[THERAPEUTIC OPTIONS FOR BRAIN OLIGOMETASTASES: COMPARISON BETWEEN SURGICAL RESECTION, STEREOTACTIC RADIOSURGERY, WHOLE BRAIN RADIATION THERAPY AND COMBINED MODULES IN RELATION TO SURVIVAL, FUNCTION AND OTHER CONSIDERATIONS].

INTRODUCTION: Brain metastases (BM) are a leading cause of morbidity and mortality in patients with systemic cancer. In the last two decades, an enormous improvement in controlling extra-cranial disease has been achieved, positively affecting the overall survival of patients. However, this has led to an increased number of patients who live long enough to develop BM. In addition, technological improvements in neurosurgery and radiotherapy caused both surgical resection and stereotactic radiosurgery (SRS) to become an integral part of the armamentarium when treating a patient with 1-4 BM. These increased therapeutic possibilities and combination of therapeutic options such as surgical resection, SRS, whole brain radiation therapy (WBRT) and lately targeted molecular therapy, have led to an enormous amount of, yet sometimes confusing, published data.

Height as a risk factor in meningioma: a study of 2 million Israeli adolescents.

BACKGROUND: Meningiomas are the most common primary central nervous system tumors. Potential risk factors include obesity, height, history of allergy/atopy, and autoimmune diseases, but findings are conflicting. This study sought to assess the role of the different risk factors in the development of meningioma in adolescents/young adults. METHODS: The cohort included 2,035,915 Jewish men and women who had undergone compulsory physical examination between 1967 and 2011, at age 16 to 19 years, prior to and independent of actual military enlistment. To determine the incidence of meningioma, the military database was matched with the Israel National Cancer Registry. Cox proportional hazard models were used to estimate the hazard ratios for meningioma according to sex, body mass index (BMI), height, and history of allergic or autoimmune disease. RESULTS: A total of 480 subjects (328 females) were diagnosed with meningioma during a follow-up of 40,304,078 person-years. Median age at diagnosis was 42.1 ± 9.4 years (range 17.4-62.6). On univariate analysis, female sex (p < 0.01) and height (p < 0.01) were associated with risk of meningioma. When the data were stratified by sex, height remained a significant factor only in men. Spline analysis of the male subjects showed that a height of 1.62 m was associated with a minimum disease risk and a height of 1.85+ meters, with a significant risk. CONCLUSIONS: This large population study showed that sex and adolescent height in males (> 1.85 m) were associated with an increased risk of meningioma in adulthood.

Neurocognitive evaluation of brain metastases patients treated with post-resection stereotactic radiosurgery: a prospective single arm clinical trial.

PURPOSE: Post-operative radiation therapy for brain metastases (BM) has become standard treatment. Concerns regarding the deleterious cognitive effects of Whole Brain Radiation Therapy spurred a trend to use focal therapies such as stereotactic radiosurgery (SRS). The purpose of this study was to prospectively evaluate the neuropsychological effects following post-resection SRS treatment since limited data exist in this context. METHODS: We conducted a prospective single arm cohort study of patients with 1-2 BM, who underwent resection of a single BM between May 2015 to December 2016. Patients were evaluated for cognitive functions (NeuroTrax computerized neuropsychological battery; Modiin, Israel) and quality of life (QOL; QLQ-30, QLQ-BN20) before and 3 months following post-resection SRS. RESULTS: Twelve out of 14 patients completed pre- and post-SRS neurocognitive assessments. Overall, we did not detect significant neurocognitive or QOL changes 3 months following SRS. In a subgroup analysis among patients younger than 60 years, median global cognitive score increased from a pre-treatment score of 88 (72-102) to 95 (79-108), 3 months following SRS treatment, p = 0.042; Wilcoxon paired non-parametric test. Immediate verbal memory and executive functions scores increased from 86 (72-98) to 98 (92-112) and 86 (60-101) to 100 (80-126), respectively, p = 0.043. No significant cognitive changes were discovered among patients at the age of 60 or older. CONCLUSIONS: Post-resection radiosurgery has a safe neuro-cognitive profile and is associated with preservation of nearly all quality of life parameters. Patients younger than 60 years benefit most and may even regain some cognitive functions within a few months after treatment.

Combined treatment approach to cerebral arteriovenous malformation in pediatric patients: stereotactic radiosurgery to partially Onyx-embolized AVM.

PURPOSE: Treatment of cerebral arteriovenous malformations (AVM)-the most common cause of stroke in the pediatric population-can be challenging due to the complexity of size, morphology, and location. There is a significant risk in comparison to AVM treatment among adults. Thus, AVM treatment in the pediatric population imposes unique challenges. Recent improvements include optimized catheter techniques and better embolization materials, such as Onyx, a non-adhesive liquid embolic agent used in the adult population. These improvements have increased the success rate of total and near-total obliteration of cerebral AVM. However, the use of Onyx causes significant distortion of the MR and CT images, which must be accounted for in any radiation treatment planning predicated on CT and MRI. These image distortions impact on the actual delivered dose to the nidus and behoove heterogeneity correction. Our group has previously shared a solution for heterogeneity correction in the adult population. The purpose of this study is to show our experience in this unique group of pediatric patients. METHODS: This is a retrospective review of pediatric patients, who were undergoing combined endovascular embolization followed by SRS. The cohort consists of 14 patients undergoing SRS treatment in our institute between November 2006 and December 2012 with a mean follow-up of 49.9 months. Within this cohort, we retrospectively reviewed 12 consecutive pediatric patients who underwent a combined endovascular and SRS approach with a mean follow-up of 52.1 months and two patients receiving SRS-only treatment were excluded. RESULTS: In our cohort of 14 patients, 7 (50%) were male, with a mean age of 17.3 years (12.0-22.9) at the time of radiosurgery treatment. Mean age of beginning the combined modality treatment was 15.3 years (8.4-20). The median time from diagnosis to SRS was 24.3 months (11.1-64.4 months) in the complete cohort and 25.6 months (11.1-64.4) in the multimodality group. The overall median follow-up period was 49.9 months (range 12.8-118.8 months) in the complete cohort and 52.1 months (range 12.8-118.8 months) in the multimodality group. Eleven (78.6%) patients had at least one episode of hemorrhage prior to treatment. Spezler-Martin grades at baseline ranged from 2 to 5 (mean 3.2). Fifty percent had grade IV and V. Patients underwent a median of 2 (range 1-5) embolization procedures. The radiosurgical treatment dose to the margin of the angiography-based nidus: median prescription dose of 21.49 Gy (14.39-27.51) with a median max dose of 27.77 Gy (18.93-32.52). The median treatment volume was 0.6 cm3 (0.1-7.3 cm3). The Onyx embolization reduced the nidus target volume by a median of 66.7% (12.0-92.7%). We confirmed 10/14 (71%) complete closures. In 2/14 (14.2%) additional patients, a significant flow reduction was noted. In 1/14 (7.1%) patients, no significant change was noted during the observation period and two (14.2%) patients were without follow-up information. In two patients, post-treatment edema was noted; however, none was clinically significant and resolved without additional intervention or treatment. CONCLUSIONS: This cohort comprises the largest combined Onyx-SRS pediatric experience in the literature. In conjunction with our adult group study, we show that the use of Onyx reduces the SRS treatment target volume significantly. Importantly, we implemented the heterogeneity correction to avoid increased radiation exposure to normal surrounding brain tissue. The combined approach appears to be safe provided that the above-mentioned corrections are implemented.

Health-related quality of life, cognitive screening, and functional status in a randomized phase III trial (EF-14) of tumor treating fields with temozolomide compared to temozolomide alone in newly diagnosed glioblastoma.

We characterized health-related quality of life (HRQoL), cognitive, and functional status in newly diagnosed glioblastoma (GBM) patients receiving Tumor treating fields (TTFields) with temozolomide (TMZ) versus TMZ alone in a planned interim analysis of a randomized phase III trial [NCT00916409], which showed significant improvement in progression-free and overall survival with TTFields/TMZ. After radiotherapy with concomitant TMZ, newly diagnosed GBM patients were randomized (2:1) to TTFields/TMZ (n = 210) or TMZ (n = 105). Interim analysis was performed in 315 patients with ≥18 months of follow-up. HRQoL, a secondary endpoint, was evaluated in per-protocol patient population and expressed as change from baseline (CFB) at 3, 6, and 9 months for each subscale in the EORTC QLQ-C30/BN20. Karnofsky performance scores (KPS) and Mini-Mental State Examination scores (MMSE) were assessed. CFB in HRQoL was balanced in treatment groups at the 12-month time point. Initially, HRQoL improved in patients treated with TTFields/TMZ (CFB3: 24% and CFB6: 13%) versus TMZ (CFB3: -7% and CFB6: -17%), though this difference was no longer evident at the 9-month point. General scales, including physical and social functioning, showed no difference at 9 and 12 months. TTFields/TMZ group reported higher concerns of "itchy skin". KPS over 12 months was just below 90 in both groups. Cognitive status (MMSE) was stable over time. HRQoL, KPS, and MMSE were balanced in both groups over time. There was no preliminary evidence that HRQoL, cognitive, and functional status is adversely affected by the continuous use of TTFields.

Effect of Tumor-Treating Fields Plus Maintenance Temozolomide vs Maintenance Temozolomide Alone on Survival in Patients With Glioblastoma: A Randomized Clinical Trial.

Importance: Tumor-treating fields (TTFields) is an antimitotic treatment modality that interferes with glioblastoma cell division and organelle assembly by delivering low-intensity alternating electric fields to the tumor. Objective: To investigate whether TTFields improves progression-free and overall survival of patients with glioblastoma, a fatal disease that commonly recurs at the initial tumor site or in the central nervous system. Design, Setting, and Participants: In this randomized, open-label trial, 695 patients with glioblastoma whose tumor was resected or biopsied and had completed concomitant radiochemotherapy (median time from diagnosis to randomization, 3.8 months) were enrolled at 83 centers (July 2009-2014) and followed up through December 2016. A preliminary report from this trial was published in 2015; this report describes the final analysis. Interventions: Patients were randomized 2:1 to TTFields plus maintenance temozolomide chemotherapy (n = 466) or temozolomide alone (n = 229). The TTFields, consisting of low-intensity, 200 kHz frequency, alternating electric fields, was delivered (≥ 18 hours/d) via 4 transducer arrays on the shaved scalp and connected to a portable device. Temozolomide was administered to both groups (150-200 mg/m2) for 5 days per 28-day cycle (6-12 cycles). Main Outcomes and Measures: Progression-free survival (tested at α = .046). The secondary end point was overall survival (tested hierarchically at α = .048). Analyses were performed for the intent-to-treat population. Adverse events were compared by group. Results: Of the 695 randomized patients (median age, 56 years; IQR, 48-63; 473 men [68%]), 637 (92%) completed the trial. Median progression-free survival from randomization was 6.7 months in the TTFields-temozolomide group and 4.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001). Median overall survival was 20.9 months in the TTFields-temozolomide group vs 16.0 months in the temozolomide-alone group (HR, 0.63; 95% CI, 0.53-0.76; P < .001). Systemic adverse event frequency was 48% in the TTFields-temozolomide group and 44% in the temozolomide-alone group. Mild to moderate skin toxicity underneath the transducer arrays occurred in 52% of patients who received TTFields-temozolomide vs no patients who received temozolomide alone. Conclusions and Relevance: In the final analysis of this randomized clinical trial of patients with glioblastoma who had received standard radiochemotherapy, the addition of TTFields to maintenance temozolomide chemotherapy vs maintenance temozolomide alone, resulted in statistically significant improvement in progression-free survival and overall survival. These results are consistent with the previous interim analysis. Trial Registration: clinicaltrials.gov Identifier: NCT00916409.

A non-aggressive, highly efficient, enzymatic method for dissociation of human brain-tumors and brain-tissues to viable single-cells.

BACKGROUND: Conducting research on the molecular biology, immunology, and physiology of brain tumors (BTs) and primary brain tissues requires the use of viably dissociated single cells. Inadequate methods for tissue dissociation generate considerable loss in the quantity of single cells produced and in the produced cells' viability. Improper dissociation may also demote the quality of data attained in functional and molecular assays due to the presence of large quantities cellular debris containing immune-activatory danger associated molecular patterns, and due to the increased quantities of degraded proteins and RNA. RESULTS: Over 40 resected BTs and non-tumorous brain tissue samples were dissociated into single cells by mechanical dissociation or by mechanical and enzymatic dissociation. The quality of dissociation was compared for all frequently used dissociation enzymes (collagenase, DNase, hyaluronidase, papain, dispase) and for neutral protease (NP) from Clostridium histolyticum. Single-cell-dissociated cell mixtures were evaluated for cellular viability and for the cell-mixture dissociation quality. Dissociation quality was graded by the quantity of subcellular debris, non-dissociated cell clumps, and DNA released from dead cells. Of all enzymes or enzyme combinations examined, NP (an enzyme previously not evaluated on brain tissues) produced dissociated cell mixtures with the highest mean cellular viability: 93 % in gliomas, 85 % in brain metastases, and 89 % in non-tumorous brain tissue. NP also produced cell mixtures with significantly less cellular debris than other enzymes tested. Dissociation using NP was non-aggressive over time-no changes in cell viability or dissociation quality were found when comparing 2-h dissociation at 37 °C to overnight dissociation at ambient temperature. CONCLUSIONS: The use of NP allows for the most effective dissociation of viable single cells from human BTs or brain tissue. Its non-aggressive dissociative capacity may enable ambient-temperature shipping of tumor pieces in multi-center clinical trials, meanwhile being dissociated. As clinical grade NP is commercially available it can be easily integrated into cell-therapy clinical trials in neuro-oncology. The high quality viable cells produced may enable investigators to conduct more consistent research by avoiding the experimental artifacts associated with the presence dead cells or cellular debris.

Stereotactic radiosurgery (SRS) in high-grade glioma: judicious selection of small target volumes improves results.

We present a retrospective review of 55 Stereotactic Radiosurgery (SRS) procedures performed in 47 consecutive patients with high-grade glioma (HGG). Thirty-three (70.2%) patients were diagnosed with glioblastoma and 14 (29.8%) with grade III glioma. The indications for SRS were small (up to 30 mm in diameter) locally progressing lesions in 32/47 (68%) or new distant lesions in 15/47 (32%) patients. The median target volume was 2.2 cc (0.2-9.5 cc) and the median prescription dose was 18 Gy (14-24 Gy). Three patients (5.5% incidence in 55 treatments) developed radiation necrosis. In eight cases (17%) patients received a second salvage SRS treatment to nine new lesions detected during follow-up. In 22/55 SRS treatments (40.0%) patients received concurrent chemo- or biological therapy, including temozolamide (TMZ) (15 patients), bevacizumab (BVZ) (6 patients) and carboplatin in one patient. Median time to progression after SRS was 5.0 months (1.0-96.4). Median survival time after SRS was 15.9 months (2.3-109.3) overall median survival (since diagnosis) was 37.4 months (9.6-193.6 months). Long-lasting responses (>12 months) after SRS were observed in 25/46 (54.3%) patients. We compared a matched (histology, age, KPS) cohort of patients with recurrent HGG treated with BVZ alone with the current study group. Median survival was significantly longer for SRS treated patients compared to the BVZ only cohort (12.6 vs. 7.3 months, p = 0.0102). SRS may be considered an effective salvage procedure for selected patients with small volume, recurrent high-grade gliomas. Long-term radiological control was observed in more than 50% of the patients.

CogState computerized memory tests in patients with brain metastases: secondary endpoint results of NRG Oncology RTOG 0933.

Whole brain radiotherapy (WBRT) is associated with memory dysfunction. As part of NRG Oncology RTOG 0933, a phase II study of WBRT for brain metastases that conformally avoided the hippocampal stem cell compartment (HA-WBRT), memory was assessed pre- and post-HA-WBRT using both traditional and computerized memory tests. We examined whether the computerized tests yielded similar findings and might serve as possible alternatives for assessment of memory in multi-institution clinical trials. Adult patients with brain metastases received HA-WBRT to 30 Gy in ten fractions and completed Hopkins Verbal Learning Test-Revised (HVLT-R), CogState International Shopping List Test (ISLT) and One Card Learning Test (OCLT), at baseline, 2 and 4 months. Tests' completion rates were 52-53 % at 2 months and 34-42 % at 4 months. All baseline correlations between HVLT-R and CogState tests were significant (p ≤ 0.003). At baseline, both CogState tests and one component of HVLT-R differentiated those who were alive at 6 months and those who had died (p ≤ 0.01). At 4 months, mean relative decline was 7.0 % for HVLT-R Delayed Recall and 18.0 % for ISLT Delayed Recall. OCLT showed an 8.0 % increase. A reliable change index found no significant changes from baseline to 2 and 4 months for ISLT Delayed Recall (z = -0.40, p = 0.34; z = -0.68, p = 0.25) or OCLT (z = 0.15, p = 0.56; z = 0.41, p = 0.66). Study findings support the possibility that hippocampal avoidance may be associated with preservation of memory test performance, and that these computerized tests also may be useful and valid memory assessments in multi-institution adult brain tumor trials.

Calcification in high grade gliomas treated with bevacizumab.

Calcification is a rare phenomenon in high grade glioma (HGG). CT scans are sensitive to mineralization but used infrequently for tumor assessment in the MRI era. The presence of calcification can be overlooked on routine MRI. Calcification may reflect chronicity and natural changes in the tumor or its milieu over time and may be accelerated by certain treatments. Calcification may have clinical significance which could signal potential risk for stroke or hemorrhage related to particular therapies; or it may be a positive prognostic factor for treatment response. The true incidence and relevance of calcification in HGG and relation to therapy is unclear. During treatment of HGG patients with bevacizumab (BVZ) we observed significant tumor calcification on brain CT. We performed a retrospective review of HGG patients treated with BVZ to quantitate the incidence of calcification in this group compared to those treated with cytotoxic therapy alone. Sixty-two patients with progressive HGG were treated with BVZ and a cytotoxic agent. Among 19 patients treated for 6+ months, 12 had a CT scan performed. We observed an unexpected phenomenon of calcification in the CT scans of several patients. We were also able to comparatively quantitate the incidence of calcification in a control group of primary glioblastoma (GB) patients not exposed to BVZ therapy. The incidence of calcification in the general GB population is increased with longer survival. The phenomenon is increased with anti-angiogenic therapy for brain tumors. Calcification may have significance as a predictor for treatment response.

Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial.

IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.

The ventricular system and choroid plexus as a primary site for renal cell carcinoma metastasis.

BACKGROUND: Brain metastases (BM) are the most common intracranial tumours amongst adults. Ten to 40 % of patients with cancer will develop BM. In this study, we observed a high affinity of renal cell carcinoma (RCC) to the ventricular system, with close association to the choroid plexus. METHODS: This is a retrospective study evaluating data of our prospectively maintained brain tumour database, focusing on consecutive BM patients, who were treated at our center between March 2003 and December 2011. Data collected included primary pathologies, anatomical distribution of the brain metastasis according to neuroimaging, and treatment modalities. RESULTS: We identified 614 patients with BM, of whom 24 (3.9 %) were diagnosed with RCC, harboring 33 lesions. Nine of the 24 patients (37.5 %) presented with an intraventricular location (10 of 33 RCC BM lesions). Of the remaining 590 patients with non-RCC pathologies, five patients (0.8 %) were diagnosed with intraventricular lesions (p < 0.0001). CONCLUSION: In this unselected, consecutive treated BM patient cohort we observed a high affinity of RCC BM to the ventricular system with close association to the choroid plexus. The reason for this affinity is unknown. Surgical approaches for resection of these lesions should be planned to include early control on the vascular supply from the choroidal vessels.

Is serum-derived exosomal hTERT transcript a marker of oncogenic activity in primary brain tumors? An exploratory study.

BACKGROUND: In order to proliferate indefinitely, all tumors require a telomere maintenance mechanism. The expression of human telomerase reverse transcriptase (hTERT) enables telomere maintenance and provides cancer cells with limitless replicative potential. As such, it may serve as an attractive biomarker for oncogenic activity. This study explored whether a liquid biopsy that analyses blood derived exosomal hTERT transcript (e-hTERT-trans) may serve as such a biomarker in gliomas and meningiomas when compared to healthy controls. METHODS: Exosomes were isolated from the pre-operative sera of patients' samples stored in the biobank of both Rabin and Sheba Medical Centers. The levels of e-hTERT-trans were measured in 81 healthy controls, 117 meningiomas, 17 low-grade gliomas, and 61 glioblastomas. Clinical parameters of the patients were collected retrospectively and compared to the levels of the e-hTERT-trans. RESULTS: The upper normal limit of controls e-hTERT-trans was 1.85 relative quantitation (RQ). The rate of detection increased with rising tumor grade and correlated with tumor recurrence in meningiomas: mean RQ without recurrence (2.17 ± 11.7) versus with recurrence (3.59 ± 4.42; p = 0.002). In glioblastomas, preoperative measurements correlated with tumor volume and with the disease course on serial sampling. CONCLUSIONS: We demonstrated for the first time that the expression of e-hTERT-trans transcript can be measured in the serum of primary brain tumors. This exosomal marker carries the potential to serve as a biomarker once used in conjunction with other clinical and radiological parameters. Future studies are required to investigate whether the sensitivity could be augmented and whether it can be implemented into routine patients care.

Synergy-S stereotactic radiosurgery for spinal tumors.

BACKGROUND: Radiation treatment of spinal and paraspinal tumors has been limited by the tolerance of the spinal cord. As such, therapeutic options are restricted to surgically accessible lesions or the use of suboptimal dosing of external beam irradiation. OBJECTIVES: To evaluate the safety and applicability of the Elekta Synergy-S radiation unit for the treatment of spinal tumors. METHODS: We retrospectively reviewed all patients treated with stereotactic radiosurgery for spinal tumors between November 2007 and June 2011. RESULTS: Thirty-four patients were treated for 41 lesions. Treatment indications were local tumor control and pain palliation. The mean follow-up was 10.8 +/- 11.6 months (range 0.5-38 months). No acute radiation toxicity or new neurological deficits occurred during the follow-up period. Local tumor control was achieved in 21 of the 24 lesions (87.5%) available for radiological follow-up at a median of 9.8 months (range 3-32 months). Good analgesia was achieved in 24/30 lesions (80%) that presented with intractable pain. CONCLUSIONS: The safety and feasibility of delivering single and multiple-fraction stereotactic spinal irradiation was demonstrated and became a standard treatment option in our institution.

Significant Systemic Insulin Resistance is Associated With Unique Glioblastoma Multiforme Phenotype.

Background: Some glioblastoma multiforme (GBM) are characterized by the presence of gemistocytes (GCs), a unique phenotype of reactive astrocytes. Certain GCs can be identified as neoplastic cells but these cells were also found to be associated with diabetes in non-neoplastic lesions of the central nervous system. Our aim was to find a correlation between insulin - resistance metabolic features and the presence of GCs in patients with newly diagnosed GBM. Methods: Medical records from histologically confirmed GBM patients were retrospectively extracted for different systemic metabolic variables. A statistic-based comparison was made between GBM, diabetic patients with and without GC. Patients with poorly controlled diabetes (ie, hemoglobin A1C ⩾ 8.0) were also compared between the 2 groups. Results: A total of 220 newly diagnosed GBM patients were included in our study. 58 (26.3%) patients had a history of diabetes mellitus type 2 (DM2) at the time of admission. The rate of poorly-controlled DM2 was nearly as twice in the GC-GBM group than in the non-GC GBM group (18.75% vs 9.5%; P = .130). In the DM2 cohort, the subgroup of GC-GBM was significantly associated with demographic and metabolic features related to insulin resistance such as male gender predominance (89% vs 50%, P = .073) and morbid obesity (weight ⩾85 kg: OR 6.16; P = .0019 and mean BMI: 34.1 ± 11.42 vs 28.7 ± 5.44; P = .034 for group with and without GCs, respectively). In the poorly-controlled DM2 group, none of the GC-GBM patients were using insulin prior to diagnosis, compared to 61.1% in the non-GC GBM patients (OR = 0.04, P = .045). Conclusion: Systemic metabolic factors related to marked insulin resistance (DM2, morbid obesity, male gender) are associated with a unique histologic phenotype of GBM, characterized by the presence of GCs. This feature is prominent in poorly-controlled DM2 GBM patients who are not using synthetic insulin. This novel finding may add to the growing data on the relevance of glucose metabolism in astrocytes and in astrocytes associated with high-grade gliomas. In GBM patients, a correlation between patients' metabolic status, tumor's histologic phenotype, tumor's molecular changes, use of anti-diabetic drugs and the respective impact of these factor on survival warrants further investigation.

Reciprocal interactions between innate immune cells and astrocytes facilitate neuroinflammation and brain metastasis via lipocalin-2.

Brain metastasis still encompass very grim prognosis and therefore understanding the underlying mechanisms is an urgent need toward developing better therapeutic strategies. We uncover the intricate interactions between recruited innate immune cells and resident astrocytes in the brain metastatic niche that facilitate metastasis of melanoma and breast cancer. We show that granulocyte-derived lipocalin-2 (LCN2) induces inflammatory activation of astrocytes, leading to myeloid cell recruitment to the brain. LCN2 is central to inducing neuroinflammation as its genetic targeting or bone-marrow transplantation from LCN2-/- mice was sufficient to attenuate neuroinflammation and inhibit brain metastasis. Moreover, high LCN2 levels in patient blood and brain metastases in multiple cancer types were strongly associated with disease progression and poor survival. Our findings uncover a previously unknown mechanism, establishing a central role for the reciprocal interactions between granulocytes and astrocytes in promoting brain metastasis and implicate LCN2 as a prognostic marker and potential therapeutic target.

Convection-enhanced delivery catheter placements for high-grade gliomas: complications and pitfalls.

Convection-enhanced delivery (CED) of compounds into brain tumors reportedly circumvents the blood brain barrier. CED intends to increase drug delivery to malignant cells, reaching high local therapeutic concentration and decreasing or eliminating systemic side effects. Clinical experience and published data on catheter placement (CP) surgery are scarce. We propose practical and technical guidelines for planning CED based on our experience. We retrospectively analyzed the medical charts and relevant neuroimages of 25 patients following the insertion of 64 CED catheters. The patients were enrolled in at least one of four clinical trials using CED for treating recurrent glioblastoma multiforme in our institution between 2003-2006. Intra- and postoperative complications related to CP surgery and the difficulties and pitfalls of planning were evaluated. There were 29 CP surgeries. Forty-four peritumoral brain tissue catheters were inserted in 16 CP surgeries following tumor resection in 16 patients, and 20 catheters were placed into the tumor in 13 procedures in 10 patients. The lesions were in or near eloquent brain tissue areas in 13 of all CP surgeries. Complications included increased edema (31%), infection (6.9%), bleeding (6.9%) and seizures (13.8%). Significant neurological deterioration occurred in 4 patients (13.8%). Difficulties in adhering to CP surgery guidelines included lesion site (superficial, mesial temporal lobe, proximity to CSF spaces), proximity to eloquent cortical areas, tissue density that interfered with the trajectory, and technical limitations of stereotactic instruments. CED procedures for high-grade gliomas may be associated with surgical morbidity. Adherence to guidelines might be difficult because of lesion site and complicated by brain and tumor tissue characteristics. This should be considered while planning clinical trials that use convection-based technology.

Detection of gene mutations and gene-gene fusions in circulating cell-free DNA of glioblastoma patients: an avenue for clinically relevant diagnostic analysis.

Glioblastoma (GBM) is the most common type of glioma and is uniformly fatal. Currently, tumour heterogeneity and mutation acquisition are major impedances for tailoring personalized therapy. We collected blood and tumour tissue samples from 25 GBM patients and 25 blood samples from healthy controls. Cell-free DNA (cfDNA) was extracted from the plasma of GBM patients and from healthy controls. Tumour DNA was extracted from fresh tumour samples. Extracted DNA was sequenced using a whole-genome sequencing procedure. We also collected 180 tumour DNA datasets from GBM patients publicly available at the TCGA/PANCANCER project. These data were analysed for mutations and gene-gene fusions that could be potential druggable targets. We found that plasma cfDNA concentrations in GBM patients were significantly elevated (22.6 ± 5 ng·mL-1 ), as compared to healthy controls (1.4 ± 0.4 ng·mL-1 ) of the same average age. We identified unique mutations in the cfDNA and tumour DNA of each GBM patient, including some of the most frequently mutated genes in GBM according to the COSMIC database (TP53, 18.75%; EGFR, 37.5%; NF1, 12.5%; LRP1B, 25%; IRS4, 25%). Using our gene-gene fusion database, ChiTaRS 5.0, we identified gene-gene fusions in cfDNA and tumour DNA, such as KDR-PDGFRA and NCDN-PDGFRA, which correspond to previously reported alterations of PDGFRA in GBM (44% of all samples). Interestingly, the PDGFRA protein fusions can be targeted by tyrosine kinase inhibitors such as imatinib, sunitinib, and sorafenib. Moreover, we identified BCR-ABL1 (in 8% of patients), COL1A1-PDGFB (8%), NIN-PDGFRB (8%), and FGFR1-BCR (4%) in cfDNA of patients, which can be targeted by analogues of imatinib. ROS1 fusions (CEP85L-ROS1 and GOPC-ROS1), identified in 8% of patient cfDNA, might be targeted by crizotinib, entrectinib, or larotrectinib. Thus, our study suggests that integrated analysis of cfDNA plasma concentration, gene mutations, and gene-gene fusions can serve as a diagnostic modality for distinguishing GBM patients who may benefit from targeted therapy. These results open new avenues for precision medicine in GBM, using noninvasive liquid biopsy diagnostics to assess personalized patient profiles. Moreover, repeated detection of druggable targets over the course of the disease may provide real-time information on the evolving molecular landscape of the tumour.

Delayed initiation of radiotherapy for glioblastoma: how important is it to push to the front (or the back) of the line?

Glioblastoma is a malignant tumor characterized by a rapid proliferation rate. Contemporary multi-modality treatment consists of maximal surgical resection followed by radiation therapy (RT) combined with cytotoxic chemotherapy. The optimal timing of these different steps is not known. Four studies from the pre-temozolomide era, encompassing a total of 4,584 subjects, have examined the consequences of a delay between resection and starting RT. Whereas the two small single-institution studies found this delay to be detrimental, two large multi-institutional studies found delay to be either slightly beneficial or at least not harmful. Here, we critically compare the methodologies and results presented in these studies, and include a novel analysis of the combined datasets. We conclude that moderate wait periods (up to 4-6 weeks post-operatively) are safe and may be modestly beneficial. Conversely, there is no evidence to justify waiting longer than 6 weeks. Underlying radiobiological principles are discussed.