Glioblastoma is the most lethal primary brain cancer. Clinical outcomes for glioblastoma remain poor, and new treatments are needed.
To investigate whether adding autologous tumor lysate-loaded ...dendritic cell vaccine (DCVax-L) to standard of care (SOC) extends survival among patients with glioblastoma.
This phase 3, prospective, externally controlled nonrandomized trial compared overall survival (OS) in patients with newly diagnosed glioblastoma (nGBM) and recurrent glioblastoma (rGBM) treated with DCVax-L plus SOC vs contemporaneous matched external control patients treated with SOC. This international, multicenter trial was conducted at 94 sites in 4 countries from August 2007 to November 2015. Data analysis was conducted from October 2020 to September 2021.
The active treatment was DCVax-L plus SOC temozolomide. The nGBM external control patients received SOC temozolomide and placebo; the rGBM external controls received approved rGBM therapies.
The primary and secondary end points compared overall survival (OS) in nGBM and rGBM, respectively, with contemporaneous matched external control populations from the control groups of other formal randomized clinical trials.
A total of 331 patients were enrolled in the trial, with 232 randomized to the DCVax-L group and 99 to the placebo group. Median OS (mOS) for the 232 patients with nGBM receiving DCVax-L was 19.3 (95% CI, 17.5-21.3) months from randomization (22.4 months from surgery) vs 16.5 (95% CI, 16.0-17.5) months from randomization in control patients (HR = 0.80; 98% CI, 0.00-0.94; P = .002). Survival at 48 months from randomization was 15.7% vs 9.9%, and at 60 months, it was 13.0% vs 5.7%. For 64 patients with rGBM receiving DCVax-L, mOS was 13.2 (95% CI, 9.7-16.8) months from relapse vs 7.8 (95% CI, 7.2-8.2) months among control patients (HR, 0.58; 98% CI, 0.00-0.76; P < .001). Survival at 24 and 30 months after recurrence was 20.7% vs 9.6% and 11.1% vs 5.1%, respectively. Survival was improved in patients with nGBM with methylated MGMT receiving DCVax-L compared with external control patients (HR, 0.74; 98% CI, 0.55-1.00; P = .03).
In this study, adding DCVax-L to SOC resulted in clinically meaningful and statistically significant extension of survival for patients with both nGBM and rGBM compared with contemporaneous, matched external controls who received SOC alone.
ClinicalTrials.gov Identifier: NCT00045968.
Background We used a positron emission tomography paradigm with the D2/3 radiotracer 11 Craclopride and an alcohol challenge to examine the magnitude of alcohol-induced dopamine release and compare ...it between young men and women. Methods Twenty-one nonalcohol-dependent young social drinkers completed two positron emission tomography scans on separate days following ingestion of a juice mix containing either ethanol (.75 mg/kg body water) or trace ethanol only. The extent of dopamine released after alcohol was estimated by the percentage difference in 11 Craclopride binding potential (ΔBPND ) between days. Results Alcohol administration significantly displaced 11 Craclopride in all striatal subregions, indicating dopamine release, with the largest effect observed in the ventral striatum. Linear mixed model analysis across all striatal subregions of regional ΔBPND with region of interest as repeated measure showed a highly significant effect of sex ( p < .001). Ventrostriatal dopamine release in men, but not in women, showed a significant positive correlation to alcohol-induced measures of subjective activation. Furthermore, we found a significant negative correlation between the frequency of maximum alcohol consumption per 24 hours and ventrostriatal ΔBPND ( r = .739, p = .009) in men. Conclusions This study provides definitive evidence that oral alcohol induces dopamine release in nonalcoholic human subjects and shows sex differences in the magnitude of this effect. The ability of alcohol to stimulate dopamine release may contribute to its rewarding effects and, thereby, to its abuse liability in humans. Our report further suggests several biological mechanisms that may mediate the difference in vulnerability for alcoholism between men and women.
Background Preclinical studies demonstrate that glutamate homeostasis in the striatum is disrupted following cocaine exposure, including a decrease in metabotropic glutamate receptor type 5 (mGluR5) ...expression and reduced glutamate turnover. The goal of this study was to use imaging of the human brain to investigate alterations in the glutamate signaling in cocaine addiction. Methods Positron emission tomography imaging with the radiotracer 11 CABP688 was used to measure mGluR5 binding and magnetic resonance spectroscopy was used to measure glutamate-glutamine levels in the striatum of cocaine-addicted participants ( n = 15) compared with healthy control subjects ( n = 15). Following the scans, the cocaine-addicted volunteers performed cocaine self-administration sessions to investigate the correlation between cocaine-seeking behavior and mGluR5 receptor binding. Results The results of the study showed that cocaine addiction was associated with a 20% to 22% reduction in 11 CABP688 binding in the striatum. A secondary analysis of cortical and subcortical regions other than the striatum showed a similar reduction in 11 CABP688 binding, suggesting that the decrease was widespread. No between-group differences were seen in the magnetic resonance spectroscopy measures of glutamate-glutamine in the left striatum. In addition, no correlation was seen between 11 CABP688 binding in the striatum and the choice to self-administer cocaine. Conclusions Overall, these results show that long-term cocaine use is associated with a decrease in mGluR5 availability compared with matched healthy control subjects and suggests that this receptor may serve as a viable target for treatment development for this disorder.
Current standard of care for glioblastoma (GBM) includes concurrent chemoradiation and maintenance temozolomide (TMZ) with Tumor Treating Fields (TTFields). Preclinical studies suggest TTFields and ...radiation treatment have synergistic effects. We conducted a pilot clinical trial of concurrent chemoradiation with TTFields and report pattern of progression.
Materials and Methods
This is a single arm pilot study (clinicaltrials.gov Identifier: NCT03477110). Adult patients (age ≥ 18 years) with KPS ≥ 60 with newly diagnosed GBM were eligible. All patients received concurrent scalp-sparing radiation (60 Gy in 30 fractions), standard concurrent TMZ and TTFields. Maintenance therapy included standard TMZ and continuation of TTFields. Radiation treatment was delivered through TTFields arrays. Incidence and location of progression was documented. Distant recurrence was defined as recurrence more than 2 cm from the primary enhancing lesion.
Results
Thirty patients were enrolled on the trial. Twenty were male with median age 58 years (19–77 years). Median KPS was 90 (70–100). Median follow-up was 15.2 months (1.7–23.6 months). Ten (33.3%) patients had a methylated promoter status. Twenty-seven patients (90%) had progression, with median PFS of 9.3 months (range 8.5 to 11.6 months). Six patients presented with distant recurrence, with median distance from primary lesion of 5.05 cm (2.26–6.95 cm). One infratentorial progression was noted.
Conclusions
We observed improved local control using concurrent chemoradiation with TTFields for patients with newly diagnosed when compared to historical controls. Further data are needed to validate this finding.
Trial Registration
Clinicaltrials.gov Identifier NCT03477110.
Acoustics is new on Mars: it allows the characterization of turbulence at smaller scales than previously possible within the lowest part of the Planetary Boundary Layer. Sound speed measurements, by ...the SuperCam instrument and its microphone onboard the NASA Perseverance rover, allow the retrieval of atmospheric temperatures at 0.77 m above the ground, at 3 Hz, with a ∼10 ms response time that is 20–100 times shorter than for typical thermocouple sensors used on Mars. Here we report on the first measurements of the sound speed‐derived temperature and its fluctuations near the surface. Data highlight large and rapid fluctuations up to ±7 K/s, whose amplitude over such a timescale has never been reported, nor predicted by atmospheric models. These fluctuations follow the daytime pattern of the turbulence and highlight occasional high amplitude events that are likely due to the conjunction of low thermal inertia and strong winds.
Plain Language Summary
The atmospheric surface layer of Mars, is prone to various interactions between the surface and the atmosphere, which control most of the climate and the weather of the red planet. There, large temperature gradients generate an intense turbulence during the daytime. Hence, the measurement of the air temperature variations close to the surface is important to understand the spatial and temporal scales of this turbulence. The SuperCam instrument onboard the NASA Perseverance rover enables the retrieval of the near‐surface atmospheric temperatures, and their fluctuations, at an unprecedented short timescale. Sound speed‐derived temperatures, also call sonic temperatures, collected over the Northern spring and summer of Martian Year 36 reveal large and rapid thermal fluctuations up to ±7 K/s, whose amplitude over such a timescale is not reported by any weather station sensors, nor predicted by models that simulate small‐scale eddies. These fluctuations follow the daytime pattern of the turbulence with a maximum amplitude early afternoon. Some occasional high temperature fluctuation events are observed, suggesting a complex effect of ground properties and local meteorological conditions on the turbulence. Overall, acoustics is a new and promising technique that records a unique view of atmospheric temperature variations near the surface of Mars.
Key Points
Sound speed derived temperature is used to study the microscale turbulence at an unprecedented short response time
Air temperature experiences fluctuations as high as ±7 K/s, which has never been reported in situ, nor resolved by mesoscale atmospheric models
Sonic temperature fluctuations follow the daytime turbulence pattern and find their origin in complex surface‐atmosphere interactions
Although the habitability of early Mars is now well established, its suitability for conditions favorable to an independent origin of life (OoL) has been less certain. With continued exploration, ...evidence has mounted for a widespread diversity of physical and chemical conditions on Mars that mimic those variously hypothesized as settings in which life first arose on Earth. Mars has also provided water, energy sources, CHNOPS elements, critical catalytic transition metal elements, as well as B, Mg, Ca, Na and K, all of which are elements associated with life as we know it. With its highly favorable sulfur abundance and land/ocean ratio, early wet Mars remains a prime candidate for its own OoL, in many respects superior to Earth. The relatively well-preserved ancient surface of planet Mars helps inform the range of possible analogous conditions during the now-obliterated history of early Earth. Continued exploration of Mars also contributes to the understanding of the opportunities for settings enabling an OoL on exoplanets. Favoring geochemical sediment samples for eventual return to Earth will enhance assessments of the likelihood of a Martian OoL.
Chronic obstructive pulmonary disease (COPD) is associated with a two-to-five fold increase in the risk of coronary artery disease independent of shared risk factors. This association is hypothesized ...to be mediated by systemic inflammation but this link has not been established.
We included 300 participants enrolled in the SPIROMICS cohort, 75 each of lifetime non-smokers, smokers without airflow obstruction, mild-moderate COPD, and severe-very severe COPD. We quantified emphysema and airway disease on computed tomography, characterized visual emphysema subtypes (centrilobular and paraseptal) and airway disease, and used the Weston visual score to quantify coronary artery calcification (CAC). We used the Sobel test to determine whether markers of systemic inflammation mediated a link between spirometric and radiographic features of COPD and CAC.
FEV
/FVC but not quantitative emphysema or airway wall thickening was associated with CAC (p = 0.036), after adjustment for demographics, diabetes mellitus, hypertension, statin use, and CT scanner type. To explain this discordance, we examined visual subtypes of emphysema and airway disease, and found that centrilobular emphysema but not paraseptal emphysema or bronchial thickening was independently associated with CAC (p = 0.019). MMP3, VCAM1, CXCL5 and CXCL9 mediated 8, 8, 7 and 16% of the association between FEV
/FVC and CAC, respectively. Similar biomarkers partially mediated the association between centrilobular emphysema and CAC.
The association between airflow obstruction and coronary calcification is driven primarily by the centrilobular subtype of emphysema, and is linked through bioactive molecules implicated in the pathogenesis of atherosclerosis.
ClinicalTrials.gov: Identifier: NCT01969344 .
Anaplastic oligodendroglioma (AO) and anaplastic oligoastrocytoma (AOA) are chemotherapy-sensitive tumors with prolonged survival after radiochemotherapy. We report a prospective trial using ...induction temozolomide (TMZ) followed by myeloablative high-dose chemotherapy (HDC) with autologous stem-cell transplant (ASCT) as a potential strategy to defer radiotherapy.
Patients with AO/AOA received 6 cycles of TMZ (200 mg/m2 × 5/28 day). Responding patients were eligible for HDC (thiotepa 250 mg/m2/day × 3 days, then busulfan 3.2 mg/kg/day × 3 days), followed by ASCT. Genomic characterization was performed using next-generation sequencing.
Forty-one patients were enrolled; 85% had 1p/19q codeleted tumors. After induction, 26 patients were eligible for HDC-ASCT and 21 agreed to proceed. There were no unexpected adverse events or toxic deaths. After median follow-up of 66 months, 2-year progression-free survival (PFS) for transplanted patients was 86%, 5-year PFS 60%, and no patient has died. Among all 1p/19q codeleted patients (N = 33), 5-year PFS was 50% and 5-year overall survival (OS) 93%, with median time to radiotherapy not reached. Next-generation sequencing disclosed typical oligodendroglioma-related mutations, including IDH1, TERT, CIC, and FUBP1 mutations in 1p/19q codeleted patients, and glioblastoma-like signatures in 1p/19q intact patients. Aside from IDH1, potentially oncogenic/actionable mutations were variable, depicting wide molecular heterogeneity within oligodendroglial tumors.
TMZ followed by HDC-ASCT can be safely administered to patients with newly diagnosed 1p/19q codeleted AO. This strategy was associated with promising PFS and OS, suggesting that a chemotherapy-based approach may delay the need for radiotherapy and radiation-related toxicities. Raw data for further genomic and meta-analyses are publicly available at http://cbioportal.org/study?id=odg_msk_2017, accessed 6 January 2017.
NCT00588523.
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