Phase 3 Randomized Trial of Prophylactic Cranial Irradiation With or Without Hippocampus Avoidance in SCLC (NCT01780675)

Introduction: To compare neurocognitive functioning in patients with SCLC who received prophylactic cranial irradiation (PCI) with or without hippocampus avoidance (HA). Methods: In a multicenter, randomized phase 3 trial (NCT01780675), patients with SCLC were randomized to standard PCI or HA-PCI of 25 Gy in 10 fractions. Neuropsychological tests were performed at baseline and 4, 8, 12, 18, and 24 months after PCI. The primary end point was total recall on the Hopkins Verbal Learning Test-Revised at 4 months; a decline of at least five points from baseline was considered a failure. Secondary end points included other cognitive outcomes, evaluation of the incidence, location of brain metastases, and overall survival. Results: From April 2013 to March 2018, a total of 168 patients were randomized. The median follow-up time was 26.6 months. In both treatment arms, 70% of the patients had limited disease and baseline characteristics were well balanced. Decline on the Hopkins Verbal Learning Test-Revised total recall score at 4 months was not significantly different between the arms: 29% of patients on PCI and 28% of patients on HA-PCI dropped greater than or equal to five points (p = 1.000). Performance on other cognitive tests measuring memory, executive function, attention, motor function, and processing speed did not change significantly different over time between the groups. The overall survival was not significantly different (p = 0.43). The cumulative incidence of brain metastases at 2 years was 20% (95% confidence interval: 12%-29%) for the PCI arm and 16% (95% confidence interval: 7%-24%) for the HA-PCI arm. Conclusions: This randomized phase 3 trial did not find a lower probability of cognitive decline in patients with SCLC receiving HA-PCI compared with conventional PCI. No increase in brain metastases at 2 years was observed in the HA-PCI arm. (C) 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved

A lab-based comparison of differential ratings of perceived exertion between a run and jump protocol involving low or high impacts on the lower extremities: Influence of impacts on differential RPE

The rating of perceived exertion method (RPE) allows to describe training intensity in a single value. To better understand the underlying components, the separate rating of perceived breathlessness (RPE-B) and leg-muscle exertion (RPE-L) has been proposed. Here we hypothesised that the separation between the two components may (partly) be determined by the impacts on the lower extremities. In this study, we aimed to experimentally evaluate the differential effect of high versus low impact running and jumping on RPE-B and RPE-L in team sport activities by manipulating the movement strategy (heel strike and passive landing pattern versus forefoot strike and active landing pattern). Eighteen recreational team sport players participated in two submaximal tests consisting of a sequence of running and jumping bouts, whilst ground reaction forces (GRF) were collected. RPE-B and RPE-L data were collected after each bout using the CR100 scale. Paired-samples t-tests were used to analyse between-session differences in these variables. GRF analysis showed that absorption mechanics differed considerably between the two sessions. RPE-L was on average 6.50 AU higher in the low impact session (p = 0.006). However, RPE-B was also increased by 4.96 AU with low impact (p = 0.009). We conclude that the extent to which the lower extremities are being exposed to high or low impacts does not explain a possible separation between the two RPE types

Neurovascular tract and simple schematics of connections.

<p>(<b>A</b>) Photograph of the tenotomised FCU and its myofascial connections to extramuscular connective tissue (EMCT) consisting of general fascia and neurovascular tracts (NVT). Note that, although not visible in the image, there are also connections to the epimysia of surrounding muscles (i.e. m. extensor carpi ulnaris and flexor digitorum superficialis/profundus). Via these connections, force can be transmitted between the stroma of FCU and extramuscular connective tissue such as general fascia, septa or NVT (i.e. epimuscular force transmission) and other muscles. This will cause loading in proximal as well as distal directions on a fraction of FCU. Distal loading of spastic FCU via myofascial connections has been shown after FCU tenotomy suggesting enhanced epimuscular loading (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101038#pone.0101038.s001" target="_blank">Movie S1</a>) <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0101038#pone.0101038-Smeulders2" target="_blank">[64]</a>. As branches of the NVTs generally enter the muscle from proximal directions, loading of the NVTs may chiefly yield proximally directed epimuscular loading of FCU. (<b>B</b>) Schematic diagram illustrating how concurrent proximal and distal epimuscular loads may cause high local sarcomere strains. Myofibres are represented by three sarcomeres in series, with myofascial connections to extramuscular connective tissues.</p

Increased thickness of tertiary perimysium within cross-sections of fascicles within spastic muscle.

<p>Typical examples of light micrographs of Sirius Red stained cross-sections of FCU biopsies: (<b>A</b>) control muscle. (<b>B</b>) Spastic muscle. Bars represent 250 µm. (<b>C</b>) Individual data of tertiary perimysium thickness within FCU biopsies plotted as function of age. Mean thickness of tertiary perimysium in FCU (indicated by horizontal lines) of spastic subjects (n = 23) was significantly higher than in FCU of control subjects (n = 9).</p

Stress relaxation of myofibres and fascicles at different sarcomere lengths.

<p>Representative passive forces of a spastic single myofibre segment from a spastic FCU as a function of sarcomere length (ℓsarc). Forces were measured immediately (time  = 0 min), and 2, 4, and 6 minutes after imposing each sarcomere strain increment. Note that effects of stress relaxation are small after at least 4 minutes, therefore sarcomere length-tension curves of myofibre and fascicle segments were assessed based on the forces measured after 4 minutes.</p

Myofibre typing and myofibre cross-sectional area within fascicles from spastic and control FCU.

<p>Typical examples of light micrographs of ATPase stained cross-section of biopsies from: (<b>A</b>) Control muscle, (<b>B</b>) Spastic muscle. Myofibre types I, IIA and IIAX are assigned; bars represent 100 µm. (<b>C</b>) Fibre type distribution within cross-sections from FCU. Fibre type distribution was not significantly different between CP (n = 26) and control (n = 10) samples. (<b>D</b>) For all fibre types, myofibre cross-sectional area (A_MF) in all spastic samples was significantly smaller than in controls. (<b>E</b>). Individual data for A_MF plotted as a function of age. For spastic muscle of all ages taken together, Spearman's Rank coefficient of correlation for A_MF and age was significant and moderately high. Note that A_MF of spastic patients ≥20 years was not significantly different from that of (adult) control muscles. Means and SEM are shown; * indicates significant difference between spastic and control FCU.</p

CD40 stimulation of B-cell chronic lymphocytic leukaemia cells enhances the anti-apoptotic profile, but also Bid expression and cells remain susceptible to autologous cytotoxic T-lymphocyte attack

To enhance the poor antigen-presenting capacity of B-cell chronic lymphocytic leukaemia (B-CLL), CD40 triggering has been considered as an active immunotherapy. However, CD40 stimulation also has an anti-apoptotic effect and may further impair the dysregulated response of B-CLL to apoptotic stimuli. Therefore, we measured the expression of virtually all regulators of apoptosis before and after CD40 stimulation. These findings were correlated with sensitivity for chemotherapy- and death-receptor-induced apoptosis and T-cell-mediated killing. CD40 stimulation enhanced the constitutive anti-apoptotic profile of B-CLL cells by upregulation of Bcl-xL and Bfl-1 and downregulation of the BH3-only protein Harakiri. Unexpectedly, the BH3-only protein Bid was strongly induced. Functionally, CD40-stimulated B-CLL cells became resistant to drug-induced apoptosis and, despite upregulation of CD95 and Bid, were not sensitive to CD95L. In contrast, autologous T cell killing, triggered by loading CLL cells with viral (CMV) peptides, was very efficient both before and after CD40 stimulation. Upon CTL interaction, CLL targets underwent mitochondrial depolarization and caspase-3 activation. Thus, despite an increased anti-apoptotic profile, CD40 triggered B-CLL cells remain excellent targets for resident cytotoxic T cells. These data support therapeutic exploitation of CD40 stimulation in B-CLL, provided that a strong CTL component is induce

Quality assurance and safety of hippocampal avoidance prophylactic cranial irradiation in the multicenter randomized phase III trial (NCT01780675)

Abstract: Objective: NCT01780675, a multicenter randomized phase III trial of prophylactic cranial irradiation (PCI) versus PCI with hippocampal sparing in small cell lung cancer (SCLC) investigated neurocognitive decline and safety. As part of quality assurance, we evaluated if hippocampal avoidance (HA)-PCI was performed according to the NCT01780675 trial protocol instructions, and performed a safety analysis to study the incidence and location of brain metastases for patients treated with HA-PCI.Methods: This retrospective analysis evaluated the quality of the irradiation given in the randomized controlled trial (RCT) comparing SCLC patients receiving PCI with or without hippocampal avoidance, using intensity mod-ulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT). The dose distribution for each patient receiving HA-PCI was retrieved and analyzed to evaluate if the treatment dose constraints were met. A ques-tionnaire was sent out to all participating sites, and data on radiotherapy technique, pre-treatment dummy runs, phantom measurements and treatment electronic portal imaging device (EPID) dosimetry were collected and analyzed. As part of the safety analysis, the follow-up magnetic resonance imaging (MRI) or computerized to-mography (CT) scans on which cranial disease progression was first diagnosed were collected and matched to the radiotherapy planning dose distribution. The matched scans were reviewed to analyze the location of the brain metastases in relation to the prescribed dose.Results: A total of 168 patients were randomized in the NCT01780675 trial in 10 centers in the Netherlands and Belgium from April 2013 until March 2018. Eighty two patients receiving HA-PCI without evidence of brain metastases were analyzed. All patients were treated with 25 Gy in 10 fractions. Dummy runs and phantom measurements were performed in all institutions prior to enrolling patients into the study. The radiotherapy (RT) plans showed a median mean bilateral hippocampal dose of 8.0 Gy, range 5.4-11.4 (constraint <= 8.5 Gy). In six patients (7.3%) there was a protocol violation of the mean dose in one or both hippocampi. In four of these six patients (4.9%) the mean dose to both hippocampi exceeded the constraint, in 1 patient (1.2%) only the left and in 1 patient (1.2%) only the right hippocampal mean dose was violated (average median dose left and right 8.9 Gy). All patients met the trial dose constraint of V 115% PTV <= 1%; however the D max PTV constraint of <= 28.75 Gy was violated in 22.0% of the patients. The safety analysis showed that 14 patients (17.1%) developed cranial progression. No solitary brain metastases in the underdosed region were found. Two out of 11 patients with multiple brain metastasis developed metastasis in the underdosed region(s). Conclusions: The radiotherapy quality within the HA-PCI trial is performed according to the protocol guidelines. The dose constraints to the hippocampi are met in the vast majority of cases. In all patients, the volume of the brain for which a higher dose was accepted, is according to the trial. However, within this volume there are small areas with higher doses than advised

Quality assurance and safety of hippocampal avoidance prophylactic cranial irradiation in the multicenter randomized phase III trial (NCT01780675)

Objective: NCT01780675, a multicenter randomized phase III trial of prophylactic cranial irradiation (PCI) versus PCI with hippocampal sparing in small cell lung cancer (SCLC) investigated neurocognitive decline and safety. As part of quality assurance, we evaluated if HA-PCI was performed according to the NCT01780675 trial protocol instructions, and performed a safety analysis to study the incidence and location of brain metastases for patients treated with HA-PCI. Methods: This retrospective analysis evaluated the quality of the irradiation given in the randomized controlled trial (RCT) comparing SCLC patients receiving PCI with or without hippocampal avoidance, using intensity modulated radiotherapy (IMRT) or volumetric modulated arc therapy (VMAT). The dose distribution for each patient receiving HA-PCI was retrieved and analyzed to evaluate if the treatment dose constraints were met. A questionnaire was sent out to all participating sites, and data on radiotherapy technique, pre-treatment dummy runs, phantom measurements and treatment electronic portal imaging device (EPID) dosimetry were collected and analyzed. As part of the safety analysis, the follow-up magnetic resonance imaging (MRI) or computerized tomography (CT) scans on which cranial disease progression was first diagnosed were collected and matched to the radiotherapy planning dose distribution. The matched scans were reviewed to analyze the location of the brain metastases in relation to the prescribed dose. Results: A total of 168 patients were randomized in the NCT01780675 trial in 10 centers in the Netherlands and Belgium from April 2013 until March 2018. Eighty two patients receiving HA-PCI without evidence of brain metastases were analyzed. All patients were treated with 25 Gy in 10 fractions. Dummy runs and phantom measurements were performed in all institutions prior to enrolling patients into the study. The radiotherapy (RT) plans showed a median mean bilateral hippocampal dose of 8.0 Gy, range 5.4–11.4 (constraint ≤ 8.5 Gy). In six patients (7.3%) there was a protocol violation of the mean dose in one or both hippocampi. In four of these six patients (4.9%) the mean dose to both hippocampi exceeded the constraint, in 1 patient (1.2%) only the left and in 1 patient (1.2%) only the right hippocampal mean dose was violated (average median dose left and right 8.9 Gy). All patients met the trial dose constraint of V115% PTV ≤ 1%; however the Dmax PTV constraint of ≤ 28.75 Gy was violated in 22.0% of the patients. The safety analysis showed that 14 patients (17.1%) developed cranial progression. No solitary brain metastases in the underdosed region were found. Two out of 11 patients with multiple brain metastasis developed metastasis in the underdosed region(s). Conclusions: The radiotherapy quality within the HA-PCI trial is performed according to the protocol guidelines. The dose constraints to the hippocampi are met in the vast majority of cases. In all patients, the volume of the brain for which a higher dose was accepted, is according to the trial. However, within this volume there are small areas with higher doses than advised