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Objectives: To investigate: (i) the chronicity and phasic variability of sleep patterns and restriction in recruits during basic military training (BMT); and (ii) identify subjective sleep quality in young adult recruits prior to entry into BMT.Design: Prospective observational study.Methods: Sleep was monitored using wrist-worn actigraphy in Army recruits (n = 57, 18-43 y) throughout 12-weeks of BMT. The Pittsburgh Sleep Quality Index (PSQI) was completed in the first week of training to provide a subjective estimate of pre-BMT sleep patterns. A mixed-effects model was used to compare week-to-week and training phase (Orientation, Development, Field, Drill) differences for rates of sub-optimal sleep (6-7 h), sleep restriction (≤6 h), and actigraphy recorded sleep measures.Results: Sleep duration was 06:24 ± 00:18h (mean ± SD) during BMT with all recruits experiencing sub-optimal sleep and 42% (n = 24) were sleep restricted for ≥2 consecutive weeks. During Field, sleep duration (06:06 ± 00:36h) and efficiency (71 ± 6%; p < 0.01) were reduced by 15-18 min (minimum - maximum) and 7-8% respectively; whereas, sleep latency (30 ± 15 min), wake after sleep onset (121 ± 23 min), sleep fragmentation index (41 ± 4%) and average awakening length (6.5 ± 1.6 min) were greater than non-Field phases (p < 0.01) by 16-18 min, 28-33 min, 8-10% and 2.5-3 min respectively. Pre-BMT global PSQI score was 5 ± 3, sleep duration and efficiency were 7.4 ± 1.3 h and 88 ± 9% respectively. Sleep schedule was highly variable at pre-BMT (bedtime: 22:34 ± 7:46 h; wake time: 6:59 ± 1:42 h) unlike BMT (2200-0600 h).Conclusions: The chronicity of sub-optimal sleep and sleep restriction is substantial during BMT and increased training demands exacerbate sleep disruption. Exploration of sleep strategies (e.g. napping, night-time routine) are required to mitigate sleep-associated performance detriments and maladaptive outcomes during BMT. [ABSTRACT FROM AUTHOR]

Objectives: To determine the effect of a novel low volume high intensity concurrent training regimen and warm-up on physiological performance and musculoskeletal injury in Australian recruits.Design: Controlled longitudinal intervention.Methods: Military recruits completed 12 weeks of either experimental (EXP: n=78, 6-8RM resistance loads, and high intensity intervals) or basic military (CON: n=69, usual practice) matched for total sessions and time. Endurance (3.2km 22kg-load carriage, V˙O2 peak, multi-stage fitness test (MSFT)), 1RM strength and local muscle endurance (bench, squat, box-lift and push-ups) and power (squat jump) were assessed at Weeks 1,6,12. Body composition, physical activity (PAC·min-1) and heart rate reserve (HRR%), were assessed at Weeks 2,7,9. Musculoskeletal injury and mechanism were recorded. Two-way repeated measures ANOVA interaction (group×time), mean difference and effect size (ES) are reported p≤0.05.Results: A significant interaction over 12 weeks was observed for load carriage (ES -0.30), squat jump (ES 0.65), V˙O2 peak (ES 0.58), MSFT (ES 0.41), push-ups (ES 0.26), 1RM bench (ES 0.26), squat (ES 1.05) and box lift (ES 0.27) in EXP compared to CON. At Week 12 significantly greater squat (38.9kg), MSFT (2.1mL·kg-1·min-1), and faster load carriage (49.9s) was observed in EXP than CON, but no difference in body composition. EXP had a lower PAC·min-1 (641.1±63.1) but higher HRR% (21.8±4.0) compared to CON. EXP had a lower number of injuries (6) compared to CON (17).Conclusions: The inclusion of compound-specific resistance exercise and high intensity intervals improved physical function and was associated with reduced musculoskeletal injury. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to conduct the first injury surveillance study in sub-elite football in Australia, using methods from the international football consensus statement.Design: Descriptive epidemiological study.Methods: 1049 sub-elite football players were recruited during the 2016 season. Injury and exposure data was collected by trained Primary Data Collectors (PDCs) who attended every training session and match.Results: There were 1041 time loss injuries recorded during 52,127h of exposure resulting in an injury incidence rate of 20 injuries/1000h (95% Confidence Interval [CI]: 15.9-23.3). The injury burden (days lost to injury relative to exposure) was 228days lost/1000h. Muscle and ligament injuries were the most prevalent (41% and 26%) and incurred the highest injury burden (83 and 80days lost/1000h, respectively). The most common injuries were observed at the thigh (22%) and ankle (17%), with hamstring (13%) the highest reported muscle injury. The profile of injury severity was: mild - 35%; minor - 29%; moderate - 28% and severe - 8%. Recurrent injuries accounted for 20% of all injuries.Conclusions: By addressing issues identified with injury recording in sub-elite football, this study found that the injury incidence was twice that observed in previous research in elite and sub-elite football cohorts. Injury burden was also twice that of the elite setting, with similar injuries associated with the highest burden. The results highlight the need for investment into medical provision, facilities, coach education and injury mitigation programmes to reduce healthcare costs to sub-elite players in Australia. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the heterogeneity of physical adaptation in Australian Army recruits completing a 12-week basic military training regimen.Design: A prospective research design.Methods: Volunteer recruits (n=195) completed 12-weeks of basic military training. Recruit physical fitness was assessed at week 1, weeks 6-8 and week 12. Recruits in the upper (75th) and lower (25th) quartiles for each assessment were then analysed using a repeated measures two-way ANOVA. The relative magnitude of recruit adaptions were classified as positive response (Rpositive, ≥5%), limited response (Rlimited, >-5% to <5%) and negative response (Rnegative, ≤-5%); Chi-square analysis determined the proportional differences in the distribution of each quartile.Results: An interaction (p<0.001) was observed in the lower and upper recruit quartiles for all assessments of physical fitness at each time point. After 12 weeks of military training the mean difference of the highest quartile was; 20-m multi-stage fitness test 7.4mL·kg-1·min-1, (CI:5.8:9.1), 2-min push-ups 20.1 reps, (CI:16.2:23.9), 1RM box lift 5.6kg, (CI:2.6:5.8) and load carriage 222.1s, (CI:174.7:269.4) compared to the lowest recruit quartile. The highest quartile demonstrated no improvement in 1RM box lift (-4%, -1%) and push-ups (2%, 0%) performance at weeks 6-8 and week 12 respectively. In contrast, adaptations in the lowest quartile for 1RM box lift (16%, 21%) and push-ups (46%, 46%) over the same time periods were observed.Conclusions: A significant proportion of recruits may complete basic military training with a decline in physical performance. Higher relative-intensity cardiorespiratory and resistance exercise should be considered to facilitate physical adaptation in all recruits. [ABSTRACT FROM AUTHOR]

Highlights • Obstacles for CED of CAR T cells are sedimentation, tube clogging, low viability. • LV Hydrogel is a biodegradable hyaluronic acid based biomaterial. • LV Hydrogel provides 20-fold increase in the delivery rate of CAR T cells. • Migration capacity and cytotoxicity of CAR T cells remain the same after infusion. • LV hydrogel has no toxic effect on rodent brain and fully disintegrated after 2 weeks. Abstract Convection Enhanced Delivery (CED) infuses therapeutic agents directly into the intracranial area continuously under pressure. The convection improves the distribution of therapeutics such as those aimed at brain tumors. Although CED successfully delivers small therapeutic agents, this technique fails to effectively deliver cells largely due to cell sedimentation during delivery. To overcome this limitation, we have developed a low viscosity hydrogel (LVHydrogel), which is capable of retaining cells in suspension. In this study, we evaluated whether LVHydrogel can effectively act as a carrier for the CED of tumor-specific chimeric antigen receptor (CAR) T cells. CAR T cells were resuspended in saline or LVHydrogel carriers, loaded into syringes, and passed through the CED system for 5 h. CAR T cells submitted to CED were counted and the efficiency of delivery was determined. In addition to delivery, the ability of CAR T cells to migrate and induce cytotoxicity was evaluated. Our studies demonstrate that LVHydrogel is a superior carrier for CED in comparison to saline. The efficiency of cell delivery in saline carrier was only ∼3–5% of the total cells whereas delivery by the LVHydrogel carrier was much higher, reaching ∼45–75%. Migration and Cytotoxicity was similar in both carriers in non-infused samples but we found superior cytotoxicity in LVHydrogel group post-infusion. We demonstrate that LVHydrogel, a biodegradable biomaterial which does not cause acute toxicity on preclinical animal models, prevents cellular sedimentation during CED and presents itself as a superior carrier to the current carrier, saline, for the CED of CAR T cells. [ABSTRACT FROM AUTHOR]

In almost all patients, malignant glioma recurs following initial treatment with maximal safe resection, conformal radiotherapy, and temozolomide. This review describes the many options for treatment of recurrent malignant gliomas, including reoperation, alternating electric field therapy, chemotherapy, stereotactic radiotherapy or radiosurgery, or some combination of these modalities, presenting the evidence for each approach. No standard of care has been established, though the antiangiogenic agent, bevacizumab; stereotactic radiotherapy or radiosurgery; and, perhaps, combined treatment with these 2 modalities appear to offer modest benefits over other approaches. Clearly, randomized trials of these options would be advantageous, and novel, more efficacious approaches are urgently needed. [ABSTRACT FROM AUTHOR]

Objectives: Mechanical and neuromuscular benefits arise during ballistic stretch-shortening cycle muscle activation, yet resistance training regimens are typically non-ballistic, and in contrast to ballistic movement, require a concentric deceleration phase. Design: Twelve healthy males performed a unilateral, six repetition maximum non-ballistic elbow flexion-extension task during; (i) rapid shortening (RS), (ii) stretch-shortening cycle (SSC) and (iii) a 2-s eccentric and 2-s concentric control (C). Methods: A load cell and shaft encoder recorded respectively force and velocity. Surface electromyographic root mean square amplitude (EMGRMS) was recorded in the biceps and triceps brachii, and is reported as the relative (%) difference, normalised to control (C). Results: The average lengthening and shortening velocity of SSC (0.57±0.03ms−1; 0.43±0.02ms−1) was significantly greater than RS (0.22±0.01ms−1; 0.35±0.01ms−1), and C (0.17±0.00ms−1, 0.20±0.00ms−1). Peak eccentric force was increased (P <0.0001) and in the first 5% of concentric movement during SSC, in the first and last repetitions respectively (194.7±8.4N, 164.1±7.5N) when compared to RS (163.3±8.9N, 152.4±7.5N) and C (155.9±8.5N, 152.2±8.7N). Eccentric EMGRMS in the biceps brachii was significantly increased during the first three and final repetitions of SSC (31.9±10.9%, 46.7±12.4, 69.3±13.6%, 92.0±16.4%), and the third and last repetitions of RS (35.9±7.4%, 50.3±10.9%), compared to C (0.00%, 15.8±4.0%, 23.7±4.1%, 39.2±8.6%). Conclusions: In the current study, eccentric limb velocity potentiated eccentric and concentric force, concentric velocity, and eccentric EMG amplitude during non-ballistic exercise. [ABSTRACT FROM AUTHOR]

Abstract: We report a unique case of a dural-based inflammatory pseudotumor (IPT) arising in the left cavernous sinus of a patient with a history of juvenile Still’s disease. The patient presented with hemi-facial paresthesias, dull, constant headaches, and transient episodes of sharp pain along the temporalis region. Treatment with oral steroid therapy resulted in complete regression of the lesion and accompanied neuralgia symptoms. Because intracranial IPT can mimic meningiomas both clinically and radiographically and can be associated with systemic arthritic diseases, neurosurgeons should be familiar with this entity in order to avoid unnecessary radical surgery and alternatively consider a tapering course of steroid therapy. [Copyright &y& Elsevier]

We aim to summarize data from studies of trastuzumab in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) and brain metastasis and to describe novel methods being developed to circumvent the blood-brain barrier (BBB). A literature search was conducted to obtain data on the clinical efficacy of trastuzumab and lapatinib in patients with HER2-positive MBC and brain metastasis, as well as the transport of therapeutic molecules across the BBB. Trastuzumab-based therapy is the standard of care for patients with HER2-positive MBC. Post hoc and retrospective analyses show that trastuzumab significantly prolongs overall survival when given after the diagnosis of central nervous system (CNS) metastasis; this is probably attributable to its control of extracranial disease, although trastuzumab may have a direct effect on CNS disease in patients with local or general perturbation of the BBB. In patients without a compromised BBB, trastuzumab is thought to have limited access to the brain, because of its relatively large molecular size. Several approaches are being developed to enhance the delivery of therapeutic agents to the brain. These include physical or pharmacologic disruption of the BBB, direct intracerebral drug delivery, drug manipulation, and coupling drugs to transport vectors. Available data suggest that trastuzumab extends survival in patients with HER2-positive MBC and brain metastasis. Novel methods for delivery of therapeutic agents into the brain could be used in the future to enhance access to the CNS by trastuzumab, thereby improving its efficacy in this setting. [ABSTRACT FROM AUTHOR]

Summary: The immunologic treatment of cancer has long been heralded as a targeted molecular therapeutic with the promise of eradicating tumor cells with minimal damage to surrounding normal tissues. However, a demonstrative example of the efficacy of immunotherapy in modulating cancer progression is still lacking for most human cancers. Recent breakthroughs in our understanding of the mechanisms leading to full T-cell activation, and recognition of the importance of overcoming tumor-induced immunosuppressive mechanisms, have shed new light on how to generate effective anti-tumor immune responses in humans, and sparked a renewed and enthusiastic effort to realize the full potential of cancer immunotherapy. The immunologic treatment of invasive malignant brain tumors has not escaped this re-invigorated endeavor, and promising therapies are currently under active investigation in dozens of clinical trials at several institutions worldwide. This review will focus on some of the most important breakthroughs in our understanding of how to generate potent anti-tumor immune responses, and some of the clear challenges that lie ahead in achieving effective immunotherapy for the majority of patients with malignant brain tumors. A review of immunotherapeutic strategies currently under clinical evaluation, as well as an outline of promising novel approaches on the horizon, is included to provide perspective on the active and stalwart progress toward effective immunotherapy for the treatment of malignant brain tumors. [Copyright &y& Elsevier]

The article offers information on oncolytic virotherapy (OV) using an oxidative stress inhibition. It informs that OV is the manipulation of replication-competent virus to selectively infect and lyse malignant cells while leaving normal cells untouched. OV represents a novel, tumor-targeted therapy for a variety of cancers intractable to current multimodality standards of care. Glioblastoma (GBM), the most aggressive of brain tumors.

Preoperative assessment is important for neurosurgical risk stratification, but the level of evidence for individual screening tests is low. In preoperative urinalysis (UA), testing may significantly increase costs and lead to inappropriate antibiotic treatment. We prospectively evaluated whether eliminating preoperative UA was noninferior to routine preoperative UA as measured by 30-day readmission for surgical site infection in adult elective neurosurgical procedures. A single-institution prospective, pragmatic study of patients receiving elective neurosurgical procedures from 2018 to 2020 was conducted. Patients were allocated based on same-day versus preoperative admission status. Rates of preoperative UA and subsequent wound infection were measured along with detailed demographic, surgical, and laboratory data. The study included 879 patients. The most common types of surgery were cranial (54.7%), spine (17.4%), and stereotactic/functional (19.5%). No preoperative UA was performed in 315 patients, while 564 underwent UA. Of tested patients, 103 (18.3%) met criteria for suspected urinary tract infection, and 69 (12.2%) received subsequent antibiotic treatment. There were 14 patients readmitted within 30 days (7 without UA [2.2%] vs. 7 with UA [1.2%]) for subsequent wound infection with a risk difference of 0.98% (95% confidence interval −0.89% to 2.85%). The upper limit of the confidence interval exceeded the preselected noninferiority margin of 1%. In this prospective study of preoperative UA for elective neurosurgical procedures using a pragmatic, real-world design, risk of readmission due to surgical site infection was very low across the study cohort, suggesting a limited role of preoperative UA for elective neurosurgical procedures. [ABSTRACT FROM AUTHOR]

Abstract: Chimeric antigen receptors (CAR)-transduced T cells hold great promise in the treatment of malignant disease. Here, we demonstrate that intracerebral injection with a human, epidermal growth factor receptor variant III (EGFRvIII)-specific, third generation CAR successfully treats glioma in mice. Importantly, these results endorse clinical translation of this CAR in patients with EGFRvIII-expressing brain tumors. [Copyright &y& Elsevier]

Several Phase II and III clinical trials have demonstrated that immunotherapy can induce objective responses in otherwise refractory malignancies in tumors outside the central nervous system. In large part, effector T cells mediate much of the antitumor efficacy in these trials, and potent antitumor T cells can be generated through vaccination, immune checkpoint blockade, adoptive transfer, and genetic manipulation. However, activated T cells must still traffic to, infiltrate, and persist within tumor in order to mediate tumor lysis. These requirements for efficacy pose unique challenges for brain tumor immunotherapy, due to specific anatomical barriers and populations of specialized immune cells within the central nervous system that function to constrain immunity. Both autoimmune and infectious diseases of the central nervous system provide a wealth of information on how T cells can successfully migrate to the central nervous system and then engender sustained immune responses. In this review, we will examine the commonalities in the efferent arm of immunity to the brain for autoimmunity, infection, and tumor immunotherapy to identify key factors underlying potent immune responses. [ABSTRACT FROM AUTHOR]

Objective To evaluate accuracy of a computed tomography (CT)–guided frameless stereotactic drilling and catheter system. Methods A prospective, single-arm study was performed using human cadaver heads to evaluate placement accuracy of a novel, flexible intracranial catheter and stabilizing bone anchor system and drill kit. There were 20 catheter placements included in the analysis. The primary endpoint was accuracy of catheter tip location on intraoperative CT. Secondary endpoints included target registration error and entry and target point error before and after drilling. Measurements are reported as mean ± SD (median, range). Results Target registration error was 0.46 mm ± 0.26 (0.50 mm, −1.00 to 1.00 mm). Two (10%) target point trajectories were negatively impacted by drilling. Intracranial catheter depth was 59.8 mm ± 9.4 (60.5 mm, 38.0–80.0 mm). Drilling angle was 22° ± 9 (21°, 7°–45°). Deviation between planned and actual entry point on CT was 1.04 mm ± 0.38 (1.00 mm, 0.40–2.00 mm). Deviation between planned and actual target point on CT was 1.60 mm ± 0.98 (1.40 mm, 0.40–4.00 mm). No correlation was observed between intracranial catheter depth and target point deviation (accuracy) (Pearson coefficient 0.018) or between technician experience and accuracy (Pearson coefficient 0.020). There was no significant difference in accuracy with trajectories performed for different cadaver heads ( P = 0.362). Conclusions Highly accurate catheter placement is achievable using this novel flexible catheter and bone anchor system placed via frameless stereotaxy, with an average deviation between planned and actual target point of 1.60 mm ± 0.98 (1.40 mm, 0.40–4.00 mm). [ABSTRACT FROM AUTHOR]

Purpose To identify an optimal margin about the gross target volume (GTV) for stereotactic radiosurgery (SRS) of brain metastases, minimizing toxicity and local recurrence. Methods and Materials Adult patients with 1 to 3 brain metastases less than 4 cm in greatest dimension, no previous brain radiation therapy, and Karnofsky performance status (KPS) above 70 were eligible for this institutional review board–approved trial. Individual lesions were randomized to 1- or 3- mm uniform expansion of the GTV defined on contrast-enhanced magnetic resonance imaging (MRI). The resulting planning target volume (PTV) was treated to 24, 18, or 15 Gy marginal dose for maximum PTV diameters less than 2, 2 to 2.9, and 3 to 3.9 cm, respectively, using a linear accelerator–based image-guided system. The primary endpoint was local recurrence (LR). Secondary endpoints included neurocognition Mini-Mental State Examination, Trail Making Test Parts A and B, quality of life (Functional Assessment of Cancer Therapy-Brain), radionecrosis (RN), need for salvage radiation therapy, distant failure (DF) in the brain, and overall survival (OS). Results Between February 2010 and November 2012, 49 patients with 80 brain metastases were treated. The median age was 61 years, the median KPS was 90, and the predominant histologies were non–small cell lung cancer (25 patients) and melanoma (8). Fifty-five, 19, and 6 lesions were treated to 24, 18, and 15 Gy, respectively. The PTV/GTV ratio, volume receiving 12 Gy or more, and minimum dose to PTV were significantly higher in the 3-mm group (all P <.01), and GTV was similar ( P =.76). At a median follow-up time of 32.2 months, 11 patients were alive, with median OS 10.6 months. LR was observed in only 3 lesions (2 in the 1 mm group, P =.51), with 6.7% LR 12 months after SRS. Biopsy-proven RN alone was observed in 6 lesions (5 in the 3-mm group, P =.10). The 12-month DF rate was 45.7%. Three months after SRS, no significant change in neurocognition or quality of life was observed. Conclusions SRS was well tolerated, with low rates of LR and RN in both cohorts. However, given the higher potential risk of RN with a 3-mm margin, a 1-mm GTV expansion is more appropriate. [ABSTRACT FROM AUTHOR]

Purpose: Patients with recurrent malignant gliomas treated with stereotactic radiosurgery (SRS) and multiagent systemic therapies were reviewed to determine the effects of patient- and treatment-related factors on survival and toxicity. Methods and Materials: A retrospective analysis was performed on patients with recurrent malignant gliomas treated with salvage SRS from September 2002 to March 2010. All patients had experienced progression after treatment with temozolomide and radiotherapy. Salvage SRS was typically administered only after multiple postchemoradiation salvage systemic therapies had failed. Results: 63 patients were treated with SRS for recurrent high-grade glioma; 49 patients had World Health Organization (WHO) Grade 4 disease. Median follow-up was 31 months from primary diagnosis and 7 months from SRS. Median overall survival from primary diagnosis was 41 months for all patients. Median progression-free survival (PFS) and overall survival from SRS (OS-SRS) were 6 and 10 months for all patients, respectively. The 1-year OS-SRS for patients with Grade 4 glioma who received adjuvant (concurrent with or after SRS) bevacizumab was 50% vs. 22% for patients not receiving adjuvant bevacizumab (p = 0.005). Median PFS for patients with a WHO Grade 4 glioma who received adjuvant bevacizumab was 5.2 months vs. 2.1 months for patients who did not receive adjuvant bevacizumab (p = 0.014). Karnofsky performance status (KPS) and age were not significantly different between treatment groups. Treatment-related Grade 3/4 toxicity for patients receiving and not receiving adjuvant BVZ was 10% and 14%, respectively (p = 0.58).On multivariate analysis, the relative risk of death and progression with adjuvant bevacizumab was 0.37 (confidence interval [CI] 0.17–0.82) and 0.45 (CI 0.21–0.97). KPS >70 and age <50 years were significantly associated with improved survival. Conclusions: The combination of salvage radiosurgery and bevacizumab to treat recurrent malignant gliomas is well tolerated and seems to be associated with improved outcomes. Prospective multiinstitutional studies are required to determine efficacy and long-term toxicity with this approach. [ABSTRACT FROM AUTHOR]

Purpose: To describe our experience and clinical strategy for stereotactic body radiotherapy (SBRT) of spinal lesions. Methods and Materials: Thirty-two patients with 33 spinal lesions underwent computed tomography–based simulation while free breathing. Gross/clinical target volumes included involved portions of the vertebral body and paravertebral/epidural tumor. Planning target volume (PTV) expansion was 6 mm axially and 3 mm radially; the cord was excluded from the PTV. Biologic equivalent dose was calculated using the linear quadratic model with α/β = 3 Gy. Treatment was linear accelerator based with on-board imaging; dose was adjusted to maintain cord dose within tolerance. Survival, local control, pain, and neurologic status were monitored. Results: Twenty-one patients are alive at 1 year (median survival, 14 months). Median follow-up is 6 months for all patients (7 months for survivors). Mean previous radiotherapy dose to 22 patients was 35 Gy, and median interval was 17 months. Renal (31%), breast, and lung (19% each) were the most common histologic sites. Three SBRT fractions (range, one to four fractions) of 7 Gy (range, 5–16 Gy) were delivered. Median cord and target biologic equivalent doses were 70 Gy3 and 34.3 Gy10, respectively. Thirteen patients reported complete and 17 patients reported partial pain relief at 1 month. There were four failures (mean, 5.8 months) with magnetic resonance imaging evidence of in-field progression. No dosimetric parameters predictive of failure were identified. No treatment-related toxicity was seen. Conclusions: Spinal SBRT is effective in the palliative/re-treatment setting. Volume expansion must ensure optimal PTV coverage while avoiding spinal cord toxicity. The long-term safety of spinal SBRT and the applicability of the linear-quadratic model in this setting remain to be determined, particularly the time-adjusted impact of prior radiotherapy. [Copyright &y& Elsevier]

The ELISpot assay prevails as one of the most sensitive and meaningful assays for the detection of antigen-specific, effector immune responses. Acquisition of cellular analyte for ELISpot analysis is typically not problematic when derived from tissues enriched in lymphocytes (e.g., lymphoid organs and blood); however, cell processing becomes more difficult when lymphocytes represent only a very minor population relative to the source tissue, especially when the source tissue is in limited supply (e.g., small mouse tumors). Traditional enzymatic-based methods for dissociating tumors often result in poor yields, inconsistent lymphocyte enrichment, and can have deleterious effects on lymphocyte phenotype and function. To address these limitations, we have developed an enzyme-free protocol for processing tumor infiltrating lymphocytes (TILs) from small mouse tumors, which enables the enumeration of antigen-specific effector lymphocytes using ELISpot analysis. This procedure is predicated on the dissociation of tumor tissue using gentle agitation with a paddle blender followed by a brief in vitro culture period to remove adherent cells, as well as to revive lymphocytes from a non-responsive state. Although this method is demonstrated with mouse intracerebral tumors, we have found that this protocol is applicable to peripheral tumors and may likely extend to alternative tissue sources wherein lymphocytes exist in low numbers. [ABSTRACT FROM AUTHOR]

Abstract: Developments in the field of bispecific antibodies have progressed rapidly in recent years, particularly in their potential role for the treatment of malignant disease. However, manufacturing stable molecules has proven to be costly and time-consuming, which in turn has hampered certain aspects of preclinical evaluation including the unavailability of appropriate “negative” controls. Bispecific molecules (e.g., bispecific tandem scFv) exhibit two specificities, often against a tumor antigen as well as an immune-activation ligand such as CD3. While for IgG antibodies, isotype-matched controls are well accepted, when considering smaller antibody fragments it is not possible to adequately control for their biological activity through the use of archetypal isotypes, which differ dramatically in affinity, size, structure, and design. Here, we demonstrate a method for the rapid production of negative control tandem scFvs through complementarity determining region (CDR) mutagenesis, using a recently described bispecific T-cell engager (BiTE) targeting a tumor-specific mutation of the epidermal growth factor receptor (EGFRvIII) as an example. Four independent control constructs were developed by this method through alteration of residues spanning individual CDR domains. Importantly, while target antigen affinity was completely impaired, CD3 binding affinity was conserved in each molecule. These results have a potential to enhance the sophistication by which bispecific antibodies can be evaluated in the preclinical setting and may have broader applications for an array of alternative antibody-derived therapeutic platforms. [Copyright &y& Elsevier]

Abstract: Cellulose acetate (CA) with a degree of substitution (DS) of 2.5 has been plasticized using eco-friendly plasticizers such as triacetin, tripropionin, triethyl citrate, tributyl citrate, tributyl 2-acetyl citrate and poly(ethylene glycol) of low molecular weight. Thermo-mechanical properties and hydrophilicity of the modified CA have been measured and correlated with the content and nature of the plasticizer used and compared with unplasticized CA. The increase in toughening and the change in the hydrophilicity by the plasticization were evaluated in terms of aging and weathering stability under accelerated conditions. Samples were exposed to UV-degradation with water spray periods. The treated samples were removed periodically and characterized by several analytical techniques. The results are discussed with particular emphasis toward the effects of plasticization on enhancement of the degradation rate of CA. The plasticization of CA triggered an increase of the weight loss between 50 and 90%, where low molecular weight plasticizers were shown to be more effective. A right balance between hydrophilicity and plasticization efficiency (reduction of T g ) is needed to increase the degradation rate of CA. [Copyright &y& Elsevier]

Purpose: Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG. Methods and Materials: Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status. Results: One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months. Conclusions: Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach. [Copyright &y& Elsevier]

Purpose: To determine the safety of the addition of bevacizumab to standard radiation therapy and daily temozolomide for newly diagnosed glioblastoma multiforme (GBM). Methods and Materials: A total of 125 patients with newly diagnosed GBM were enrolled in the study, and received standard radiation therapy and daily temozolomide. All patients underwent a craniotomy and were at least 2 weeks postoperative. Radiation therapy was administered in 1.8-Gy fractions, with the clinical target volume for the primary course treated to a dose of 45 to 50.4 Gy, followed by a boost of 9 to 14.4 Gy, to a total dose of 59.4 Gy. Patients received temozolomide at 75 mg/m2 daily throughout the course of radiation therapy. Bevacizumab was given at 10 mg/kg intravenously every 14 days, beginning a minimum of 4 weeks postoperatively. Results: Of the 125 patients, 120 (96%) completed the protocol-specified radiation therapy. Five patients had to stop the protocol therapy, 2 patients with pulmonary emboli, and 1 patient each with a Grade 2 central nervous system hemorrhage, Grade 4 pancytopenia, and wound dehiscence requiring surgical intervention. All 5 patients ultimately finished the radiation therapy. After radiation therapy, 3 patients had progressive disease, 2 had severe fatigue and decreased performance status, 1 patient had a colonic perforation, and 1 had a rectal fissure; these 7 patients therefore did not proceed with the protocol-specified adjuvant temozolomide, bevacizumab, and irinotecan. However, 113 patients (90%) were able to continue on study. Conclusions: The addition of bevacizumab to standard radiation therapy and daily temozolomide was found to be associated with minimal toxicity in patients newly diagnosed with GBM. [ABSTRACT FROM AUTHOR]

Abstract: Glioblastoma multiforme (GBM) is the most frequent and aggressive malignant glioma (MG), with a median survival time of 12–15 months, despite current best treatment based on surgery, radiotherapy and systemic chemotherapy. Many potentially active therapeutic agents are not effective by systemic administration, because they are unable to cross the blood–brain barrier (BBB). As intracerebral administration bypasses the BBB, it increases the number of drugs that can be successfully delivered to the brain, with the possibility of minor systemic toxicity and better effectiveness. This review summarizes the results of the extensive clinical research conducted on intracerebral therapy. Biodegradable drug carriers, implantable subcutaneous reservoirs and convection-enhanced delivery (CED) represent the main techniques for intracerebral delivery, while conventional chemotherapy agents, radiolabeled antibodies and receptor-targeted toxins are the main classes of drugs for intracerebral therapy. At the present time, biodegradable carmustine wafers, commercialized as Gliadel®, are the only FDA-approved treatment for intracerebral chemotherapy of MG, but intracavitary delivery of mitoxantrone and radiolabeled antitenascin antibodies via implantable reservoirs has yielded promising results in uncontrolled trials. The pressure-driven flow generated by CED can potentially distribute convected drugs over large volumes of the brain, independently on their intrinsic diffusivity. Nevertheless, prominent technical problems, like backflow, are yet to be properly addressed and contributed to the disappointing results of two phase III trials that investigated CED of cintredekin besudotox and TransMid™ in patients with recurrent GBM. [Copyright &y& Elsevier]

Abstract: Introduction: Carcinomatous meningitis (CM) is a devastating disease characterized by the dissemination of malignant tumor cells into the subarachnoid space along the brain and spine. Systemic treatment with monoclonal antibody (mAb) trastuzumab can be effective against HER2-positive systemic breast carcinoma but, like other therapies, is ineffective against CM. The goal of this study was to evaluate the therapeutic effect of α-particle emitting 211At-labeled trastuzumab following intrathecal administration in a rat model of breast carcinoma CM. Methods: Athymic rats were injected intrathecally with MCF-7/HER2-18 breast carcinoma cells through a surgically implanted indwelling intrathecal catheter. In Experiment 1, animals received 33 or 66 μCi 211At-labeled trastuzumab, cold trastuzumab or saline. In Experiment 2, animals were inoculated with a lower tumor burden and received 46 or 92 μCi 211At-labeled trastuzumab or saline. In Experiment 3, animals received 28 μCi 211At-labeled trastuzumab, 30 μCi 211At-labeled TPS3.2 control mAb or saline. Histopathological analysis of the neuroaxis was performed at the end of the study. Results: In Experiment 1, median survival increased from 21 days for the saline and cold trastuzumab groups to 45 and 48 days for 33 and 66 μCi 211At-labeled trastuzumab, respectively. In Experiment 2, median survival increased from 23 days for saline controls to 68 and 92 days for 46 and 92 μCi 211At-labeled trastuzumab, respectively. In Experiment 3, median survival increased from 20 days to 29 and 36 days for animals treated with 211At-labeled TPS3.2 and 211At-labeled trastuzumab, respectively. Long-term survivors were observed exclusively in the 211At-trastuzumab-treated groups. Conclusion: Intrathecal 211At-labeled trastuzumab shows promise as a treatment for patients with HER2-positive breast CM. [Copyright &y& Elsevier]

Abstract: The epidermal growth factor receptor variant III (EGFRvIII) is a consistent tumor-specific mutation that is widely expressed in glioblastoma multiforme (GBM) and other neoplasms. As such it represents a truly tumor-specific target for antitumor immunotherapy. Although endogenous humoral responses to EGFRvIII have been reported in patients with EGFRvIII-expressing breast cancer, it is not known whether de novo responses can be generated or endogenous responses enhanced with an EGFRvIII-specific vaccine. To assess this in clinical trials, we have developed and validated an immunoassay to measure and isolate anti-EGFRvIII and anti-KLH antibodies from the serum of patients vaccinated with an EGFRvIII-specific peptide (PEPvIII) conjugated to keyhole limpet hemocyanin (KLH). Using magnetic beads with immobilized antigen we captured and detected anti-EGFRvIII and anti-KLH antibodies in serum from patients before and after vaccinations. Using this assay, we found that significant levels of antibody for tumor-specific antigen EGFRvIII (>4 µg/mL) and KLH could be induced after vaccination with PEPvIII-KLH. [Copyright &y& Elsevier]

Immunotherapy is a promising area of therapy in patients with neuro-oncological malignancies. However, early-phase studies show unique challenges associated with the assessment of radiological changes in response to immunotherapy reflecting delayed responses or therapy-induced inflammation. Clinical benefit, including long-term survival and tumour regression, can still occur after initial disease progression or after the appearance of new lesions. Refinement of the response assessment criteria for patients with neuro-oncological malignancies undergoing immunotherapy is therefore warranted. Herein, a multinational and multidisciplinary panel of neuro-oncology immunotherapy experts describe immunotherapy Response Assessment for Neuro-Oncology (iRANO) criteria based on guidance for the determination of tumour progression outlined by the immune-related response criteria and the RANO working group. Among patients who demonstrate imaging findings meeting RANO criteria for progressive disease within 6 months of initiating immunotherapy, including the development of new lesions, confirmation of radiographic progression on follow-up imaging is recommended provided that the patient is not significantly worse clinically. The proposed criteria also include guidelines for the use of corticosteroids. We review the role of advanced imaging techniques and the role of measurement of clinical benefit endpoints including neurological and immunological functions. The iRANO guidelines put forth in this Review will evolve successively to improve their usefulness as further experience from immunotherapy trials in neuro-oncology accumulate. [ABSTRACT FROM AUTHOR]