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WALK behaviors | napping | Physical activity and sedentary time were measured objectively with actigraphy. Participants wore tri-axial accelerometer (Actigraph GT3X, Actigraph, Pensacola, FL) on the hip using an elastic belt or clip. Data collected at 80 Hz were downloaded (Actilife software, v6.13.3, Actigraph, Pensacola, FL, USA). Activity counts were analyzed at the minute-level from the vertical axis of the device. Classification of activity was determined using cut-points to categorize minutes in sedentary behavior (< 100 counts per minute), light (100–2019 CPM), moderate (2020–5998 CPM), and vigorous physical activity (5999 + CPM) [Physical activity actigraphy data were merged with sleep actigraphy data at the minute-level to determine “daytime” physical activity measures between morning sleep offset and nighttime sleep onset, which identifies true sedentary behavior that does not include nighttime sleep or napping. Physical activity days were determined invalid if there were > 25% non-wear minutes during the “daytime” portion of the day, or if there was < 20 h within the day that was “forced-ended” due to an invalid sleep period. Sleep and physical activity actigraphy temporal alignment and valid day criteria methods are detailed elsewhere [ | PMC10496245 | |
SLEEP behaviors | Sleep was measured objectively with actigraphy and subjectively with self-report. Objective sleep measures were collected using an accelerometer (Actiwatch Spectrum Plus; Philips-Respironics, Murrysville, PA) worn on the non-dominant wrist for one week. Data were collected and exported at 30-s epochs, where at least two independent scorers visually determined validity of data and set sleep intervals for periods greater or equal to 20 min using a graphical user interface. Together, the scorers reviewed each recording to determine the final number of valid days and sleep intervals using a validated scoring procedure [ | PMC10496245 | ||
Data analysis | depressive, OSF, sleep behaviors | We were interested in whether the EWS intervention improved key eat, walk, and sleep behaviors. In pre-planned analyses approved by the funder, we compared changes in key eat, walk, and sleep behaviors between the 2 groups that received EWS and the group that did not, across timepoints. Independent variables were experimental assignment (SS vs EWS vs EWS + MTM) and timepoint (baseline, 12-months, 15-months) and the dependent variables were as above. Descriptive statistics include means with standard deviations. Linear mixed models was used to test for change between groups. We first tested for differences between the two groups that received EWS intervention, i.e., EWS and EWS + MTM groups and, as expected, they showed a similar profile on the outcome variables. Thus, they were combined in the testing using contrasts statement and compared with the SS group. The linear contrasts tested for differences between the combined EWS/EWS + MTM group versus the SS group in the change from baseline to both the 12-month and 15-month time points. The physical activity and nutrition outcomes deviated severely from normality and typical transformations were unsuccessful in rectifying the issue. Therefore, values were converted to ranks and the mixed models were applied to the ranked data. For effect size Cohen’s d is reported for differences between experimental arms (EWS/EWS + MTM) and control arm (SS) at 12-months and 15-months.The nonparametric Spearman correlation was used to explore the relationship between change from baseline to 12-months in sleep, physical activity, and nutrition with change in primary outcomes of HbA1c, depressive symptoms, and logHOMA-IR. A significant correlation would suggest that the respective behavior may be mechanistically related to the primary outcomes, thus supporting targeting the behavior. In the EWS + MTM group, we calculated the proportion of participants for whom Metformin was recommended, who actually initiated Metformin treatment at any point across the 15 months. All available observations were used in the analyses and missing imputation was not performed as study retention was excellent (96% at 15-month follow-up). Statistical significance was set at an alpha level of 0.05. Analyses were conducted in SPSS v28 and syntax code is stored on the OSF link | PMC10496245 | |
Discussion | obesity, sleep disturbance, mood disorders, trauma, post-traumatic symptoms, diet-related non-communicable diseases, post-traumatic stress symptoms, traumatic, perspiration, depressive, post-traumatic stress disorder, PTSD, malnutrition, depression, posttraumatic stress, diabetes | OBESITY, UNDERNUTRITION, INSULIN RESISTANCE, MALNUTRITION, HEAT, DIABETES | The main findings from this study are that individuals who received the EWS lifestyle intervention successfully increased their brown rice consumption and their moderate-to-vigorous activity. And whereas we previously reported that the intervention improved self-reported sleep quality, here we found that it did not impact objective sleep duration, timing, efficiency or WASO. Across groups, individuals who increased brown rice consumption, increased vigorous activity and decreased total sleep time variability showed improved HbA1c. This is the first randomized trial specifically designed to reduce risk for diabetes in refugees with depression [Healthy nutrition changes are complicated by historical experiences of nutritional hardship. Refugee households may experience nutritional “double burden”. The double burden of malnutrition is characterized by the coexistence of undernutrition along with overweight, obesity or diet-related non-communicable diseases, within individuals, households and populations, and across the life-course [Eating in refugee populations is also influenced by high levels of post-traumatic stress symptoms. Cambodians specifically endured famine and forced starvation at the hands of Khmer Rouge. Starvation is often described as one of the most traumatic aspects of the Pol Pot regime. Deliberate withholding of food and forced communal meals to regulate intake were widespread. Individuals with post-traumatic stress disorder (PTSD) exhibit more emotional eating in response to stressors than those without PTSD [Physical activity is also complicated by a history of trauma. Individuals with symptoms of posttraumatic stress may tend to seek physiological quiescence and avoid physical arousal, including the increased heart rate, respiration, and perspiration caused by physical activity. Cambodians experienced forced labor under the Khmer Rouge, with long hours of inhumane work such as digging ditches and breaking rocks in intense heat. Thus, physical activity may trigger post-traumatic symptoms. We should note that EWS participants were not only willing, but enthusiastic, to join in group exercise as part of the EWS sessions. Actigraphy showed that the physical activity during this structured, supervised, and supportive setting successfully generalized to more moderate-to-vigorous activity in daily life outside of intervention sessions. The effect sizes for increases in physical activity at 12-months were small-to-moderate.Individuals with mood disorders and trauma history often experience sleep disturbance [In exploratory analyses, we examined how changes in health behaviors were associated with changes that we have previously reported in our primary outcomes, i.e., HbA1c, depressive symptoms, and insulin resistance [We were surprised that no health behavior changes were associated with improved depression or change in insulin resistance. We hypothesize that the improvements in depression experienced by the intervention groups, previously reported [ | PMC10496245 |
Limitations and conclusions | depressive | SECONDARY, INSULIN RESISTANCE | Because the randomized trial was powered to detect group changes in our primary outcomes—HbA1c, insulin resistance, and depressive symptoms—these secondary analyses may be limited by low statistical power. For the secondary outcomes reported here, the sample size had acceptable power (80%) to detect approximately a medium size effect (d ~ 0.5) and so was underpowered to detect small effects. Like all self-reports, our food frequency questionnaire may be subject to demand characteristics. The period of follow-up (3 months after post-treatment) may not adequately test the durability of effects. The details of the Cambodian American experience may not apply to all refugee groups, especially younger and newly arriving groups.Modifying nutrition, physical activity and sleep is important for delaying or preventing a rise in HbA1c among high-risk individuals [ | PMC10496245 |
Acknowledgements | Not applicable. | PMC10496245 | ||
Authors’ contributions | Julie Wagner provided overall scientific direction and wrote the initial draft of the manuscript. Angela Bermúdez-Millán, Thomas Buckley, and Orfeu M. Buxton directed data collection, interpreted results and edited the manuscript. Richard Feinn analyzed the data and prepared the tables and results section. Lindsay Master managed actigraphy data, wrote actigraphy methods and interpreted actigraphy results. Sengly Kong, Theanvy Kuoch, and Mary Scully supervised interventionists and data collectors and edited the manuscript. | PMC10496245 | ||
Funding | Digestive, Diabetes | KIDNEY DISEASES, DIABETES | National Institute of Diabetes and Digestive and Kidney Diseases, DK103663 to Julie Wagner. The funder had no role in the design of the study, collection, analysis, and interpretation of data, nor in writing the manuscript. | PMC10496245 |
Availability of data and materials | OSF | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Analyses were conducted in SPSS v28 and syntax code is stored on the OSF link | PMC10496245 | |
Declarations | PMC10496245 | |||
Ethics approval and consent to participate | All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from all individual participants included in the study. | PMC10496245 | ||
Consent for publication | All authors consent to publication of this manuscript. | PMC10496245 | ||
Competing interests | None. Outside of the current work, Orfeu M. Buxton discloses that he received subcontract grants to Penn State from Proactive Life LLC (formerly Mobile Sleep Technologies) doing business as SleepScape (NSF/STTR #1622766, NIH/NIA SBIR R43-AG056250, R44-AG056250), received honoraria/travel support for lectures from Boston University, Boston College, Tufts School of Dental Medicine, Eric H. Angle Society of Orthodontists, New York University, University of Miami, University of South Florida, University of Utah, University of Miami, and Allstate, and receives an honorarium for his role as the Editor in Chief of Sleep Health (sleephealthjournal.org). The other authors have nothing to disclose. | PMC10496245 | ||
References | PMC10496245 | |||
Abstract | Co-last. | PMC10322142 | ||
Background | mTNBC, breast cancer | BREAST CANCER | This trial evaluated the safety and efficacy of ipatasertib in combination with carboplatin, carboplatin/paclitaxel, or capecitabine/atezolizumab in patients with metastatic triple–negative breast cancer (mTNBC). | PMC10322142 |
Methods | DISEASE, METASTATIC DISEASE | Eligibility criteria were mTNBC, RECIST 1.1 measurable disease, no prior use of platinum for metastatic disease (Arms A and B), and no prior exposure to immune checkpoint inhibitor (Arm C). Primary endpoints were safety and RP2D. Secondary endpoints were progression–free survival (PFS), response rate, and overall survival. | PMC10322142 | |
Results | RP2D for Arm A ( | PMC10322142 | ||
Conclusions | TNBCs | Continuous dosing of ipatasertib with chemotherapy was safe and well-tolerated. Further study is warranted in understanding the role of AKT inhibition in treatment of TNBCs. | PMC10322142 | |
Trial registration | TNBC | TRIPLE-NEGATIVE BREAST CANCER | NCT03853707.More effective therapeutic strategies targeting underlying genomic drivers, as well as novel combinations, are urgently needed for treatment of triple-negative breast cancer (TNBC). This article evaluates the safety and efficacy of ipatasertib in combination with carboplatin, carboplatin/paclitaxel, or capecitabine/atezolizumab in patients with metastatic TNBC. | PMC10322142 |
Implications for Practice | tumors, TNBCs | TUMORS | Ipatasertib is a selective pan-AKT inhibitor and displays synergy with chemotherapy preclinically. This study was designed to determine the dose, safety, and preliminary efficacy of ipatasertib plus carboplatin, carboplatin/paclitaxel, or capecitabine/atezolizumab in mTNBC. The combination was safe and well-tolerated at the recommended doses, with empirically higher efficacy seen in tumors harboring PIK3CA/AKT/PTEN alterations. In addition, androgen receptor-positivity was associated with an empirically higher response rate. This study was stopped early due to a Phase III study combining ipatasertib plus paclitaxel that failed to show PFS or OS benefit. Further analysis is warranted in understanding the role of AKT inhibition in the treatment of TNBCs. | PMC10322142 |
Introduction | TNBC, tumor, mTNBC, Cancer | TUMOR, DISEASE, TRIPLE-NEGATIVE BREAST CANCER, TRIPLE NEGATIVE BREAST CANCER, CANCER | Metastatic triple-negative breast cancer (mTNBC), defined as lack of estrogen receptor (ER), progression receptor (PR), and human epidermal growth factor receptor 2 (HER2) overexpression, remains a disease of unmet need. This is largely attributed to tumor heterogeneity and chemotherapy resistance.The Cancer Genome Atlas data demonstrated that the most frequently altered genomic drivers in TNBC include the phosphatidylinositol 3-kinase-AKT-mTOR (PI3K-AKT-mTOR) signaling pathway.DNA–damaging agents such as platinum drugs are active in TNBC. The randomized Triple Negative Breast Cancer Trial (TNT) showed no overall response rate (ORR) difference between carboplatin and docetaxel in the overall population: 31.4% vs 34% (The Impassion130 study demonstrated the addition of atezolizumab (anti–PD-L1) to | PMC10322142 |
Materials and Methods | Cancer | MAY, CANCER | This open-label single institutional Phase I/Ib trial was conducted between May 2019 and June 2022 with institutional review board (IRB 18496) approval at the City of Hope National Cancer Center. The trial was conducted in accordance with the World Medical Association Declaration of Helsinki, International Conference on Harmonization Good Clinical Practice guidelines, and the US code of federal regulations. Informed consent forms were signed by all patients prior to study entry. This study is registered at the ClinicalTrials.gov under number NCT03853707. | PMC10322142 |
Eligibility Criteria | toxicities, TNBC | BRAIN METASTASIS, DISEASE, METASTASIS, METASTATIC DISEASE | Main eligibility criteria were: ≥18 years; histologically confirmed TNBC defined by ER or PR ≤ 10% by IHC and HER2 negative per ASCO/CAP guidelines; ECOG performance status 0-1; life expectancy ≥3 months; RECIST 1.1 measurable disease for Arm C only (patients on Arms A and B could have non–measurable disease), available baseline archival tissue for PIK3CA/AKT/mTOR status, and adequate organ function. Main exclusion criteria included unresolved grade 3 toxicities, prior exposure to PIK3CA/AKT/mTOR pathway inhibitors, prior exposure to carboplatin (Arms A and B) for metastatic disease, prior exposure to paclitaxel (Arm A) for metastatic disease, prior exposure to capecitabine or ICIs (Arm C) in the metastatic setting, or untreated or unstable brain metastasis or leptomeningeal metastasis. | PMC10322142 |
Study Endpoints and Assessments | toxicities, tumor | ADVERSE EVENTS, DISEASE PROGRESSION, TUMOR | The primary objective of the study was to evaluate safety and determine the recommended Phase II dose (RP2D) of ipatasertib plus carboplatin and paclitaxel (Arm A), carboplatin (Arm B), or capecitabine and atezolizumab (Arm C). Secondary endpoints were RR, PFS, and OS. Responses were assessed by RECIST 1.1, and safety analysis was carried out based on toxicities assessed by CTCAE 5.0. Immune-related adverse events (irAEs) were also collected for Arm C.Patients underwent tumor assessments with CT scan of chest, abdomen, pelvis, and bone scan of at baseline, every 3 cycles (12 weeks) following treatment initiation regardless of dose delays, until radiographic disease progression per RECIST v1.1 or intolerance. All measurable and evaluable lesions were re-assessed at each subsequent tumor evaluation. An objective response was confirmed by repeat assessments ≥4 weeks after initial response. | PMC10322142 |
Statistical Design for Arms A and B | toxicity, intra-dose | DISEASE, SECONDARY | The combination of paclitaxel and ipatasertib was determined to be safe and well tolerated in previous Phase Ib (PAM 4983g)Treatment Arms are shown in Treatment Arms showing patients included in the study (To confirm the RP2D obtained from the dose escalation, and for an initial assessment of response, correlatives, and PFS estimates, an additional cohort of patients was enrolled until the number treated and evaluable for DLT considerations at the recommended Phase II dose was 14 patients for Arm B and Arm A. All eligible patients who started treatment at the recommended Phase II dose were considered in the calculation of the RR.Arms A and B had an expected sample size of 14 patients, for an expected total sample-size of 28 patients. Protocol allowed for the addition of cohorts (6-8 patients) if level 1 was not well-tolerated (a lower dose was necessary).For Arm C safety-lead in, a 3-at-risk design was utilized to assess toxicity for the combination therapy. The DLT period was 1-cycle (28 days). Each participant remained on the dosing level according to the escalation dose level they were enrolled in, and intra-dose level escalations were not allowed, even if the MTD was defined at a higher dose level. If a patient came off study in the first 28 days for any reason outside of toxicity (unrelated AE, withdrawal of consent, progression of disease, etc), this patient was not considered as evaluable for DLT and this patient was replaced.When a maximum tolerable dose (MTD) level was defined by the dose escalation portion of the study, and the recommended Phase II dose (RP2D not to exceed the MTD) was selected, additional patients were accrued to confirm the tolerability of the regimen. The plan was for at least 12 patients to be treated at the RP2D to confirm tolerability. Additional patients beyond the 12 at the RP2D could be accrued if the total number of patients accrued did not exceed 21 patients. With 12 patients, any specific severe toxicity with 20% incidence would be observed with 93% probability.Survival endpoints were evaluated using Kaplan-Meier methods. Clinical activity was described based on the secondary objectives, with a description of the activity based on PD-L1 status. Other biological correlative studies were considered exploratory in the context of this limited Phase I study. | PMC10322142 |
Tumor Immune Biomarker | tumor, Tumor, Breast Cancer | BREAST CANCER, TUMOR, TUMOR, INFILTRATING, STROMAL TUMOR | Tumor biopsies were formalin-fixed paraffin-embedded (FFPE). Percentage of stromal tumor infiltrating lymphocytes (TILs) in tumor was evaluated using H&E diagnostic sections per International Immuno-Oncology Biomarker Working Group on Breast Cancer Guidelines. | PMC10322142 |
Results | PMC10322142 | |||
Patients | TNBC | MAY | A total of 28 patients with metastatic TNBC were enrolled between May 2019 and April 2021: 10, 12, and 6, respectively, to Arms A, B, and C (Baseline patient characteristics (
| PMC10322142 |
Toxicities | DLTs, stomach pain, diarrhea, rash, pain | ADVERSE EVENT | For Arm A, 3 patients developed DLT (1 grade 3 diarrhea, 1 grade 3 stomach pain, and 1 persistent grade 2 diarrhea) leading to dose delay (less than 75% planned ipatasertib dosing) (DLTs within the first cycle (representing 5 unique patients).
Adverse events at RP2D per CTCAE 5.0 (
As previously mentioned, of the 10 patients in Arm A, 3 had DLTs including 2 patients with grade 2-3 diarrhea and 1 patient with grade 3 stomach pain within the first 28-day cycle, which led to de–escalation to dose -1 with ipatasertib (300 mg daily). Of the 12 patients in Arm B, 1 had grade 3 maculopapular rash in cycle 1, which led to dose delay of ipatasertib (<75% completion) during the first 28 days. Of the 6 patients in Arm C, 1 had grade 3 maculopapular rash attributed to atezolizumab. After appropriate treatment, both patients with maculopapular rash had resolution of rash (Median (range) of cycles completed was 4 (2-15), including 4 (2-7) for Arm A, 4 (2-15) for Arm B, and 6 (2-10) for Arm C. A total of 11 (39%) had dose delay, including 4 (40%) in Arm A, 6 (50%) in Arm B, and 1 (17%) in Arm C. Ten (36%) had dose reduction, including 6 (60%) in Arm A, 3 (25%) in Arm B, and 1 (17%) in Arm C. The RP2D for Arm A was ipatasertib 300 mg daily, carboplatin AUC2 and paclitaxel 80 mg m | PMC10322142 |
Response and Survival | PD | DISEASE | The best responses for patients in Arm A (carboplatin/paclitaxel plus ipatasertib) included 2 (20%) PR (for the RP2D it was 2/7, 29%), 4 (40%) SD, and 4 (40%) PD. Arm B (carboplatin plus ipatasertib) best response included 1 (8%) CR, 2 (17%) PR, 6 (50%) SD, and 3 (25%) PD. Arm C (capecitabine, atezolizumab, and plus ipatasertib) best response included 2 (33%) PR, 3 (50%) SD, and 1 (17%) was called progressive disease, but we noted the patient was HER2+ on biopsy of progressive disease (Response per RECIST 1.1 (
The median PFS for Arm A was 4.8 months (95% CI 2.8, NA), Arm B was 3.9 months (95% CI 2.8, NA), and Arm C was 8.2 months (95% CI 4.6, NA). The median OS for Arm A (Progression-free survival (PFS) and overall survival (OS) (A swimmer plot with response to treatment over time is shown for Arm A (Swimmer plot ( | PMC10322142 |
Immune Correlatives | PD-L1 testing for Arm C patients showed 4 patients who were PD-L1 positive by SP142 and 2 patients who were PD-L1 negative ( | PMC10322142 | ||
Androgen Receptor | A total of 10 patients were AR positive (defined by IHC AR ≥2+ and ≥30%, | PMC10322142 | ||
Tumor Genomics | NextGen exome sequencing was performed with commercial testing ( | PMC10322142 | ||
Discussion | TNBC, tumors, mTNBC | TUMORS | The results of the current trial provide evidence that combining ipatasertib with continuous daily dosing with weekly carboplatin or carboplatin/paclitaxel is safe and has modest clinical activity in patients with mTNBC. In addition, ipatasertib (21 days on and 7 days off) combined with capecitabine and atezolizumab is safe and showed clinical activity. In patients with PIK3CA/AKT/PTEN alteration, ORR was 33% (5/15, including 1 CR). In AR+ TNBC, ORR was 40% (4/10). Due to limited sample size, these results are hypothesis-generating. The KEYNOTE-355 trial already established ICI plus chemotherapy for standard management of first–line patients with PD-L1+ TNBC.ICI plus chemotherapy combinations are now standard of care for PD-L1 positive mTNBC. Atezolizumab was initially granted FDA approval in March 2019 based on significant PFS benefit when atezolizumab was combined with nab–paclitaxel vs nab–paclitaxel alone seen in from IMpassion130 trial (HR, 0.60; 95% CI, 0.48-0.77; In LOTUS trial, ipatasertib added to first–line paclitaxel for mTNBC improved PFS with an enhanced effect in patients with PIK3CA/AKT1/PTEN–altered tumors.TNBC is molecularly heterogeneous with at least 4-6 molecular subtypes defined by mRNA expression. Among these, approximately 10% are luminal androgen receptor positive (LAR).Other AKT inhibitors are currently undergoing vigorous clinical investigation. In the PAKT trial, the addition of the pan-AKT inhibitor capivasertib to first-line paclitaxel therapy for TNBC resulted in longer PFS and OS. The median PFS was 5.9 months with capivasertib plus paclitaxel and 4.2 months with placebo plus paclitaxel (hazard ratio [HR], 0.74; 95% CI, 0.50-1.08; 1-sided There are several limitations of this study including early discontinuation due to withdrawal of funding, limited enrollment per arm, variation of chemotherapy backbone, lack of randomized Phase II design, and underlying molecular heterogeneity of mTNBC. An appropriately designed randomized Phase II trial may facilitate better understanding the role of ipatasertib in treating patients with TNBC who have specific molecular alterations or phenotypes. | PMC10322142 |
Conclusions | TNBC | Results from this study showed that continuous dosing of ipatasertib in combination with carboplatin-based therapy or capecitabine/atezolizumab is safe; however, moderate efficacy was seen in TNBC patients with PI3K/AKT/PTEN alterations. Encouraging efficacy was seen in luminal androgen receptor TNBC. Future studies with larger patient cohorts and randomized designs are required to confirm the current findings. | PMC10322142 | |
Supplementary Material | Click here for additional data file. | PMC10322142 | ||
Acknowledgments | Cancer | CANCER | We thank Genentech for providing funding and the study drug, ipatasertib, for NCT03853707, and the patients and their families for participating. The COH Biostatistics Core was supported by the National Cancer Institute of the National Institutes of Health (P30CA033572). | PMC10322142 |
Funding | Cancer | CANCER | Genentech provided funding and the study drug, ipatasertib. The COH Biostatistics Core was supported by the National Cancer Institute of the National Institutes of Health (P30CA033572). | PMC10322142 |
Ethics Approval | The study was approved by City of Hope Internal Review Board (IRB). Procedures were performed in accordance with the ethical standards of the City of Hope, the National Research Committee, and the 1964 Declaration of Helsinki and International Conference on Harmonization Guidelines for Good Clinical Practice and later amendments. | PMC10322142 | ||
Conflict of Interest | Yuan Yuan has contracted research sponsored by Merck, Eisai, Novartis, Puma, Genentech, Celgene, and Pfizer; is a consultant for Pfizer and Gilead; and is on the Speakers Bureau for Merck, Genentech, AstraZeneca, Daiichi Sankyo, and Immunomedics. The other authors indicated no financial relationships. | PMC10322142 | ||
Author Contributions | Conception/design: Y.Y. Provision of study material or patients: Y.Y., J.W., N.P., L.V., L.T., D.P. Collection and/or assembly of data: S.E.Y., Y.C., C.R., M.M., A.T., N.M., D.S., M.B., P.H.F. Data analysis and interpretation: Y.C., C.R., P.H.F. Manuscript writing: Y.Y., S.E.Y. Final approval of manuscript: All authors. | PMC10322142 | ||
Data Availability | The data underlying this article will be shared on reasonable request to the corresponding author. | PMC10322142 | ||
References | PMC10322142 | |||
Introduction | hypertriglyceridemia, ALL | CARDIOVASCULAR DISEASE, ACUTE LYMPHOBLASTIC LEUKEMIA, DEL, SECONDARY, HYPERTRIGLYCERIDEMIA | Edited by: Jessie Zurita-Cruz, Hospital Infantil de México Federico Gómez, MexicoReviewed by: Juan Carlos Núñez-Enríquez, Instituto Mexicano del Seguro Social, Mexico; Ornella Guardamagna, University of Turin, Italy; Miguel Villasis-Keever, Mexican Social Security Institute (IMSS), MexicoThis article was submitted to Pediatric Endocrinology, a section of the journal Frontiers in EndocrinologyIncreased triglycerides (TGs) are a major risk factor for cardiovascular disease. Furthermore, hypertriglyceridemia is commonly associated with a reduction of high-density lipoprotein cholesterol (HDL-C) and an increase in atherogenic small-dense low-density lipoprotein (LDL-C) levels. Studies provide support that polyunsaturated omega-3 fatty acids (ω3-LCPUFAs) are cardioprotective and have antithrombotic and anti-inflammatory effects. The potential effects of ω3-LCPUFAs on cardiometabolic factors and anti-inflammatory actions in children with acute lymphoblastic leukemia (ALL) are limited. This is a secondary analysis of a previous clinical trial registered at clinical trials.gov (# NCT01051154) that was conducted to analyze the effect of ω3-LCPUFAs in pediatric patients with ALL who were receiving treatment.Objective: To examine the effect of supplementation with ω3-LCPUFAs on cardiometabolic factors in children with ALL undergoing treatment. | PMC10140550 |
Methods | ALL | Thirty-four children (placebo group: 20 patients; ω3-LCPUFAs group: 14 patients) aged 6.7 ± 2.7 years who were newly diagnosed with ALL were evaluated. Children were randomized to receive either ω3-LCPUFAs or placebo capsules (sunflower oil). ω3-LCPUFAs were administered in the form of 500-mg soft capsules. The ω3-LCPUFA capsules contained 225 mg of DHA, 45 mg of EPA, and 20 mg of another ω3-LCPUFAs. The omega-3 dose was administered at a rate of 0.100 g/kg of body weight/day for three months. Main outcomes: Fasting cholesterol, HDL-C, very-low-density lipoprotein (VLDL-C), TGs, atherogenic index of plasma (AIP), android/gynoid ratio (A/GR), IL-6, TNF-α, and percentage of fat mass (DXA) were measured in all patients. Fatty acid analyses in red blood cells were performed with gas chromatography. | PMC10140550 | |
Results | hypertriglyceridemia | HYPERTRIGLYCERIDEMIA | We found significantly lower levels of TGs (p=0.043), VLDL-C (p=0.039), IL-6 (p=0.025), and AIP (p=0.042) in the ω3-LCPUFAs group than in the placebo group at three months. In contrast, the total cholesterol concentration was higher at 3 months in the ω3-LCPUFAs group than in the placebo group (155 mg/dl vs. 129 mg/dl, p=0.009). The number of children with hypertriglyceridemia (85% vs. 50%; p=0.054) tended to be lower between the time of diagnosis and after 3 months of supplementation with ω3-LCPUFAs. | PMC10140550 |
Conclusion | cardiometabolic, ALL | These findings support the use of ω3-LCPUFAs to reduce some adverse cardiometabolic and inflammatory risk factors in children with ALL. | PMC10140550 | |
Clinical trial registration | PMC10140550 | |||
Introduction | TNF-α, cardiovascular disease, malignancy, cancer, inflammation, leukemia, ALL | CARDIOVASCULAR DISEASE, CHILDHOOD CANCER, CANCER, INFLAMMATION, LEUKEMIA, ACUTE LYMPHOBLASTIC LEUKEMIA, SECONDARY, INFLAMMATORY RESPONSE | Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy, accounting for almost one-third of all childhood cancers worldwide, with an incidence of 20-35 per million children under 15 years (Different authors have found associations between android fat (abdominal fat located around the trunk of the body) and gynoid fat (gluteal-femoral fat deposited around the hips and thighs) and/or the android/gynoid ratio (A/GR) and different risk factors for cardiovascular disease in children and adolescents (Different studies have shown that patients with ALL presents a proinflammatory state at the time of diagnosis and during and after chemotherapy for up to 5 years after the start of treatment, characterized by increased levels of cytokines (IL-1β, IL-6, and TNF-α) (On the other hand, several studies suggest that dietary supplementation with ω3-LCPUFAs, such as DHA and EPA, can be beneficial for cancer treatment, as it decreases metabolic risk; modulates several aspects of the inflammatory response; decreases inflammatory markers, plasma levels of TGs and LDL-C; and increases HDL-C (However, to our knowledge, there are no randomized controlled clinical trials comparing the direct changes in the lipid profile and inflammation markers induced by ω3-LCPUFA supplementation and assessing adherence to treatment by gas chromatography (gold standard) in ALL patients.Therefore, we present results from a secondary analysis of data obtained in a randomized clinical trial that was previously conducted to evaluate the effect of supplementation with ω3-LCPUFAs on body composition in children with leukemia (under review).The aim of the present analysis was to examine the effect of supplementation with ω3-LCPUFAs on several cardiometabolic factors in children undergoing treatment for ALL with the hypothesis that ω3-LCPUFAs reduce inflammatory cytokine and TGs levels and increase HDL-C in these patients. | PMC10140550 |
Materials and methods | PMC10140550 | |||
Study design | leukemia | LEUKEMIA, REMISSION, DEL | This analysis is part of a randomized clinical trial designed to evaluate the effect of supplementation with ω3-LCPUFAs on body composition in children with leukemia at the end of the remission phase and three months after supplementation, registered in the ClinicalTrials.gov database (clinicaltriasl.gov #: NCT01051154). This study was conducted in accordance with the Declaration of Helsinki, and it was approved by the National Committee of Scientific Research of Instituto Mexicano del Seguro Social (IMSS) and was conducted in the Unit of Research in the Medical Nutrition in a Pediatric Hospital in Mexico City (Approval # 2009-785-107). All parents or legal guardians of the children provided written informed consent prior to study entry. | PMC10140550 |
Patients | death, allergies, neutropenic colon, ALL | SECONDARY, COMPLICATIONS, ALLERGIES | We included 72 children with ALL at the Pediatric Hospital of the National Medical Center XXI Century IMSS, National Medical Center, and at the “Gaudencio González Garza” General Hospital, of the “La Raza” National Medical Center. Eligibility criteria were children newly diagnosed with ALL (established according to bone marrow aspirate, immunophenotyping, and immunohistochemistry) at the start of their chemotherapy treatment. Children who had previously been treated with chemotherapy in another institution, those with severe comorbidities, using corticosteroids, taking fish oil supplements during the previous weeks, who were unable to swallow ω3-LCPUFA or placebo capsules, and those who reported allergies to fish intake were excluded. From 72 children with ALL, in this secondary analysis, only 34 children were included (placebo group: 20 patients; ω3-LCPUFA group: 14 patients), due to participants dropping out for different reasons, such as discontinued intervention, death, clinical complications (neutropenic colon), or lack of adherence. We have reported this information in the manuscript of a clinical trial on body composition and omega 3 in children with ALL (currently under review by Clinical Nutrition ID YCLNU-D-23-00112). | PMC10140550 |
Recruitment and allocation | Patients who met all the inclusion criteria and volunteered to participate were randomized in a 1:1 ratio. Selected children were randomly assigned to the placebo group (control) or to the ω3-LCPUFA group (intervention) by a computer-generated list of random numbers using software for parallel groups (Random Allocation Software, | PMC10140550 | ||
Intervention | EPS | Children received either capsules of ω3-LCPUFAs or placebo capsules. ω3-LCPUFAs were administered in the form of 500 mg soft capsules of natural TGs, made from gelatin, formulated without artificial colors or flavors, molecularly distilled, and of pharmaceutical grade (Nordic Naturals, Inc., Watsonville CA, USA). The omega dose was administered at a rate of 0.100 g/kg of baseline body weight/day. The ω3-LCPUFAs comply with the principles established for fats according to the European Pharmacopoeia Standard (EPS) and according to the Council for Responsible Nutrition (CRN) and the Global Organization (CRNGO). Consequently, ω3-LCPUFAs are a safe product that does not exceed the maximal allowances for contaminants such as peroxides, heavy metals, dioxins, and PCBs. The placebo capsule contained 500 mg of sunflower oil (Progela, S.A. de C.V., México). All capsules contained vitamin E to act as an antioxidant. The odor and appearance of the ω3-LCPUFA capsules and the placebo capsules were comparable, and both were strawberry-flavored to mask their taste. During the study time, all the participants were provided with an oral supplement of the brand Fressenius | PMC10140550 | |
Compliance | When the patient was discharged, compliance was monitored by the leftover pill count at their next appointment. In addition, the concentration of polyunsaturated fatty acids in erythrocyte membranes was determined before and during intervention with ω3-LCPUFAs. All side effects that the children presented during the intervention with ω3-LCPUFAs, or placebo were documented and registered by one of the researchers. | PMC10140550 | ||
Procedures | PMC10140550 | |||
Anthropometry and adiposity | obesity, overweight | OBESITY, DISEASE | Participants arrived at the medical center between 8:00 and 9:00 am after an overnight fast. Body weight was measured with an electronic scale (TANITA BWB-700, Tanita Corporation, Tokyo, Japan) with the subjects wearing lightweight clothing. Height was measured to the nearest 0.1 cm with a wall-mounted stadiometer (SECA 222, SECA Corp., Oakland Center, Columbia, MD, USA). BMI percentiles for age and sex were calculated according to the Centers for Disease Control (CDC) normative curves using the computer software Epi-info (obesity was defined conventionally as ≥ 95th percentile, overweight as 85 | PMC10140550 |
Analytical methods | Stored serum aliquots were used to determine the lipid profile and cytokines. TGs, total cholesterol, and HDL-C were measured by the enzymatic colorimetric method (SPIN 120 automatic analyzer, Shenzhen, Mindray) with commercially available kits. TGs levels were considered acceptable <75/<90 mg/dL, borderline 75-99/90-129 mg/dL, and high ≥100/≥130 mg/dL for children aged < 10 and ≥ 10 respectively. HDL-C levels were considered low at <40 mg/dL (Inflammatory markers such as IL-6 and TNF-α were determined in duplicate using high-sensitivity enzyme-linked immunosorbent assay (ELISA) kits, according to the manufacturer’s instructions (R&D Systems, INC., Minneapolis, MN, USA and DSL UK Ltd., Oxon, UK). All assays were carried out in duplicate; coefficients of variation were 8% for ELISAs. | PMC10140550 | ||
Fatty acid analyses by gas chromatography | Analyses were performed with a 7820A gas chromatograph (Agilent Technologies, Santa Clara, CA, USA) with a flame ionization detector (FID) as described previously ( | PMC10140550 | ||
Statistical analysis | The data were analyzed using SPSS 21.0 software for Windows (SPSS, Inc. IBM, NY, USA). Data are presented as the mean ± standard deviation (SD) or as the median (minimal, maximal), according to data (determined by the Shapiro-Wilk test), while categorical variables are presented as frequency (percentages) and were analyzed by Pearson’s chi-square test and Fisher’s exact test as appropriate. The crude significance of within-group and intergroup differences was tested by Student’s t test, paired-samples t test, the Wilcoxon test, or the Mann–Whitney U test, as appropriate. Values of | PMC10140550 | ||
Results | leukemia | LEUKEMIA | We summarize the Consolidated Standards of Reporting Trials followed in this study in Flow diagram of the progress through the phases of the clinical trial and present analysis.Demographic, clinical, and baseline markers characteristics of children with leukemia.Data are presented as mean ± Standard Deviation (SD), at median (minimum, maximum) or as number (percentage). ω3-LCPUFAs, Omega-3 long chain-PUFA; BMI, Body Mass Index; The data were analyzed with an independent-sample t-test or Mann-Whitney U test; Pearson-chi square test or Fisher. | PMC10140550 |
Lipids and inflammatory markers | acute lymphoblastic leukemia, Necrosis, Tumor, ALL | TUMOR, ACUTE LYMPHOBLASTIC LEUKEMIA, NECROSIS, ACUTE LYMPHOBLASTIC LEUKEMIA, BLOOD | Blood lipid profiles for each group at baseline and after 3 months of intervention are shown in Blood Lipid profile at baseline and 3 months of intervention in children with acute lymphoblastic leukemia.Data are presented as mean ± Standard Deviation (SD), at median (minimum, maximum) or as number (percentage); TC, Total cholesterol; HDL-C, High-density lipoprotein cholesterol; LDL-C, Low-density lipoprotein cholesterol; VLDL-C, Very-low-density lipoprotein cholesterol; AIP, Atherogenic index of plasma; A/GR Android/Gynecoid ratio. *A/GR in the placebo group, one patient was not included due to missing information.Changes in triglyceride levels. Data are expressed as mean ± standard deviation (SD). Data represent the triglyceride differences during the three months and basal time of treatment. Dependent-sample t-test was performed.Changes in VLDL-Cholesterol levels. Data are expressed as mean ± Standard Deviation (SD). Data represent the differences in VLDL-C during the three months and basal time of treatment. Dependent-sample t-test was performed.Inflammatory markers in children with ALL from baseline and after three months of supplementation with placebo or ω3-LCPUFA capsules are shown in Inflammatory markers in children with acute lymphoblastic leukemia from baseline and three months of supplementation with placebo or ω3-LCPUFA capsules.Data are presented as median (minimum, maximum): IL-6, Interleukin 6; TNF-α, Tumor Necrosis Factor.
Fatty acid composition of erythrocyte membranes in children with acute lymphoblastic leukemia from baseline and three months of treatment with ω3-LCPUFAs.Data are presented as median (minimal, maximal); EPA, Eicosapentaenoic Acid; DHA, Docosahexaenoic acid; ALA, Linolenic acid; LA, Linoleic acid; AA, Arachidonic acid. Significant differences between the two time points were determined by Mann-Whitney U-test and the intragroup by Wilcoxon signed rank test. | PMC10140550 |
Discussion | obesity, TNF-α, inflammation, cancer, AIP, ALL, hypertriglyceridemia | OBESITY, DYSLIPIDEMIA, CANCER, EVENT, INFLAMMATION, SECONDARY, HYPERTRIGLYCERIDEMIA, ATHEROGENIC DYSLIPIDEMIA | In this secondary analysis, we confirmed the effect of ω3-LCPUFA supplementation at a rate of 0.100 g/kg/day on the lipid profile, specifically on the TGs and VLDL-C concentrations during the first 3 months of ALL treatment. We observed a significantly lower concentration of TGs and VLDL-C in the ω3-LCPUFA group than in the placebo group. We found that 82.4% (28/34) of the children had hypertriglyceridemia and low levels of HDL at the time of ALL diagnoses. These results are consistent with previous findings from ALL studies (There is considerable evidence that EPA and DHA have independent effects on multiple cardiometabolic risk factors, including blood pressure and cardiac function and lipids, as well as anti-platelet, anti-inflammatory, pro-resolving, and antioxidative actions (On the other hand, in a retrospective study, Salvador et al. (In contrast, we found differences in the total cholesterol between the groups at 3 months of supplementation; however, unexpectedly, the ω3-LCPUFA group presented a higher total cholesterol concentration (On the other hand, we did not find significant differences in HDL-C and LDL-C levels between the groups. In our study, we probably did not find differences since the shake provided in both groups contained 4.3 g of saturated fatty acids which might have influenced the result.The AIP is a biomarker of atherogenic dyslipidemia that, through non-HDL-C and/or the TG/HDL-C ratio, can predict the risk of a future atherogenic cardiometabolic event from an early age (Data on the potential effects of ω3-LCPUFAs on anti-inflammatory actions and cardiometabolic factors in children with ALL are scarce. Nevertheless, there is evidence that ω3-LCPUFAs, reduce inflammatory markers in adult oncology patients (Based on these results, we should discuss the strengths and limitations of our work. A strength of the study was the use of a prospective cohort, which improved the accuracy of data collection. Another added benefit was the use of controls. In addition, supplementation at a rate of 0.100 g/kg/d (like Bayram et al.) (Although ω3-LCPUFAs have a positive effect on cancer patients, in ALL pediatric patients there is no sufficient data for recommendations. As we stated above, available studies from randomized placebo-controlled trials the supplements evaluated have varied in dose, source, time of intervention and kind of supplements used in these of ω3-LCPUFAs (Dyslipidemia and inflammation have some common pathological links, such as obesity and cancer. Recent literature mentions that lipids have a fundamental role in the activation of inflammatory pathways, thus increasing the production of inflammatory cytokines (TNF-α, IL-6 and IL-1), which can promote the interruption of lipid metabolism, especially the reverse transport of cholesterol; this is related to a decrease in HDL-C, which could stimulate compensatory changes, such as the synthesis and accumulation of VLDL-C and hypertriglyceridemia, and ultimately increase cardiometabolic risk ( | PMC10140550 |
Conclusion | dyslipidemia, cancer, cardiometabolic, ALL | CANCER, DYSLIPIDEMIA | These findings support the use of omega-3 fatty acids to reduce some adverse cardiometabolic and inflammatory risk factors in children with ALL. Our findings show that an ω3-LCPUFA intervention is feasible, and the results suggest that ω3-LCPUFA supplementation in these patients could help prevent, delay, and/or mitigate the development of dyslipidemia and cardiometabolic conditions that can have a negative impact on them. It is unknown if the effect of omega-3 may last longer than 3 months. We consider that large-scale trials are needed in children with cancer to confirm these results. | PMC10140550 |
Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC10140550 | ||
Ethics statement | This study was approved by the Research and Ethics Committee of the Pediatric Hospital at the Mexican Social Security Institute (2009-785-107). We obtained written informed consent from parents and informed assent from children. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin. | PMC10140550 | ||
Author contributions | ZH-P | LB-C, designed the study, analyzed data, obtained funding, and prepared the manuscript; SA-M, EJ-A, JM-T and FM-B, contributed to the analysis and interpretation of data and helped prepare the manuscript; ML-A, JM-A performed the analysis and interpretation of data, and helped prepare the manuscript; SD-P, BG, JD-P, AA-B, human resource management, contributed to the analysis and interpretation of data, S-LK, BB-M, AJ-M, ZH-P, EJ-H, LE-H, NN-V, RP-C contributed to the acquisition of data. All authors contributed to the article and approved the submitted version. | PMC10140550 | |
Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10140550 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10140550 | ||
References | PMC10140550 | |||
ABSTRACT. | malaria, deaths, malaria infection, neutropenia | RECRUITMENT, NEUTROPENIA, MALARIA, ADVERSE EVENTS, ADVERSE EVENT, EVENT, TERATOGENICITY, MALARIA | Financial support: The study was funded, designed, conducted, and analyzed by Medicines for Malaria Venture. Medicines for Malaria Venture is funded by several donors. Unrestricted funding comes from several donors, including the Foreign Commonwealth and Development Office, German Ministry for Education and Research, Bill & Melinda Gates Foundation, Ireland Department of Foreign Affairs and Trade (IrishAid), Australia Department of Foreign Affairs and Trade, Swiss Agency for Development and Cooperation, and the Principality of Monaco. These funders had no role in the design, conduct, or analysis of the trial.This work was supported, in whole or in part, by the Bill & Melinda Gates Foundation (grant number INV-007155). Under the grant conditions of the Foundation, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission.Data availability: Anonymised subject data are available on reasonable request from the corresponding author.Disclosure: A.C.M., C.D., and S.D. are employees of Medicines for Malaria Venture. H.J. is a former independent consultant for Medicines for Malaria Venture.Authors’ addresses: Rezika Mohammed and Mezgebu Silamsaw Asres, Department of Internal Medicine, University of Gondar Hospital, Gondar, Ethiopia, E-mails: An open label, phase IIa study conducted in Ethiopia evaluated the efficacy, safety, tolerability, and pharmacokinetics of a single 120-mg dose of the phosphatidylinositol 4-kinase inhibitor MMV390048 in Malaria remains major threat to global health.MMV390048 is a phosphatidylinositol 4-kinase inhibitor with in vitro activity against all This open label, adaptive, phase IIa study was designed to evaluate the efficacy, safety, tolerability, and pharmacokinetics of a single 120-mg dose of MMV390048 in adult patients with uncomplicated malaria. The study was conducted between October 6, 2017 and January 5, 2018 at two hospitals in Ethiopia (in Gondar and Jimma). Recruitment was suspended on December 4, 2017 to allow assessment of a teratogenicity signal in a concurrent investigation in rodents.The study protocol was approved by the independent Ethics Committees of the College of Public Health and Medical Sciences, Jimma University (now the Institute of Health Institutional Review Board), the Institutional Review Board of the University of Gondar, Ethiopia, and the Ethiopian National Research Ethics Review Committee and Ethiopian Food and Drug Administration, Addis Ababa, and was registered with ClinicalTrials.gov (NCT02880241). Study conduct conformed to the national regulatory requirements of Ethiopia and the Declaration of Helsinki.Planned enrollment was for three Eligible patients were adults aged 18–55 years, weighing 40–90 kg with microscopically confirmed Giemsa-stained thick and thin blood films for parasite identification and enumeration were prepared using standard methods.The primary outcome for The eight enrolled patients were males, self-defined as black, mean age 24.5 years (range 20–50 years), with a mean (SD) body mass index of 18.1 (1.2) kg/mThe primary endpoint of ACPR at day 14 was 100% (8/8). Asexual parasites were cleared by 24 hours postdose in four patients, by 48 hours in two patients, and by 66 hours in the remaining two patients (Parasite counts for Gametocytes were detected in all patients at baseline and were cleared by 24 hours postdose in four patients, by 30 hours in two patients, and by 78 hours in two patients (Using qPCR, parasite clearance was achieved between 20 and 161 hours (MMV390048 pharmacokinetic parameters are shown in Plasma pharmacokinetic parameters for a single 120-mg dose of MMV390048 in adult patients with Values are geometric mean (coefficient of variation), except for The reported There were no deaths, serious adverse events, or adverse events leading to study discontinuation. A total of 27 adverse events were reported during the study across all eight patients (Adverse events of any causeAdverse event of special interest.There were three adverse events of special interest occurring in two patients. One patient had neutropenia, considered possibly drug related. This event started on day 2 (baseline neutrophil count 3.39 × 10Clinical laboratory tests showed no drug-related trends. Baseline low platelet and hemoglobin levels, consistent with malaria infection, tended to improve throughout the study. There were no other safety concerns.In summary, a single oral dose of 120-mg MMV390048 rapidly cleared asexual parasites and gametocytes in eight male patients with | PMC9833083 |
ACKNOWLEDGMENTS | MALARIA | We thank the patients for their participation. The contributions of the study staff are acknowledged, including Cherinet Abebe, Alemseged Abdissa Lencho, Abebe Genetu Bayih, Gebrehiwot Lemma, Solomon Afework, Zeleke Alemu, Mubarik Taju, Meseret Birhanie Fentahune, Abdulhakim Abamecha Abafogi, Seid Amdala, Kaleab Eskinder, Gelila Meneberu, Rawuda Ebrhaim, Kinde W/Giyorgis, Eshetu Mulisa, Zerihun Befkadu, Bizuworek Sharew, Yeneneh Berhanu, Ligabaw Worku Gebremariam, Melese Abera, Mulugeta Aemro, Begosew Debas, Asnakew Engidaw, and Habtie Tesfa Delelegn. The contributions of Helen Demarest, Susan Podmore, and Charles Stoyanov for additional support in study management are acknowledged. We thank the Swiss Tropical Public Health Institute and Harald Noedl for their contributions to laboratory training during the study and Martina Wibberg of DATAMAP GmbH for statistical support. Naomi Richardson of Magenta Communications, funded by Medicines for Malaria Venture, wrote the first draft of this article and provided editorial and graphic services. The authors confirm that all ongoing and related trials for this drug/intervention are registered (#NCT02880241).This trial is registered at ClinicalTrials.gov (#NCT02880241, | PMC9833083 | |
REFERENCES | PMC9833083 | |||
Methods | arterial stiffness, asthma, tumor necrosis | REACTIVE HYPEREMIA, TUMOR NECROSIS, ASTHMA, ARTERIAL STIFFNESS, DILATION | Twenty-six people with asthma and 25 controls underwent three airway challenges (placebo, mannitol, and methacholine) in random order. Markers of cardiovascular risk, including serum C-reactive protein, interleukin-6, and tumor necrosis factor, endothelial function (flow-mediated dilation), microvascular function (blood-flow following reactive hyperemia), and arterial stiffness (pulse wave velocity) were evaluated at baseline and within one hour following each challenge. The systemic responses in a) asthma/control and b) positive airway challenges were analyzed. (ClinicalTrials.gov reg# | PMC10351735 |
Results | Both the mannitol and methacholine challenges resulted in clinically significant reductions in forced expiratory volume in 1 second (FEV | PMC10351735 | ||
Conclusion | pulmonary inflammation, asthma exacerbations | INFLAMMATION, PULMONARY INFLAMMATION, SECONDARY | Neither acutely induced bronchoconstriction nor pulmonary inflammation and bronchoconstriction resulted in meaningful changes in systemic inflammatory or vascular function. These findings question whether the increased cardiovascular risk associated with asthma exacerbations is secondary to acute bronchoconstriction or inflammation, and suggest that other factors need to be further evaluated such as the cardiovascular impacts of short-acting inhaled beta-agonists. | PMC10351735 |
Data Availability | All relevant data are within the paper and its | PMC10351735 | ||
Introduction | chest tightness, asthma-like, inflammation, wheezing, pulmonary inflammation, breathlessness, airway hypersensitivity, Asthma | INFLAMMATION, CHRONIC AIRWAY DISEASE, PULMONARY INFLAMMATION, ASTHMA, EVENTS | Asthma is a chronic airway disease characterized by recurrent episodes of pulmonary inflammation leading to bronchoconstriction and symptoms such as breathlessness, wheezing, and chest tightness [Findings from animal studies suggest that increased levels of systemic inflammation during asthma-like events originate in the lungs [The mannitol airway challenge is a widely accepted to identify airway hypersensitivity. Inhaled mannitol is known to activate mast cells within the airways [ | PMC10351735 |
Methods | This case-control, cross-over randomized controlled clinical trial-study was approved by the University of Alberta Ethics Board (Pro0054047), Health Canada (#9427-G0890-88C), registered on ClinicalTrials.gov ( | PMC10351735 | ||
Research participants | asthma | LUNG, ASTHMA, ASTHMA | Patients with physician-diagnosed asthma between the ages of 18 and 45 years were identified by chart review from the University of Alberta Asthma Clinic and The Lung Health Clinic, Edmonton, Alberta 2015–2021. Asthma was confirmed if the participant tested positive for one of the following: a) more than 12% and 200 ml reversibility in the forced expiratory volume in 1 second (FEV | PMC10351735 |
Study design | ARTERIAL STIFFNESS, BLIND, ASTHMA | Following signing informed consent, reporting medical history, and filling out the Asthma Control Questionnaire (ACQ) [The subsequent study consisted of three experimental days where the participant received either: 1) mannitol airway challenge, 2) methacholine airway challenge, or 3) saline airway challenge (i.e. placebo). The order of challenges was computer-randomized independently from allocation and the subjects were blinded to the type of airway challenge administered. Because of potential bronchoconstriction, it was not possible to fully blind the researchers obtaining post-challenge data. However, vascular and inflammatory data were analyzed blind to the intervention. Each visit occurred at a minimum of one week apart to allow for recovery and to minimize potential carry-over effects between challenges. All participants were asked to withhold caffeinated drinks, food, alcohol, and exercise for a minimum of 12 hours prior to each study visit. While no changes were made to individual medication plans, all participants withheld short-acting beta-agonists for eight hours and long-acting controller medication for 48 hours prior to each test day [Each test visit started with the participant resting in the supine position for 10 minutes in a dimly lit room. Baseline brachial blood pressure was measured in duplicate, and a stable baseline was established when the variance between systolic blood pressure measurements was less than five percent. Arterial stiffness and vascular function were then evaluated. Serum was collected for systemic inflammatory measurements. Following baseline measurements, participants completed one of the three bronchial challenges. For consistency, independent of the airway response to the given intervention, each participant received 400°g salbutamol inhalation powder at the end of each intervention, within five minutes of challenge termination. Follow-up testing occurred within one hour after each bronchial challenge, and all measurements were repeated in the same order as at baseline. | PMC10351735 | |
Mannitol | The mannitol challenge was performed according to manufacturer guidelines [ | PMC10351735 | ||
Methacholine | The methacholine challenge was performed using the incremental two-minute tidal breath-protocol [ | PMC10351735 | ||
Placebo | The placebo challenge was performed identical to the methacholine challenge; however, no methacholine was added to the inhaled saline (i.e. participant inhaled saline only). The challenge was terminated following five rounds of saline. | PMC10351735 | ||
Outcome measurements | PMC10351735 | |||
Systemic inflammation | tumor necrosis | TUMOR NECROSIS | Ten ml of blood was collected from a vein in the antecubital fossa using standard venipuncture technique. The samples were allowed to coagulate for a minimum of 30 minutes at room temperature, then centrifuged at 12,000 rpm for 10 minutes. Serum was then collected and aliquoted into samples of 100°L and stored in a -80 degrees Celsius freezer. Analyses of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor (TNF) levels was done in duplicates using immunofluorescent technique (CRP DuoSet ELISA kit; Human IL-6 Quantikine ELISA Kit; Human TNF-alpha Quantikine ELISA Kit, R&D Systems, Bio-Techne Corporation, Minneapolis, MN, USA). | PMC10351735 |
Vascular function | Vascular function (main study outcome), including endothelial function and microvascular function, was evaluated according to guidelines [ | PMC10351735 | ||
Arterial stiffness | Central arterial stiffness | Central arterial stiffness was evaluated between the carotid and femoral arteries using automated applanation tonometry (Complior, Alam Medical, Saint Quentin Fallavier, France) [ | PMC10351735 | |
Divergences from the early protocol | exhaled breath condensate | INFLAMMATION | This study reports data from a large research initiative registered on ClinicalTrails.gov (ID#: NCT02630511) in 2015. The study has since evolved and the following updates to the research procedures were made: a) pulmonary inflammatory markers were to be evaluated in exhaled breath condensate (EBC). Initial testing determined that EBC did not contain detectable levels of analytes and EBC testing was thus discontinued. b) The initial protocol planned for testing at 15 minutes, 1h and 24h following each challenge, which was proven unfeasible from operational and participant time-commitment perspectives. As such, data were only collected at the 1h time-point; and c) the analysis of inflammatory markers was planned to be outsourced to an external laboratory; however, more cost-effective options within our institution were discovered and used (see Outcome measures–systemic inflammation). | PMC10351735 |
Statistical analysis | asthma | ASTHMA | Baseline characteristics for controls and asthma were summarized as mean with standard deviation (SD) for continuous variables and proportions for categorical variables. Differences in baseline clinical characteristics, including lung function and results from the cardiopulmonary exercise test, were evaluated using the student’s t-test or chi-square (χ | PMC10351735 |
Results | PMC10351735 | |||
Participant characteristics | asthma | ASTHMA | One hundred and nineteen potential participants were initially identified from the general population and through chart review. Of these, 25 control participants and 26 participants with asthma were included in the study ( | PMC10351735 |
Consort diagram of recruitment, selection, testing, and analysis. | PMC10351735 | |||
Clinical characteristics, control vs asthma. | LUNG, ASTHMA | Values are expressed as mean (standard deviation) unless otherwise indicated. Lung function values reported were assessed without inhaled bronchodilators prior to testing.BMI: body mass index; ACQ: asthma control questionnaire; FEV | PMC10351735 | |
Pulmonary responses to bronchial challenges | The overall responses in FEV | PMC10351735 | ||
Unadjusted mean change and 95% Cl in FEV | DILATION, ARTERIAL STIFFNESS | FMD: flow-mediated dilation; VHR: velocity time integral adjusted for heart rate; cPWV: central arterial stiffness. | PMC10351735 | |
Systemic responses following positive bronchial challenges | SECONDARY, INFLAMMATORY RESPONSES | The secondary analysis examined vascular and inflammatory responses among only those with a positive test (i.e., a reduction of ≥10% in FEV | PMC10351735 | |
Unadjusted mean change and 95% Cl in FEV | DILATION, ARTERIAL STIFFNESS | FMD: flow-mediated dilation; VHR: velocity time integral adjusted for heart rate; cPWV: central arterial stiffness. | PMC10351735 | |
Systemic inflammatory responses to positive airway challenges regardless of asthma status. | tumor necrosis | TUMOR NECROSIS | Values are expressed as unadjusted means (SD).CRP: C-reactive protein; TNF: tumor necrosis factor; IL-6: interleukin-6. | PMC10351735 |
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