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Purpose: A multi-site Phase I trial was conducted to determine the safety, maximum tolerated dose, and pharmacokinetics (PK) of Veliparib, a Poly (ADP-ribose) polymerase [PARP] enzyme inhibitor, when administered with temozolomide (TMZ) alone and then with temozolomide and radiation (RT) in patients with newly diagnosed glioblastoma. Methods: Given the potential for myelosuppression when a PARP inhibitor is combined with chemotherapy, the first 6 patients accrued were given Veliparib 10 mg bid and TMZ 75 mg/m2/d daily for six weeks. If this was well tolerated, the same doses of Veliparib and TMZ would be tested along with standard radiation with plans to dose escalate the Veliparib in subsequent patient cohorts. Once a maximal tolerated dose was determined, a 78 patient phase II study was planned. Peripheral blood pharmacokinetics were assessed. Results: Twenty-four patients were enrolled. In the first 6 patients who received 6 weeks of TMZ with Veliparib only one dose limiting toxicity (DLT) occurred. The next 12 patients received 6 weeks of RT + TMZ + veliparib and 4/12 (33%) had dose limiting hematologic toxicities. As a result, Veliparib was reduced by 50% to 10 mg BID every other week, but again 3/3 patients had dose limiting hematologic toxicities. The trial was then terminated. The mean clearance (± SD) CL/F of Veliparib for the initial dose (27.0 ± 9.0 L/h, n = 16) and at steady-state for 10 mg BID (23.5 ± 10.4 L/h, n = 18) were similar. Accumulation for BID dosing was 56% (± 33%). Conclusions: Although Veliparib 10 mg BID administered with TMZ 75 mg/m2 for six weeks was well tolerated, when this regimen was combined with standard partial brain irradiation it was severely myelosuppressive even when the dose was reduced by 50%. This study again highlights the potential of localized cranial radiotherapy to significantly increase hematologic toxicity of marginally myelosuppressive systemic therapies. [ABSTRACT FROM AUTHOR]

Purpose: In our center, five Gamma Knife proceduralists differed in opioid administration practices prior to Leksell frame removal, providing the opportunity to improve the care of patients with brain metastases by studying whether opioid medications improve pain scores and patient satisfaction during Gamma Knife treatment in a prospective, pseudorandomized fashion. Methods: We prospectively administered a questionnaire to patients undergoing Gamma Knife Radiosurgery for metastases between November, 2017 and July, 2018. Using multivariable methods, we assessed whether opioid pain medication administration influenced the change in pain scores after frame removal, and whether they influenced patient satisfaction on how often their pain was controlled, and their overall satisfaction. Results: We included 142 patients. Mean age was 65.2 ± 10.8 years and 52.7% were female. Morphine was the most commonly administered medication. Pain increases were greater around frame removal than placement. Opioids were not associated with any difference in the change in pain scores before and after frame removal, or patient satisfaction. Patients with higher pre-removal pain scores had smaller increases in pain scores after removal; they also had worse pain control and overall satisfaction with their treatment. Conclusion: Morphine administration prior to frame removal did not improve pain scores or pain control satisfaction. Absence of efficacy may be related to delayed onset of action, and stronger and faster-acting agents should be explored. Pre-removal pain scores were associated with decreased pain control and overall satisfaction, further identifying earlier and stronger pain treatment as a potential area for improvement. [ABSTRACT FROM AUTHOR]

Purpose: Distinguishing radiation necrosis from tumor progression among patients with brain metastases previously treated with stereotactic radiosurgery represents a common diagnostic challenge. We performed a prospective pilot study to determine whether PET/CT with 18F-fluciclovine, a widely available amino acid PET radiotracer, repurposed intracranially, can accurately diagnose equivocal lesions. Methods: Adults with brain metastases previously treated with radiosurgery presenting with a follow-up tumor-protocol MRI brain equivocal for radiation necrosis versus tumor progression underwent an 18F-fluciclovine PET/CT of the brain within 30 days. The reference standard for final diagnosis consisted of clinical follow-up until multidisciplinary consensus or tissue confirmation. Results: Of 16 patients imaged from 7/2019 to 11/2020, 15 subjects were evaluable with 20 lesions (radiation necrosis, n = 16; tumor progression, n = 4). Higher SUVmax statistically significantly predicted tumor progression (AUC = 0.875; p = 0.011). Lesion SUVmean (AUC = 0.875; p = 0.018), SUVpeak (AUC = 0.813; p = 0.007), and SUVpeak-to-normal-brain (AUC = 0.859; p = 0.002) also predicted tumor progression, whereas SUVmax-to-normal-brain (p = 0.1) and SUVmean-to-normal-brain (p = 0.5) did not. Qualitative visual scores were significant predictors for readers 1 (AUC = 0.750; p < 0.001) and 3 (AUC = 0.781; p = 0.045), but not for reader 2 (p = 0.3). Visual interpretations were significant predictors for reader 1 (AUC = 0.898; p = 0.012) but not for reader 2 (p = 0.3) or 3 (p = 0.2). Conclusions: In this prospective pilot study of patients with brain metastases previously treated with radiosurgery presenting with a contemporary MRI brain with a lesion equivocal for radiation necrosis versus tumor progression, 18F-fluciclovine PET/CT repurposed intracranially demonstrated encouraging diagnostic accuracy, supporting the pursuit of larger clinical trials which will be necessary to establish diagnostic criteria and performance. [ABSTRACT FROM AUTHOR]

Purpose: We sought to evaluate the effects of concurrent temozolomide-based chemoradiation therapy on neurocognitive function in patients with low-grade glioma (LGG). Materials/methods: We included adult patients with LGG who were treated postoperatively with radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ). Patients were evaluated with comprehensive psychometric tests at baseline (prior to RT + TMZ) and at various time intervals following RT + TMZ. Baseline cognitive performance was analyzed by sex, age, education history, history of seizures, IDH mutation status, and 1p/19q codeletion status. Changes in neurocognitive performance were evaluated over time. Results: Thirty-seven LGG patients (mean age 43.6, 59.5% male) had baseline neurocognitive evaluation. Patients with an age > 40 years old at diagnosis and those with an education > 16 years demonstrated superior baseline verbal memory as assessed by HVLT. No other cognitive domains showed differences when stratified by the variables mentioned above. A total of 22 LGG patients had baseline and post RT + TMZ neurocognitive evaluation. Overall, patients showed no statistical difference between group mean test scores prior to and following RT + TMZ on all psychometric measures (with the exception of HVLT Discrimination). Conclusion: Cognitive function remained stable following RT + TMZ in LGG patients evaluated prospectively up to 2 years. The anticipated analysis of RTOG 0424 will provide valuable neurocognitive outcomes specifically for high risk LGG patients treated with RT + TMZ. [ABSTRACT FROM AUTHOR]

Purpose: Low-grade glioma (LGG) exhibits longer median survival than high-grade brain tumors, and thus impact of our therapies on patient quality of life remains a crucial consideration. This study evaluated the effects of concurrent temozolomide-based chemoradiation (RT + TMZ) or observation on quality of life (QOL) in patients with low-grade glioma. Methods: We completed a retrospective cross-sectional study of adults with LGG who underwent surgery with known molecular classification from 1980 to 2018. Postoperatively, patients were either observed or received adjuvant concurrent temozolomide-based chemoradiation. EQ-5D and PHQ-9 depression screen were completed before outpatient visits every 2–3 months. Baseline score was defined as ± 30 days within initial operation. Results: Of the 63 patients (mean age 44 ± 17 years, 51% female) with baseline EQ-5D or PHQ-9 depression screen data and at least one follow-up measure, 30 (48%) were observed and 33 (52%) received RT + TMZ. No significant decline was seen in EQ-5D or PHQ-9 scores at 3, 6, 9, 12, and 24 months compared to baseline scores for all patients. At each time point, there was no significant difference between those who were observed or received adjuvant therapy. The linear mixed model estimating PHQ-9 value or EQ-5D index demonstrated that there was no significant difference in PHQ-9 or EQ-5D index between treatment groups (p = 0.42 and p = 0.54, respectively) or time points (p = 0.24 and p = 0.99, respectively). Conclusion: Our study found no significant decline in patient QOL or depression scores as assessed by patient- reported outcome measures for patients with low-grade glioma up to 2 years following surgery. We found no difference between RT + TMZ compared to observation during this time frame. Additional follow-up can help identify the longer-term impact of treatment strategy on patient experience. [ABSTRACT FROM AUTHOR]

Ascaroside pheromones stimulate dispersal, a key nematode behavior to find a new food source. Ascarosides produced by entomopathogenic nematodes (EPNs) drive infective juvenile (IJ) emergence from consumed cadavers and dispersal in soil. Without ascarosides from host cadavers, Steinernema feltiae (EPN) reduce dispersal substantially. To determine whether other Steinernema spp. exhibit the same behavior, we compared S. feltiae and S. carpocapsae IJs without host cadaver pheromones. Unlike S. feltiae, S. carpocapsae IJs continued to disperse. However, S. carpocapsae IJs exhibited a temperature-dependent quiescent period. The IJ quiescent period increased at ≤20 °C but did not appear at ≥25 °C. Consistent with this, S. carpocapsae IJ quiescence increased from 30 min to 24 h at ≤20 °C over 60 days. The quiescent period was overcome by dispersal pheromone extracts of their own, other Steinernema spp. and Heterorhabditis spp. Furthermore, S. carpocapsae IJ ambush foraging associated behaviors (tail standing, waving, and jumping) were unaffected by the absence or presence of host cadaver pheromones. For S. feltiae, IJ dispersal declined at all temperatures tested. Understanding the interaction between foraging strategies and pheromone signals will help uncover molecular mechanisms of host seeking, pathogenicity and practical applications to improve the EPN's efficacy as biocontrol agents. [ABSTRACT FROM AUTHOR]

Introduction: Dovitinib is an oral, potent inhibitor of FGFR and VEGFR, and can be a promising strategy in patients with recurrent or progressive glioblastoma (GBM). Methods: This was an open label phase II study of two arms: Arm 1 included anti-angiogenic naïve patients with recurrent GBM and Arm 2 included patients with recurrent GBM that had progressed on prior anti-angiogenic therapy. Nineteen subjects were enrolled in Arm 1 and 14 subjects in Arm 2. The primary endpoint was 6-month progression-free survival (PFS-6) in Arm 1 and time to progression (TTP) in Arm 2. The secondary endpoints were toxicity, objective response rate (ORR) and overall survival. Results: Patients in Arm 2 (compared to Arm 1) tended to have longer intervals from diagnosis to study entry (median 26.9 vs. 8.9 months, p = 0.002), experienced more recurrences (64%, had 3–4 prior recurrences compared to 0, p < 0.0001) and tended to be heavily pretreated (71% vs. 26–32% p = 0.04 or 0.02). 6-month PFS was 12% ± 6% for the Arm 1 and 0% for Arm 2. TTP was similar in both treatment arms (median 1.8 months Arm 1 and 0.7–1.8 months Arm 2, p = 0.36). Five patients (15%) had grade 4 toxicities and 22 patients (67%) had grade 3 toxicities. There were no significant differences between the two arms with respect to the amount of change in the levels of biomarkers from baseline. Conclusion: Dovitinib was not efficacious in prolonging the PFS in patients with recurrent GBM irrespective of prior treatment with anti-angiogenic therapy (including bevacizumab). [ABSTRACT FROM AUTHOR]

To investigate late toxicity among patients with newly-diagnosed brain metastases undergoing stereotactic radiosurgery (SRS) with concurrent systemic therapies with or without whole-brain radiation therapy (WBRT). Patients with newly-diagnosed brain metastasis who underwent SRS at a single tertiary-care institution from 1997 to 2015 were eligible for inclusion. The class and timing of all systemic therapies were collected for each patient. The primary outcome was the cumulative incidence of radiographic radiation necrosis (RN). Multivariable competing risks regression was used to adjust for confounding. During the study period, 1650 patients presented with 2843 intracranial metastases. Among these, 445 patients (27%) were treated with SRS and concurrent systemic therapy. Radiographic RN developed following treatment of 222 (8%) lesions, 120 (54%) of which were symptomatic. The 12-month cumulative incidences of RN among lesions treated with and without concurrent therapies were 6.6 and 5.3%, respectively ( p = 0.14). Concurrent systemic therapy was associated with a significantly increased rate of RN among lesions treated with upfront SRS and WBRT (8.7 vs. 3.7%, p = 0.04). In particular, concurrent targeted therapies significantly increased the 12-month cumulative incidence of RN (8.8 vs. 5.3%, p < 0.01). Among these therapies, significantly increased rates of RN were observed with VEGFR tyrosine kinase inhibitors (TKIs) (14.3 vs. 6.6%, p = 0.04) and EGFR TKIs (15.6 vs. 6.0%, p = 0.04). Most classes of systemic therapies may be safely delivered concurrently with SRS in the management of newly-diagnosed brain metastases. However, the rate of radiographic RN is significantly increased with the addition of concurrent systemic therapies to SRS and WBRT. [ABSTRACT FROM AUTHOR]

To retrospectively analyze and assess the outcomes and prognostic factors in patients with anaplastic meningioma (AM) (WHO Grade III). Clinical data and outcome [overall (OS) and progression-free (PFS) survival] from 18 patients with Grade III meningioma (AM, based on World Health Organization 2016 definition) initially treated between March 2000 and June 2015 were analyzed. Eleven patients (61%) were male, median age at diagnosis was 63 (range 48-86), and 55% (10/18 patients) had good performance status (KPS ≥ 80). Eight patients (45%) had lower grade disease (Grade I-n = 2; Grade II-n = 6) prior to being upgraded to AM. Ten patients had fractionated radiation after primary surgery, eight patients had salvage fractionated RT, stereotactic radiosurgery (SRS) boost along with primary RT in 1 patient, and salvage SRS to 18 separate areas in 14 patients. Salvage chemotherapy was mainly considered in third or fourth recurrences. 13 (72%) patients recurred and 10 (56%) have died. Median PFS was 14.5 months (95% CI 6.9-22.2). The 5-year survival rate was 40 ± 15% and median OS was 55.8 months (95% CI 27.7-80.3). Of all factors examined, only Karnofsky performance status (KPS) affected outcome (PFS p = 0.0003; OS p = 0.0003). With median OS of 55 months (4.6 years) our results are consistent with existing reports of the poor outcomes for AM patients. From the available data, surgical resection followed by RT and salvage radiosurgery and/or chemotherapy can lead to extended survival; however the benefit may decrease with successive treatments. [ABSTRACT FROM AUTHOR]

Little is known on the natural history, recurrence patterns, neurocognitive outcomes and prognostic factors associated with survival in long-term survivors (≥10 years) from brain metastasis (BM). In this study, the records of 1953 patients who underwent treatment for BM with a potential for ≥10 years of follow-up were reviewed. Cox regression analysis identified factors predictive for overall survival (OS). The median age at brain metastasis diagnosis was 60 years and the median OS was 6.4 months. The 1-year OS rate was 29.9, 12.1 % at 2 years, 3.0 % at 5 years, and 1.3 % at 10 years. On multivariable analysis, factors associated with worse OS included gender (males, HR 1.2), multiple brain metastases (HR 1.3), no surgery (HR 1.8), and no stereotactic radiosurgery (HR 1.8) (p < 0.0001 each). Fifty-six patients (2.9 %) survived ≥5 years; 23 patients (1.2 %) survived ≥10 years and the median survival for ≥10 year survivors was 18.5 years. Six of the 10-year survivors had an intracranial recurrence, five occurred within 11 years from the first treatment. Presence of a solitary lesion or single lesion at the time of brain metastasis diagnosis was associated with improved survival. Eight of the ≥10 year survivors (34.8 %) had no neurological symptoms at last follow-up; none of the 10-year survivors were documented to have a neurologic death. Our study demonstrates that patients with favorable prognostic features should undergo multimodality treatment. Albeit rare, patients who are alive 10 years after treatment for their brain metastases may be considered cured from their intracranial disease. [ABSTRACT FROM AUTHOR]

Current therapies for recurrent or progressive high-grade gliomas (HGG, WHO grade 3-4) produce a 6-month progression-free survival of only 10-25%. Migration and invasion by HGG is mediated in part by matrix metalloproteases (MMPs) which promote remodeling of the extracellular matrix. Several HIV protease inhibitors (HIVPI) decrease the expression of MMPs in astrocytes and microglia. Given these mechanisms of antitumor activity of HIVPI, we evaluated the efficacy of ritonavir/lopinavir, a combination HIVPI, in patients with progressive or recurrent HGG in an open label phase II trial. Nineteen patients were treated in this study. Patients received ritonavir/lopinavir (400 mg/100 mg) orally twice daily. All patients were treated until progression of disease or unacceptable toxicity. A complete response was seen in one patient (5%). Three patients (16%) had stable disease as the best response. Fifteen patients (79%) had progressive disease. The 6-month progression free survival (PFS) was 11% (2 of 19 patients). Ritonavir/lopinavir was well tolerated in patients with heavily pretreated refractory HGG, and no grade 3 or 4 toxicity was seen. The activity at the dose and schedule used in this study, however, was modest and the study did not meet its efficacy endpoint. [ABSTRACT FROM AUTHOR]

Approximately 40–50% of glioblastomas (GBM) overexpress epidermal growth factor receptor (EGFR). Erlotinib is a specific and potent EGFR tyrosine kinase inhibitor active against refractory GBM. Patients with non-small cell lung cancer and ≥grade 2 erlotinib-induced rash have improved survival. This phase 2 study assessed the efficacy and safety of concurrent radiation therapy (RT) and temozolomide with pharmacodynamic dose escalation of erlotinib in patients with newly diagnosed GBM. Patients received RT 60 Gy in 30 fractions with concurrent temozolomide 75 mg/m2/day × 42 days, followed in four weeks by temozolomide 150–200 mg/m2/day × 5, every 28 days for 12 cycles. Patients received erlotinib, 50 mg/day and increased by 50 mg/day every 2 weeks until the occurrence of grade 2 rash or to a maximum dose of 150 mg/day, from day 1 until disease progression. Twenty-seven patients were treated in this study. Twenty-two (81%) patients came off study for progressive disease (18 [67%]) or adverse events (4 [15%]). Eighteen patients (67%) have died. Median progression-free survival was 2.8 months, and the median overall survival was 8.6 months. Five patients remain on study with a median follow-up of 16 months. Grade 3/4 toxicities included thrombocytopenia, anemia, lymphopenia, fatigue, and febrile neutropenia. There were four deaths on study, three definitely treatment-related; therefore, the trial was terminated after accrual of 27 of 30 planned patients. Erlotinib co administered with RT and temozolomide was not efficacious and had an unacceptable toxicity. [ABSTRACT FROM AUTHOR]

While soil resource heterogeneity and root herbivory can have significant direct influences on plant growth, soil heterogeneity may also have indirect effects by influencing the foraging behavior of root herbivores. We used sand-filled greenhouse pots to assess root herbivore foraging behavior and potential interactions between patch quality, herbivore foraging, and plant biomass production (yield). Individual pots were divided into four quarters: one fertilized, and three unfertilized, two of which were planted with tree seedlings. Two treatments were used to create fertilized quarters: high-organic manure fertilizer, and slow-release mineral fertilizer. Seedlings of red maple ( Acer rubrum L.) and Virginia pine ( Pinus virginiana L.) were used to create two single-species and one mixed-species treatments. Root-feeding beetle larvae were added to the pots and allowed to forage freely for ∼8 weeks. At harvest, root herbivores in organic-fertilized pots were strongly attracted to fertilized quarters despite their relatively low-root biomass. Herbivore distribution was significantly different in mineral fertilized pots, where larvae were most abundant in planted quarters, which is also where most of the plant roots occurred. Whole pot plant yield was significantly reduced by larvae; this effect was stronger in the mineral fertilized pots than organic fertilized pots. While one of the plant species appeared more sensitive to herbivory, root herbivores had a greater influence on yield in mixed-species pots than in single-species pots. Overall, these results suggest that patch quality influences on herbivore foraging may indirectly alter yield and plant community composition. [ABSTRACT FROM AUTHOR]

More than 200,000 patients are diagnosed with primary or metastatic brain tumors each year in the United States. Of these patients, 20% to 40% will develop seizures at presentation, and another 20% to 40% will require treatment for seizures during their illness. Although the use of antiepileptic drugs (AEDs) in patients who have had seizures seems reasonable, the issue of prophylactic AED use for patients who have not had a seizure is an intensely debated subject. The American Academy of Neurology released a position statement in May 2000 addressing the use of anticonvulsants in newly diagnosed brain tumor patients who have never had a seizure. After a review of the literature, including all trials showing class I evidence, multivariate analysis using calculated odds ratios failed to show a prophylactic benefit of preventing a first seizure versus the risk of side effects and recommended not using prophylactic anticonvulsants in newly diagnosed patients with brain tumor. Despite this recommendation, a recent survey of the American Association of Neurologic Surgeons revealed that most neurosurgeons still use anticonvulsants prophylactically in patients with brain tumor. This review mainly includes primary brain tumors, but most of the concepts are transferable to patients with metastatic tumors. [ABSTRACT FROM AUTHOR]

Controls of fine dynamics were investigated in a Pinus palustris Mill. (longleaf pine) woodland subjected to two understory vegetation treatments (control versus removed) and four overstory treatments (no gap control, and canopy gaps of three sizes with constant total gap area per stand). Fine root (<2 mm diameter) dynamics were measured over 11 months using ingrowth cores (all treatments) and minirhizotrons (understory removed in no gap control and large gap treatments only). At the fine (microsite) spatial scale, pine and non-pine root mass production responded negatively to each other (P=0.033). Each life form was significantly (P≤0.028) related to nearby overstory density, and pine root production compensated for reductions in non-pine roots if understory vegetation was removed. Soil moisture and NO3 mineralization rate were negatively related to pine root mass production (ingrowth cores; P<0.001 and P=0.052) and positively related to pine root length production, mortality and turnover (minirhizotrons; P from <0.001 to 0.078). Temperature variance was negatively related to pine root lifespan (P<0.001) and positively related to pine root turnover (P=0.003). At the ecosystem scale, pattern of overstory disturbance (gap size and number) had no significant effect on non-pine, pine, or total root production. However, the presence of gaps (versus the no-gap control) increased non-pine root mass production (ANOVA, P=0.055) in natural understory conditions, and reduced pine root mass production (P=0.035) where the understory was removed. Ecosystem-wide pine root length production, mortality and turnover were positively related to weekly soil temperature (P≤0.02). In natural systems, fine root dynamics are highly variable and strongly affected by biotic factors. Roots quickly close belowground gaps because one life form (pine or non-pine) compensates for the absence of the other. When understory vegetation is removed, however, pine roots respond to the local abiotic environment, particularly moisture and NO3. [ABSTRACT FROM AUTHOR]

This retrospective analysis details the experience of a tertiary care center with survival and results for patients with recurrent glioblastoma multiforme (GBM) treated with stereotactic radiosurgery (SRS). Between August 1990 and June 1999, 23 patients were treated for recurrent GBM with SRS using either modified 6-MV linear accelerator (linac) or γ-knife. Twenty-two patients (96%) had an initial histological diagnosis of GBM, while 1 patient had an initial diagnosis of anaplastic astrocytoma that was biopsied at recurrence and found to have upgraded to GBM. The median Karnofsky performance score at the time of SRS was 80; the median age was 53. The median-treated tumor volume was 9.9 cm3, with a dose of 15 Gy delivered to the 60% isodose line. Median progression-free survival was 4.7 months. Median survival time after SRS was 10.3 months. No prognostic factors were found to be significant. Patients with a KPS of 80 or higher had longer median survival times than those with lower KPS scores, but this was not found to be statistically significant. Our results suggest that for selected patients with recurrent GBM, SRS appears to be an appropriate salvage therapy. [ABSTRACT FROM AUTHOR]