Introduction
Tumor Treating Fields (TTFields; antimitotic treatment) delivers low-intensity, intermediate-frequency, alternating electric fields through skin-applied transducer arrays. TTFields ...(200 kHz) was FDA-approved in glioblastoma (GBM), based on the phase 3 EF-11 (recurrent GBM, rGBM) and EF-14 (newly diagnosed GBM, ndGBM) trials. The most common TTFields-related adverse event (AE) in both trials was array-associated skin irritation. We now report on TTFields-related AEs in the real-world, clinical practice setting.
Methods
Unsolicited, post-marketing surveillance data from TTFields-treated patients (October 2011–February 2019) were retrospectively analyzed using MedDRA v21.1 preferred terms, stratified by region (US, EMEA Europe, Middle East, Africa, Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma/oligodendroglioma, other brain tumors), and age (< 18 pediatric, 18–64 adults, ≥ 65 elderly; years of age).
Results
Of 11,029 patients, 53% were diagnosed with ndGBM and 39% were diagnosed with rGBM at any line of disease recurrence. Most were adults (73%), 26% were elderly, and the male-to-female ratio was ~ 2:1 (close to published ratios of typical GBM populations). The most commonly reported TTFields-related AE was array-associated skin reaction, occurring in patients with ndGBM (38%), rGBM (29%), anaplastic astrocytoma/oligodendroglioma (38%), and other brain tumors (31%); as well as 37% of pediatric, 34% of adult, and 36% of elderly patients. Most skin AEs were mild/moderate and manageable. Other TTFields-related AEs in patients with ndGBM/rGBM included under-array heat sensation (warmth; 11%, 10%, respectively) and electric sensation (tingling; 11%, 9%, respectively), and headache (7%, 6%, respectively).
Conclusions
This TTFields safety surveillance analysis in > 11,000 patients revealed no new safety concerns, with a favorable safety profile comparable with published TTFields/GBM trials. The safety profile remained consistent among subgroups, suggesting feasibility in multiple populations, including elderly patients.
Graphic abstract
Glioblastomas (GBMs) preferentially generate acetyl-CoA from acetate as a fuel source to promote tumor growth. O-GlcNAcylation has been shown to be elevated by increasing O-GlcNAc transferase (OGT) ...in many cancers and reduced O-GlcNAcylation can block cancer growth. Here, we identify a novel mechanism whereby OGT regulates acetate-dependent acetyl-CoA and lipid production by regulating phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by cyclin-dependent kinase 5 (CDK5). OGT is required and sufficient for GBM cell growth and regulates acetate conversion to acetyl-CoA and lipids. Elevating O-GlcNAcylation in GBM cells increases phosphorylation of ACSS2 on Ser-267 in a CDK5-dependent manner. Importantly, we show that ACSS2 Ser-267 phosphorylation regulates its stability by reducing polyubiquitination and degradation. ACSS2 Ser-267 is critical for OGT-mediated GBM growth as overexpression of ACSS2 Ser-267 phospho-mimetic rescues growth in vitro and in vivo. Importantly, we show that pharmacologically targeting OGT and CDK5 reduces GBM growth ex vivo. Thus, the OGT/CDK5/ACSS2 pathway may be a way to target altered metabolic dependencies in brain tumors.
Safety is the basis of all production and living behaviors, and is an important guarantee for the safety of employees’ lives and enterprises’ property. This study focuses on the construction site ...safety management as the research object, and analyzes the current situation and shortcomings of the construction site safety management. This paper tries to explain the deep causes of the current situation by the theory of learning organization, and gives some suggestions to further improve the safety management of the construction site.
Circadian disruption has been linked to cancer development, progression, and radiation response. Clinical evidence to date shows that circadian genetic variation and time of treatment affect ...radiation response and toxicity for women with breast cancer. At the molecular level, there is interplay between circadian clock regulators such as PER1, which mediates ATM and p53-mediated cell cycle gating and apoptosis. These molecular alterations may govern aggressive cancer phenotypes, outcomes, and radiation response. Exploiting the various circadian clock mechanisms may enhance the therapeutic index of radiation by decreasing toxicity, increasing disease control, and improving outcomes. We will review the body's natural circadian rhythms and clock gene-regulation while exploring preclinical and clinical evidence that implicates chronobiological disruptions in the etiology of breast cancer. We will discuss radiobiological principles and the circadian regulation of DNA damage responses. Lastly, we will present potential rational therapeutic approaches that target circadian pathways to improve outcomes in breast cancer. Understanding the implications of optimal timing in cancer treatment and exploring ways to entrain circadian biology with light, diet, and chronobiological agents like melatonin may provide an avenue for enhancing the therapeutic index of radiotherapy.
There are several popular treatment options currently available for stereotactic radiosurgery (SRS) of multiple brain metastases:
Co sources and cone collimators around a spherical geometry ...(GammaKnife), multi-aperture dynamic conformal arcs on a linac (BrainLab Elements™ v1.5), and volumetric arc therapy on a linac (VMAT) calculated with either the conventional optimizer or with the Varian HyperArc™ solution. This study aimed to dosimetrically compare and evaluate the differences among these treatment options in terms of dose conformity to the tumor as well as dose sparing to the surrounding normal tissues.
Sixteen patients and a total of 112 metastases were analyzed. Five plans were generated per patient: GammaKnife, Elements, HyperArc-VMAT, and two Manual-VMAT plans to evaluate different treatment planning styles. Manual-VMAT plans were generated by different institutions according to their own clinical planning standards. The following dosimetric parameters were extracted: RTOG and Paddick conformity indices, gradient index, total volume of brain receiving 12Gy, 6Gy, and 3Gy, and maximum doses to surrounding organs. The Wilcoxon signed rank test was applied to evaluate statistically significant differences (
< 0.05).
For targets ≤ 1 cm, GammaKnife, HyperArc-VMAT and both Manual-VMAT plans achieved comparable conformity indices, all superior to Elements. However, GammaKnife resulted in the lowest gradient indices at these target sizes. HyperArc-VMAT performed similarly to GammaKnife for V
parameters. For targets ≥ 1 cm, HyperArc-VMAT and Manual-VMAT plans resulted in superior conformity vs. GammaKnife and Elements. All SRS plans achieved clinically acceptable organs-at-risk dose constraints. Beam-on times were significantly longer for GammaKnife. Manual-VMAT
and Elements resulted in shorter delivery times relative to Manual-VMAT
and HyperArc-VMAT.
The study revealed that Manual-VMAT and HyperArc-VMAT are capable of achieving similar low dose brain spillage and conformity as GammaKnife, while significantly minimizing beam-on time. For targets smaller than 1 cm in diameter, GammaKnife still resulted in superior gradient indices. The quality of the two sets of Manual-VMAT plans varied greatly based on planner and optimization constraint settings, whereas HyperArc-VMAT performed dosimetrically superior to the two Manual-VMAT plans.
Spine SBRT target delineation is time-consuming due to the complex bone structure. Recently, Elements SmartBrush Spine (ESS) was developed by Brainlab to automatically generate a clinical target ...volume (CTV) based on gross tumor volume (GTV). The aim of this project is to evaluate the accuracy and efficiency of ESS auto-segmentation.
Twenty spine SBRT patients with 21 target sites treated at our institution were used for this retrospective comparison study. Planning CT/MRI images and physician-drawn GTVs were inputs for ESS. ESS can automatically segment the vertebra, split the vertebra into 6 sectors, and generate a CTV based on the GTV location, according to the International Spine Radiosurgery Consortium (ISRC) Consensus guidelines. The auto-segmented CTV can be edited by including/excluding sectors of the vertebra, if necessary. The ESS-generated CTV contour was then compared to the clinically used CTV using qualitative and quantitative methods. The CTV contours were compared using visual assessment by the clinicians, relative volume differences (RVD), distance of center of mass (DCM), and three other common contour similarity measurements such as dice similarity coefficient (DICE), Hausdorff distance (HD), and 95% Hausdorff distance (HD95).
Qualitatively, the study showed that ESS can segment vertebra more accurately and consistently than humans at normal curvature conditions. The accuracy of CTV delineation can be improved significantly if the auto-segmentation is used as the first step. Conversely, ESS may mistakenly split or join different vertebrae when large curvatures in anatomy exist. In this study, human interactions were needed in 7 of 21 cases to generate the final CTVs by including/excluding sectors of the vertebra. In 90% of cases, the RVD were within ±15%. The RVD, DCM, DICE, HD, and HD95 for the 21 cases were 3% ± 12%, 1.9 ± 1.5 mm, 0.86 ± 0.06, 13.34 ± 7.47 mm, and 4.67 ± 2.21 mm, respectively.
ESS can auto-segment a CTV quickly and accurately and has a good agreement with clinically used CTV. Inter-person variation and contouring time can be reduced with ESS. Physician editing is needed for some occasions. Our study supports the idea of using ESS as the first step for spine SBRT target delineation to improve the contouring consistency as well as to reduce the contouring time.
This study evaluated the therapeutic efficacy of combining vascular disrupting agents with antiangiogenic agents.
Human clear cell renal carcinoma (Caki-1) tumors were established in nude mice. ...Treatments consisted of Avastin (2 mg/kg) administered twice a week; CA4P (100 mg/kg) or OXi4503 (25 mg/kg) administered 3 times a week for a period of 2 weeks; or a combination of Avastin and CA4P or OXi4503. Tumor response was assessed by growth delay.
The tumor growth delays were 8, 6, and 18 days for Avastin, CA4P, and OXi4503, respectively. When the two therapies were combined, there was a significantly greater tumor response than what was achieved with single-agent treatments. For example, Avastin plus CA4P led to a growth delay of 13 days, and 27 days for Avastin plus OXi4503.
Vascular-directed therapies that include both antiangiogenic and vascular disrupting therapeutics can result in significantly enhanced antitumor effects.
Background
The standard of care for CNS lymphoma typically includes high dose methotrexate followed by whole brain radiation therapy, but there is an increased risk of neurotoxicity with this ...regimen. In our institution, we offered stereotactic radiosurgery (SRS) for disease refractory to HD-MTX in a subset of patients. A search of the literature on this modality for CNS lymphoma was also conducted.
Methods
Medical records of six patients who received partial brain radiation therapy for persistent CNS lymphoma were reviewed. SRS was given via 1–3 fractions to doses of 21 or 24 Gy. PubMed, SCOPUS, and Cochrane Library databases were systematically searched for articles reporting on outcomes for CNS lymphoma treated with SRS.
Results
Six patients (eleven lesions) were treated with SRS for CNS lymphomas. Median follow up was 15.6 months (range 3.3–37.8). Median RT dose per lesion was 21 Gy and median time to progression was 12.7 months. Median overall survival was not reached. Four patients had distant intracranial failure with two developing local recurrence. The search strategy yielded 16 studies of which only one was prospective and included a control group. 183 out of 256 evaluated lesions (69%) responded completely to treatment and 13 of 204 patients (6%) recurred within the treatment area at last follow-up. Overall, the treatment was well tolerated.
Conclusion
SRS may provide favorable local control in patients with refractory CNS lymphomas. A prospective trial is warranted to validate the efficacy of such an approach.
Introduction
Despite optimal surgical resection, meningiomas may recur, with increasing grade and the degree of resection being predictive of risk. We hypothesize that an increasing Ki67 correlates ...with a higher risk of recurrence of resected WHO grade I meningiomas.
Methods
The study population consisted of patients with resected WHO grade 1 meningiomas in locations outside of the base of skull. Digitally scanned slides stained for Ki67 were analyzed using automatic image analysis software in a standardized fashion.
Results
Recurrence was observed in 53 (17.7%) of cases with a median follow up time of 25.8 months. Ki67 ranged from 0 to 30%. Median Ki67 was 5.1% for patients with recurrence and 3.5% for patients without recurrence. In unadjusted analyses, high Ki-67 (≥ 5 vs. < 5) vs. ≥ 5) was associated with over a twofold increased risk of recurrence (13.1% vs. 27% respectively; HR 2.1731; 95% CI 1.2534, 3.764; p = 0.006). After Adjusting for patient or tumor characteristics, elevated Ki-67 remained significantly correlated with recurrence. Grade 4 Simpson resection was noted in 71 (23.7%) of patients and it was associated with a significantly increased risk of recurrence (HR 2.56; 95% CI 1.41, 4.6364; p = 0.002).
Conclusions
WHO grade 1 meningiomas exhibit a significant rate of recurrence following resection. While Ki-67 is not part of the WHO grading criteria of meningiomas, a value greater than 5% is an independent predictor for increased risk of local recurrence following surgical resection.
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