by
Adriana E. Tron;
Matthew A. Belmonte;
Ammar Adam;
Brian M. Aquila;
Lawrence Boise;
Elisabetta Chiarparin;
Justin Cidado;
Kevin J. Embrey;
Eric Gangl;
Francis D. Gibbons;
Gareth P. Gregory;
David Hargreaves;
J. Adam Hendricks;
Jeffrey W. Johannes;
Ricky W. Johnstone;
Steven L. Kazmirski;
Jason G. Kettle;
Michelle L. Lamb;
Shannon Matulis;
Ajay Nooka;
Martin J. Packer;
Bo Peng;
Philip B. Rawlins;
Daniel W. Robbins;
Alwin G. Schuller;
Nancy Su;
Wenzhan Yang;
Qing Ye;
Xiaolan Zheng;
J. Paul Secrist;
Edwin A. Clark;
David M. Wilson;
Stephen E. Fawell;
Alexander W. Hird
Mcl-1 is a member of the Bcl-2 family of proteins that promotes cell survival by preventing induction of apoptosis in many cancers. High expression of Mcl-1 causes tumorigenesis and resistance to anticancer therapies highlighting the potential of Mcl-1 inhibitors as anticancer drugs. Here, we describe AZD5991, a rationally designed macrocyclic molecule with high selectivity and affinity for Mcl-1 currently in clinical development. Our studies demonstrate that AZD5991 binds directly to Mcl-1 and induces rapid apoptosis in cancer cells, most notably myeloma and acute myeloid leukemia, by activating the Bak-dependent mitochondrial apoptotic pathway. AZD5991 shows potent antitumor activity in vivo with complete tumor regression in several models of multiple myeloma and acute myeloid leukemia after a single tolerated dose as monotherapy or in combination with bortezomib or venetoclax. Based on these promising data, a Phase I clinical trial has been launched for evaluation of AZD5991 in patients with hematological malignancies (NCT03218683).
In the past, rehabilitation research initiatives for low back pain (LBP) have targeted outcome enhancement through personalized treatment approaches, namely through classification systems (CS). Although the use of CS has enhanced outcomes, common management practices have not changed, the prevalence of LBP is still high, and only selected patients meet the CS profile, namely those with a nociceptive context. Similarly, although practice guidelines propose some level of organization and occasionally a timeline of care provision, each mainly provides best practice for isolated treatment approaches. Moreover, there is no theoretical framework that has been proposed that guides the rehabilitation management process of mechanical LBP. In this commentary, we propose a model constituted of five domains (nociceptive drivers, nervous system dysfunction drivers, comorbidities drivers, cognitive-emotional drivers, and contextual drivers) grounded as mechanisms driving pain and/or disability in LBP. Each domain is linked to the International Classification of Functioning, Disability and Health, where once a patient is deemed suitable for rehabilitation, the clinician assesses elements of each domain in order to identify where the relative treatment efforts should be focused. This theoretical model is designed to provide a more comprehensive management overview, by appreciating the relative contribution of each domain driving pain and disability. Considering that the multiple domains driving pain and disability, and their interaction, requires a model that is comprehensive enough to identify and address each related issue, we consider that the proposed model has several positive implications for rehabilitation of this painful and highly prevalent musculoskeletal disorder.
This work reports the use of a head-motion monitoring system to record patient head movements while completing in-home exercises for vestibular rehabilitation therapy. Based upon a dual-axis gyroscope (yaw and pitch, ± 500-degrees/sec maximum), angular head rotations were measured and stored via an on-board memory card. The system enabled the clinician to document exercises at home. Several measurements were recorded in one patient with unilateral vestibular hypofunction: The total time of exercise for the week (118 minutes) was documented and compared with expected weekly exercise time (140 minutes). For gaze stabilization exercises, execution time of 60 sec was expected, and observed times ranged from 75-100 sec. An absence of rest periods between each exercise instead of the recommended one minute rest period was observed. Maximum yaw head velocities from approximately 100-350 degrees/sec were detected. A second subject provided feedback concerning the ease of use of the HAMMS device. This pilot study demonstrates, for the first time, the capability to capture the head-motion "signature" of a patient while completing vestibular rehabilitation exercises in the home and to extract exercise regime parameters and monitor patient adherence. This emerging technology has the potential to greatly improve rehabilitation outcomes for individuals completing in-home gaze stabilization exercises.
Background: An adductor canal block (ACB) and preoperative oral gabapentin have each been shown to decrease postoperative pain scores and opioid usage in patients undergoing anterior cruciate ligament (ACL) reconstruction. Purpose/Hypothesis: This study evaluated the efficacy of preoperative gabapentin on postoperative analgesia in patients who received an ACB. We hypothesized that patients undergoing ACL reconstruction with an ACB who utilized a single dose of preoperative oral gabapentin would have decreased pain and opioid consumption in the 24 to 72 hours after surgery compared with patients who did not utilize gabapentin. Study Design: Cohort study; Level of evidence, 3. Methods: Between January and October 2016, patients at a single institution who underwent ACL reconstruction and received an ACB were identified. Patients who underwent surgery before May 2016 were placed in the control group, and patients seen after May 2016 received a preoperative dose of gabapentin and were placed in the gabapentin group. All patients completed a pain log via a smartphone application to record pain scores and opioid usage after surgery. Results: A total of 74 patients were identified: 41 in the gabapentin group and 33 in the control group. There were no significant differences between groups in demographics and operative characteristics. There were no differences in pain scores on postoperative day 1 (gabapentin vs control: 5.53 vs 5.56; P =.95), day 2 (4.58 vs 4.83; P =.59), or day 3 (4.15 vs 3.87; P =.59). The mean opioid consumption in oral morphine equivalents was not different on postoperative day 1 (gabapentin vs control: 47.2 vs 48.1; P =.90), day 2 (29.9 vs 33.5; P =.60), or day 3 (17.4 vs 18.7; P =.80). Conclusion: Preoperative gabapentin did not reduce pain scores or opioid usage in patients who received an ACB and underwent ACL reconstruction in this retrospective cohort study.
by
Suzanne V. Arnold;
John A. Spertus;
Yang Lei;
Philip Green;
Ajay J. Kirtane;
Samir Kapadia;
Vinod Thourani;
Howard C. Herrmann;
Nirat Beohar;
Alan Zajarias;
Michael J. Mack;
Martin B. Leon;
David Cohen
Purpose:
To introduce a novel, deep-learning method to generate synthetic computed tomography (SCT) scans for proton treatment planning and evaluate its efficacy.
Materials and Methods:
50 Patients with base of skull tumors were divided into 2 nonoverlapping training and study cohorts. Computed tomography and magnetic resonance imaging pairs for patients in the training cohort were used for training our novel 3-dimensional generative adversarial network (cycleGAN) algorithm. Upon completion of the training phase, SCT scans for patients in the study cohort were predicted based on their magnetic resonance images only. The SCT scans obtained were compared against the corresponding original planning computed tomography scans as the ground truth, and mean absolute errors (in Hounsfield units [HU]) and normalized cross-correlations were calculated. Proton plans of 45 Gy in 25 fractions with 2 beams per plan were generated for the patients based on their planning computed tomographies and recalculated on SCT scans. Dose-volume histogram endpoints were compared. A c-index analysis along 3 cardinal planes intercepting at the isocenter was performed. Proton distal range along each beam was calculated.
Results:
Image quality metrics show agreement between the generated SCT scans and the ground truth with mean absolute error values ranging from 38.65 to 65.12 HU and an average of 54.55 6 6.81 HU and a normalized cross-correlation average of 0.96 6 0.01. The dosimetric evaluation showed no statistically significant differences (p. 0.05) within planning target volumes for dose-volume histogram endpoints and other metrics studied, with the exception of the dose covering 95% of the target volume, with a relative difference of 0.47%. The c-index analysis showed an average passing rate of 98% with a 10% threshold and 2% and 2-mm criteria. Proton ranges of 48 of 50 beams (96%) in this study were within clinical tolerance adopted by 4 institutions.
Conclusions:
This study shows our method is capable of generating SCT scans with acceptable image quality, dose distribution agreement, and proton distal range compared with the ground truth. Our results set a promising approach for magnetic resonance imaging-based proton treatment planning.
by
Mark R. Gilbert;
Meihua Wang;
Kenneth D. Aldape;
Roger Stupp;
Monika E. Hegi;
Kurt A. Jaeckle;
Terri S. Armstrong;
Jeffrey S. Wefel;
Minhee Won;
Deborah T. Blumenthal;
Anita Mahajan;
Christopher J. Schultz;
Sara Erridge;
Brigitta Baumert;
Kristin I. Hopkins;
Tzahala Tzuk-Shina;
Paul D. Brown;
Arnab Chakravarti;
Walter Curran Jr;
Minesh Mehta
Purpose:
Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM.
Patients and Methods:
This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status.
Results:
A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue.
Conclusion:
This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.
Background and Purpose: The objectives of this pilot study were to (1) evaluate the feasibility and investigate the efficacy of a 3-week, high-volume (450 minutes per week) Adapted Tango intervention for community-dwelling individuals with mild-moderate Parkinson disease (PD) and (2) investigate the potential efficacy of Adapted Tango in modifying electromyographic (EMG) activity and center of body mass (CoM) displacement during automatic postural responses to support surface perturbations. Methods: Individuals with PD (n = 26) were recruited for highvolume Adapted Tango (15 lessons, 1.5 hour each over 3 weeks). Twenty participants were assessed with clinical balance and gait measures before and after the intervention. Nine participants were also assessed with support-surface translation perturbations. Results: Overall adherence to the intervention was 77%. At posttest, peak forward CoM displacement was reduced (4.0 ± 0.9 cm, pretest, vs 3.7 ± 1.1 cm, posttest; P = 0.03; Cohen's d = 0.30) and correlated to improvements on Berg Balance Scale (p = .0.68; P = 0.04) and Dynamic Gait Index (p =.0.75; P = 0.03). Overall antagonist onset time was delayed (27 ms; P = 0.02; d = 0.90) and duration was reduced (56 ms, .39%, P = 0.02; d = 0.45). Reductions in EMG magnitude were also observed (P < 0.05). Discussion and Conclusions: Following participation in Adapted Tango, changes in kinematic and some EMG measures of perturbation responses were observed in addition to improvements in clinical measures. We conclude that 3-week, high-volume Adapted Tango is feasible and represents a viable alternative to longer duration adapted dance programs.
Objective: This is the first study to examine Wolf Motor Function Test (WMFT) tasks among EXCITE Trial participants that could not be completed at baseline or 2 weeks later.
Methods: Data were collected from participants who received constraint-induced movement therapy (CIMT) immediately at the time of randomization (CIMT-I, n = 106) and from those for whom there was a delay of 1 year in receiving this intervention (CIMT-D, n = 116). Data were collected at baseline and at a 2-week time point, during which the CIMT-I group received the CIMT intervention and the CIMT-D group did not. Generalized estimating equation (GEE) analyses were used to examine repeated binary data and count values. Group and visit interactions were assessed, adjusting for functional level, affected side, dominant side, age, and gender covariates.
Results: In CIMT-I participants, there was an increase in the proportion of completed tasks at posttest compared with CIMT-D participants, particularly with respect to those tasks requiring dexterity with small objects and total incompletes (P < .0033). Compared with baseline, 120 tasks governing distal limb use for CIMT-I and 58 tasks dispersed across the WMFT for CIMT-D could be completed after 2 weeks. Common movement components that may have contributed to incomplete tasks include shoulder stabilization and flexion, elbow flexion and extension, wrist pronation, supination and ulnar deviation, and pincer grip.
Conclusion: CIMT training should emphasize therapy for those specific movement components in patients who meet the EXCITE criteria for baseline motor control.
Background:
Previous studies investigating nigral iron accumulation used T 2 or T 2 *-weighted contrasts to define the regions of interest (ROIs) in the substantia nigra with mixed results. Because these contrasts are not sensitive to neuromelanin, ROIs may have inadvertently missed the SNpc. An approach sensitive to neuromelanin should yield consistent results. We examine iron deposition in ROIs derived from neuromelanin-sensitive and T 2 *-weighted contrasts, respectively.
Methods:
T 1 -weighted and multiecho gradient echo imaging data were obtained in 2 cohorts. Multiecho gradient echo imaging data were analyzed using neuromelanin-sensitive SNpc ROIs as well as T 2 *-weighted SNr ROIs.
Results: When compared with controls, significantly larger R 2 * values were seen in the SNpc of PD patients in both cohorts. Mean R 2 * values in the SNr of PD patients showed no consistency, with 1 cohort showing a small, statistically significant increase, whereas the other cohort exhibited no statistical difference.
Conclusion: Mean R 2 * in the SNpc defined by neuromelanin-sensitive MRI is significantly increased in PD.