7503
Background: To date, an overall survival (OS) benefit from upfront treatment for new treatment combinations over existing approaches has rarely been shown in first-line classical Hodgkin ...lymphoma (cHL). With the introduction of newer active therapies for relapsed/refractory disease, demonstration of improved OS with first-line therapy has been challenging. In ECHELON-1 (NCT01712490), 5-year follow-up analyses supported the long-term progression-free survival (PFS) benefit with first-line brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in patients (pts) with stage III/IV cHL, independent of interim positron emission tomography status. A+AVD had a manageable long-term safety profile, with numerically fewer second malignancies and a greater number of pregnancies reported vs ABVD (Connors et al, NEJM 2018; Straus et al, Lancet Haematol 2021). We report a prespecified OS analysis after approximately 6 years’ follow-up (cut-off, June 1, 2021). Methods: Pts were randomized 1:1 to receive up to 6 cycles of A+AVD (n = 664) or ABVD (n = 670) on day 1 and 15 every 28 days. OS was the key secondary endpoint and was an event-driven, pre-specified, alpha-controlled analysis in the intention to treat population. Results: At a median follow-up of 73 months, 39 and 64 OS events occurred in A+AVD and ABVD arms, respectively: OS significantly favored A+AVD vs ABVD (HR 0.590; 95% confidence interval CI 0.396–0.879; p = 0.009). Estimated 6-year OS rates (95% CI) were 93.9% (91.6–95.5) vs 89.4% (86.6–91.7) with A+AVD vs ABVD, respectively. There was a consistent OS benefit for A+AVD vs ABVD across prespecified subgroups. The 6-year PFS estimate was 82.3% (79.1–85.0) vs 74.5% (70.8–77.7) with A+AVD vs ABVD, respectively (HR 0.678 95% CI 0.532–0.863). Overall, A+AVD had a comparable long-term safety profile to ABVD. Treatment-emergent peripheral neuropathy continued to resolve or improve in both arms, with 86% (379/443) and 87% (249/286) of cases in the A+AVD and ABVD arms either completely resolving (72% vs 79%) or improving (14% vs 8%) by last follow-up. Fewer second malignancies were reported in the A+AVD vs ABVD arm (23 vs 32). More female patients reported pregnancy (49 vs 28) or live births (42 vs 19 in females) in the A+AVD vs the ABVD arm; no stillbirths were reported. No new safety signals were identified. Conclusions: A+AVD treatment resulted in a statistically significant 41% reduction in the risk of death vs ABVD, with a manageable safety profile consistent with prior reports. These outcomes confirm A+AVD as a preferred option for pts with previously untreated stage III/IV cHL. Clinical trial information: NCT01712490.
Abstract Background High velocity thrust (HVT) cervical techniques have been associated with serious vertebral artery (VA) trauma. Despite numerous studies, the nature of this association is ...uncertain. Previous studies have failed to demonstrate haemodynamic effects on the VA in simulated pre-thrust positions. No study has investigated haemodynamic affects during or immediately following HVT, nor sufficiently controlled for the influence of the thrust. Objectives To investigate the immediate effects of HVT of the atlanto-axial joint upon haemodynamics in the sub-occipital portion of the vertebral artery (VA3). Design Randomized Controlled Trial. Method Twenty-three healthy participants (14 women, 9 men; mean age 40, range 27–69 years of age) were randomly assigned to two groups: an intervention group (MANIP, n = 11) received HVT to the atlanto-axial segment whilst a control group (CG, n = 12) was held in the pre-manipulative hold position. Colour-flow Doppler ultrasound was used to measure VA3 haemodynamics. Primary outcome measures were peak systolic (PSV) and end diastolic velocities (EDV) of three cardiac cycles measured at neutral (N1), pre-HVT (PreMH), post-HVT (PostMH), post-HVT-neutral (N2) positions. Results Test-retest reliability for the Doppler measures demonstrated intra-class correlation coefficient (ICC) of 0.99 (95% CI 0.98–1.0) for PSV and 0.91 (95% CI 0.84–0.96) for EDV. Visually, EDV were lower in the MANIP group than in the CONTROL group across the four measurements. However, there were no significantly different changes (at p ≤ 0.01) between the MANIP and CONTROL groups for any measurement variable. Conclusions HVT to the atlanto-axial joint segment does not affect the haemodynamics of the sub-occipital portion of the vertebral artery during or immediately following HVT in healthy subjects.
To lend insight into the overwintering strategy of the Alaska blackfish (
Dallia pectoralis
), we acclimated fish to 15 or 5 °C and then utilized whole-cell patch clamp to characterize the effects of ...thermal acclimation and acute temperature change on the density and kinetics of ventricular L-type Ca
2+
current (
I
Ca
). Peak
I
Ca
density at 5 °C (−1.1 ± 0.1 pA pF
−1
) was 1/8th that at 15 °C (−8.8 ± 0.6 pA pF
−1
). However, alterations of the Ca
2+
- and voltage-dependent inactivation properties of L-type Ca
2+
channels partially compensated against the decrease. The time constant tau (
τ
) for the kinetics of inactivation of
I
Ca
was ~4.5 times greater at 5 °C than at 15 °C, and the voltage for half-maximal inactivation was shifted from −23.3 ± 1.0 mV at 15 °C to −19.8 ± 1.2 mV at 5 °C. These modifications increase the open probability of the channel and culminate in an approximate doubling of the L-type Ca
2+
window current, which contributes to approximately 15 % of the maximal Ca
2+
conductance at 5 °C. Consequently, the charge density of
I
Ca
(
Q
Ca
) and the total Ca
2+
transferred through the L-type Ca
2+
channels (ΔCa
2+
) were not as severely reduced at 5 °C as compared to peak
I
Ca
density. In combination, the results suggest that while the Alaska blackfish substantially down-regulates
I
Ca
with acclimation to low temperature, there is sufficient compensation in the kinetics of the L-type Ca
2+
channel to support the level of cardiac performance required for the fish to remain active throughout the winter.
To lend insight into the overwintering strategy of the Alaska blackfish (Dallia pectoralis), we acclimated fish to 15 or 5 °C and then utilized whole-cell patch clamp to characterize the effects of ...thermal acclimation and acute temperature change on the density and kinetics of ventricular L-type Ca(2+) current (I Ca). Peak I Ca density at 5 °C (-1.1 ± 0.1 pA pF(-1)) was 1/8th that at 15 °C (-8.8 ± 0.6 pA pF(-1)). However, alterations of the Ca(2+)- and voltage-dependent inactivation properties of L-type Ca(2+) channels partially compensated against the decrease. The time constant tau (τ) for the kinetics of inactivation of I Ca was ~4.5 times greater at 5 °C than at 15 °C, and the voltage for half-maximal inactivation was shifted from -23.3 ± 1.0 mV at 15 °C to -19.8 ± 1.2 mV at 5 °C. These modifications increase the open probability of the channel and culminate in an approximate doubling of the L-type Ca(2+) window current, which contributes to approximately 15% of the maximal Ca(2+) conductance at 5 °C. Consequently, the charge density of I Ca (Q Ca) and the total Ca(2+) transferred through the L-type Ca(2+) channels (ΔCa(2+)) were not as severely reduced at 5 °C as compared to peak I Ca density. In combination, the results suggest that while the Alaska blackfish substantially down-regulates I Ca with acclimation to low temperature, there is sufficient compensation in the kinetics of the L-type Ca(2+) channel to support the level of cardiac performance required for the fish to remain active throughout the winter.
To lend insight into the overwintering strategy of the Alaska blackfish (Dallia pectoralis), we acclimated fish to 15 or 5 °C and then utilized whole-cell patch clamp to characterize the effects of ...thermal acclimation and acute temperature change on the density and kinetics of ventricular L-type Ca^sup 2+^ current (I ^sub Ca^). Peak I ^sub Ca^ density at 5 °C (-1.1 ± 0.1 pA pF^sup -1^) was 1/8th that at 15 °C (-8.8 ± 0.6 pA pF^sup -1^). However, alterations of the Ca^sup 2+^- and voltage-dependent inactivation properties of L-type Ca^sup 2+^ channels partially compensated against the decrease. The time constant tau (tau) for the kinetics of inactivation of I ^sub Ca^ was ~4.5 times greater at 5 °C than at 15 °C, and the voltage for half-maximal inactivation was shifted from -23.3 ± 1.0 mV at 15 °C to -19.8 ± 1.2 mV at 5 °C. These modifications increase the open probability of the channel and culminate in an approximate doubling of the L-type Ca^sup 2+^ window current, which contributes to approximately 15 % of the maximal Ca^sup 2+^ conductance at 5 °C. Consequently, the charge density of I ^sub Ca^ (Q ^sub Ca^) and the total Ca^sup 2+^ transferred through the L-type Ca^sup 2+^ channels (DeltaCa^sup 2+^) were not as severely reduced at 5 °C as compared to peak I ^sub Ca^ density. In combination, the results suggest that while the Alaska blackfish substantially down-regulates I ^sub Ca^ with acclimation to low temperature, there is sufficient compensation in the kinetics of the L-type Ca^sup 2+^ channel to support the level of cardiac performance required for the fish to remain active throughout the winter.
To lend insight into the overwintering strategy of the Alaska blackfish (Dallia pectoralis), we acclimated fish to 15 or 5 degree C and then utilized whole-cell patch clamp to characterize the ...effects of thermal acclimation and acute temperature change on the density and kinetics of ventricular L-type Ca super(2+) current (I sub(Ca)). Peak I sub(Ca) density at 5 degree C (-1.1 plus or minus 0.1 pA pF super(-1)) was 1/8th that at 15 degree C (-8.8 plus or minus 0.6 pA pF super(-1)). However, alterations of the Ca super(2+)- and voltage-dependent inactivation properties of L-type Ca super(2+) channels partially compensated against the decrease. The time constant tau ( tau ) for the kinetics of inactivation of I sub(Ca) was ~4.5 times greater at 5 degree C than at 15 degree C, and the voltage for half-maximal inactivation was shifted from -23.3 plus or minus 1.0 mV at 15 degree C to -19.8 plus or minus 1.2 mV at 5 degree C. These modifications increase the open probability of the channel and culminate in an approximate doubling of the L-type Ca super(2+) window current, which contributes to approximately 15 % of the maximal Ca super(2+) conductance at 5 degree C. Consequently, the charge density of I sub(Ca) (Q sub(Ca)) and the total Ca super(2+) transferred through the L-type Ca super(2+) channels ( Delta Ca super(2+)) were not as severely reduced at 5 degree C as compared to peak I sub(Ca) density. In combination, the results suggest that while the Alaska blackfish substantially down-regulates I sub(Ca) with acclimation to low temperature, there is sufficient compensation in the kinetics of the L-type Ca super(2+) channel to support the level of cardiac performance required for the fish to remain active throughout the winter.
The Alaska blackfish (Dallia pectoralis) remains active at cold temperature when experiencing aquatic hypoxia without air access. To discern the cardiophysiological adjustments that permit this ...behaviour, we quantified the effect of acclimation from 15°C to 5°C in normoxia (15N and 5N fish), as well as chronic hypoxic submergence (6-8 weeks; ∼6.3-8.4 kPa; no air access) at 5°C (5H fish), on in vivo and spontaneous heart rate (fH), electrocardiogram, ventricular action potential (AP) shape and duration (APD), the background inward rectifier (IK1) and rapid delayed rectifier (IKr) K+ currents and ventricular gene expression of proteins involved in excitation-contraction coupling. In vivo fH was ∼50% slower in 5N than 15N fish, but 5H fish did not display hypoxic bradycardia. Atypically, cold acclimation in normoxia did not induce shortening of APD or alter resting membrane potential. Rather, QT interval and APD were ∼2.6-fold longer in 5N than 15N fish because outward IK1 and IKr were not upregulated in 5N fish. By contrast, chronic hypoxic submergence elicited a shortening of QT interval and APD, driven by an upregulation of IKr. The altered electrophysiology of 5H fish was accompanied by increased gene expression of kcnh6 (3.5-fold; Kv11.2 of IKr), kcnj12 (7.4-fold; Kir2.2 of IK1) and kcnj14 (2.9-fold; Kir2.4 of IK1). 5H fish also exhibited a unique gene expression pattern that suggests modification of ventricular Ca2+ cycling. Overall, the findings reveal that Alaska blackfish exposed to chronic hypoxic submergence prioritize the continuation of cardiac performance to support an active lifestyle over reducing cardiac ATP demand.
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