b. The safety profile of combination tiragolumab plus atezolizumab in phase 1b was similar in the dose-escalation and dose-expansion cohorts. The confirmed ORR was 46% (6 of 13) in the non-small cell lung cancer (NSCLC) cohort (median duration of response [DOR], NR) and 28% (5 of 18) in the esophageal cancer (EC) cohort (median DOR, 15.2 [95% CI, 7.0 to NR] months).
CONCLUSIONS AND RELEVANCE
In this nonrandomized controlled trial, tiragolumab was well tolerated with or without atezolizumab; no new safety signals were observed. Preliminary antitumor activity was demonstrated for the combination regimen in patients with cancer immunotherapy-naive metastatic NSCLC or EC.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02794571.
Topics: Humans; Female; Middle Aged; Male; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antineoplastic Agents; Esophageal Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Receptors, Immunologic
PubMed: 37768658
DOI: 10.1001/jamaoncol.2023.3867 -
American Journal of Respiratory and... May 2024Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The PEXIVAS (Plasma Exchange... (Randomized Controlled Trial)
Randomized Controlled Trial
Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The PEXIVAS (Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody-Associated Vasculitis) (NCT00987389) trial was the largest in AAV and the first to enroll participants with DAH requiring mechanical ventilation. Evaluate characteristics, treatment effects, and outcomes for patients with AAV with and without DAH. PEXIVAS randomized 704 participants to plasma exchange (PLEX) or no-PLEX and reduced or standard-dose glucocorticoids (GC). DAH status was defined at enrollment as no-DAH, nonsevere, or severe (room air oxygen saturation of ⩽ 85% as measured by pulse oximetry, or use of mechanical ventilation). At enrollment, 191 (27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3 (proteinase 3)-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH ( = 513; 72.9%). Among those with DAH, 8/95 (8.4%) receiving PLEX died within 1 year versus 15/96 (15.6%) with no-PLEX (hazard ratio, 0.52; confidence interval [CI], 0.21-1.24), whereas 13/96 (13.5%) receiving reduced GC died versus 10/95 (10.5%) with standard GC (hazard ratio, 1.33; CI, 0.57-3.13). When ventilated, ventilator-free days were similar with PLEX versus no-PLEX (medians, 25; interquartile range [IQR], 22-26 vs. 22-27) and fewer with reduced GC (median, 23; IQR, 20-25) versus standard GC (median, 26; IQR, 25-28). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within 1 year versus 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments. Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality. Original clinical trial registered with www.clinicaltrials.gov (NCT00987389).
Topics: Humans; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Male; Female; Middle Aged; Hemorrhage; Aged; Plasma Exchange; Glucocorticoids; Respiration, Artificial; Lung Diseases; Pulmonary Alveoli; Adult; Treatment Outcome
PubMed: 38346237
DOI: 10.1164/rccm.202308-1426OC -
Academic Emergency Medicine : Official... Feb 2024An aortic dissection (AoD) is a potentially life-threatening emergency with mortality rates exceeding 50%. While computed tomography angiography remains the diagnostic... (Observational Study)
Observational Study
OBJECTIVES
An aortic dissection (AoD) is a potentially life-threatening emergency with mortality rates exceeding 50%. While computed tomography angiography remains the diagnostic standard, patients may be too unstable to leave the emergency department. Investigators developed a point-of-care ultrasound (POCUS) protocol combining transthoracic echocardiography (TTE) and the abdominal aorta. The study objective was to determine the test characteristics of this protocol.
METHODS
This was an institutional review board-approved, multicenter, prospective, observational, cohort study of a convenience sample of adult patients. Patients suspected of having an AoD received a TTE and abdominal aorta POCUS. Three sonographic signs suggested AoD: a pericardial effusion, an intimal flap, or an aortic outflow track diameter measuring more than 35 mm. Investigators present continuous and categorical data as medians with interquartile ranges or proportions with 95% confidence intervals (CIs) and utilized standard 2 × 2 tables on MedCalc (Version 19.1.6) to calculate test characteristics with 95% CI.
RESULTS
Investigators performed 1314 POCUS examinations, diagnosing 21 Stanford type A and 23 Stanford type B AoD. Forty-one of the 44 cases had at least one of the aforementioned sonographic findings. The protocol has a sensitivity of 93.2% (95% CI 81.3-98.6), specificity of 90.9 (95% CI 89.2-92.5), positive and negative predictive values of 26.3% (95% CI 19.6-33.9) and 99.7% (95% CI 99.2-100), respectively, and an accuracy of 91% (95% CI 89.3-92.5).
CONCLUSIONS
The SPEED protocol has an overall sensitivity of 93.2% for AoD.
Topics: Adult; Humans; Aortic Dissection; Cohort Studies; Echocardiography; Prospective Studies; Ultrasonography
PubMed: 38010071
DOI: 10.1111/acem.14839 -
Journal of Forensic and Legal Medicine Jan 2024Donepezil is one of the primary treatments options for patients suffering from Alzheimer's Disease. In a review of more than 2200 postmortem donepezil positive blood... (Review)
Review
Donepezil is one of the primary treatments options for patients suffering from Alzheimer's Disease. In a review of more than 2200 postmortem donepezil positive blood specimens, 76% of concentrations were higher than the proposed therapeutic range. Means and medians were similar between central blood specimens and peripheral specimens, indicating minimal postmortem redistribution. Postmortem concentrations may not reflect those circulating antemortem. Mean and median postmortem blood concentrations were approximately 3-fold higher than those in antemortem blood specimens. Additionally, in cases where antemortem blood was available for testing, large increases in donepezil concentrations were reported between antemortem and postmortem specimens without documented administration by medical personnel. Elevated blood donepezil concentrations have been reported in multiple postmortem cases where cause of death was unrelated. The blood concentrations reported in cases where donepezil did not contribute to death overlapped with those in suspected drug overdose cases where other drugs may have been present. In 4 out of 5 suspected donepezil overdose cases, blood concentrations greater than 1000 ng/mL were reported, whereas less than 1% of all postmortem blood samples reviewed achieved these concentrations. Blood concentrations greater than 1000 ng/mL should be considered contributory when a drug overdose is suspected. Postmortem donepezil concentrations should be interpreted with caution in the context of a comprehensive case history.
Topics: Humans; Donepezil; Postmortem Changes; Autopsy; Drug Overdose
PubMed: 38043240
DOI: 10.1016/j.jflm.2023.102625 -
Zhonghua Fu Chan Ke Za Zhi Jul 2023To investigate the familial heritability of endometriosis and to compare the clinical characteristics of patients with or without a family history of endometriosis....
To investigate the familial heritability of endometriosis and to compare the clinical characteristics of patients with or without a family history of endometriosis. From January 2020 to June 2022, 850 patients with endometriosis confirmed by laparotomy or laparoscopy in Peking University Third Hospital were included in this study. Clinical data were collected, family history was followed up, and the differences of clinical indicators between patients with and without family history of endometriosis were compared. A total of 850 patients were enrolled, with an average age of (33.8±7.0) years old, 315 (37.1%, 315/850) patients in stage Ⅲ and 496 (58.4%, 496/850) patients in stage Ⅳ. There were 100 patients with family history of endometriosis, accounting for 11.8% (100/850). Most of the 113 relatives involved were mothers, daughters and sisters (76.1%, 86/113), 81.5% (22/27) of the second and third degree relatives were maternal relatives. The median ages of patients with and without family history of endometriosis were 30 and 33 years old respectively at the time of diagnosis. The unmarried rate of patients with family history was higher [42.0% (42/100) vs 26.3% (197/750)]. The percentage of dysmenorrhea patients with family history was higher [89.0% (89/100) vs 55.5% (416/750)]. The medians of dysmenorrhea score in patients with and without family history were 6 and 2, and the median durations of dysmenorrhea were 10 and 1 years. There were significant differences in age, marital status, percentage of dysmenorrhea, dysmenorrhea score and duration (all <0.001). The median levels of serum cancer antigen (CA) 125 in patients with family history and patients without family history at the time of diagnosis were 57.5 and 46.9 kU/L respectively, with a statistically significant difference (<0.05). However, there were no significant differences between the two groups in nationality, bady mass index, menarche age, menstrual cycle, menstrual period, menstrual volume, serum CA level, cyst location and size, stage, history of adverse pregnancy and childbirth, infertility, adenomyosis and deep infiltrating endometriosis (all >0.05). By comparing the specific conditions of dysmenorrhea patients with and without family history of endometriosis, there were no significant differences between the two groups in terms of the age of onset of dysmenorrhea, duration of dysmenorrhea, primary and secondary dysmenorrhea, and progressive aggravation of dysmenorrhea (all >0.05). The difference in the degree of dysmenorrhea in dysmenorrhea patients with family history of endometriosis was significant (<0.001). The incidence of endometriosis has a familial tendency, and most of the involved relatives are the first degree relatives. Compared with patients without family history of endometriosis, endometriosis patients with family history are diagnosed at an earlier age, with higher percentage of dysmenorrhea, had more severe dysmenorrhea and higher serum CA level.
Topics: Pregnancy; Female; Humans; Adult; Endometriosis; Dysmenorrhea; Menstruation; Menstrual Cycle; Adenomyosis
PubMed: 37474323
DOI: 10.3760/cma.j.cn112141-20221222-00768 -
Frontiers in Cardiovascular Medicine 2023The klotho and fibroblast growth factor 23 (FGF-23) pathway is implicated in cardiovascular pathophysiology. This substudy aimed to assess the changes in klotho and...
The klotho and fibroblast growth factor 23 (FGF-23) pathway is implicated in cardiovascular pathophysiology. This substudy aimed to assess the changes in klotho and FGF-23 levels 1-month after dapagliflozin in patients with stable heart failure and reduced ejection fraction (HFrEF). The study included 29 patients (32.2% of the total), with 14 assigned to the placebo group and 15 to the dapagliflozin, as part of the double-blind, randomized clinical trial [DAPA-VO (NCT04197635)]. Blood samples were collected at baseline and after 30 days, and Klotho and FGF-23 levels were measured using ELISA Kits. Between-treatment changes (raw data) were analyzed by using the Mann-Whitney test and expressed as median (p25%-p75%). Linear regression models were utilized to analyze changes in the logarithm (log) of klotho and FGF-23. The median age was 68.3 years (60.8-72.1), with 79.3% male and 81.5% classified as NYHA II. The baseline medians of left ventricular ejection fraction, glomerular filtration rate, NT-proBNP, klotho, and FGF-23 were 35.8% (30.5-37.8), 67.4 ml/min/1.73 m (50.7-82.8), 1,285 pg/ml (898-2,305), 623.4 pg/ml (533.5-736.6), and 72.6 RU/ml (62.6-96.1), respectively. The baseline mean peak oxygen uptake was 13.1 ± 4.0 ml/kg/min. Compared to placebo, patients on dapagliflozin showed a significant median increase of klotho [Δ+29.5, (12.9-37.2); = 0.009] and a non-significant decrease of FGF-23 [Δ-4.6, (-1.7 to -5.4); = 0.051]. A significant increase in log-klotho ( = 0.011) and a decrease in log-FGF-23 ( = 0.040) were found in the inferential analysis. In conclusion, in patients with stable HFrEF, dapagliflozin led to a short-term increase in klotho and a decrease in FGF-23.
PubMed: 37745119
DOI: 10.3389/fcvm.2023.1242108 -
The Journals of Gerontology. Series A,... Oct 2023Older adults with discordant biological and chronological ages (BA and CA) may vary in cognitive and physical function from those with concordant BA and CA.
BACKGROUND
Older adults with discordant biological and chronological ages (BA and CA) may vary in cognitive and physical function from those with concordant BA and CA.
METHODS
To make our approach clinically accessible, we created easy-to-interpret participant groups in the Health, Aging, and Body Composition Study (N = 2 458, 52% female participants, 65% White participants, age: 73.5 ± 2.8) based on medians of CA, and a previously validated BA index comprised of readily available clinical tests. Joint models estimated associations of BA-CA group with cognition (Modified Mini-Mental State Examination [3MS] and Digit Symbol Substitution Test [DSST]) and frailty over 10 years.
RESULTS
The sample included the following: 32%, Young group (BA and CA < median); 21%, Prematurely Aging group (BA ≥ median, CA < median), 27%, Old group (BA and CA ≥ median), and 20%, Resilient group (BA < median, CA ≥ median). In education-adjusted models of cognition, among those with CA < median, the Prematurely Aging group performed worse than the Young at baseline (3MS and DSST p < .0001), but among those with CA ≥ median, the Resilient group did not outperform the Old group (3MS p = .31; DSST p = .25). For frailty, the Prematurely Aging group performed worse than the Young group at baseline (p = .0001), and the Resilient group outperformed the Old group (p = .003). For all outcomes, groups did not differ on change over time based on the same pairwise comparisons (p ≥ .40).
CONCLUSIONS
Discordant BA and CA identify groups who have greater cognitive and physical functional decline or are more protected than their CA would suggest. This information can be used for risk stratification.
Topics: Humans; Female; Aged; Male; Frailty; Neuropsychological Tests; Cognitive Dysfunction; Cognition; Aging
PubMed: 37480573
DOI: 10.1093/gerona/glad174 -
American Journal of Perinatology Apr 2024This study aimed to compare the ventilator-free days (VFDs) at day 28 and the short-term outcomes in neonates with and without ventilator-associated pneumonia (VAP...
OBJECTIVE
This study aimed to compare the ventilator-free days (VFDs) at day 28 and the short-term outcomes in neonates with and without ventilator-associated pneumonia (VAP and non-VAP groups).
STUDY DESIGN
We performed a cohort study in a Thai neonatal intensive care unit between 2014 and 2020 to identify the VFDs in VAP and non-VAP neonates. Univariate and multivariate analyses were performed.
RESULTS
The incidences of VAP rates were 5.76% (67/1,163 neonates) and 10.86 per 1,000 (92/8,469) ventilator days. The medians (interquartile ranges [IQRs]) of gestational age and birth weight in the VAP versus non-VAP groups were 31 (27-35) versus 34 (30-38) weeks, and 1,495 (813-2,593) versus 2,220 (1,405-2,940) g ( < 0.001, both), respectively. The medians (IQRs) of VFDs at 28 days in the VAP and non-VAP groups were 5 (0-16) and 24 (20-26) days ( < 0.001). From the univariate analysis, the lower VFDs, longer ventilator days, and higher rates of moderate-to-severe bronchopulmonary dysplasia (BPD), postnatal steroids for BPD, length of stay, and daily hospital cost in the VAP group were significantly higher than in the non-VAP group. From the multivariate analysis, the VAP group had significantly lower VFDs (regression coefficient = -10.99, standard error = 1.11, < 0.001) and higher BPD (adjusted risk ratio = 18.70; 95% confidence interval = 9.17-39.5, < 0.001) than the non-VAP group.
CONCLUSION
Neonatal VAP lead to lower VFDs and a higher frequency of BPD. A multimodal strategy with a VAP prevention bundle care should be used in indicated cases to reduce the occurrence of neonatal VAP.
KEY POINTS
· The VFDs of the neonatal VAP was lower than reported in adult study.. · There are limited data on VFDs in VAP during the neonatal period.. · Neonatal VAP reduces VFDs and increases BPD rates compared with non-VAP infants..
Topics: Infant, Newborn; Infant; Humans; Pneumonia, Ventilator-Associated; Cohort Studies; Birth Weight; Intensive Care Units, Neonatal; Ventilators, Mechanical; Bronchopulmonary Dysplasia
PubMed: 35026853
DOI: 10.1055/a-1739-3678