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OBJECTIVES: Ketone bodies are endogenous metabolites produced during fasting or a ketogenic diet that have pleiotropic effects on aging pathways. Ketone esters (KEs) are compounds that induce ketosis without dietary changes, but KEs have not been studied in an older adult population. The primary objective of this trial was to assess the tolerability and safety of KE ingestion in a cohort of older adults. DESIGN: Randomized, placebo-controlled, double-blinded, parallel-arm trial (NCT05585762). SETTING: General community, Northern California, USA. PARTICIPANTS: Community-dwelling older adults, independent in activities of daily living, with no unstable acute medical conditions (n = 30; M = 15, F = 15; age = 76 y, range 65-90 y) were randomized and n = 23 (M = 14, F = 9) completed the protocol. INTERVENTION: Participants were randomly allocated to consume either KE (25 g bis-octanoyl (R)-1,3-butanediol) or a taste, appearance, and calorie-matched placebo (PLA) containing canola oil daily for 12 weeks. MEASUREMENTS: Tolerability was assessed using a composite score from a daily log for 2-weeks, and then via a bi-weekly phone interview. Safety was assessed by vital signs and lab tests at screening and weeks 0, 4 and 12, along with tabulation of adverse events. RESULTS: There was no difference in the prespecified primary outcome of proportion of participants reporting moderate or severe nausea, headache, or dizziness on more than one day in a two-week reporting period (KE n = 2 (14.3% [90% CI = 2.6-38.5]); PLA n = 1 (7.1% [90% CI = 0.4-29.7]). Dropouts numbered four in the PLA group and two in the KE group. A greater number of symptoms were reported in both groups during the first two weeks; symptoms were reported less frequently between 2 and 12 weeks. There were no clinically relevant changes in safety labs or vital signs in either group. CONCLUSIONS: This KE was safe and well-tolerated in this study of healthy older adults. These results provide an initial foundation for use of KEs in clinical research with older adults.
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AIMS: We conducted a clinical trial to determine the efficacy of the combination of vitamin E and/or docosahexaenoic acid (DHA) versus placebo in reducing liver fat content after 6 months of intervention in adults with MASLD. METHODS: Adults with MASLD were randomised to one of four treatment arms (vitamin E 1000 mg/daily + DHA 1.89 g/daily or combination arm, vitamin E 1000 mg alone, DHA 1.89 g alone or placebo) following a 2:1:1:2 randomisation. The primary objective was to determine the efficacy of DHA + vitamin E versus placebo in reducing hepatic fat fraction (%) relative to baseline after 6 months of intervention. Secondary objectives were to determine the effect of vitamin E or DHA alone versus placebo on reducing liver fat at 6 months. RESULTS: Our cohort consisted of 203 subjects with a mean age of 51 years, 53% female, 91% White, 59% Hispanic ethnicity. The combination of vitamin E + DHA had no effect on the primary endpoint of reducing hepatic steatosis as determined by MRI-PDFF (p = 0.98). Neither vitamin E alone (p = 0.91) nor DHA alone (p = 0.14) significantly reduced hepatic steatosis compared to placebo. However, the trial was not powered adequately for this analysis. Compared with placebo, no statistically significant differences were detected in the 3-month or 6-month levels for ALT (U/L) or AST (U/L) in all three intervention groups. CONCLUSIONS: The combination of DHA + vitamin E or either agent alone did not demonstrate efficacy on reducing liver fat or aminotransferases in the studied population.
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Ácidos Docosahexaenoicos , Hígado Graso , Vitamina E , Humanos , Femenino , Masculino , Ácidos Docosahexaenoicos/uso terapéutico , Ácidos Docosahexaenoicos/administración & dosificación , Vitamina E/uso terapéutico , Vitamina E/administración & dosificación , Persona de Mediana Edad , Método Doble Ciego , Adulto , Hígado Graso/tratamiento farmacológico , Resultado del Tratamiento , Anciano , Quimioterapia Combinada , Hígado/efectos de los fármacos , Hígado/metabolismoRESUMEN
Objectives: Ketone bodies are endogenous metabolites produced during fasting or a ketogenic diet that have pleiotropic effects on aging pathways. Ketone esters (KEs) are compounds that induce ketosis without dietary changes, but KEs have not been studied in an older adult population. The primary objective of this trial was to determine tolerability and safety of KE ingestion in older adults. Design: Randomized, placebo-controlled, double-blinded, parallel-arm trial, with a 12-week intervention period ( NCT05585762 ). Setting: General community, Northern California, USA. Participants: Community-dwelling older adults, independent in activities of daily living, with no unstable acute medical conditions (n=30) were randomized and n=23 (M= 14, F=9) completed the protocol. Intervention: Participants were randomly allocated to consume either KE (bis-octanoyl (R)-1,3-butanediol) or a taste, appearance, and calorie-matched placebo (PLA) containing canola oil. Measurements: Tolerability was assessed using a composite score from a daily log for 2-weeks, and then via a bi-weekly phone interview. Safety was assessed by vital signs and lab tests at screening and weeks 0, 4 and 12, along with tabulation of adverse events. Results: There was no difference in the prespecified primary outcome of proportion of participants reporting moderate or severe nausea, headache, or dizziness on more than one day in a two-week reporting period (KE n =2 (14.3% [90% CI = 2.6 - 38.5]); PLA n=1 (7.1% [90% CI = 0.4 - 29.7]). Dropouts numbered four in the PLA group and two in the KE group. A greater number of symptoms were reported in both groups during the first two weeks; symptoms were reported less frequently between 2 - 12 weeks. There were no clinically relevant changes in safety labs or vital signs in either group. Conclusions: This KE was safe and well-tolerated in healthy older adults. These results provide a foundation for use of KEs in aging research. Highlights: Ketones esters induce ketosis without dietary changes and may target aging biologyStudies of ketone esters were limited in duration and focused on younger adultsWe found ketone esters were safe and tolerable for 12 weeks in healthy older adults.
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Background: Frailty is a geriatric syndrome characterized by chronic inflammation and metabolic insufficiency that creates vulnerability to poor outcomes with aging. We hypothesize that geroscience interventions, which target mechanisms of aging, could ameliorate frailty. Metabolites such as ketone bodies are candidate geroscience interventions, having pleiotropic effects on inflammo-metabolic aging mechanisms. Ketone esters (KEs) induce ketosis without dietary changes, but KEs have not been studied in an older adult population. Our long-term goal is to examine if KEs modulate geroscience mechanisms and clinical outcomes relevant to frailty in older adults. Objectives: The primary objective of this randomized, placebo-controlled, double-blinded, parallel-group, pilot trial is to determine tolerability of 12-weeks of KE ingestion in a generalizable population of older adults (≥ 65 years). Secondary outcomes include safety and acute blood ketone kinetics. Exploratory outcomes include physical function, cognitive function, quality of life, aging biomarkers and inflammatory measures. Methods: Community-dwelling adults who are independent in activities of daily living, with no unstable acute medical conditions (n=30) will be recruited. The study intervention is a KE or a taste, appearance, and calorie matched placebo beverage. Initially, acute 4-hour ketone kinetics after 12.5g or 25g of KE consumption will be assessed. After collection of baseline safety, functional, and biological measurements, subjects will randomly be allocated to consume KE 25g or placebo once daily for 12-weeks. Questionnaires will assess tolerability daily for 2-weeks, and then via phone interview at bi-monthly intervals. Safety assessments will be repeated at week 4. All measures will be repeated at week 12. Conclusion: This study will evaluate feasibility, tolerability, and safety of KE consumption in older adults and provide exploratory data across a range of geroscience-related endpoints. This data will inform design of larger trials to rigorously test KE effects on geroscience mechanisms and clinical outcomes relevant to frailty.
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The probiotic strain Lacticaseibacillus paracasei (previously Lactobacillus casei) strain Shirota (LcS) has demonstrated its survivability in the gastrointestinal tract across populations in different countries. The objective of this study was to validate this survivability in the United States, where evidence is lacking. Faecal samples were collected from 26 healthy individuals (age: 32.0 ± 5.9 years) at baseline, after 7 and 14 days of daily consumption of 80 mL fermented milk containing 108 colony forming units (CFU) LcS/mL, and after a subsequent 14-days of no product consumption. Live LcS counts significantly (p < 0.001) increased after 7 and 14 days of product consumption (6.37 ± 1.18 and 5.24 ± 1.81 log10 CFU/g faeces, respectively) and returned to baseline in 87% of participants. These results indicate LcS survives passage through the gastrointestinal tract of generally healthy U.S. adults, providing support for its uniquely accumulated evidence of universal survival capacity in the gastrointestinal tract.
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Lacticaseibacillus paracasei , Probióticos , Adulto , Humanos , Animales , Leche , Lacticaseibacillus , Tracto GastrointestinalRESUMEN
Introduction: Bis-hexanoyl (R)-1,3-butanediol (BH-BD) is a novel ketone ester that, when consumed, is hydrolyzed into hexanoic acid (HEX) and (R)-1,3-butanediol (BDO) which are subsequently metabolized into beta-hydroxybutyrate (BHB). Methods: We undertook a randomized, parallel, open-label study in healthy adults (n = 33) to elucidate blood BHB, HEX and BDO concentrations for 8 h following consumption of three different serving sizes (SS) of BH-BD (12.5, 25 and 50 g/day) before (Day 0) and after 7 days of daily BH-BD consumption (Day 7). Results: Maximal concentration and area under the curve of all metabolites increased proportionally to SS and were greatest for BHB followed by BDO then HEX on both Day 0 and 7. Metabolite half-life tended to decrease with increasing SS for BHB and HEX. Time to peak concentration increased with increasing SS for BHB and BDO on both days. In vitro incubation of BH-BD in human plasma demonstrated BH-BD undergoes rapid spontaneous hydrolysis. Conclusion: These results demonstrate that orally ingested BH-BD is hydrolyzed into products that appear in the plasma and undergo conversion to BHB in a SS dependent manner, and that metabolism of BH-BD neither becomes saturated at serving sizes up to 50 g nor displays consistent adaptation after 7 days of daily consumption.
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Dietary fibre modulates gastrointestinal (GI) health and function, providing laxation, shifting microbiota, and altering bile acid (BA) metabolism. Fruit juice production removes the polyphenol- and fibre-rich pomace fraction. The effects of orange and apple pomaces on GI outcomes were investigated in healthy, free-living adults. Healthy adults were enrolled in two double-blinded, crossover trials, being randomised by baseline bowel movement (BM) frequency. In the first trial, subjects (n 91) received orange juice (OJ, 0 g fibre/d) or OJ + orange pomace (OJ + P, 10 g fibre/d) for 4 weeks, separated by a 3-week washout. Similarly, in the second trial, subjects (n 90) received apple juice (AJ, 0 g fibre/d) or AJ + apple pomace (AJ + P, 10 g fibre/d). Bowel habit diaries, GI tolerance surveys and 3-d diet records were collected throughout. Fresh faecal samples were collected from a participant subset for microbiota and BA analyses in each study. Neither pomace interventions influenced BM frequency. At Week 4, OJ + P tended to increase (P = 0·066) GI symptom occurrence compared with OJ, while AJ + P tended (P = 0·089) to increase flatulence compared with AJ. Faecalibacterium (P = 0·038) and Negativibacillus (P = 0·043) were differentially abundant between pre- and post-interventions in the apple trial but were no longer significant after false discovery rate (FDR) correction. Baseline fibre intake was independently associated with several microbial genera in both trials. Orange or apple pomace supplementation was insufficient to elicit changes in bowel habits, microbiota diversity or BA of free-living adults with healthy baseline BM. Future studies should consider baseline BM frequency and habitual fibre intake.
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Citrus sinensis , Malus , Microbiota , Humanos , Adulto , Frutas , Ácidos y Sales Biliares , Defecación , Heces/microbiología , Fibras de la Dieta/farmacología , HábitosRESUMEN
We investigated the gastrointestinal (GI) tolerance of soluble corn fibre (SCF) compared with inulin in children 3-9 years old. SCF (3-8 g/d for 10d) was tolerated as well as inulin: no differences were identified in stool frequency and consistency, proportion of subjects with at least one loose stool or reporting symptoms during bowel movement. Compared to inulin, 6 g/d of SCF lowered gas severity in children aged 3-5 years old. No differences were noted for alpha and beta diversity, relative abundance of Bacteroidota, Firmicutes, Ruminococcaceae, or the Firmicutes to Bacteroidota ratio. Relative abundance of some specific strains (i.e. Anaerostipes, Bifidobacterium, Fusicatenibacter, Parabacteroides) varied depending on the fibre type and dose level. Fortification at a level of 6-8 g/d of SCF and/or inulin could help addressing the fibre gap without any GI discomfort.
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Inulina , Zea mays , Niño , Humanos , Preescolar , Fibras de la Dieta , Heces/microbiología , BifidobacteriumRESUMEN
Abstract: Durable spore-forming probiotics are increasingly formulated into foods, beverages, and dietary supplements. To help meet this demand, the safety and efficacy of daily supplementation of Bacillus subtilis BS50 for 6 weeks was investigated in a randomized, double-blind, placebo-controlled, parallel clinical trial of 76 healthy adults. Before and during supplementation, gastrointestinal symptoms were recorded daily using a multi-symptom questionnaire. Clinical chemistry, hematology, plasma lipids, and intestinal permeability and inflammation markers were measured at baseline and end of study. Compared to placebo, 2 × 109 colony-forming units (CFU) BS50 per day increased the proportion of participants showing improvement from baseline to week 6 in the composite score for bloating, burping, and flatulence (47.4% vs. 22.2%), whereby the odds of detecting an improvement were higher with BS50 (OR [95% CI]: 3.2 [1.1, 8.7], p = .024). Analyses of individual gastrointestinal symptoms indicate that BS50 increased the proportion of participants showing an improvement at week 6 compared to placebo for burping (44.7% vs. 22.2%, p = .041) and bloating (31.6% vs. 13.9%, p = .071), without affecting other symptoms. There were no clinically meaningful changes in clinical chemistry, hematology, plasma lipids and intestinal permeability and other inflammation markers. In conclusion, the results suggest that dietary supplementation of 2 × 109 CFU Bacillus subtilis BS50 per day is a well-tolerated and safe strategy to alleviate gas-related gastrointestinal symptoms in healthy adults. ABBREVIATIONS: AE adverse event; BHD bowel habits diary; BMI body mass index; BSS Bristol Stool Scale; CFU colony-forming unit; CRP C-reactive protein; FGID functional gastrointestinal disorder; GI gastrointestinal; GITQ Gastrointestinal Tolerance Questionnaire; GLP-1 glucagon-like peptide 1; GSRS Gastrointestinal Symptom Rating Scale; HDL-C high-density lipoprotein-cholesterol; IBS irritable bowel syndrome; IL-10 interleukin-10; ITT intent-to-treat; LBP lipopolysaccharide binding protein; LDL-C low-density lipoprotein-cholesterol; PP per protocol; PYY peptide YY; TG triglyceride; total-C total cholesterol.
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Bacillus subtilis , Enfermedades Gastrointestinales , Microbioma Gastrointestinal , Síndrome del Colon Irritable , Probióticos , Adulto , Humanos , Proteína C-Reactiva , LDL-Colesterol , Método Doble Ciego , Enfermedades Gastrointestinales/terapia , Péptido 1 Similar al Glucagón , Interleucina-10 , Síndrome del Colon Irritable/terapia , Lipopolisacáridos , Lipoproteínas HDL , Péptido YY , Probióticos/uso terapéutico , Resultado del Tratamiento , TriglicéridosRESUMEN
BACKGROUND/OBJECTIVES: Although thromboembolism (TE) is a serious complication in patients with acute lymphoblastic leukemia (ALL), thromboprophylaxis is not commonly used due to the inherent bleeding risk in this population. Identifying prothrombotic risk factors will help target thromboprophylaxis to those at highest thrombotic risk. We aimed to define predictors and the impact of TE on ALL outcome in children (1-18 years) treated on the Dana-Farber Cancer Institute ALL 05-001 trial. METHODS: Clinical and laboratory data including TE events were prospectively collected. PCR-based allelic discrimination assay identified single-nucleotide polymorphisms (SNP) for prothrombin G20210A (rs1799963) and Factor V G1691A (rs6025). Univariate and multivariable competing risk regression models evaluated the effect of diagnostic clinical (age, sex, body mass index, ALL-immunophenotype, risk group) and laboratory variables (presenting leukocyte count, blood group, SNPs) on the cumulative incidence of TE. Cox regression modeling explored the impact of TE on survival. RESULTS: Of 794 patients [median age 4.97 (range, 1.04-17.96) years; males 441], 100 developed TE; 25-month cumulative incidence 13.0% (95% CI, 10.7%-15.5%). Univariate analyses identified older age (≥10 years), presenting leucocyte count, T-ALL, high-risk ALL, and non-O blood group as risk factors. Age and non-O blood group were independent predictors of TE on multivariable regression; the blood group impact being most evident in patients 1-5 years of age (P = 0.011). TE did not impact survival. Induction TE was independently associated with induction failure (OR 6.45; 95% CI, 1.64-25.47; P = 0.008). CONCLUSION: We recommend further evaluation of these risk factors and consideration of thromboprophylaxis for patients ≥10 years (especially those ≥15 years) when receiving asparaginase.
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Antígenos de Grupos Sanguíneos , Leucemia-Linfoma Linfoblástico de Células Precursoras , Trombosis , Tromboembolia Venosa , Anticoagulantes/efectos adversos , Antígenos de Grupos Sanguíneos/uso terapéutico , Niño , Preescolar , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Factores de Riesgo , Trombosis/inducido químicamente , Trombosis/epidemiologíaRESUMEN
BACKGROUND: Ocular abnormalities (OA) in pediatric patients with acute lymphoblastic leukemia (ALL) are common findings both at diagnosis and later in follow-up. The frequency, predictors, and prognostic impact of OA in the context of recent ALL protocols are not well characterized. PROCEDURE: Single-center retrospective analysis of the medical records of 224 patients with ALL enrolled on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001. RESULTS: Overall, 217 (98%) patients had at least one ophthalmic exam. Retinal hemorrhages were the most frequent abnormalities at diagnosis (11%) and cataracts at later time points (13%). OA at diagnosis were associated with age ≥10 years and with the severity of anemia and thrombocytopenia; they were also univariately associated with lower 5-year event-free survival (EFS) (high risk [HR] = 3.09 [95% CI: 1.38-6.94]; p = .006), but not in a disease-free survival (DFS) model adjusted for end-induction minimal residual disease (p = .82). The cumulative incidence of cataract was 13.1% ± 2.8% at 43 months from diagnosis; its development was associated with high presenting white blood cell count (≥50,000/µl) (p = .010), male sex (p = .036), higher risk group (p = .025), and cranial radiation (p = .004). Cataract was associated with decreased visual acuity. CONCLUSIONS: OA at diagnosis, present in 12% of patients, were associated with older age, anemia, and thrombocytopenia and did not carry a significant prognostic impact. Cataracts were detected in over 10% of patients and were associated with decreased visual acuity, thus supporting routine screening after completion of therapy, especially for those treated with high-risk protocols.
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Catarata , Leucemia-Linfoma Linfoblástico de Células Precursoras , Trombocitopenia , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica , Catarata/etiología , Niño , Supervivencia sin Enfermedad , Humanos , Lactante , Masculino , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Pronóstico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
We sought to assess the safety of adding ixazomib, an oral proteasome inhibitor, to a multi-agent treatment regimen for older adults with acute lymphoblastic leukemia (ALL). Patients 51 to 75 years of age with newly diagnosed ALL were screened. Induction consisted of prednisone (P), vincristine (V), and doxorubicin (D). For BCR-ABL1+ patients, dasatinib was added. On Days 1, 8, 15 of induction, ixazomib was given orally. After induction patients received 1 cycle of consolidation in which ixazomib was given on Days 1, 8, 15. After consolidation, patients in remission (CR) were offered stem cell transplantation. Among the 19 patients treated, 15 (79%) [90% CI, 58-92%] achieved CR or CRi. At 2 years, the overall survival was 47% [95%CI, 29-72%]. In this study the dose of 2.3 mg of ixazomib in combination was the MTD for older patients with ALL and is the recommended dose for future phase 2 studies.
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Protocolos de Quimioterapia Combinada Antineoplásica , Leucemia-Linfoma Linfoblástico de Células Precursoras , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Compuestos de Boro/efectos adversos , Glicina/análogos & derivados , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/etiología , Inducción de Remisión , Resultado del Tratamiento , Vincristina/uso terapéuticoRESUMEN
Home confinement during the COVID-19 pandemic is accompanied by dramatic changes in lifestyle and dietary behaviors that can significantly influence health. We conducted an online cross-sectional survey to assess COVID-19 pandemic-induced dietary and lifestyle changes and their association with perceived health status and self-reported body weight changes among 1000 Indian adults in early 2021. Positive improvements in dietary habits, e.g., eating more nutritious (85% of participants) and home-cooked food (89%) and an increase in overall nutrition intake (79%), were observed. Sixty-five percent of participants self-reported increased oat consumption to support immunity. There were some negative changes, e.g., more binge eating (69%), eating more in between meals (67%), and increasing meal portion size (72%). Two-thirds of participants reported no change in lifestyles, whereas 21 and 23% reported an increase, and 13 and 10% reported a decrease in physical activity and sleep, respectively. Overall, 64 and 65% of participants reported an improvement in perceived health and an increase in body weight during the COVID-19 period compared to pre-COVID-19, respectively. The top motivations for improving dietary habits included improving physical and mental health and building immunity. In conclusion, the overall perceived health was improved and there was an increase in self-reported body weight in most participants during COVID-19. Diet emerged as the most crucial determinant for these changes.
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COVID-19 , Dieta Saludable , Ejercicio Físico , Conducta Alimentaria , Cuarentena , Sueño , Adolescente , Adulto , Estudios Transversales , Encuestas sobre Dietas , Femenino , Preferencias Alimentarias , Humanos , Sistema Inmunológico/fisiología , India , Masculino , Salud Mental , Persona de Mediana Edad , Estado Nutricional , Valor Nutritivo , Estudios Prospectivos , Factores de Tiempo , Adulto JovenRESUMEN
PURPOSE: Dana-Farber Cancer Institute Acute Lymphoblastic Leukemia (ALL) Consortium Protocol 11-001 assessed efficacy and toxicity of calaspargase pegol (calaspargase), a novel pegylated asparaginase formulation with longer half-life, compared with the standard formulation pegaspargase. METHODS: Patients age 1 to ≤ 21 years with newly diagnosed ALL or lymphoblastic lymphoma were randomly assigned to intravenous pegaspargase or calaspargase, 2,500 IU/m2/dose. Patients received one induction dose. Beginning week 7, pegaspargase was administered every 2 week for 15 doses and calaspargase every 3 week for 10 doses (30 weeks). Serum asparaginase activity (SAA) (≥ 0.1 IU/mL considered therapeutic) was assessed 4, 11, 18, and 25 days after the induction dose and before each postinduction dose. RESULTS: Between 2012 and 2015, 239 eligible patients enrolled (230 ALL, nine lymphoblastic lymphoma); 120 were assigned to pegaspargase and 119 to calaspargase. After the induction dose, SAA was ≥ 0.1 IU/mL in ≥ 95% of patients on both arms 18 days after dosing. At day 25, more patients had SAA ≥ 0.1 IU/mL with calaspargase (88% v 17%; P Ë .001). Postinduction, median nadir SAAs were similar (≥ 1.0 IU/mL) for both arms. Of 230 evaluable patients, 99% of pegaspargase and 95% of calaspargase patients achieved complete remission (P = .12), with no difference in frequency of high end-induction minimal residual disease among evaluable patients with B acute lymphoblastic leukemia (B-ALL). There were no differences in frequencies of asparaginase allergy, pancreatitis, thrombosis, or hyperbilirubinemia. With 5.3 years median follow-up, 5-year event-free survival for pegaspargase was 84.9% (SE ± 3.4%) and 88.1% (± SE 3.0%) for calaspargase (P = .65). CONCLUSION: Every 3-week calaspargase had similar nadir SAA, toxicity, and survival outcomes compared with every 2-week pegaspargase. The high nadir SAA observed for both preparations suggest dosing strategies can be further optimized.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamiento farmacológico , Adolescente , Adulto , Asparaginasa/administración & dosificación , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Polietilenglicoles/administración & dosificación , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Tasa de Supervivencia , Estados Unidos/epidemiología , Adulto JovenRESUMEN
Nutritional ketosis is a state of mildly elevated blood ketone concentrations resulting from dietary changes (e.g., fasting or reduced carbohydrate intake) or exogenous ketone consumption. In this study, we determined the tolerability and safety of a novel exogenous ketone diester, bis-hexanoyl-(R)-1,3-butanediol (BH-BD), in a 28-day, randomized, double-blind, placebo-controlled, parallel trial (NCT04707989). Healthy adults (n = 59, mean (SD), age: 42.8 (13.4) y, body mass index: 27.8 (3.9) kg/m2) were randomized to consume a beverage containing 12.5 g (Days 0-7) and 25 g (Days 7-28) of BH-BD or a taste-matched placebo daily with breakfast. Tolerability, stimulation, and sedation were assessed daily by standardized questionnaires, and blood and urine samples were collected at Days 0, 7, 14, and 28 for safety assessment. There were no differences in at-home composite systemic and gastrointestinal tolerability scores between BH-BD and placebo at any time in the study, or in acute tolerability measured 1-h post-consumption in-clinic. Weekly at-home composite tolerability scores did not change when BH-BD servings were doubled. At-home scores for stimulation and sedation did not differ between groups. BH-BD significantly increased blood ketone concentrations 1-h post-consumption. No clinically meaningful changes in safety measures including vital signs and clinical laboratory measurements were detected within or between groups. These results support the overall tolerability and safety of consumption of up to 25 g/day BH-BD.
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Butileno Glicoles/farmacología , Cetosis/inducido químicamente , Adulto , Bebidas , Glucemia/análisis , Butileno Glicoles/administración & dosificación , Butileno Glicoles/efectos adversos , Butileno Glicoles/sangre , Método Doble Ciego , Femenino , Humanos , Cuerpos Cetónicos/sangre , Masculino , Encuestas y CuestionariosRESUMEN
OBJECTIVE: Promising evidence suggests beneficial health effects of arabinogalactan, but little is known about the effect of this non-digestible carbohydrate on the gut microbiota, a crucial mediator of human health. The objective of this study was to investigate the effect of an arabinogalactan product (ResistAid) on the fecal microbiome and short-chain fatty acids and gastrointestinal tolerance in healthy adults in a randomized, double-blind, crossover trial. METHODS: Thirty adults were randomly assigned to consume 15 g/d maltodextrin (control) or ResistAid for 6 wk. RESULTS: At week 6, compared to placebo, ResistAid supplementation led to a significant decrease in the ratio of fecal Firmicutes to Bacteroidetes, driven by an increase in Bacteroidetes and a decrease in Firmicutes. Moreover, the relative abundance of Bifidobacterium tended to increase with ResistAid supplementation. Additionally, ResistAid significantly decreased the α-diversity of the fecal microbiome. Predicted functional abundances based on 16S rRNA sequences showed that ResistAid supplementation increased the gene abundance of the gut microbiome for α-l-rhamnosidase, ß-fructosidase, and levanase, as well as tricarboxylic acid and vitamin B6 biosynthesis pathways. Fecal isovaleric, valeric, and hexanoic acids were significantly lower after ResistAid consumption. There were no statistically significant changes in bowel habit, stool consistency, gastrointestinal tolerance symptoms, chemistry profile, metabolic panel, or vitals, suggesting that consumption of 15 g daily ResistAid over 6 wk is safe. CONCLUSION: These results demonstrate that the gut microbiome composition and predicted functions can be modulated by ResistAid consumption, perhaps suggesting a mechanistic explanation on its reported benefits in metabolic parameters and the immune system.
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Microbioma Gastrointestinal , Adulto , Estudios Cruzados , Galactanos , Humanos , ARN Ribosómico 16S/genéticaRESUMEN
Despite a remarkable increase in the genomic profiling of cancer, integration of genomic discoveries into clinical care has lagged behind. We report the feasibility of rapid identification of targetable mutations in 153 pediatric patients with relapsed/refractory or high-risk leukemias enrolled on a prospective clinical trial conducted by the LEAP Consortium. Eighteen percent of patients had a high confidence Tier 1 or 2 recommendation. We describe clinical responses in the 14% of patients with relapsed/refractory leukemia who received the matched targeted therapy. Further, in order to inform future targeted therapy for patients, we validated variants of uncertain significance, performed ex vivo drug-sensitivity testing in patient leukemia samples, and identified new combinations of targeted therapies in cell lines and patient-derived xenograft models. These data and our collaborative approach should inform the design of future precision medicine trials. SIGNIFICANCE: Patients with relapsed/refractory leukemias face limited treatment options. Systematic integration of precision medicine efforts can inform therapy. We report the feasibility of identifying targetable mutations in children with leukemia and describe correlative biology studies validating therapeutic hypotheses and novel mutations.See related commentary by Bornhauser and Bourquin, p. 1322.This article is highlighted in the In This Issue feature, p. 1307.
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Leucemia/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Biomarcadores de Tumor/genética , Niño , Estudios de Cohortes , Progresión de la Enfermedad , Estudios de Factibilidad , Femenino , Humanos , Leucemia/genética , Leucemia/mortalidad , Masculino , Terapia Molecular Dirigida , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/mortalidad , Estudios Prospectivos , Estados UnidosRESUMEN
The study describes patient-reported experiences and recommendations to improve the genetic counseling and multigene panel testing (MGPT) process. A descriptive mixed-method study with concurrently collected and integrated qualitative and quantitative data was conducted. Eligible participants were English-speaking adults with a breast or gynecologic cancer diagnosis who had received genetic counseling and testing with a MGPT from one Comprehensive Cancer Center. Satisfaction with the genetic counseling, genetic knowledge using a recently validated scale (KnowGene), the multidimensional impact of cancer risk assessment (MICRA), family communication, and the association with demographic factors were evaluated. To supplement the large quantitative data set, qualitative focus group responses and open-ended text items were collected. Univariate and multivariable associations between each outcome of interest and personal characteristics were assessed. Qualitative data were content-analyzed. 603 participants completed the survey (48% response rate) and 10 individuals participated in the focus groups. Participants were mostly Caucasian, educated with a college degree or more, and female with median age 58 (24-91), and 78% of participants had a breast cancer diagnosis. Of all individuals undergoing genetic testing using a MGPT, 13% had a pathogenic variant identified, and 30% had a variant of uncertain significance (VUS). Overall, participants reported satisfaction with the genetic counseling and testing process (mean 36.9 [SD 4.7]). On average, participants had 7 incorrect answers out of 19 on the genetic knowledge scale (mean 12.3 [SD 3.4]). MICRA scores showed overall low levels of distress and uncertainty, as well as positive experiences, with wide variability (median 17 [0-84]). Age, marital status, education level, type of cancer diagnosis, and genetic testing results were significantly associated with outcomes. Most participants communicated genetic testing results to mainly female first-degree relatives. A wide range of individual preferences affecting overall satisfaction, or suggestions for improvement were shared. As new models of streamlined cancer genetic services are being clinically implemented, approaches should continue to assess and tailor the process based on patients' informational and emotional needs.
Asunto(s)
Neoplasias de la Mama , Predisposición Genética a la Enfermedad , Adulto , Neoplasias de la Mama/genética , Femenino , Asesoramiento Genético , Pruebas Genéticas , Humanos , Persona de Mediana Edad , IncertidumbreRESUMEN
INTRODUCTION: Men diagnosed with localized prostate cancer must navigate a highly preference-sensitive decision between treatment options with varying adverse outcome profiles. We evaluated whether use of a decision support tool previously shown to decrease decisional conflict also impacted the secondary outcome of post-treatment decision regret. METHODS: Participants were randomized to receive personalized decision support via the Personal Patient Profile-Prostate or usual care prior to a final treatment decision. Symptoms were measured just before randomization and 6 months later; decision regret was measured at 6 months along with records review to ascertain treatment choices. Regression modeling explored associations between baseline variables including race and D`Amico risk, study group, and 6-month variables regret, choice, and symptoms. RESULTS: At 6 months, 287 of 392 (73%) men returned questionnaires of which 257 (89%) had made a treatment choice. Of that group, 201 of 257 (78%) completely answered the regret scale. Regret was not significantly different between participants randomized to the P3P intervention compared to the control group (Pâ¯=â¯0.360). In univariate analyses, we found that Black men, men with hormonal symptoms, and men with bowel symptoms reported significantly higher decision regret (all P < 0.01). Significant interactions were detected between race and study group (intervention vs. usual care) in the multivariable model; use of the Personal Patient Profile-Prostate was associated with significantly decreased decisional regret among Black men (Pâ¯=â¯0.037). Interactions between regret, symptoms and treatment revealed that (1) men choosing definitive treatment and reporting no hormonal symptoms reported lower regret compared to all others; and (2) men choosing active surveillance and reporting bowel symptoms had higher regret compared to all others. CONCLUSION: The Personal Patient Profile-Prostate decision support tool may be most beneficial in minimizing decisional regret for Black men considering treatment options for newly-diagnosed prostate cancer. TRIAL REGISTRATION: NCT01844999.