Tanshinone IIA (TSA) is a lipid soluble agent derived from the root of Salvia miltiorrhiza (Danshen). This plant is a traditional Chinese herb, which has been used widely in China especially for enhancing circulation. However mechanisms underlying its efficacy remain poorly understood. The present study was designed to illuminate events that may underlie the apparently neuroprotective effects of TSA following ischemic insult. Adult Sprague-Dawley rats were subjected to transient focal cerebral ischemia by use of a middle cerebral artery occlusion model. They were then randomly divided into a sham-operated control group, and cerebral ischemia/reperfusion groups receiving a two-hour occlusion. Further subsets of groups received the same durations of occlusion or were sham-operated but then received daily i.p. injections of high or low doses of TSA, for seven or 15days. Hematoxylin and eosin staining revealed lesions in the entorhinal cortex of both rats subject to ischemia and to a lesser extent to those receiving TSA after surgery. Levels of glial fibrillary acidic protein (GFAP), caspase-3 and caspase-8, were quantified by both immunohistochemistry and Western blotting. TSA treatment after middle cerebral artery occlusion, markedly reduced infarct size, and reduced the expression of caspase-3 and caspase-8. These changes were considered protective and were generally proportional to the dose of TSA used. These results suggest that TSA may effect neuroprotection by way of reduction of the extent of cell inflammation and death within affected regions.

The stream interaction region (SIR), formed when a fast stream overtakes a preceding slow stream, is the predominant large-scale solar wind structure at this early phase of the STEREO mission. Using multi-spacecraft observations from STEREO A and B, ACE, Wind, and Ulysses in 2007, we analyze three stream interaction events in depth in May, August, and November of 2007, respectively, when the spacecraft had quite different spatial separations. We attempt to determine the causes of the differences in the SIR properties, whether they are spatial or temporal variations, and also to examine the steepening or widening of the SIR during its radial evolution. The presence and characteristics of associated shocks, the relation to the heliospheric current sheet, and other structures are also studied.

We investigate the organization of the low energy energetic particles (≤1 MeV) by solar wind structures, in particular corotating interaction regions (CIRs) and shocks driven by interplanetary coronal mass ejections, during the declining-to-minimum phase of Solar Cycle 23 from Carrington rotation 1999 to 2088 (January 2003 to October 2009). Because CIR-associated particles are very prominent during the solar minimum, the unusually long solar minimum period of this current cycle provides an opportunity to examine the overall organization of CIR energetic particles for a much longer period than during any other minimum since the dawn of the Space Age. We find that the particle enhancements associated with CIRs this minimum period recurred for many solar rotations, up to 30 at times, due to several high-speed solar wind streams that persisted. However, very few significant CIR-related energetic particle enhancements were observed towards the end of our study period, reflecting the overall weak high-speed streams that occurred at this time. We also contrast the solar minimum observations with the declining phase when a number of solar energetic particle events occurred, producing a mixed particle population. In addition, we compare the observations from this minimum period with those from the previous solar cycle. One of the main differences we find is the shorter recurrence rate of the high-speed solar wind streams (∼10 solar rotations) and the related CIR energetic particle enhancements for the Solar Cycle 22 minimum period. Overall our study provides insight into the coexistence of different populations of energetic particles, as well as an overview of the large-scale organization of the energetic particle populations approaching the beginning of Solar Cycle 24.

It has been realized for some time that the slow solar wind with its embedded heliospheric current sheet often exhibits complex features suggesting at least partially transient origin. In this paper we investigate the structure of the slow solar wind using the observations by the Wind and STEREO spacecraft during two Carrington rotations (2054 and 2055). These occur at the time of minimum solar activity when the interplanetary medium is dominated by recurrent high-speed streams and large-scale interplanetary coronal mass ejections (ICMEs) are rare. However, the signatures of transients with small scale-sizes and/or low magnetic field strength (comparable with the typical solar wind value, ∼ 5 nT) are frequently found in the slow solar wind at these times. These events do not exhibit significant speed gradients across the structure, but instead appear to move with the surrounding flow. Source mapping using models based on GONG magnetograms suggests that these transients come from the vicinity of coronal source surface sector boundaries. In situ they are correspondingly observed in the vicinity of high density structures where the dominant electron heat flux reverses its flow polarity. These weak transients might be indications of dynamical changes at the coronal hole boundaries or at the edges of the helmet streamer belt previously reported in coronagraph observations. Our analysis supports the idea that even at solar minimum, a considerable fraction of the slow solar wind is transient in nature.

Building on an initiative to enhance clinical trial participation involving the Society for Neuro-Oncology, the Response Assessment in Neuro-Oncology Working Group, patient advocacy groups, clinical trial cooperative groups, and other partners, we evaluate the impact of eligibility criteria and trial conduct on neuro-oncology clinical trial participation. Clinical trials often carry forward eligibility criteria from prior studies that may be overly restrictive and unnecessary and needlessly limit patient accrual. Inclusion and exclusion criteria should be evaluated based on the goals and design of the study and whether they impact patient safety and/or treatment efficacy. In addition, we evaluate clinical trial conduct as a barrier to accrual and discuss strategies to minimize such barriers for neuro-oncology trials.

Background

Evidence from single and multicenter phase II trials have suggested diffusion MRI is a predictive imaging biomarker for survival benefit in recurrent glioblastoma (rGBM) treated with anti-VEGF therapy. The current study confirms these findings in a large, randomized phase III clinical trial.

Methods

Patients with rGBM were enrolled in a phase III randomized (1:1), controlled trial (NCT02511405) to compare the efficacy and safety of bevacizumab (BV) versus BV in combination with ofranergene obadenovec (BV+VB-111), an anti-cancer viral therapy. In 170 patients with diffusion MRI available, pretreatment enhancing tumor volume and ADC histogram analysis were used to phenotype patients as having high (>1.24 µm²/ms) or low (<1.24 µm²/ms) ADC_L, the mean value of the lower peak of the ADC histogram, within the contrast enhancing tumor.

Results

Baseline tumor volume (P = .3460) and ADC_L (P = .2143) did not differ between treatment arms. Univariate analysis showed patients with high ADC_L had a significant survival advantage in all patients (P = .0006), as well as BV (P = .0159) and BV+VB-111 individually (P = .0262). Multivariable Cox regression accounting for treatment arm, age, baseline tumor volume, and ADC_L identified continuous measures of tumor volume (P < .0001; HR = 1.0212) and ADC_L phenotypes (P = .0012; HR = 0.5574) as independent predictors of OS.

Conclusion

Baseline diffusion MRI and tumor volume are independent imaging biomarkers of OS in rGBM treated with BV or BV+VB-111.

Background

Treatment options for unresectable new and recurrent glioblastoma remain limited. Laser ablation has demonstrated safety as a surgical approach to treating primary brain tumors. The LAANTERN prospective multicenter registry (NCT02392078) data were analyzed to determine clinical outcomes for patients with new and recurrent IDH wild-type glioblastoma.

Methods

Demographics, intraprocedural data, adverse events, KPS, health economics, and survival data were prospectively collected and then analyzed on IDH wild-type newly diagnosed and recurrent glioblastoma patients who were treated with laser ablation at 14 US centers between January 2016 and May 2019. Data were monitored for accuracy. Statistical analysis included individual variable summaries, multivariable differences in survival, and median survival numbers.

Results

A total of 29 new and 60 recurrent IDH wild-type WHO grade 4 glioblastoma patients were treated. Positive MGMT promoter methylation status was present in 5/29 of new and 23/60 of recurrent patients. Median physician-estimated extent of ablation was 91%-99%. Median overall survival (OS) was 9.73 months (95% confidence interval: 5.16, 15.91) for newly diagnosed patients and median post-procedure survival was 8.97 months (6.94, 12.36) for recurrent patients. Median OS for newly diagnosed patients receiving post-LITT chemo/radiation was 16.14 months (6.11, not reached). Factors associated with improved survival were MGMT promoter methylation, adjuvant chemotherapy within 12 weeks, and tumor volume <3 cc.

Conclusions

Laser ablation is a viable option for patients with new and recurrent glioblastoma. Median OS for IDH wild-type newly diagnosed glioblastoma is comparable to outcomes observed in other tumor resection studies when those patients undergo radiation and chemotherapy following LITT.

Background

Ofranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab.

Methods

This pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS).

Results

Enrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91-1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3-5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction.

Conclusions

In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results.

Clinical trials registration

NCT02511405.

Background

Ofranergene obadenovec (VB-111) is an anticancer viral therapy that demonstrated in a phase II study a survival benefit for patients with recurrent glioblastoma (rGBM) who were primed with VB-111 monotherapy that was continued after progression with concomitant bevacizumab.

Methods

This pivotal phase III randomized, controlled trial compared the efficacy and safety of upfront combination of VB-111 and bevacizumab versus bevacizumab monotherapy. Patients were randomized 1:1 to receive VB-111 1013 viral particles every 8 weeks in combination with bevacizumab 10 mg/kg every 2 weeks (combination arm) or bevacizumab monotherapy (control arm). The primary endpoint was overall survival (OS), and secondary endpoints were objective response rate (ORR) by Response Assessment in Neuro-Oncology (RANO) criteria and progression-free survival (PFS).

Results

Enrolled were 256 patients at 57 sites. Median exposure to VB-111 was 4 months. The study did not meet its primary or secondary goals. Median OS was 6.8 versus 7.9 months in the combination versus control arm (hazard ratio, 1.20; 95% CI: 0.91-1.59; P = 0.19) and ORR was 27.3% versus 21.9% (P = 0.26). A higher rate of grades 3-5 adverse events was reported in the combination arm (67% vs 40%), mainly attributed to a higher rate of CNS and flu-like/fever events. Trends for improved survival with combination treatment were seen in the subgroup of patients with smaller tumors and in patients who had a posttreatment febrile reaction.

Conclusions

In this study, upfront concomitant administration of VB-111 and bevacizumab failed to improve outcomes in rGBM. Change of treatment regimen, with the lack of VB-111 monotherapy priming, may explain the differences from the favorable phase II results.

Clinical trials registration

NCT02511405.

Following publication of the original article [1], the authors reported an error in the spelling of one of the author names. In this Correction the incorrect and correct author names are indicated and the author name has been updated in the original publication. The authors also reported an error in the Methods section of the original article. In this Correction the incorrect and correct versions of the affected sentence are indicated. The original article has not been updated with regards to the error in the Methods section.