Determinants of Symptomatic Intracranial Progression After an Initial Stereotactic Radiosurgery Course.

Purpose: Clinical and imaging surveillance of patients with brain metastases is important after stereotactic radiosurgery (SRS) because many will experience intracranial progression (ITCP) requiring multidisciplinary management. The prognostic significance of neurologic symptoms at the time of ITCP is poorly understood. Methods and Materials: This was a multi-institutional, retrospective cohort study from 2015 to 2020, including all patients with brain metastases completing an initial course of SRS. The primary outcome was overall survival (OS) by presence of neurologic symptoms at ITCP. OS, freedom from ITCP (FF-ITCP), and freedom from symptomatic ITCP (FF-SITCP) were assessed via Kaplan-Meier method. Cox proportional hazard models tested parameters impacting FF-ITCP and FF-SITCP. Results: Among 1383 patients, median age was 63.4 years, 55% were female, and common primaries were non-small cell lung (49%), breast (15%), and melanoma (9%). At a median follow-up of 8.72 months, asymptomatic and symptomatic ITCP were observed in 504 (36%) and 194 (14%) patients, respectively. The majority of ITCP were distant ITCP (79.5%). OS was worse with SITCP (median, 10.2 vs 17.9 months, P < .001). SITCP was associated with clinical factors including total treatment volume (P = .012), melanoma histology (P = .001), prior whole brain radiation therapy (P = .003), number of brain metastases (P < .001), interval of 1 to 2 years from primary and brain metastasis diagnosis (P = .012), controlled extracranial disease (P = .042), and receipt of pre-SRS chemotherapy (P = .015). Patients who were younger and received post-SRS chemotherapy (P = .001), immunotherapy (P < .001), and targeted or small-molecule inhibitor therapy (P < .026) had better FF-SITCP. Conclusions: In this cohort study of patients with brain metastases completing SRS, neurologic symptoms at ITCP is prognostic for OS. This data informs post-SRS surveillance in clinical practice as well as future prospective studies needed in the modern management of brain metastases.

Intracranial and Extracranial Progression and Their Correlation With Overall Survival After Stereotactic Radiosurgery in a Multi-institutional Cohort With Brain Metastases.

Importance: Clinical trials for metastatic malignant neoplasms are increasingly being extended to patients with brain metastases. Despite the preeminence of progression-free survival (PFS) as a primary oncologic end point, the correlation of intracranial progression (ICP) and extracranial progression (ECP) events with overall survival (OS) is poorly understood for patients with brain metastases following stereotactic radiosurgery (SRS). Objective: To determine the correlation of ICP and ECP with OS among patients with brain metastases completing an initial SRS course. Design, Setting, and Participants: This multi-institutional retrospective cohort study was conducted from January 1, 2015, to December 31, 2020. We included patients who completed an initial course of SRS for brain metastases during the study period, including receipt of single and/or multifraction SRS, prior whole-brain radiotherapy, and brain metastasis resection. Data analysis was performed on November 15, 2022. Exposures: Non-OS end points included intracranial PFS, extracranial PFS, PFS, time to ICP, time to ECP, and any time to progression. Progression events were radiologically defined, incorporating multidisciplinary clinical consensus. Main Outcomes and Measures: The primary outcome was correlation of surrogate end points to OS. Clinical end points were estimated from time of SRS completion via the Kaplan-Meier method, while end-point correlation to OS was measured using normal scores rank correlation with the iterative multiple imputation approach. Results: This study included 1383 patients, with a mean age of 63.1 years (range, 20.9-92.8 years) and a median follow-up of 8.72 months (IQR, 3.25-19.68 months). The majority of participants were White (1032 [75%]), and more than half (758 [55%]) were women. Common primary tumor sites included the lung (757 [55%]), breast (203 [15%]), and skin (melanoma; 100 [7%]). Intracranial progression was observed in 698 patients (50%), preceding 492 of 1000 observed deaths (49%). Extracranial progression was observed in 800 patients (58%), preceding 627 of 1000 observed deaths (63%). Irrespective of deaths, 482 patients (35%) experienced both ICP and ECP, 534 (39%) experienced ICP (216 [16%]) or ECP (318 [23%]), and 367 (27%) experienced neither. The median OS was 9.93 months (95% CI, 9.08-11.05 months). Intracranial PFS had the highest correlation with OS (ρ = 0.84 [95% CI, 0.82-0.85]; median, 4.39 months [95% CI, 4.02-4.92 months]). Time to ICP had the lowest correlation with OS (ρ = 0.42 [95% CI, 0.34-0.50]) and the longest median time to event (median, 8.76 months [95% CI, 7.70-9.48 months]). Across specific primary tumor types, correlations of intracranial PFS and extracranial PFS with OS were consistently high despite corresponding differences in median outcome durations. Conclusions and Relevance: The results of this cohort study of patients with brain metastases completing SRS suggest that intracranial PFS, extracranial PFS, and PFS had the highest correlations with OS and time to ICP had the lowest correlation with OS. These data may inform future patient inclusion and end-point selection for clinical trials.

Intra-operative Radiation Therapy for Colorectal or Anal Cancer at Risk for Margin-Positive Resection: Initial Results of a Single-Institution Registry.

PURPOSE: Pelvic recurrence of rectal or anal cancers is associated with considerable morbidity and mortality. We report our initial experience with an aggressive intra-operative radiotherapy (IORT) program. METHODS: Patients with locally advanced or recurrent rectal or anal cancers considered to have a high likelihood of R1 or R2 resection after multi-disciplinary review underwent surgical excision and IORT using a high-dose-rate afterloader (Ir-192) and HAM applicator. Endpoints included local or distant recurrence, and acute and late toxicity graded using the American College of Surgeons (ACS) NSQIP and the LENT-SOMA scale. RESULTS: Twenty-one patients, largely with prior history of both pelvic external beam radiotherapy (EBRT, median 50.4 Gy) and surgical resection, underwent excision with IORT (median dose 12.5 Gy, range 10-15). Median follow-up was 20 months. Twelve (57%) patients had failure at the IORT site. Freedom from failure (FFF) within the IORT field was associated with resection status (FFF at 1 year 75% for R0 vs 15% for R1/2, p = 0.0065) but not re-irradiation EBRT or IORT dose (p > 0.05). Twelve, 5, and 13 patients experienced local, regional, and distant failure, respectively; 3 (14%) patients were disease-free at last follow-up. The most frequent acute toxicity was sepsis/abscess (24%). One patient (5%) required a ureteral stent; no patients developed neuropathy attributable to IORT. CONCLUSIONS: In patients treated with excision and IORT for locally recurrent cancer, R0 resection is a critical determinant of local control. For patients with R1/2 resection, poor disease-free outcomes warrant consideration of a different treatment strategy.

Prognostic Model for Intracranial Progression after Stereotactic Radiosurgery: A Multicenter Validation Study.

Stereotactic radiosurgery (SRS) is a standard of care for many patients with brain metastases. To optimize post-SRS surveillance, this study aimed to validate a previously published nomogram predicting post-SRS intracranial progression (IP). We identified consecutive patients completing an initial course of SRS across two institutions between July 2017 and December 2020. Patients were classified as low- or high-risk for post-SRS IP per a previously published nomogram. Overall survival (OS) and freedom from IP (FFIP) were assessed via the Kaplan−Meier method. Assessment of parameters impacting FFIP was performed with univariable and multivariable Cox proportional hazard models. Among 890 patients, median follow-up was 9.8 months (95% CI 9.1−11.2 months). In total, 47% had NSCLC primary tumors, and 47% had oligometastatic disease (defined as ≤5 metastastic foci) at the time of SRS. Per the IP nomogram, 53% of patients were deemed high-risk. For low- and high-risk patients, median FFIP was 13.9 months (95% CI 11.1−17.1 months) and 7.6 months (95% CI 6.4−9.3 months), respectively, and FFIP was superior in low-risk patients (p < 0.0001). This large multisite BM cohort supports the use of an IP nomogram as a quick and simple means of stratifying patients into low- and high-risk groups for post-SRS IP.

Test-retest and repositioning effects of white matter microstructure measurements in selected white matter tracts.

We used intra-class effect decomposition (ICED) to evaluate the reliability of myelin water fraction (MWF) and geometric mean T2 relaxation time (geomT2IEW) estimated from a multi-echo MRI sequence. Our evaluation addressed test-retest reliability, with and without participant re-positioning, for seven commonly assessed white matter tracts: anterior and posterior limbs of the internal capsule, dorsal and ventral branches of the cingulum, the inferior fronto-occipital fasciculus, the superior longitudinal fasciculus, and the fornix in 20 healthy adults. We acquired two back-to-back scans in a single session, and a third after a break and repositioning the participant in the scanner. For both indices and for all white matter tracts assessed, reliability for an immediate retest, and after the participant's repositioning in the scanner was high. Variance partitioning revealed that in addition to measurement noise, which was significant in all regions, repositioning contributed to unreliability mainly in longer association fibers. Hemispheric location did not significantly contribute to unreliability in any region of interest (ROI). Thus, despite non-negligible error of measurement, for all ROIs, MWF and geomT2IEW have good test-retest reliability, regardless of the hemispheric location and are, therefore, suitable for longitudinal investigations in healthy adults.

Microstructure of Human Corpus Callosum across the Lifespan: Regional Variations in Axon Caliber, Density, and Myelin Content.

The myeloarchitecture of the corpus callosum (CC) is characterized as a mosaic of distinct differences in fiber density of small- and large-diameter axons along the anterior-posterior axis; however, regional and age differences across the lifespan are not fully understood. Using multiecho T2 magnetic resonance imaging combined with multi-T2 fitting, the myelin water fraction (MWF) and geometric-mean of the intra-/extracellular water T2 (geomT2IEW) in 395 individuals (7-85 years; 41% males) were examined. The approach was validated where regional patterns along the CC closely resembled the histology; MWF matched mean axon diameter and geomT2IEW mirrored the density of large-caliber axons. Across the lifespan, MWF exhibited a quadratic association with age in all 10 CC regions with evidence of a positive linear MWF-age relationship among younger participants and minimal age differences in the remainder of the lifespan. Regarding geomT2IEW, a significant linear age × region interaction reflected positive linear age dependence mostly prominent in the regions with the highest density of small-caliber fibers-genu and splenium. In all, these two indicators characterize distinct attributes that are consistent with histology, which is a first. In addition, these results conform to rapid developmental progression of CC myelination leveling in middle age as well as age-related degradation of axon sheaths in older adults.

COVID-19 infection presenting with acute epiglottitis.

In this case report, we present a novel presentation of acute epiglottitis in a patient with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) who presented to the emergency room in extremis and respiratory failure requiring emergent cricothyrotomy. Epiglottitis has become less common since the introduction and widespread use of the Haemophilus influenzae type B (Hib) vaccine. This reduction in cases has shifted demographics of the disease from the pediatric population towards adults with comorbid conditions. Interestingly there is a high degree of overlap between many of the comorbidities between epiglottitis and COVID-19. The novel severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), also referred to as coronavirus disease 19 (COVID-19), has been reported to affect the gastrointestinal tract and neural tissue and has been implicated in necrotizing encephalitis. We report the first known case of the novel SARS-CoV-2 virus presenting with acute epiglottitis.

White-matter microstructural properties of the corpus callosum: test-retest and repositioning effects in two parcellation schemes.

We investigated test-retest reliability of two MRI-derived indices of white-matter microstructural properties in the human corpus callosum (CC): myelin water fraction (MWF) and geometric mean T2 relaxation time of intra/extracellular water (geomT2IEW), using a 3D gradient and multi spin-echo sequence in 20 healthy adults (aged 24-69 years, 10 men). For each person, we acquired two back-to-back acquisitions in a single session, and the third after a break and repositioning the participant in the scanner. We assessed the contribution of session-related variance to reliability, using intra-class effect decomposition (ICED) while comparing two CC parcellation schemes that divided the CC into five and ten regions. We found high construct-level reliability of MWF and geomT2IEW in all regions of both schemes, except the posterior body-a slender region with a smaller number of large myelinated fibers. Only in that region, we observed significant session-specific variance in the MWF, interpreted as an effect of repositioning in the scanner. The geomT2IEW demonstrated higher reliability than MWF across both parcellation schemes and all CC regions. Thus, in both CC parcellation approaches, MWF and geomT2IEW have good test-retest reliability and are, therefore, suitable for longitudinal investigations in healthy adults. However, the five-region scheme appears more appropriate for MWF, whereas both schemes are suitable for geomT2IEW studies. Given the lower reliability in the posterior body, which may reflect sensitivity to the repositioning of the participant in the scanner, caution should be exercised in interpreting differential findings in that region.

Sellar Atypical Teratoid/Rhabdoid Tumor Presenting with Subarachnoid and Intraventricular Hemorrhage.

BACKGROUND: Atypical teratoid/rhabdoid tumors (ATRT) are uncommon malignancies of the central nervous system and are often difficult to distinguish radiographically and pathologically from other common tumors. We present the first case of sellar ATRT presenting with subarachnoid hemorrhage (SAH) and intraventricular hemorrhage (IVH). CASE DESCRIPTION: A 62-year-old woman, who had presented with symptoms of headache, diabetes insipidus, hypothyroidism, and seizures, was found to have a sellar tumor with hemorrhagic transformation. Surgical resection was performed. The pathological examination findings were consistent with ATRT. Despite early surgical intervention, she later died before starting craniospinal radiotherapy and chemotherapy. CONCLUSION: To the best of our knowledge, although known to present with intratumoral hemorrhage, to date, no cases of sellar ATRT have presented with SAH or IVH have been reported. Considering our finding that ATRT can present with SAH and IVH, establishing the correct diagnosis using radiographic imaging, gender, pathological findings, and molecular markers is paramount for speedy treatment and management.

Automated Voxel Placement: A Linux-based Suite of Tools for Accurate and Reliable Single Voxel Coregistration.

BACKGROUND: Single-voxel proton magnetic resonance spectroscopy (1H MRS) is a powerful technique for studying in vivo neurochemistry, but has an often-overlooked source of error variance: inconsistent voxel placement between scans. We developed and evaluated an Automated Voxel Placement (AVP) procedure for accurate and reliable 1H MRS voxel prescription. AVP is a suite of Linux-based programs that facilitate automated template-driven single-voxel coregistration. METHODS: Three studies were conducted to evaluate AVP for prescription of one voxel: left dorsolateral prefrontal cortex. First, we evaluated how robust AVP was to 'extreme' subject head positions/angulations within the scanner head coil. Second, subjects (N = 13) were recruited and underwent MR scans. Manual voxel prescription (n = 5) was contrasted with AVP (n = 8). A subset of AVP subjects (n = 4) completed a second scan. Third, ongoing data collection (n = 16; recruited for a separate study) helped evaluate AVP. Voxel placement accuracy was quantified as 3D geometric voxel overlap percentage between each subject's voxel and the template voxel. Reliability was quantified as 3D geometric voxel overlap percentage across subjects at each time point and within subjects who completed two scans. RESULTS: Results demonstrated that AVP was robust to 'extreme' head positions (97.5% - 97.9% overlap with the template voxel). AVP was significantly more accurate (baseline and follow-up: 96.2% ± 3.0% and 97.6% ± 1.4% overlap) than manual voxel placement (67.7% ± 22.8% overlap; ps<.05). AVP was reliable within- (97.9%) and between-subjects (94.2% and 97.2% overlap; baseline and follow-up; respectively). Finally, ongoing data collection indicates AVP is accurate (96.0%). CONCLUSION: These pilot studies demonstrated that AVP was feasible, accurate, and reliable method for automated single voxel coregistration.

Functional dynamics of hippocampal glutamate during associative learning assessed with in vivo 1H functional magnetic resonance spectroscopy.

fMRI has provided vibrant characterization of regional and network responses associated with associative learning and memory; however, their relationship to functional neurochemistry is unclear. Here, we introduce a novel application of in vivo proton functional magnetic resonance spectroscopy (1H fMRS) to investigate the dynamics of hippocampal glutamate during paired-associated learning and memory in healthy young adults. We show that the temporal dynamics of glutamate differed significantly during processes of memory consolidation and retrieval. Moreover, learning proficiency was predictive of the temporal dynamics of glutamate such that fast learners were characterized by a significant increase in glutamate levels early in learning, whereas this increase was only observed later in slow learners. The observed functional dynamics of glutamate provides a novel in vivo marker of brain function. Previously demonstrated N-methyl-D-aspartate (NMDA) receptor mediated synaptic plasticity during associative memory formation may be expressed in glutamate dynamics, which the novel application of 1H MRS is sensitive to. The novel application of 1H fMRS can provide highly innovative vistas for characterizing brain function in vivo, with significant implications for studying glutamatergic neurotransmission in health and disorders such as schizophrenia.

Age differences in arterial and venous extra-cerebral blood flow in healthy adults: contributions of vascular risk factors and genetic variants.

Sufficient cerebral blood flow (CBF) and venous drainage are critical for normal brain function, and their alterations can affect brain aging. However, to date, most studies focused on arterial CBF (inflow) with little attention paid to the age differences in venous outflow. We measured extra-cerebral arterial and venous blood flow rates with phase-contrast MRI and assessed the influence of vascular risk factors and genetic polymorphisms (ACE insertion/deletion, COMT val158met, and APOEε4) in 73 adults (age 18-74 years). Advanced age, elevated vascular risk, ACE Deletion, and COMT met alleles were linked to lower in- and outflow, with no effects of APOE ε4 noted. Lower age-related CBF rate was unrelated to brain volume and was observed only in val homozygotes of COMTval158met. Thus, in a disease-free population, age differences in CBF may be notable only in persons with high vascular risk and carriers of genetic variants associated with vasoconstriction and lower dopamine availability. It remains to be established if treatments targeting alleviation of the mutable factors can improve the course of cerebrovascular aging in spite of the immutable genetic influence.

Test-retest reliability and concurrent validity of in vivo myelin content indices: Myelin water fraction and calibrated T1 w/T2 w image ratio.

In an age-heterogeneous sample of healthy adults, we examined test-retest reliability (with and without participant repositioning) of two popular MRI methods of estimating myelin content: modeling the short spin-spin (T2 ) relaxation component of multi-echo imaging data and computing the ratio of T1 -weighted and T2 -weighted images (T1 w/T2 w). Taking the myelin water fraction (MWF) index of myelin content derived from the multi-component T2 relaxation data as a standard, we evaluate the concurrent and differential validity of T1 w/T2 w ratio images. The results revealed high reliability of MWF and T1 w/T2 w ratio. However, we found significant correlations of low to moderate magnitude between MWF and the T1 w/T2 w ratio in only two of six examined regions of the cerebral white matter. Notably, significant correlations of the same or greater magnitude were observed for T1 w/T2 w ratio and the intermediate T2 relaxation time constant, which is believed to reflect differences in the mobility of water between the intracellular and extracellular compartments. We conclude that although both methods are highly reliable and thus well-suited for longitudinal studies, T1 w/T2 w ratio has low criterion validity and may be not an optimal index of subcortical myelin content. Hum Brain Mapp 38:1780-1790, 2017. © 2017 Wiley Periodicals, Inc.

Adult age differences in subcortical myelin content are consistent with protracted myelination and unrelated to diffusion tensor imaging indices.

Post mortem studies suggest protracted myelination of subcortical white matter into the middle age followed by gradual decline in the late adulthood. To date, however, establishing the proposed inverted-U pattern of age-myelin association proved difficult, as the most common method of investigating white matter, diffusion tensor imaging (DTI), usually reveals only linear associations between DTI indices and age among healthy adults. Here we use a novel method of estimating Myelin Water Fraction (MWF) based on modeling the short spin-spin (T2) relaxation component from multi-echo T2 relaxation imaging data and assess subcortical myelin content within six white matter tracts in a sample of healthy adults (N=61, age 18-84 years). Myelin content evidenced a quadratic relationship with age, in accord with the pattern observed postmortem studies. In contrast, DTI-derived indices that are frequently cited as proxies for myelination, fractional anisotropy (FA) and radial diffusivity (RD), exhibited linear or null relationships with age. Furthermore, the magnitude of age differences in MWF varied across the white matter tracts. Myelin content estimated by MWF was unrelated to FA and correlated with RD only in the splenium. These findings are consistent with the notion that myelination continues throughout the young adulthood into the middle age. The results demonstrate that single-tensor DTI cannot serve as a source of specific proxies for myelination of white matter tracts.