Diagnostic delay in children with central nervous system tumors and the need to improve education


EGFR gene amplification in monocentric and multicentric glioblastoma


Longitudinal analysis of quality of life following treatment with Asunercept plus reirradiation versus reirradiation in progressive glioblastoma patients

Abstract

Purpose

Glioblastoma is an aggressive malignant cancer of the central nervous system, with disease progression associated with deterioration of neurocognitive function and quality of life (QoL). As such, maintenance of QoL is an important treatment goal. This analysis presents time to deterioration (TtD) of QoL in patients with recurrent glioblastoma receiving Asunercept plus reirradiation (rRT) or rRT alone.

Methods

Data from patients with a baseline and ≥ 1 post-baseline QoL assessment were included in this analysis. TtD was defined as the time from randomisation to the first deterioration in the EORTC QLQ-C15, PAL EORTC QLQ-BN20 and Medical Research Council (MRC)-Neurological status. Deterioration was defined as a decrease of ≥ 10 points from baseline in the QLQ-C15 PAL overall QoL and functioning scales, an increase of ≥ 10 points from baseline in the QLQ-C15 PAL fatigue scale and the QLQ-BN20 total sum of score, and a rating of “Worse” in the MRC-Neurological status. Patients without a deterioration were censored at the last QoL assessment. Kaplan–Meier estimates were used to describe TtD and treatment groups (Asunercept + rRT or rRT alone) were compared using the log-rank test.

Results

Treatment with Asunercept + rRT was associated with significant improvement of TtD compared with rRT alone for QLQ-CL15 PAL overall QoL and physical functioning, and MRC Neurological Status (p ≤ 0.05). In the Asunercept + rRT group, QoL was maintained beyond progresison of disease (PoD).

Conclusion

Treatment with Asunercept plus rRT significantly prolongs TtD and maintains QoL versus rRT alone in recurrent glioblastoma patients.

Surgical and radiosurgical treatment strategies for Cushing’s disease

Abstract

Introduction

Cushing’s disease (CD) is rare disorder that should be adequately managed to optimize long-term prognosis. Treatment of CD is multidisciplinary and often includes surgical resection, adjuvant stereotactic radiosurgery (SRS), and medical treatment. Here we review surgical and radiosurgical treatment strategies for ACTH producing pituitary adenomas.

Methods

A comprehensive literature review was carried out to review remission and recurrence rates, and complications of surgical and SRS treatments of ACTH producing pituitary adenomas.

Results

Surgical resection plays a central role in the management of ACTH secreting pituitary adenomas and usually allows rapid endocrine remission that ranges from 69 to 90%. The most common complications after resection include some degree of new hypopituitarism, diabetes insipidus and CSF leak. Devastating complications, such as injury of vascular and neural structures, are very rare. Surgeon experience and adequate pre-operative imaging are important for safe and successful surgery. Endocrine recurrence rates after resection range from 9 to 30%. SRS is often employed for incompletely resected adenomas. Endocrine remission after SRS ranges from 35 to 72%. The most common complication of SRS is new anterior pituitary gland deficiency. Recurrence rates after GKRS range from 18 to 24%.

Conclusions

Transsphenoidal resection of ACTH producing pituitary adenoma is a safe and highly effective procedure for CD in experienced hands. Radiosurgery is more frequently used as treatment of residual and recurrent adenoma and persistent CD. Long-term endocrine and imaging follow-up is important as delayed recurrences and hypopituitarism are not infrequent.

Radiation chronotherapy—clinical impact of treatment time-of-day: a systematic review

Abstract

Purpose

Many brain tumor patients suffer from radiation-induced toxicities. Chronotherapy is a treatment modality that utilizes circadian rhythms to optimize the effect on tumor while minimizing negative outcomes on healthy tissue. This review aims to systematically examine the literature on the application of a radiation chronotherapeutic for all cancers and determine the possible advantages of incorporating a circadian-based fixed time-of-day for radiotherapy into CNS cancers.

Methods

A systematic review of the literature was conducted in two electronic databases from inception to February 1, 2019. Primary research manuscripts were screened for those related to adult human subjects exposed to ionizing radiation using the chronotherapy technique.

Results

Nine manuscripts were included in the review from 79 eligible articles. Three were prospective randomized trails and 6 were retrospective reviews. This survey revealed that overall survival and tumor control do not have consistent effects with only 60% and 55.5% of paper which included the variables having some significance, respectively. Treatment symptoms were the primary endpoint for both the prospective trials and were examined in 3 of the retrospective reviews; effects were observed in sensitive tissue for all 5 studies including mucosal linings and skin basal layer.

Conclusions

Existing literature suggests that the application of radiation chronotherapy may reduce negative symptom outcome within highly proliferative tissues. Further examination of radiation chronotherapy in well-designed prospective trials and studies in brain tumor patients are merited.

Fractionated stereotactic radiosurgery for malignant gliomas: comparison with single session stereotactic radiosurgery

Abstract

Purpose

Stereotactic radiosurgery (SRS) is feasible for malignant glioma; however, delivering the optimal radiation dose with sufficient large-volume coverage is a major concern. We aimed to investigate the clinical efficacy and safety of fractionated SRS (fSRS) versus single-session SRS (sSRS) for malignant gliomas.

Methods

We retrospectively reviewed 58 malignant glioma patients who underwent gamma knife SRS from January 2015 to December 2018. Forty-one underwent sSRS, and 17 underwent fSRS. Median dose for fSRS was 28 Gy (range 24–35 Gy), with a median dose of 6 Gy per fraction (range 5–7 Gy). Patients received 4 or 5 fractions on consecutive days. Median dose for sSRS was 18 Gy (range 11–25 Gy), with a median isodose of 50% (range 50–65%). Mean target volumes were 5.9 and 19.3 cc for sSRS and fSRS, respectively (p < 0.001, two-sided t test).

Results

After SRS, median progression-free survival (PFS) was 4.5 and 4.6 months (p = 0.58), and median overall survival (OS) was 12.7 and 12.6 months for sSRS and fSRS (p = 0.41), respectively (log-rank test). The incidence of clinically significant radiation necrosis was 20.5% (8/39) and 18.8% (3/16) for sSRS and fSRS, respectively (p = 1, Fisher’s exact test).

Conclusion

fSRS for malignant glioma conferred local control and survival comparable with conventional sSRS. The radiation necrosis incidence was comparable between groups when a parallel biological effective dose was administered to the larger target volumes in the fSRS group. fSRS can be a better alternative to sSRS if re-irradiation is considered for large malignant gliomas.

Shortened ex vivo manufacturing time of EGFRvIII-specific chimeric antigen receptor (CAR) T cells reduces immune exhaustion and enhances antiglioma therapeutic function

Abstract

Background

Non-viral manufacturing of CAR T cells via the Sleeping Beauty transposon is cost effective and reduces the risk of insertional mutagenesis from viral transduction. However, the current gold standard methodology requires ex vivo numerical expansion of these cells on artificial antigen-presenting cells (AaPCs) for 4 weeks to generate CAR T cells of presumed sufficient quantity and function for clinical applications.

Method

We engineered EGFRvIII-specific CAR T cells and monitored phenotypic changes throughout their ex vivo manufacturing. To reduce the culture time required to generate the CAR T-cell population, we selected for T cells in peripheral blood mononuclear cells prior to CAR modification (to eliminate the competing NK cell population).

Results

While we found increased expression of exhaustion markers (such as PD-1, PD-L1, TIM-3, and LAG-3) after 2 weeks in culture, whose levels continued to rise over time, we were able to generate a CAR+ T-cell population with comparable CAR expression and cell numbers in 2 weeks, thereby reducing manufacturing time by 50%, with lower expression of immune exhaustion markers. The CAR T cells manufactured at 2 weeks showed superior therapeutic efficacy in mice bearing established orthotopic EGFRvIII+ U87 gliomas.

Conclusion

These findings demonstrate a novel, rapid method to generate CAR T cells by non-viral modification that results in CAR T cells superior in phenotype and function and further emphasizes that careful monitoring of CAR T-cell phenotype prior to infusion is critical for generating an optimal CAR T-cell product with full antitumor potential.