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Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with a 5-year disease-free survival (DFS) ranging from under 10% to over 70% for distinct groups of patients. At our institution, cytarabine, etoposide and busulfan are used in first or se

Purpose: Management of CNS involvement in leukemia may include craniospinal irradiation (CSI), though data on CSI efficacy are limited., Methods: We retrospectively reviewed leukemia patients who underwent CSI at our institution between 2009 and 2021 for CNS involvement. CNS local recurrence (CNS-LR), any recurrence, progression-free survival (PFS), CNS PFS, and overall survival (OS) were estimated., Results: Of thirty-nine eligible patients treated with CSI, most were male (59%) and treated as young adults (median 31 years). The median dose was 18 Gy to the brain and 12 Gy to the spine. Twenty-five (64%) patients received CSI immediately prior to allogeneic hematopoietic cell transplant, of which 21 (84%) underwent total body irradiation conditioning (median 12 Gy). Among 15 patients with CSF-positive disease immediately prior to CSI, all 14 assessed patients had pathologic clearance of blasts (CNS-response rate 100%) at a median of 23 days from CSI start. With a median follow-up of 48 months among survivors, 2-year PFS and OS were 32% (95% CI 18-48%) and 43% (95% CI 27-58%), respectively. Only 5 CNS relapses were noted (2-year CNS-LR 14% (95% CI 5-28%)), which occurred either concurrently or after a systemic relapse. Only systemic relapse after CSI was associated with higher risk of CNS-LR on univariate analysis. No grade 3 or higher acute toxicity was seen during CSI., Conclusion: CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Control of systemic disease after CSI may be important for CNS local control. CNS recurrence may reflect reseeding from the systemic space., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

High-dose cytarabine is associated with gastrointestinal and cerebellar toxicity, precluding its use for older or unfit patients with acute myeloid leukemia (AML). Aspacytarabine, an inactive prodrug of cytarabine, was evaluated as monotherapy in a phase 2b study of patients unfit for intensive chemotherapy (NCT03435848). Sixty-five patients with AML were treated with aspacytarabine 4.5 g/m2 per day (equimolar to 3 g/m2 per day cytarabine) for 6 doses per treatment. The median age was 75 years; 60.6% of patients had de novo AML, 28.8% had AML secondary to myelodysplastic syndrome, and 10.6% had therapy-related AML. Overall, 36.9% achieved complete remission (CR) with full count recovery. CR rates in patients with secondary AML, patients with prior treatment with hypomethylating agents, and patients with TP53 mutation were 26.7%, 25%, and 36%, respectively. Median overall survival was 9 months (range, 6-15.9) and was not reached among responders. Hematologic recovery was observed in all responding patients by day 26 without prolonged cytopenias. Adverse events typically precluding the use of high-dose cytarabine in older or unfit patients were not observed. These data suggest that aspacytarabine may be an effective regimen with a reduction in the attendant toxicities associated with high-dose cytarabine, an important consideration when treating AML and other hematologic disorders that use high-dose cytarabine. This trial was registered at www.clinicaltrials.gov as #NCT03435848., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

Older age and poor performance status lead to worse outcomes in acute myeloid leukemia (AML) patients. Hypoalbuminemia is a negative predictor of morbidity and mortality in several malignancies. We evaluated the relationship between baseline serum albumin levels on treatment-related complications, as well as short-term mortality and overall survival (OS) in 756 newly diagnosed AML patients. We conducted a retrospective multicenter study to examine treatment-related complications and OS according to pretreatment serum albumin levels: normal albumin ≥3.5 g/dl, marked hypoalbuminemia <2.5 g/dl, and hypoalbuminemia 2.5-3.4 g/dl. In an adjusted multivariate analysis, a lower baseline albumin was independently associated with a higher number of grade ≥3 complications when adjusting for age, secondary AML, sex and intensive treatment. When comparing normal to markedly low albumin levels, the estimated mean number of complications increases by a factor of 1.35. Patients who had a normal baseline albumin had a 30 day-mortality rate of 4.8%, which was significantly lower compared with patients with hypoalbuminemia (16.5%) and marked hypoalbuminemia (33.9%; p < 0.01). Similarly, 60-day mortality rate was significantly higher in the hypoalbuminemia group (24.0%) and marked hypoalbuminemia group (45%) compared with normal albumin group (8.3%; p < 0.01). Patients with lower baseline albumin levels have increased treatment-related morbidity and mortality, suggesting that pre-treatment serum albumin is an important independent prognostic marker., (© 2021 John Wiley & Sons, Ltd.)

Acute myeloid leukemia (AML) patients often undergo allogeneic hematopoietic cell transplantation (alloHCT) in first complete remission (CR). We examined the effect of depth of clinical response, including incomplete count recovery (CRi) and/or measurable residual disease (MRD), in patients from the Center for International Blood and Marrow Transplantation Research (CIBMTR) registry. We identified 2492 adult patients (1799 CR and 693 CRi) who underwent alloHCT between January 1, 2007 and December 31, 2015. The primary outcome was overall survival (OS). Multivariable analysis was performed to adjust for patient-, disease-, and transplant-related factors. Baseline characteristics were similar. Patients in CRi compared to those in CR had an increased likelihood of death (HR: 1.27; 95% confidence interval: 1.13-1.43). Compared to CR, CRi was significantly associated with increased non-relapse mortality (NRM), shorter disease-free survival (DFS), and a trend toward increased relapse. Detectable MRD was associated with shorter OS, shorter DFS, higher NRM, and increased relapse compared to absence of MRD. The deleterious effects of CRi and MRD were independent. In this large CIBMTR cohort, survival outcomes differ among AML patients based on depth of CR and presence of MRD at the time of alloHCT. Further studies should focus on optimizing post-alloHCT outcomes for patients with responses less than CR., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Secondary acute myeloid leukemia (sAML) is biologically and clinically distinct from de novo AML and shares specific genetic mutations with myelodysplastic syndromes (MDS). We retrospectively analyzed data from 295 adults with MDS or AML with mutational analysis by next-generation sequencing (NGS), and examined differences in functional grouping of mutations and relation between morphologic blast count and variant allele frequency (VAF) of mutations. Our analysis showed the distribution of mutations differed in MDS and AML. However, these differences largely disappeared when we compared MDS with excess blasts (MDS-EB) and sAML. VAF of mutations generally did not correlate with morphologic blast count and the distribution of VAF was similar above and below the 20% cutpoint. Complete remission (CR) rate was similar in MDS-EB and sAML following high intensity therapy and survival was also similar. These results support that MDS-EB and sAML have overlapping features and may represent a spectrum of the same disease.Key pointsThe distribution of genetic mutations is similar in myelodysplastic syndrome with excess blasts (MDS-EB) and secondary acute myeloid leukemia (sAML) regardless of morphologic blast count.Variant allele frequencies (VAFs) of gene mutations do not correlate well with morphologic blast counts, particularly in MDS-EB and sAML.Complete remission (CR) rate was similar in MDS-EB and sAML following high intensity or low intensity therapy.

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

Background: Low-intensity regimens have been increasingly used to treat older patients with acute myeloid leukemia (AML). Recent studies, however, suggest older patients can tolerate and potentially benefit from intensive chemotherapeutic regimens. The ability to compare the utility of varying regimen intensities in AML is hindered by the lack of a standardized definition of "regimen intensity.", Methods: We conducted a survey asking AML physicians which of 38 regimens they would consider intensive vs less-intensive. Electronic medical records of 592 patients receiving many of these regimens were used to design a model characterizing regimens as intensive vs less-intensive as identified by ≥75% physician consensus. Variables included frequency and length of hospitalizations, intensive care unit admissions, severe gastrointestinal toxicities, time to nadir, and recovery of neutrophil/platelet count., Results: Physicians agreed at a rate of 75%-100% on the assignment of degree of intensity to the majority (n = 28) of these regimens, while the level of agreement was <75% for the remaining 10 regimens (26%). Logistic regression analyses identified number and length of hospitalizations to be significantly associated with intensive regimens and count recovery with less-intensive regimens. We created the "regimen-intensity per count-recovery and hospitalization" (RICH) index with an AUC of 0.87. Independent model validation yielded an AUC of 0.75., Conclusions: We were able to generate a novel model that defines regimen intensity for many therapies used to treat AML. Results facilitate a future randomized study comparing intensive vs less-intensive regimens., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Patients with newly diagnosed (ND) and relapsed/refractory (RR) acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS, ≥10% blasts) often receive intensive chemotherapy at diagnosis and relapse. We retrospectively identified 365 patients and categorized the reasons for receiving treatment off study (medical, logistical, or unclear). The pretreatment characteristics of the on and off study groups were similar. Rates of the complete remission (CR) without measurable residual disease were significantly higher for ND patients treated on versus off study (61% versus 35%), but CR rates and survival were low for all RR patients regardless of study assignment. The subset of ND patients treated off study for medical reasons had significantly decreased overall survival and relapse-free survival. Standard, stringent study eligibility criteria may delineate a population of ND, but not RR, patients with improved outcomes with intensive induction chemotherapy.

We examined the effect of brief intermittent stair climbing exercise on glycemic control using continuous glucose monitoring in people with type 2 diabetes (n = 7, 5 men; 2 women; age, 21-70 years). The protocol involved three 60-s bouts of vigorously ascending and slowly descending a flight of stairs. Mean 24-h blood glucose was unchanged after an acute session (p = 0.43) and following 18 sessions over 6 weeks (p = 0.13). The protocol was well tolerated by participants but seemingly insufficient to alter glycemic control.

Midostaurin is a multitargeted tyrosine kinase inhibitor (TKI) that potently inhibits activated fms-related tyrosine kinase 3 (FLT3) in the nanomolar range and other kinases including platelet-derived growth factor receptors α (PDGFR- α) and β (PDGFR- β), cyclin-dependent kinase, proto-oncogene tyrosine-protein kinase Src, tyrosine-protein kinase Fgr, spleen tyrosine kinase (Syk), KIT proto-oncogene receptor tyrosine kinase and the major vascular endothelial growth factor receptor (VEGFR). Activating mutations in FLT3, which is one of the more common acute myeloid leukemia (AML) mutations, particularly those that result in an FLT3-ITD (internal tandem duplication) mutation, confer poor prognosis and represent a therapeutic target. Small molecule TKIs that vary in potency and selectivity for FLT3 are under investigation. Here, we provide a comprehensive review of the preclinical and clinical activity of midostaurin, a recently approved drug indicated to be used in combination with cytarabine and daunorubicin induction and cytarabine consolidation chemotherapy for the treatment of AML featuring an FLT3 mutation., (Copyright 2017 Clarivate Analytics.)

Acute myeloid leukemia (AML) is rare and difficult to treat. Although remission is achieved in most patients with newly diagnosed disease, relapse occurs in most cases. For more than 40 years, the standard up-front induction treatment has been a combination of continuous-infusion cytarabine and an anthracycline. Risk stratification by molecular and cytogenetic characteristics and measurable residual disease (MRD) status informs decisions regarding referral to consolidative allogeneic hematopoietic cell transplant. In 2017, for the first time in years, 4 drugs are under consideration for approval by the US Food and Drug Administration. One of these agents, the multikinase inhibitor midostaurin, has already been approved for the treatment of patients with FLT3-mutated AML. The heterogeneity of AML suggests that single-target agents are unlikely to succeed at curing large numbers of patients, and that combinations of novel agents and traditional chemotherapy will be required to achieve this goal. Additionally, the 2017 European LeukemiaNet criteria suggest that treating physicians should strive for the new, stringent remission category (ie, complete remission without MRD). How the new drug approvals in 2017 will change practice is not clear, and further work remains to be done in treating and curing patients with AML.

The diagnosis of acute myeloid leukemia (AML) can be made based on peripheral blood or bone marrow blasts. In this review, we will discuss the role of bone marrow evaluation and peripheral blood monitoring in the diagnosis, management, and follow up of AML patients. For patients with circulating blasts, it is reasonable to perform the necessary studies needed for diagnosis and risk stratification, including multiparametric flow cytometry, cytogenetics, and molecular analysis, on a peripheral blood specimen. The day 14 marrow is used to document hypocellularity in response to induction chemotherapy, but it is unclear if that assessment is necessary as it often does not affect immediate management. Currently, response assessments performed at count recovery for evaluation of remission and measurable residual disease rely on bone marrow sampling. For monitoring of relapse, peripheral blood evaluation may be adequate, but the sensitivity of bone marrow testing is in some cases superior. While bone marrow evaluation can certainly be avoided in particular situations, this cumbersome and uncomfortable procedure currently remains the de facto standard for response assessment., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The outcome of sequential azacitidine with lenalidomide has not been reported in previously treated patients with acute myeloid leukemia (AML) and higher risk myelodysplastic syndrome (MDS). This study describes a phase 2 study evaluating the safety and efficacy of this combination in elderly patients with AML and MDS with prior hypomethylating agent (HMA) and/or immunomodulatory agent exposure. Patients were treated on a 42-day cycle with azacitidine at 75 mg/m2 SQ/IV daily on days 1-7, followed by lenalidomide 50 mg orally daily on days 8-28. The median number of treatment cycles on study was two (range = 1-11). Of 32 evaluable patients, the overall response rate was 25%. Neutropenic fever was the most common serious adverse event, but overall the combination was well-tolerated. The median overall survival (OS) for responders vs non-responders was 9.8 vs 4.0 months, respectively (HR = 0.36, p = 0.016). In conclusion, this combination demonstrated modest clinical activity in this poor risk population.

Sprint interval training (SIT), repeated bouts of high-intensity exercise, improves skeletal muscle oxidative capacity and exercise performance. β-alanine (β-ALA) supplementation has been shown to enhance exercise performance, which led us to hypothesize that chronic β-ALA supplementation would augment work capacity during SIT and augment training-induced adaptations in skeletal muscle and performance. Twenty-four active but untrained men (23 ± 2 yr; VO2peak = 50 ± 6 mL · kg(-1) · min(-1)) ingested 3.2 g/day of β-ALA or a placebo (PLA) for a total of 10 weeks (n = 12 per group). Following 4 weeks of baseline supplementation, participants completed a 6-week SIT intervention. Each of 3 weekly sessions consisted of 4-6 Wingate tests, i.e., 30-s bouts of maximal cycling, interspersed with 4 min of recovery. Before and after the 6-week SIT program, participants completed a 250-kJ time trial and a repeated sprint test. Biopsies (v. lateralis) revealed that skeletal muscle carnosine content increased by 33% and 52%, respectively, after 4 and 10 weeks of β-ALA supplementation, but was unchanged in PLA. Total work performed during each training session was similar across treatments. SIT increased markers of mitochondrial content, including cytochome c oxidase (40%) and β-hydroxyacyl-CoA dehydrogenase maximal activities (19%), as well as VO2peak (9%), repeated-sprint capacity (5%), and 250-kJ time trial performance (13%), but there were no differences between treatments for any measure (p < .01, main effects for time; p > .05, interaction effects). The training stimulus may have overwhelmed any potential influence of β-ALA, or the supplementation protocol was insufficient to alter the variables to a detectable extent.

We tested the hypothesis that ingestion of sodium bicarbonate (NaHCO3) prior to an acute session of high-intensity interval training (HIIT) would augment signaling cascades and gene expression linked to mitochondrial biogenesis in human skeletal muscle. On two occasions separated by ∼1 wk, nine men (mean ± SD: age 22 ± 2 yr, weight 78 ± 13 kg, V̇O(2 peak) 48 ± 8 ml·kg(-1)·min(-1)) performed 10 × 60-s cycling efforts at an intensity eliciting ∼90% of maximal heart rate (263 ± 40 W), interspersed with 60 s of recovery. In a double-blind, crossover manner, subjects ingested a total of 0.4 g/kg body weight NaHCO3 before exercise (BICARB) or an equimolar amount of a placebo, sodium chloride (PLAC). Venous blood bicarbonate and pH were elevated at all time points after ingestion (P < 0.05) in BICARB vs. PLAC. During exercise, muscle glycogen utilization (126 ± 47 vs. 53 ± 38 mmol/kg dry weight, P < 0.05) and blood lactate accumulation (12.8 ± 2.6 vs. 10.5 ± 2.8 mmol/liter, P < 0.05) were greater in BICARB vs. PLAC. The acute exercise-induced increase in the phosphorylation of acetyl-CoA carboxylase, a downstream marker of AMP-activated protein kinase activity, and p38 mitogen-activated protein kinase were similar between treatments (P > 0.05). However, the increase in PGC-1α mRNA expression after 3 h of recovery was higher in BICARB vs. PLAC (approximately sevenfold vs. fivefold compared with rest, P < 0.05). We conclude that NaHCO3 before HIIT alters the mRNA expression of this key regulatory protein associated with mitochondrial biogenesis. The elevated PGC-1α mRNA response provides a putative mechanism to explain the enhanced mitochondrial adaptation observed after chronic HIIT supplemented with NaHCO3 in rats., (Copyright © 2015 the American Physiological Society.)

Commencing some training sessions with reduced carbohydrate (CHO) availability has been shown to enhance skeletal muscle adaptations, but the effect on exercise performance is less clear. We examined whether restricting CHO intake between twice daily sessions of high-intensity interval training (HIIT) augments improvements in exercise performance and mitochondrial content. Eighteen active but not highly trained subjects (peak oxygen uptake [VO2peak] = 44 ± 9 ml/kg/min), matched for age, sex, and fitness, were randomly allocated to two groups. On each of 6 days over 2 weeks, subjects completed two training sessions, each consisting of 5 × 4-min cycling intervals (60% of peak power), interspersed by 2 min of recovery. Subjects ingested either 195 g of CHO (HI-HI group: ~2.3 g/kg) or 17 g of CHO (HI-LO group: ~0.3 g/kg) during the 3-hr period between sessions. The training-induced improvement in 250-kJ time trial performance was greater (p = .02) in the HI-LO group (211 ± 66 W to 244 ± 75 W) compared with the HI-HI group (203 ± 53 W to 219 ± 60 W); however, the increases in mitochondrial content was similar between groups, as reflected by similar increases in citrate synthase maximal activity, citrate synthase protein content and cytochrome c oxidase subunit IV protein content (p > .05 for interaction terms). This is the first study to show that a short-term "train low, compete high" intervention can improve whole-body exercise capacity. Further research is needed to determine whether this type of manipulation can also enhance performance in highly-trained subjects.

Background: Acute myeloid leukemia (AML) is treated with conventional induction chemotherapy shortly after diagnosis for the majority of patients aged ≤ 65 years. A recent report suggested a substantial decline in the early, or 1-month, mortality rate in patients treated on clinical trials over the past 2 decades. It is unknown whether a similar improvement has been observed in the general population., Methods: The authors examined the 1-month mortality rate in a large population-based series of 9380 patients with AML who were aged ≤ 65 years and were diagnosed and treated with chemotherapy between 1973 and 2010., Results: A significant decline was observed in the 1-month mortality rate from 18.7% among patients diagnosed from 1973 through 1977 (95% confidence interval [95% CI], 16.4%-21.2%) to 5.8% for those diagnosed between 2008 and 2010 (95% CI, 4.5%-7.6%) (P <.001). The median overall survival improved significantly from 6 months (95% CI, 5 months-7 months) in 1973 to 1977 to 23 months (95% CI, 16 months-20 months) in 2008 to 2010 (P <.001). Although age and geographic variation were found to significantly influence the 1-month mortality for the period between 1973 and 1977, these differences in 1-month mortality were no longer significant among patients with AML who were treated more recently (2008-2010)., Conclusions: Over the past 4 decades, early mortality has become uncommon in younger patients (aged ≤ 65 years) with newly diagnosed AML undergoing induction chemotherapy. It is encouraging that the improvements noted in 1-month mortality rate among a selective cohort of patients in clinical trials have also been observed in a population-based analysis., (© 2015 American Cancer Society.)

Unlabelled: Supplementation with green tea extract (GTE) in animals has been reported to induce numerous metabolic adaptations including increased fat oxidation during exercise and improved performance. However, data regarding the metabolic and physiological effects of GTE during exercise in humans are limited and equivocal., Purpose: To examine the effects of short-term GTE treatment on resting energy expenditure (REE), wholebody substrate utilization during exercise and time trial performance., Methods: Fifteen active men (24 ± 3 y; VO(2)peak = 48 ± 7 ml · kg · min(-1); BMI = 26 ± 3 kg · m(2)((-1))) ingested GTE (3x per day = 1,000 mg/d) or placebo (PLA) for 2 day in a double-blind, crossover design (each separated by a 1 week wash-out period). REE was assessed in the fasted state. Subjects then ingested a standardized breakfast (~5.0 kcal · kg(-1)) and 90 min later performed a 60 min cycling bout at an intensity corresponding to individual maximal fat oxidation (44 ± 11% VO(2)peak), followed by a 250 kJ TT., Results: REE, whole-body oxygen consumption (VO2) and substrate oxidation rates during steady-state exercise were not different between treatments. However, mean heart rate (HR) was lower in GTE vs. PLA (115 ± 16 vs. 118 ± 17 beats · min(-1); main effect, p = .049). Mixed venous blood [glycerol] was higher during rest and exercise after GTE vs. PLA (p = .006, main effect for treatment) but glucose, insulin and free-fatty acids were not different. Subsequent time trial performance was not different between treatments (GTE = 25:38 ± 5:32 vs. PLA = 26:08 ± 8:13 min; p = .75)., Conclusion: GTE had minimal effects on whole-body substrate metabolism but significantly increased plasma glycerol and lowered heart rate during steady-state exercise, suggesting a potential increase in lipolysis and a cardiovascular effect that warrants further investigation.

We investigated whether a training protocol that involved 3 min of intense intermittent exercise per week--within a total training time commitment of 30 min including warm up and cool down--could increase skeletal muscle oxidative capacity and markers of health status. Overweight/obese but otherwise healthy men and women (n = 7 each; age = 29±9 y; BMI = 29.8±2.7 kg/m2) performed 18 training sessions over 6 wk on a cycle ergometer. Each session began with a 2 min warm-up at 50 W, followed by 3×20 s "all-out" sprints against 5.0% body mass (mean power output: ∼450-500 W) interspersed with 2 min of recovery at 50 W, followed by a 3 min cool-down at 50 W. Peak oxygen uptake increased by 12% after training (32.6±4.5 vs. 29.1±4.2 ml/kg/min) and resting mean arterial pressure decreased by 7% (78±10 vs. 83±10 mmHg), with no difference between groups (both p<0.01, main effects for time). Skeletal muscle biopsy samples obtained before and 72 h after training revealed increased maximal activity of citrate synthase and protein content of cytochrome oxidase 4 (p<0.01, main effect), while the maximal activity of β-hydroxy acyl CoA dehydrogenase increased in men only (p<0.05). Continuous glucose monitoring measured under standard dietary conditions before and 48-72 h following training revealed lower 24 h average blood glucose concentration in men following training (5.4±0.6 vs. 5.9±0.5 mmol/L, p<0.05), but not women (5.5±0.4 vs. 5.5±0.6 mmol/L). This was associated with a greater increase in GLUT4 protein content in men compared to women (138% vs. 23%, p<0.05). Short-term interval training using a 10 min protocol that involved only 1 min of hard exercise, 3x/wk, stimulated physiological changes linked to improved health in overweight adults. Despite the small sample size, potential sex-specific adaptations were apparent that warrant further investigation.

Interval training refers to the basic concept of alternating periods of relatively intense exercise with periods of lower-intensity effort or complete rest for recovery. Low-volume interval training refers to sessions that involve a relatively small total amount of exercise (i.e. ≤10 min of intense exercise), compared with traditional moderate-intensity continuous training (MICT) protocols that are generally reflected in public health guidelines. In an effort to standardize terminology, a classification scheme was recently proposed in which the term 'high-intensity interval training' (HIIT) be used to describe protocols in which the training stimulus is 'near maximal' or the target intensity is between 80 and 100 % of maximal heart rate, and 'sprint interval training' (SIT) be used for protocols that involve 'all out' or 'supramaximal' efforts, in which target intensities correspond to workloads greater than what is required to elicit 100 % of maximal oxygen uptake (VO2max). Both low-volume SIT and HIIT constitute relatively time-efficient training strategies to rapidly enhance the capacity for aerobic energy metabolism and elicit physiological remodeling that resembles changes normally associated with high-volume MICT. Short-term SIT and HIIT protocols have also been shown to improve health-related indices, including cardiorespiratory fitness and markers of glycemic control in both healthy individuals and those at risk for, or afflicted by, cardiometabolic diseases. Recent evidence from a limited number of studies has highlighted potential sex-based differences in the adaptive response to SIT in particular. It has also been suggested that specific nutritional interventions, in particular those that can augment muscle buffering capacity, such as sodium bicarbonate, may enhance the adaptive response to low-volume interval training.

Subjects performed high-intensity interval training (HIIT) and continuous moderate-intensity training (END) to evaluate 24-h oxygen consumption. Oxygen consumption during HIIT was lower versus END; however, total oxygen consumption over 24 h was similar. These data demonstrate that HIIT and END induce similar 24-h energy expenditure, which may explain the comparable changes in body composition reported despite lower total training volume and time commitment.

High-intensity interval training (HIIT) performed in an 'all-out' manner (e.g. repeated Wingate tests) is a time-efficient strategy to induce skeletal muscle remodelling towards a more oxidative phenotype. A fundamental question that remains unclear, however, is whether the intermittent or 'pulsed' nature of the stimulus is critical to the adaptive response. In study 1, we examined whether the activation of signalling cascades linked to mitochondrial biogenesis was dependent on the manner in which an acute high-intensity exercise stimulus was applied. Subjects performed either four 30 s Wingate tests interspersed with 4 min of rest (INT) or a bout of continuous exercise (CONT) that was matched for total work (67 ± 7 kJ) and which required ∼4 min to complete as fast as possible. Both protocols elicited similar increases in markers of adenosine monophosphate-activated protein kinase (AMPK) and p38 mitogen-activated protein kinase activation, as well as Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) mRNA expression (main effects for time, P ≤ 0.05). In study 2, we determined whether 6 weeks of the CONT protocol (3 days per week) would increase skeletal muscle mitochondrial content to a similar extent to what we have previously reported after 6 weeks of INT. Despite similar acute signalling responses to the CONT and INT protocols, training with CONT did not increase the maximal activity or protein content of a range of mitochondrial markers. However, peak oxygen uptake was higher after CONT training (from 45.7 ± 5.4 to 48.3 ± 6.5 ml kg(-1) min(-1); P < 0.05) and 250 kJ time trial performance was improved (from 26:32 ± 4:48 to 23:55 ± 4:16 min:s; P < 0.001) in our recreationally active participants. We conclude that the intermittent nature of the stimulus is important for maximizing skeletal muscle adaptations to low-volume, all-out HIIT. Despite the lack of skeletal muscle mitochondrial adaptations, our data show that a training programme based on a brief bout of high-intensity exercise, which lasted <10 min per session including warm-up, and performed three times per week for 6 weeks, improved peak oxygen uptake in young healthy subjects., (© 2014 The Authors. Experimental Physiology © 2014 The Physiological Society.)

Maternal obesity is associated with an increased risk of a number of pregnancy complications, including fetal demise, which may be linked to impaired placental development as a result of altered trophoblast invasion and vessel remodeling. Therefore, we examined these parameters in pregnant rats fed a control (normal weight) or high fat (HF) diet (obese) at 2 critical times of rat placental development. Early trophoblast invasion was increased by approximately 2-fold in HF-fed dams with a concomitant increase in the expression of matrix metalloproteinase 9 protein, a mediator of tissue remodeling and invasion. Furthermore, we observed significantly higher levels of smooth muscle actin surrounding the placental spiral arteries of HF-fed dams, suggesting impaired spiral artery remodeling. Taken together, the results of this study suggest that altered placental development is an important contributor to the poor pregnancy outcomes and increased fetal demise in our model of lifelong maternal obesity.

Objective: To investigate the effects of low-volume high-intensity interval training (HIT) performed in the fasted (FAST) versus fed (FED) state on body composition, muscle oxidative capacity, and glycemic control in overweight/obese women., Design and Methods: Sixteen women (27 ± 8 years, BMI: 29 ± 6 kg/m(2) , VO2peak : 28 ± 3 ml/kg/min) were assigned to either FAST or FED (n = 8 each) and performed 18 sessions of HIT (10× 60-s cycling efforts at ∼90% maximal heart rate, 60-s recovery) over 6 weeks., Results: There was no significant difference between FAST and FED for any measured variable. Body mass was unchanged following training; however, dual energy X-ray absorptiometry revealed lower percent fat in abdominal and leg regions as well as the whole body level (main effects for time, P ≤ 0.05). Fat-free mass increased in leg and gynoid regions (P ≤ 0.05). Resting muscle biopsies revealed a training-induced increase in mitochondrial capacity as evidenced by increased maximal activities of citrate synthase and β-hydroxyacyl-CoA dehydrogenase (P ≤ 0.05). There was no change in insulin sensitivity, although change in insulin area under the curve was correlated with change in abdominal percent fat (r = 0.54, P ≤ 0.05)., Conclusion: Short-term low-volume HIT is a time-efficient strategy to improve body composition and muscle oxidative capacity in overweight/obese women, but fed- versus fasted-state training does not alter this response., (Copyright © 2013 The Obesity Society.)

Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with a 5-year disease-free survival (DFS) ranging from under 10% to over 70% for distinct groups of patients. At our institution, cytarabine, etoposide and busulfan are used in first or second remission patients treated with a two-step approach to autologous stem cell transplantation (ASCT). In this study, we tested the hypothesis that polymorphisms in the pharmacokinetic and pharmacodynamic pathway genes of these drugs are associated with DFS in AML patients. A total of 1659 variants in 42 genes were analyzed for their association with DFS using a Cox-proportional hazards model. One hundred and fifty-four genetically European patients were used for the primary analysis. An intronic single nucleotide polymorphism (SNP) in ABCC3 (rs4148405) was associated with a significantly shorter DFS (hazard ratios (HR)=3.2, P=5.6 × 10(-6)) in our primary cohort. In addition, a SNP in the GSTM1-GSTM5 locus, rs3754446, was significantly associated with a shorter DFS in all patients (HR=1.8, P=0.001 for 154 European ancestry; HR=1.7, P=0.028 for 125 non-European patients). Thus, for the first time, genetic variants in drug pathway genes are shown to be associated with DFS in AML patients treated with chemotherapy-based autologous ASCT.

Low-volume high-intensity interval training (HIT) is emerging as a time-efficient exercise strategy for improving health and fitness. This form of exercise has not been tested in type 2 diabetes and thus we examined the effects of low-volume HIT on glucose regulation and skeletal muscle metabolic capacity in patients with type 2 diabetes. Eight patients with type 2 diabetes (63 ± 8 yr, body mass index 32 ± 6 kg/m(2), Hb(A1C) 6.9 ± 0.7%) volunteered to participate in this study. Participants performed six sessions of HIT (10 × 60-s cycling bouts eliciting ∼90% maximal heart rate, interspersed with 60 s rest) over 2 wk. Before training and from ∼48 to 72 h after the last training bout, glucose regulation was assessed using 24-h continuous glucose monitoring under standardized dietary conditions. Markers of skeletal muscle metabolic capacity were measured in biopsy samples (vastus lateralis) before and after (72 h) training. Average 24-h blood glucose concentration was reduced after training (7.6 ± 1.0 vs. 6.6 ± 0.7 mmol/l) as was the sum of the 3-h postprandial areas under the glucose curve for breakfast, lunch, and dinner (both P < 0.05). Training increased muscle mitochondrial capacity as evidenced by higher citrate synthase maximal activity (∼20%) and protein content of Complex II 70 kDa subunit (∼37%), Complex III Core 2 protein (∼51%), and Complex IV subunit IV (∼68%, all P < 0.05). Mitofusin 2 (∼71%) and GLUT4 (∼369%) protein content were also higher after training (both P < 0.05). Our findings indicate that low-volume HIT can rapidly improve glucose control and induce adaptations in skeletal muscle that are linked to improved metabolic health in patients with type 2 diabetes.