Socioeconomic predictors of case presentations and outcomes in 225 nonfunctional pituitary adenoma resections.

OBJECTIVE: Clinical presentations and outcomes of nonfunctional pituitary adenoma (NFPA) resections can vary widely, and very little prior research has analyzed this variance through a socioeconomic lens. This study sought to determine whether socioeconomic status (SES) influences NFPA presentations and postoperative outcomes, as these associations could aid physicians in understanding case prognoses and complications. METHODS: The authors retrospectively analyzed 225 NFPA resections from 2012 to 2019 at their institution. Race, ethnicity, insurance status, estimated income, and having a primary care provider (PCP) were collected as 5 markers of SES. These markers were correlated with presenting tumor burden, presenting symptoms, surgical outcomes, and long-term clinical outcomes. RESULTS: All 5 examined SES markers influenced variance in patient presentation or outcome. Insurance status's effects on patient presentations disappeared when examining only patients with PCPs. Having a PCP was associated with significantly smaller tumor size at diagnosis (effect size = 0.404, p < 0.0001). After surgery, patients with PCPs had shorter postoperative hospital lengths of stay (p = 0.043) and lower rates of readmission within 30 days of discharge (OR 0.256, p = 0.047). Despite continuing follow-up for longer durations (p = 0.0004), patients with PCPs also had lower rates of tumor recurrence (p < 0.0001). Higher estimated income was similarly associated with longer follow-up (p = 0.002) and lower rates of tumor recurrence (p = 0.013). Among patients with PCPs, income was not associated with recurrence. CONCLUSIONS: This study found that while all 5 variables (race, ethnicity, insurance, PCP status, and estimated income) affected NFPA presentations and outcomes, having a PCP was the single most important of these socioeconomic factors, impacting hospital lengths of stay, readmission rates, follow-up adherence, and tumor recurrence. Having a PCP even protected low-income patients from experiencing increased rates of tumor recurrence. These protective findings suggest that addressing socioeconomic disparities may lead to better NFPA presentations and outcomes.

Proof-of-concept single-arm trial of bevacizumab therapy for brain arteriovenous malformation.

Brain arteriovenous malformations (bAVMs) are relatively rare, although their potential for secondary intracranial haemorrhage (ICH) makes their diagnosis and management essential to the community. Currently, invasive therapies (surgical resection, stereotactic radiosurgery and endovascular embolisation) are the only interventions that offer a reduction in ICH risk. There is no designated medical therapy for bAVM, although there is growing animal and human evidence supporting a role for bevacizumab to reduce the size of AVMs. In this single-arm pilot study, two patients with large bAVMs (deemed unresectable by an interdisciplinary team) received bevacizumab 5 mg/kg every 2 weeks for 12 weeks. Due to limitations of external funding, the intended sample size of 10 participants was not reached. Primary outcome measure was change in bAVM volume from baseline at 26 and 52 weeks. No change in bAVM volume was observed 26 or 52 weeks after bevacizumab treatment. No clinically important adverse events were observed during the 52-week study period. There were no observed instances of ICH. Sera vascular endothelial growth factor levels were reduced at 26 weeks and returned to baseline at 52 weeks. This pilot study is the first to test bevacizumab for patients with bAVMs. Bevacizumab therapy was well tolerated in both subjects. No radiographic changes were observed over the 52-week study period. Subsequent larger clinical trials are in order to assess for dose-dependent efficacy and rarer adverse drug effects. Trial registration number: NCT02314377.

Maximizing the use of batch production of 18F-FDOPA for imaging of brain tumors to increase availability of hybrid PET/MR imaging in clinical setting.

BACKGROUND: Amino acid PET imaging of brain tumors has been shown to play an important role in predicting tumor grade, delineation of tumor margins, and differentiating tumor recurrence from the background of postradiation changes, but is not commonly used in clinical practice because of high cost. We propose that PET/MRI imaging of patients grouped to the day of tracer radiosynthesis will significantly decrease the cost of PET imaging, which will improve patient access to PET. METHODS: Seventeen patients with either primary brain tumors or metastatic brain tumors were recruited for imaging on 3T PET/MRI and were scanned on 4 separate days in groups of 3 to 5 patients. The first group of consecutively imaged patients contained 3 patients, followed by 2 groups of 5 patients, and a last group of 4 patients. RESULTS: For each of the patients, standard of care gadolinium-enhanced MRI and dynamic PET imaging with 18F-FDOPA amino acid tracer was obtained. The total cost savings of scanning 17 patients in batches of 4 as opposed to individual radiosynthesis was 48.5% ($28 321). Semiquantitative analysis of tracer uptake in normal brain were performed with appropriate accumulation and expected subsequent washout. CONCLUSION: Amino acid PET tracers have been shown to play a critical role in the characterization of brain tumors but their adaptation to clinical practice has been limited because of the high cost of PET. Scheduling patient imaging to maximally use the radiosynthesis of imaging tracer significantly reduces the cost of PET and results in increased availability of PET tracer use in neuro-oncology.

Radiation-induced Cavernous Malformation as a Late Sequelae of Stereotactic Radiosurgery for Epilepsy.

Stereotactic radiosurgery (SRS) is a promising treatment for medically intractable mesial temporal lobe epilepsy. SRS for epilepsy has had an acceptable safety profile with reports of radiation-induced vascular malformations confined to central nervous system pathologies with prominent angiogenesis - namely, primary brain tumors, metastases, and arteriovenous malformations. Theoretical risks for radiation-induced lesions following radiosurgery for epilepsy have yet to be established. Of 13 patients treated in a pilot trial for medial temporal lobe epilepsy, one developed multiple delayed radiation-induced cavernous malformations following radiosurgery. This patient received a prescription dose of 20 Gy delivered to the amygdala, anterior hippocampus, and parahippocampal gyrus. Eight years following treatment, computed tomography imaging demonstrated an evolving hyperdensity in the mesial temporal lobe. Magnetic resonance imaging confirmed multiple T2 hypointense lesions with a mixed-signal intensity core in the left parahippocampal gyrus and anterior temporal lobe. The patient was initially managed conservatively. However, recurrent hemorrhage ultimately caused an acute deterioration in mental status, aphasia, and hemiparesis, necessitating surgical resection. Pathology confirmed radiation-induced cavernous malformations. This represents the first case of a radiation-induced vascular lesion as a long-term sequela of radiosurgery for epilepsy and illustrates the potential for this complication even when low doses are used in patients without angiogenic lesions. Optimal timing and indications for surgical resection of radiation-induced cavernous malformations prior to the development of neurologic symptoms warrant further refinement. Long-term vigilance and clinical monitoring are required.

Resection Cavity Contraction Effects in the Use of Radioactive Sources (1-25 versus Cs-131) for Intra-Operative Brain Implants.

Background and Objectives Intra-parenchymal brain surgical resection cavities usually contract in volume following low dose rate (LDR) brachytherapy implants. In this study, we systematically modeled and assessed dose variability resulting from such changes for I-125 versus Cs-131 radioactive sources. Methods Resection cavity contraction was modeled based on 95 consecutive patient cases, using surveillance magnetic resonance (MR) images. The model was derived for single point source geometry and then fully simulated in 3D where I-125 or Cs-131 seeds were placed on the surface of an ellipsoidal resection cavity. Dose distribution estimated via TG-43 calculations and biological effective dose (BED) calculations were compared for both I-125 and Cs-131, accounting for resection cavity contractions. Results Resection cavity volumes were found to contract with an effective half-life of approximately 3.4 months (time to reach 50% of maximum volume contraction). As a result, significant differences in dose distributions were noted between I-125 and Cs-131 radioactive sources. For example, when comparing with static volume, assuming no contraction effect, I-125 exhibited a 31.8% and 30.5% increase in D90 and D10 values (i.e., the minimal dose to 90% and 10% of the volume respectively) in the peripheral target areas over the follow-up period of 20.5 months. In contrast, Cs-131 seeds only exhibited a 1.44% and 0.64% increase in D90 and D10 values respectively. Such discrepancy is likewise similar for BED calculations. Conclusion Resection cavity contractions affects Cs-131 dose distribution significantly less than that of I-125 for permanent brain implants. Care must be taken to account for cavity contractions when prescribing accumulative doses of a radioactive source in performing the brain implant procedures.

Patient-Specific Fetal Dose Determination for Multi-Target Gamma Knife Radiosurgery: Computational Model and Case Report.

A 42-year-old woman at 29 weeks gestation via in vitro fertilization who presented with eight metastatic brain lesions received Gamma Knife stereotactic radiosurgery (GKSRS) at our institution. In this study, we report our clinical experience and a general procedure of determining the fetal dose from patient-specific treatment plans and we describe quality assurance measurements to guide the safe practice of multi-target GKSRS of pregnant patients. To estimate fetal dose pre-treatment, peripheral dose-to-focal dose ratios (PFRs) were measured in a phantom at the distance approximating the fundus of uterus. Post-treatment, fetal dose was calculated from the actual patient treatment plan. Quality assurance measurements were carried out via the extrapolation dosimetry method in a head phantom at increasing distances along the longitudinal axis. The measurements were then empirically fitted and the fetal dose was extracted from the curve. The computed and measured fetal dose values were compared with each other and associated radiation risk was estimated. Based on low estimated fetal dose from preliminary phantom measurements, the patient was accepted for GKSRS. Eight brain metastases were treated with prescription doses of 15-19 Gy over 143 min involving all collimator sizes as well as composite sector mixed shots. Direct fetal dose computation based on the actual patient's treatment plan estimated a maximum fetal dose of 0.253 cGy, which was in agreement with surface dose measurements at the level of the patient's uterine fundus during the actual treatment. Later phantom measurements also estimated fetal dose to be in the range of 0.21-0.28 cGy (dose extrapolation curve R2 = 0.998). Using the National Council on Radiation Protection and Measurements (NCRP) population-based model, we estimate the fetal risk of secondary malignancy, which is the primary toxicity after 25 weeks gestation, to be less than 0.01%. Of note, the patient delivered the baby via scheduled cesarean section at 36 weeks without complications attributable to the GKSRS procedure. GKSRS of multiple brain metastases was demonstrated to be safe and feasible during pregnancy. The applicability of a general patient-specific fetal dose determination method was also demonstrated for the first time for such a treatment.

Pain experience using conventional versus angled anterior posts during stereotactic head frame placement for radiosurgery.

Stereotactic frame placement for radiosurgery is assumed to be an uncomfortable experience. We developed angled anterior posts for the Leksell frame to avoid pin penetration of the temporalis muscle. This study aimed to determine the frequency of angled post requirement and quantify the patient pain experience from frame placement. We prospectively enrolled 63 patients undergoing radiosurgery. Angled posts were used when conventional post trajectory was posterior or within 3mm of the superior temporal line to avoid temporalis muscle penetration. Pain scores (0 to 10) were collected prior to frame placement, immediately after frame placement, before radiosurgery, after radiosurgery, and a day after radiosurgery. A total of 63 patients were enrolled: 33 (48%) patients required angled posts. Women were significantly more likely to require angled posts than men (60.0% versus 33.3%, respectively; p=0.034). Mean pain scores were very low, ranging from 0.33 to 2.23. There were no significant differences in pain outcomes between both groups at all time points. Stereotactic frame placement is not perceived to be a painful procedure. This information may be useful when counseling patients about the pain experience with frame application and the option of using angled anterior posts.

Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma.

This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m(2) daily during RT and then adjuvantly at 200 mg/m(2) daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotinib and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.

Standard treatment and experimental targeted drug therapy for recurrent glioblastoma multiforme.

Glioblastoma multiforme (GBM) tumors almost invariably recur despite initial treatments. Correct diagnosis using a variety of imaging techniques and the involvement of a multidisciplinary tumor board are critical for evaluating each stage of a patient's progression and determining optimal management. Standard therapies for recurrence generally include repeated resection, radiation therapy, chemotherapy, and supportive care; however, salvage therapy must be highly individualized, and not all patients are eligible for every type of standard therapy. Factors such as the size and location of the tumor, previous treatment, and general health of the patient must be taken into consideration. Although standard therapies can prolong a patient's duration of survival, the median survival time for patients with recurrent GBM is usually less than 1 year. Experimental targeted drug therapies have been developed to inhibit aberrant cell-signaling pathways involved in tumorigenesis, and enrolling patients in clinical trials using these therapies is another option for treatment of recurrent GBM. The use of these novel therapies is often confined to large research institutions, but the severe limitations of standard treatment options make it important to highlight the potential of experimental therapies. In this paper the authors outline standard therapies and review the emerging role of targeted drug therapy in the treatment of recurrent GBM.

Diagnosis and treatment of recurrent high-grade astrocytoma.

High-grade gliomas represent a significant source of cancer-related death, and usually recur despite treatment. In this analysis of current brain tumor medicine, we review diagnosis, standard treatment, and emerging therapies for recurrent astrocytomas. Difficulties in interpreting radiographic evidence, especially with regard to differentiating between tumor and necrosis, present a formidable challenge. The most accurate diagnoses come from tissue confirmation of recurrent tumor, but a combination of imaging techniques, such as magnetic resonance spectroscopy imaging, may also be relevant for diagnosis. Repeat resection can prolong life, but repeat irradiation of the brain poses serious risks and results in necrosis of healthy brain tissue; therefore, reirradiation is usually not offered to patients with recurrent tumors. We describe the use of conventional radiotherapy, intensity-modulated radiotherapy, brachytherapy, radiosurgery, and photodynamic therapy for recurrent high-grade glioma. The use of chemotherapy is limited by drug distribution and toxicity, but the development of new drug-delivery techniques such as convection-enhanced delivery, which delivers therapeutic molecules at an effective concentration directly to the brain, may provide a way to reduce systemic exposure to cytotoxic agents. We also discuss targeted therapies designed to inhibit aberrant cell-signaling pathways, as well as new experimental therapies such as immunotherapy. The treatment of this devastating disease has so far been met with limited success, but emerging knowledge of neuroscience and the development of novel therapeutic agents will likely give patients new options and require the neuro-oncology community to redefine clinical trial design and strategy continually.

A phase II study of concurrent temozolomide and cis-retinoic acid with radiation for adult patients with newly diagnosed supratentorial glioblastoma.

PURPOSE: This Phase II study was designed to determine the median survival time of adults with supratentorial glioblastoma treated with a combination of temozolomide (TMZ) and 13-cis-retinoic acid (cRA) given daily with conventional radiation therapy (XRT). METHODS AND MATERIALS: This was a single arm, open-labeled, Phase II study. Patients were treated with XRT in conjunction with cRA and TMZ. Both drugs were administered starting on Day 1 of XRT, and chemotherapy cycles continued after the completion of XRT to a maximum of 1 year. RESULTS: Sixty-one patients were enrolled in the study. Time to progression was known for 55 patients and 6 were censored. The estimated 6-month progression-free survival was 38% and the estimated 1-year progression-free survival was 15%. Median time to progression was estimated as 21 weeks. The estimated 1-year survival was 57%. The median survival was 57 weeks. CONCLUSIONS: The combined therapy was relatively well tolerated, but there was no survival advantage compared with historical studies using XRT either with adjuvant nitrosourea chemotherapy, with TMZ alone, or with the combination of TMZ and thalidomide. Based on this study, cRA does not seem to add a significant synergistic effect to TMZ and XRT.