Transitioning from conventional photon therapy to proton therapy for primary brain tumors.

INTRODUCTION: Proton radiation therapy (PT) has become a treatment option alongside photon therapy (XRT) for lower-grade gliomas (LGG). In this single-institution retrospective study, we investigate the patient characteristics and treatment outcomes, including pseudo-progression (PsP), for LGG patients selected for PT. METHOD: Adult patients with grade 2-3 glioma consecutively treated with radiotherapy (RT) from May 2012 to December 2019 were retrospectively included in this cohort study. Tumor characteristics and treatment data were collected. The groups treated with PT and XRT were compared regarding treatment characteristics, side effects, occurrence of PsP, and survival outcomes. PsP was defined as new or growing lesions followed by either decrease or stabilization during a 12 month-period with no treatment. RESULTS: Out of 143 patients meeting the inclusion criteria, 44 were treated with PT, 98 with XRT and one with mixed PT + XRT. The patients receiving PT were younger, had a lower tumor grade, more oligodendrogliomas and received a lower mean brain and brainstem dose. PsP was observed in 21 out of 126 patients, with no difference between XRT and PT (p = .38). The rate of fatigue in immediate connection to RT (zero to three months after) was higher for XRT than for PT (p = .016). The PT patients had a significantly better PFS and OS than the XRT patients (p = .025 and .035), but in multivariate analysis radiation modality was non-significant. Higher average dose to both brain and brainstem was associated with inferior PFS and OS (p < .001). Median follow-up time were 69 months and 26 months for XRT and PT patients, respectively. CONCLUSION: Contrary to previous studies, there was no difference in risk of PsP for XRT and PT. PT was associated with lower rates of fatigue <3 months after RT. The superior survival outcomes for PT indicates that the patients with the best prognosis were referred to PT.

A Functional MRI-Based Model for Individual Memory Assessment in Patients Eligible for Anterior Temporal Lobe Resection.

TITLE: A functional (f) MRI-based model for individual memory assessment in patients eligible for temporal lobe resection. AIM: To investigate if pre-operative fMRI memory paradigms, add predictive information with regard to post-surgical memory deficits. METHODS: Fourteen pharmacoresistant Temporal Lobe Epilepsy (TLE) patients accepted for Anterior Temporal Lobe Resection (ATLR) were included. A clinical risk assessment score (RAS 0-3) was constructed from structural MRI, neuropsychological testing and hemisphere dominance. fMRI lateralization indices (LIs) over frontal language and medial temporal regions were calculated. Predictive value from clinical risk scoring and added value from fMRI LIs were correlated to post-surgical memory change scores (significant decline -1 SD). Verbal memory outcome was classified either as expected (RAS 2-3 and post-operative decline; RAS 0-1 and intact post-operative verbal memory) or as unexpected (RAS 2-3 and intact post-operative verbal memory post-surgery; RAS 0-1 and post-operative decline). RESULTS: RAS for verbal memory decline exhibited a specificity of 67% and a sensitivity of 75%. Significant correlations were found between frontal language LIs and post-operative verbal memory (r = -0.802; p = 0.017) for left (L) TLE and between medial temporal lobe LIs and visuospatial memory (r = 0.829; p = 0.021), as well as verbal memory (r = 0.714; p = 0.055) for right (R) TLE. Ten patients had expected outcome and four patients had an unexpected outcome. In two MRI-negative RTLE patients that suffered significant verbal memory decline post-operatively, fMRI identified bilateral language and right lateralized medial temporal verbal encoding. In two LTLE patients with MRI pathology and verbal memory dysfunction, neither RAS nor fMRI identified the risk for aggravated verbal memory decline following ATLR. CONCLUSION: fMRI visualization of temporal-frontal network activation may add value to the pre-surgical work-up in epilepsy patients eligible for ATLR. Frontal language patterns are important for prediction in both L and RTLE. Strong left lateralized language in LTLE, as well as bilateral language combined with right lateralized encoding in RTLE, seems to indicate an increased risk for post-operative verbal memory decline.

Hybrid iterative reconstruction algorithm in brain CT: a radiation dose reduction and image quality assessment study.

BACKGROUND: Iterative reconstruction (IR) algorithms improve image quality and allow for radiation dose reduction in CT. Dose reduction is particularly challenging in brain CT where good low-contrast resolution is essential. Ideally, evaluation of image quality combines objective measurements and subjective assessment of clinically relevant quality criteria. Subjective assessment is associated with various pitfalls and biases. PURPOSE: To evaluate the potential of the hybrid IR algorithm iDOSE(4) to preserve image quality in phantom and clinical brain CT acquired with 30% reduced radiation dose, and to discuss the image quality assessment methods. MATERIAL AND METHODS: Forty patients underwent two consecutive brain CTs with normal radiation dose (ND) and 30% reduced dose (RD). Both ND and RD were reconstructed with FBP. In addition the reduced dose CTs were reconstructed with two levels of IR (ID2, ID4). Three image quality criteria (grey-white-matter discrimination, basal ganglia delineation, general image quality) were graded and ranked by six neuroradiologists. Noise levels and contrast-to-noise ratios (CNR) were measured in clinical data. Noise, signal-to-noise ratio (SNR), spatial resolution, and noise-power spectrum (NPS) were also assessed in a phantom. RESULTS: Subjective image quality was considered adequate for clinical use for all reconstructions, graded good or excellent in 93% of cases for ND, 83% for ID4, 79% for ID2, and 67% for RD. For all quality parameters, ID4 and ID2 were graded better than RD (P < 0.0055 and P < 0.035), but worse than ND (P < 0.001). In clinical images, objective measurements showed lower noise and significantly higher CNR in ID4 compared with ND and RD (P < 0.001). CNR was similar for ID2 and ND. In the phantom, IR reduced noise while maintaining spatial resolution and NPS. CONCLUSION: The IR algorithm improves image quality of reduced dose CTs and consistently delivers sufficient image quality for clinical purposes. Pitfalls related to subjective assessment can be addressed with careful study design.

fMRI memory assessment in healthy subjects: a new approach to view lateralization data at an individual level.

We present a comprehensive and clinically applicable fMRI test-including both a verbal and a visuospatial task-for assessment of hemispheric specific memory in the medial temporal lobe (MTL). fMRI data was collected from 15 healthy right-handed volunteers. Whole-brain activation was analyzed as well as activation in two regions of interest: the MTL and the anterior speech area. Laterality indices (LI) and LI-curves were calculated using the LI toolbox of Wilke and Lidzba, 2007. The fMRI paradigms successfully visualized memory-related activity in the MTL, the verbal memory measure also provided information of language lateralization. Eleven subjects showed left lateralized verbal encoding in the MTL, visuospatial memory activation was divided equally between left and right, and 14/15 subjects had left lateralized language. Lateralization data at the group level were consistent with previous studies, but a variety of activation effects were found at the individual level indicating differences in strategy during verbal and visuospatial processing. Further studies using the presented method are needed to determine its clinical usefulness.

Dose-fractionated radioimmunotherapy in non-Hodgkin's lymphoma using DOTA-conjugated, 90Y-radiolabeled, humanized anti-CD22 monoclonal antibody, epratuzumab.

PURPOSE: Fractionated radioimmunotherapy may improve therapeutic outcome by decreasing heterogeneity of the dose delivered to the tumor and by decreasing hematologic toxicity, thereby allowing an increased amount of radionuclide to be administered. Because humanized anti-CD22 epratuzumab can be given repeatedly, a single-center study was conducted to establish the feasibility, safety, optimal dosing, and preliminary efficacy of weekly administrations of 90Y-labeled 1,4,7,10-tetra-azacyclodecane-N,N',N'',N'''-tetraacetic acid-conjugated epratuzumab. EXPERIMENTAL DESIGN: Cohorts of three to six patients with B-cell lymphoma received 185 MBq/m2 [90Y]epratuzumab with unconjugated epratuzumab (total protein dose 1.5 mg/kg) once weekly for two to four infusions, with [(111)In]epratuzumab coadministered at first infusion for scintigraphic imaging and dosimetry. RESULTS: Sixteen patients received treatment without significant infusional reactions. The overall objective response rate was 62% (95% confidence interval, 39-86%) in both indolent (75%) and aggressive disease (50%). Complete responses (CR/CRu) occurred in 25% of patients and were durable (event-free survival, 14-41 months). Two patients receiving four infusions had hematologic dose-limiting toxicity. Serum epratuzumab levels increased with each weekly dose. Of 13 patients with tumor cell CD22 expression determined by flow cytometry, seven of eight with strongly positive results had objective responses, versus one of five with negative or weakly positive results (P = 0.032). CONCLUSIONS: Radioimmunotherapy with weekly 185 MBq/m2 [90Y]epratuzumab achieved a high objective response rate (62%) across lymphoma subtypes, including durable CRs. The findings that three weekly infusions (555 MBq/m2, total dose) can be administered safely with only minor toxicity, that antibody levels increased during treatment weeks, and that therapeutic response predominantly occurs in patients with unequivocal CD22 tumor expression provide guidance for future studies.

Change in tumor-absorbed dose due to decrease in mass during fractionated radioimmunotherapy in lymphoma patients.

PURPOSE: In radionuclide therapy, cumulated activity and tumor volume/mass are the principal quantities necessary for the calculation of the absorbed dose to the tumor. When treating a fast-responding macroscopic tumor, there may be a decrease in its mass during therapy, and at any given uptake, this will result in an increase in the absorbed dose. The purpose of the present work is to demonstrate the limitations in current internal dosimetry protocols that assume a fixed tumor mass in lymphoma patients, using a fractionated radioimmunotherapy schedule and using a single infusion. EXPERIMENTAL DESIGN: Patients with B-cell lymphoma were treated with (90)Y-labeled epratuzumab (Immunomedics, Inc., Morris Plains, NJ) using a weekly dose-fractionation schedule for 2-4 weeks. They received either 185 MBq/m(2) (5 mCi/m(2)) in each infusion or, if they had a history of high-dose chemotherapy with stem cell rescue, 92.5 MBq/m(2) (2.5 mCi/m(2)) in each infusion. All patients received (111)In-labeled epratuzumab with the first infusion to verify tumor targeting and for dosimetry. The present report is based on three selected patients, in whom repeated assessments of tumor mass were possible. In two patients, (111)In-labeled epratuzumab was also coadministered with one of the subsequent treatments, i.e. during the second and third of two and three scheduled infusions. The tumor volume was determined from computer tomography images obtained before the first infusion and on different times after the infusion. An exponential equation was fitted to the decreasing mass of the tumor and implemented in the calculation of the absorbed dose. For comparison, the absorbed dose to the tumor was also calculated using the tumor volume determined from the baseline pretreatment computer tomography examination. RESULTS: The tumor volume for the patients changed rapidly. For one patient, the pretreatment volume was 19.5 ml, and for another patient, it was 840 ml. For these two patients, the ratio of tumor volume at the beginning of therapy compared with that after 8 days and 14 days of therapy was 0.7 and 0.8, respectively. This rapid decrease in volume and subsequent mass reduction result in an increase of mean absorbed dose to the tumor of as much as a factor of 1.75. CONCLUSIONS: At a given activity uptake, a decrease in tumor mass during therapy will significantly increase the calculated absorbed dose. Taking the change in tumor mass into account when calculating absorbed dose may improve the correlation between the mean absorbed dose to the tumor and the response to the therapy.