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Molecular correlates of response to eribulin and pembrolizumab in hormone receptor-positive metastatic breast cancer.
Keenan, TE, Guerriero, JL, Barroso-Sousa, R, Li, T, O'Meara, T, Giobbie-Hurder, A, Tayob, N, Hu, J, Severgnini, M, Agudo, J, et al
Nature communications. 2021;(1):5563
Abstract
Immune checkpoint inhibitors (ICIs) have minimal therapeutic effect in hormone receptor-positive (HR+ ) breast cancer. We present final overall survival (OS) results (n = 88) from a randomized phase 2 trial of eribulin ± pembrolizumab for patients with metastatic HR+ breast cancer, computationally dissect genomic and/or transcriptomic data from pre-treatment tumors (n = 52) for molecular associations with efficacy, and identify cytokine changes differentiating response and ICI-related toxicity (n = 58). Despite no improvement in OS with combination therapy (hazard ratio 0.95, 95% CI 0.59-1.55, p = 0.84), immune infiltration and antigen presentation distinguished responding tumors, while tumor heterogeneity and estrogen signaling independently associated with resistance. Moreover, patients with ICI-related toxicity had lower levels of immunoregulatory cytokines. Broadly, we establish a framework for ICI response in HR+ breast cancer that warrants diagnostic and therapeutic validation. ClinicalTrials.gov Registration: NCT03051659.
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Ingestion of an exogenous ketone monoester improves the glycemic response during oral glucose tolerance test in individuals with impaired glucose tolerance: A cross-over randomized trial.
Nakagata, T, Tamura, Y, Kaga, H, Sato, M, Yamasaki, N, Someya, Y, Kadowaki, S, Sugimoto, D, Satoh, H, Kawamori, R, et al
Journal of diabetes investigation. 2021;(5):756-762
Abstract
AIMS/INTRODUCTION As a low-carbohydrate diet and the use of sodium-glucose transporter-2 inhibitors are both known to increase D-beta-hydroxybutyrate levels, the effect of these levels on glucose metabolism has attracted attention. We investigated the acute effects of ketone monoester (KM) ingestion on blood glucose levels during the 75-g oral glucose tolerance test (OGTT) in participants with impaired glucose tolerance. MATERIALS AND METHODS Nine Japanese adults aged 48-62 years (4 men, 5 women) with impaired glucose tolerance participated in this study. After participants fasted overnight, we carried out OGTT for 180 min with and without KM ingestion on two separate days in a randomized cross-over design. We compared the area under the curve (AUC) of D-beta-hydroxybutyrate, glucose, insulin, C-peptide, glucagon and free fatty acids during OGTT. RESULTS The AUC of D-beta-hydroxybutyrate during OGTT was significantly higher with KM than without KM (KM 5995.3 ± 1257.1 mmol/L·h; without KM 116.1 ± 33.9 mmol/L·h, P < 0.0001), and the AUC of glucose with KM was significantly lower than that without KM (KM 406.6 ± 70.6 mg/dL·h; without KM 483.2 ± 74.3 mg/dL·h, P < 0.0001). This improved glucose excursion was associated with enhanced AUC of insulin during the first half (0-90 min) of OGTT, even though the AUC of C-peptide during this period was unchanged. In contrast, the AUC of insulin, C-peptide, glucagon and free fatty acids during 180 min of OGTT were similar in both conditions. CONCLUSION The ingestion of KM decreased the AUC of glucose during 75-g OGTT in Japanese individuals with impaired glucose tolerance, and the mechanism might involve elevated levels of circulating early phase insulin.
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14-Day Ketone Supplementation Lowers Glucose and Improves Vascular Function in Obesity: A Randomized Crossover Trial.
Walsh, JJ, Neudorf, H, Little, JP
The Journal of clinical endocrinology and metabolism. 2021;(4):e1738-e1754
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Abstract
CONTEXT Postprandial hyperglycemia increases systemic inflammation and is a risk factor for cardiovascular disease. A ketone monoester (KME) drink containing β-hydroxybutyrate (β-OHB) rapidly lowers plasma glucose, which may be a strategy protecting against postprandial hyperglycemia. OBJECTIVE We hypothesized that KME would attenuate 2-hour postprandial glucose, lower systemic inflammation, and improve vascular function in adults with obesity. METHODS In a randomized crossover design, 14 participants with obesity (age = 56 ± 12 years; body mass index = 32.8 ± 7.7 kg/m2) consumed KME (12 g β-OHB) or placebo 15 minutes prior to each meal for 14 days with all meals provided and matched between conditions. Postprandial glycemia was assessed by continuous glucose monitoring. Vascular function and inflammation were assessed before and after treatment periods. RESULTS Postprandial glucose was 8.0% lower in KME versus placebo (g = 0.735; P = 0.011) and 24-hour average glucose reduced by 7.8% (g = 0.686; P = 0.0001). Brachial artery flow-mediated dilation increased from 6.2 ± 1.5% to 8.9 ± 3.3% in KME (g = 1.05; P = 0.0004) with no changes in placebo (condition × time interaction, P = 0.004). There were no changes in plasma cytokines; however, lipopolysaccharide-stimulated monocyte caspase-1 activation was lower following KME supplementation versus placebo (stimulation × condition × time interaction; P = 0.004). The KME supplement was well tolerated by participants and adherence to the supplementation regimen was very high. CONCLUSIONS In adults with obesity, 14 days of premeal KME supplementation improves glucose control, enhances vascular function, and may reduce cellular inflammation. KME supplementation may be a viable, nonpharmacological approach to improving and protecting vascular health in people with heightened cardiometabolic risk.
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Comparison of Ketogenic Diets with and without Ketone Salts versus a Low-Fat Diet: Liver Fat Responses in Overweight Adults.
Crabtree, CD, Kackley, ML, Buga, A, Fell, B, LaFountain, RA, Hyde, PN, Sapper, TN, Kraemer, WJ, Scandling, D, Simonetti, OP, et al
Nutrients. 2021;(3)
Abstract
Ketogenic diets (KDs) often contain high levels of saturated fat, which may increase liver fat, but the lower carbohydrate intake may have the opposite effect. Using a controlled feeding design, we compared liver fat responses to a hypocaloric KD with a placebo (PL) versus an energy-matched low-fat diet (LFD) in overweight adults. We also examined the added effect of a ketone supplement (KS). Overweight adults were randomized to a 6-week KD (KD + PL) or a KD with KS (KD + KS); an LFD group was recruited separately. All diets were estimated to provide 75% of energy expenditure. Weight loss was similar between groups (p > 0.05). Liver fat assessed by magnetic resonance imaging decreased after 6 week (p = 0.004) with no group differences (p > 0.05). A subset with nonalcoholic fatty liver disease (NAFLD) (liver fat > 5%, n = 12) showed a greater reduction in liver fat, but no group differences. In KD participants with NAFLD, 92% of the variability in change in liver fat was explained by baseline liver fat (p < 0.001). A short-term hypocaloric KD high in saturated fat does not adversely impact liver health and is not impacted by exogenous ketones. Hypocaloric low-fat and KDs can both be used in the short-term to significantly reduce liver fat in individuals with NAFLD.
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The Titanium-coated PEEK Cage Maintains Better Bone Fusion With the Endplate Than the PEEK Cage 6 Months After PLIF Surgery: A Multicenter, Prospective, Randomized Study.
Hasegawa, T, Ushirozako, H, Shigeto, E, Ohba, T, Oba, H, Mukaiyama, K, Shimizu, S, Yamato, Y, Ide, K, Shibata, Y, et al
Spine. 2020;(15):E892-E902
Abstract
STUDY DESIGN A multicenter, randomized, open-label, parallel-group trial. OBJECTIVE To investigate interbody bone fusion rates in titanium-coated polyetheretherketone (TiPEEK) and polyetheretherketone (PEEK) cages after posterior lumbar interbody fusion (PLIF) surgery. SUMMARY OF BACKGROUND DATA Previous clinical studies have not revealed any significant difference in bone fusion rates between TiPEEK and PEEK cages. METHODS During one-level PLIF surgery, 149 patients (84 men, 65 women, mean age 67 yr) were randomly allocated to use either a TiPEEK cage (n = 69) or PEEK cage (n = 80). Blinded radiographic evaluations were performed using computed tomography and assessed by modified intention-to-treat analysis in 149 cases and per-protocol analysis in 143 cases who were followed for 12 months. Clinical outcomes were assessed using the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire and the Oswestry Disability Index. RESULTS The interbody union rate at 12 months after surgery was 45% owing to a very strict definition of bone fusion. The rates of bone fusion were significantly higher at 4 and 6 months after surgery in the TiPEEK group than in the PEEK group in the unadjusted modified intention-to-treat analysis and were significantly higher at 6 months in the unadjusted per-protocol analysis. Binary logistic regression analysis adjusted for sex, age, body mass index, bone mineral density, and surgical level showed that using a TiPEEK cage (odds ratio, 2.27; 95% confidence interval: 1.09-4.74; P = 0.03) was independently associated with bone fusion at 6 months after surgery. Japanese Orthopaedic Association Back Pain Evaluation Questionnaire and Oswestry Disability Index results improved postoperatively in both groups. CONCLUSION Using the TiPEEK cage for PLIF enabled the maintenance of better bone fusion to the endplate than using the PEEK cage at 6 months after the surgery. Our findings suggest the possibility of an earlier return to rigorous work or sports by the use of TiPEEK cage. LEVEL OF EVIDENCE 1.
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High absolute lymphocyte counts are associated with longer overall survival in patients with metastatic breast cancer treated with eribulin-but not with treatment of physician's choice-in the EMBRACE study.
Miyoshi, Y, Yoshimura, Y, Saito, K, Muramoto, K, Sugawara, M, Alexis, K, Nomoto, K, Nakamura, S, Saeki, T, Watanabe, J, et al
Breast cancer (Tokyo, Japan). 2020;(4):706-715
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Abstract
BACKGROUND Eribulin, a nontaxane synthetic inhibitor of microtubule dynamics, is widely used to manage locally advanced or metastatic breast cancer (MBC). Eribulin has demonstrated immunomodulatory activity on the tumour microenvironment. Baseline neutrophil-to-lymphocyte ratio (NLR), a marker of immune status, may predict progression-free survival in eribulin treatment. This post hoc analysis assessed predictors for overall survival (OS). METHODS The phase 3 open-label study (EMBRACE) of eribulin versus treatment of physician's choice (TPC) in patients with MBC provided source data. Baseline absolute lymphocyte counts (ALCs) and NLR were evaluable in 751 and 713 patients, respectively. RESULTS Eribulin prolonged OS versus TPC in patients with baseline ALC ≥ 1500/µl (hazard ratio [HR] 0.586; 95% confidence interval [CI] 0.437-0.784; P < 0.001). There was no significant difference by treatment for ALC < 1500/µl (HR 1.002; 95% CI 0.800-1.253; P = 0.989). Univariate and multivariate analyses were performed and identified baseline ALC as a potential predictor of OS in eribulin-treated patients. Interaction analysis of OS supported 1500/µl as a potentially differential cutoff value. NLR at a cutoff value of 3 was associated with prolonged OS (eribulin group). However, similar results were also observed in the TPC group, without apparent interaction effect, suggesting that NLR may be a general prognostic marker rather than a specific predictor of OS for eribulin. DISCUSSION This hypothesis-generating study speculates that baseline ALC may be an independent predictor for longer OS in eribulin-treated MBC patients and could be clinically impactful because it can be evaluated without the need for additional invasive procedures. TRIAL REGISTRATION www.ClinicalTrials.gov code: NCT00388726.
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Incidence of peripheral neuropathy associated with eribulin mesylate versus vinorelbine in patients with metastatic breast cancer: sub-group analysis of a randomized phase III study.
Wu, Y, Wang, Q, Zhang, J, Cao, J, Wang, B, Hu, X
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2020;(8):3819-3829
Abstract
BACKGROUND Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most significant neurologic complications of chemotherapy, impacting patient's behavior and quality of life. CIPN is mostly sensory, with rare incidences of autonomic dysfunction and other neuropathy. METHODS We conducted a single-center sub-group analysis of patients with metastatic breast cancer enrolled in a phase III study (NCT02225470) set up to compare eribulin mesylate (1.4 mg/m2 on days 1 and 8 every 21 days) with vinorelbine (25 mg/m2 on days 1, 8, and 15 every 21 days). The analysis investigated incidence of peripheral neuropathy, time to onset of neuropathy, and safety. RESULTS Our analysis included 110 women with a mean age of 50.7 (SD = 10.9). The median accumulated dose of eribulin was 11.2 mg/m2 and 125.0 mg/m2 for vinorelbine. Among patients in the eribulin group, a performance status (ECOG PS) of 2 was correlated with peripheral sensory neuropathy (p = 0.015), and accumulated eribulin dose (≥ 10 mg/m2) was associated with all neuropathy and peripheral sensory neuropathy (p = 0.003 and p = 0.007, respectively). In the vinorelbine group, patient age (≥ 65 years) was positively associated with all neuropathy (p = 0.043). The time to onset of neuropathy appeared to be longer for eribulin versus vinorelbine (35.3 vs. 34.6 weeks; p = 0.046), with a significantly higher incidence of autonomic neuropathy at weeks 2 and 10 observed among patients receiving vinorelbine (p = 0.008 and p = 0.043, respectively). CONCLUSION Vinorelbine is associated with a higher incidence of autonomic neuropathy than eribulin in patients with metastatic breast cancer. Furthermore, the onset of neurotoxicity appears to occur earlier with vinorelbine than eribulin.
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A ketone monoester drink reduces the glycemic response to an oral glucose challenge in individuals with obesity: a randomized trial.
Myette-Côté, É, Caldwell, HG, Ainslie, PN, Clarke, K, Little, JP
The American journal of clinical nutrition. 2019;(6):1491-1501
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Abstract
BACKGROUND Exogenous ketones make it possible to reach a state of ketosis that may improve metabolic control in humans. OBJECTIVES The main objective of this study was to determine whether the ingestion of a ketone monoester (KE) drink before a 2-h oral-glucose-tolerance test (OGTT) would lower blood glucose concentrations. Secondary objectives were to determine the impact of KE on nonesterified fatty acid (NEFA) concentration and glucoregulatory hormones. METHODS We conducted a randomized controlled crossover experiment in 15 individuals with obesity (mean ± SD age: 47 ± 10 y; BMI: 34 ± 5 kg/m2). After an overnight fast, participants consumed a KE drink [(R)-3-hydroxybutyl (R)-3-hydroxybutyrate; 0.45 mL/kg body weight] or taste-matched control drink 30 min before completing a 75-g OGTT. Participants and study personnel performing laboratory analyses were blinded to each condition. RESULTS The KE increased d-β-hydroxybutyrate to a maximum of ∼3.4 mM (P < 0.001) during the OGTT. Compared with the control drink, KE reduced glucose (-11%, P = 0.002), NEFA (-21%, P = 0.009), and glucagon-like peptide 1 (-31%, P = 0.001) areas under the curve (AUCs), whereas glucagon AUC increased (+11%, P = 0.030). No differences in triglyceride, C-peptide, and insulin AUCs were observed after the KE drink. Mean arterial blood pressure decreased and heart rate increased after the KE drink (both P < 0.01). CONCLUSIONS A KE drink consumed before an OGTT lowered glucose and NEFA AUCs with no increase in circulating insulin. Our results suggest that a single drink of KE may acutely improve metabolic control in individuals with obesity. Future research is warranted to examine whether KE could be used safely to have longer-term effects on metabolic control. This trial was registered at clinicaltrials.gov as NCT03461068.
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Gastrointestinal Effects of Exogenous Ketone Drinks are Infrequent, Mild, and Vary According to Ketone Compound and Dose.
Stubbs, BJ, Cox, PJ, Kirk, T, Evans, RD, Clarke, K
International journal of sport nutrition and exercise metabolism. 2019;(6):596-603
Abstract
Exogenous ketone drinks may improve athletic performance and recovery, but information on their gastrointestinal tolerability is limited. Studies to date have used a simplistic reporting methodology that inadequately represents symptom type, frequency, and severity. Herein, gastrointestinal symptoms were recorded during three studies of exogenous ketone monoester (KME) and salt (KS) drinks. Study 1 compared low- and high-dose KME and KS drinks consumed at rest. Study 2 compared KME with isocaloric carbohydrate (CHO) consumed at rest either when fasted or after a standard meal. Study 3 compared KME+CHO with isocaloric CHO consumed before and during 3.25 hr of bicycle exercise. Participants reported symptom type and rated severity between 0 and 8 using a Likert scale at regular intervals. The number of visits with no symptoms reported after ketone drinks was n = 32/60 in Study 1, n = 9/32 in Study 2, and n = 20/42 in Study 3. Following KME and KS drinks, symptoms were acute but mild and were fully resolved by the end of the study. High-dose KS drinks caused greater total-visit symptom load than low-dose KS drinks (13.8 ± 4.3 vs. 2.0 ± 1.0; p < .05) and significantly greater time-point symptom load than KME drinks 1-2 hr postdrink. At rest, KME drinks caused greater total-visit symptom load than CHO drinks (5.0 ± 1.6 vs. 0.6 ± 0.4; p < .05). However, during exercise, there was no significant difference in total-visit symptom load between KME+CHO (4.2 ± 1.0) and CHO (7.2 ± 1.9) drinks. In summary, exogenous ketone drinks cause mild gastrointestinal symptoms that depend on time, the type and amount of compound consumed, and exercise.
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Pioglitazone prevents the increase in plasma ketone concentration associated with dapagliflozin in insulin-treated T2DM patients: Results from the Qatar Study.
Abdul-Ghani, M, Migahid, O, Megahed, A, Singh, R, Fawaz, M, DeFronzo, RA, Jayyousi, A
Diabetes, obesity & metabolism. 2019;(3):705-709
Abstract
Because of the unique mechanism of action of sodium-glucose co-transport inhibitors (SGLT2i), which is independent of insulin secretion and insulin action, members of this class of drugs effectively lower plasma glucose concentration when used in combination with all other antidiabetic agents, including insulin. Increased plasma ketone concentration has been reported in association with SGLT2i initiation, which, under certain clinical conditions, has developed into diabetic ketoacidosis. The daily insulin dose often is reduced at the time of initiating SGLT2i therapy in insulin-treated patients to avoid hypoglycaemia. However, reduction of insulin dose can increase the risk of ketoacidosis. In the present study, we examined the effect of the addition of dapagliflozin plus pioglitazone on plasma ketone concentration in insulin-treated T2DM patients and compared the results to the effect of dapagliflozin alone. A total of 18 poorly controlled, insulin-treated T2DM participants in the Qatar Study received dapagliflozin (10 mg) plus pioglitazone (30 mg), and 10 poorly controlled non-insulin-treated T2DM patients received dapagliflozin (10 mg) alone for 4 months. Dapagliflozin plus pioglitazone produced a robust decrease in HbA1c (-1.4%) and resulted in a 50% reduction in daily insulin dose, from 133 to 66 units, while dapagliflozin alone caused a 0.8% reduction in HbA1c. Dapagliflozin caused a four-fold increase in fasting plasma ketone concentration, while the combination of pioglitazone plus dapagliflozin was not associated with a significant increase (0.13 vs 0.15 mM) in plasma ketone concentration or in risk of hypoglycaemia. These results demonstrate that the addition of pioglitazone to dapagliflozin prevents the increase in plasma ketone concentration associated with SGLT2i therapy.