Laser interstitial thermal therapy (LITT) for intracranial lesions: a single-institutional series, outcomes, and review of the literature.

INTRODUCTION: Laser interstitial thermal therapy (LITT) is a minimally invasive treatment method in managing primary brain neoplasms, brain metastases, radiation necrosis, and epileptogenic lesions, many of which are located in operative corridors that would be difficult to address. Although the use of lasers is not a new concept in neurosurgery, advances in technology have enabled surgeons to perform laser treatment with the aid of real-time MRI thermography as a guide. In this report, we present our institutional series and outcomes of patients treated with LITT. METHODS: We retrospectively evaluated 19 patients (age range, 28-77 years) who underwent LITT at one or more targets from 2015 to 2019. Primary endpoint observed was mean progression free survival (PFS) and overall survival (OS). RESULTS: Seven patients with glial neoplasms and 12 patients with metastatic disease were reviewed. Average hospitalization was 2.4 days. Median PFS was 7 and 4 months in the metastatic group and primary glial neoplasm group, respectively (p = 0.01). Median OS from time of diagnosis was 41 and 32 months (p = 0.02) and median OS after LITT therapy was 25 and 24 months (p = 0.02) for the metastatic and primary glial neoplasm groups, respectively. One patient experienced immediate post-procedural morbidity secondary to increased intracerebral edema peri-lesionally while one patient experienced post-operative mortality and expired secondary to hemorrhage 1-month post-procedure. Median follow-up was 10 months. CONCLUSION: Laser interstitial thermal therapy (LITT) is a safe, minimally invasive treatment method that provides surgeons with cytoreductive techniques to treat neurosurgical conditions. Both PFS and OS appear to be more favorable after LITT in patients with metastatic disease. In properly selected patients, this modality offers improved survival outcomes in conjunction with other salvage therapies.

Ccne1 Overexpression Causes Chromosome Instability in Liver Cells and Liver Tumor Development in Mice.

BACKGROUND & AIMS: The CCNE1 locus, which encodes cyclin E1, is amplified in many types of cancer cells and is activated in hepatocellular carcinomas (HCCs) from patients infected with hepatitis B virus or adeno-associated virus type 2, due to integration of the virus nearby. We investigated cell-cycle and oncogenic effects of cyclin E1 overexpression in tissues of mice. METHODS: We generated mice with doxycycline-inducible expression of Ccne1 (Ccne1T mice) and activated overexpression of cyclin E1 from age 3 weeks onward. At 14 months of age, livers were collected from mice that overexpress cyclin E1 and nontransgenic mice (controls) and analyzed for tumor burden and by histology. Mouse embryonic fibroblasts (MEFs) and hepatocytes from Ccne1T and control mice were analyzed to determine the extent to which cyclin E1 overexpression perturbs S-phase entry, DNA replication, and numbers and structures of chromosomes. Tissues from 4-month-old Ccne1T and control mice (at that age were free of tumors) were analyzed for chromosome alterations, to investigate the mechanisms by which cyclin E1 predisposes hepatocytes to transformation. RESULTS: Ccne1T mice developed more hepatocellular adenomas and HCCs than control mice. Tumors developed only in livers of Ccne1T mice, despite high levels of cyclin E1 in other tissues. Ccne1T MEFs had defects that promoted chromosome missegregation and aneuploidy, including incomplete replication of DNA, centrosome amplification, and formation of nonperpendicular mitotic spindles. Whereas Ccne1T mice accumulated near-diploid aneuploid cells in multiple tissues and organs, polyploidization was observed only in hepatocytes, with losses and gains of whole chromosomes, DNA damage, and oxidative stress. CONCLUSIONS: Livers, but not other tissues of mice with inducible overexpression of cyclin E1, develop tumors. More hepatocytes from the cyclin E1-overexpressing mice were polyploid than from control mice, and had losses or gains of whole chromosomes, DNA damage, and oxidative stress; all of these have been observed in human HCC cells. The increased risk of HCC in patients with hepatitis B virus or adeno-associated virus type 2 infection might involve activation of cyclin E1 and its effects on chromosomes and genomes of liver cells.

Calcification in Human Intracranial Aneurysms Is Highly Prevalent and Displays Both Atherosclerotic and Nonatherosclerotic Types.

OBJECTIVE: Although the clinical and biological importance of calcification is well recognized for the extracerebral vasculature, its role in cerebral vascular disease, particularly, intracranial aneurysms (IAs), remains poorly understood. Extracerebrally, 2 distinct mechanisms drive calcification, a nonatherosclerotic, rapid mineralization in the media and a slower, inflammation driven, atherosclerotic mechanism in the intima. This study aims to determine the prevalence, distribution, and type (atherosclerotic, nonatherosclerotic) of calcification in IAs and assess differences in occurrence between ruptured and unruptured IAs. Approach and Results: Sixty-five 65 IA specimens (48 unruptured, 17 ruptured) were resected perioperatively. Calcification and lipid pools were analyzed nondestructively in intact samples using high resolution (0.35 µm) microcomputed tomography. Calcification is highly prevalent (78%) appearing as micro (<500 µm), meso (500 µm-1 mm), and macro (>1 mm) calcifications. Calcification manifests in IAs as both nonatherosclerotic (calcification distinct from lipid pools) and atherosclerotic (calcification in the presence of lipid pools) with 3 wall types: Type I-only calcification, no lipid pools (20/51, 39%), Type II-calcification and lipid pools, not colocalized (19/51, 37%), Type III-calcification colocalized with lipid pools (12/51, 24%). Ruptured IAs either had no calcifications or had nonatherosclerotic micro- or meso-calcifications (Type I or II), without macro-calcifications. CONCLUSIONS: Calcification in IAs is substantially more prevalent than previously reported and presents as both nonatherosclerotic and atherosclerotic types. Notably, ruptured aneurysms had only nonatherosclerotic calcification, had significantly lower calcification fraction, and did not contain macrocalcifications. Improved understanding of the role of calcification in IA pathology should lead to new therapeutic targets.

Spinal cord atrophy as a primary outcome measure in phase II trials of progressive multiple sclerosis.

OBJECTIVES: To measure the development of spinal cord (SC) atrophy over 1 year in patients with progressive multiple sclerosis (PMS) and determine the sample sizes required to demonstrate a reduction in spinal cord cross-sectional area (SC-CSA) as an outcome measure in clinical trials. METHODS: In total, 44 PMS patients (26 primary progressive multiple sclerosis (PPMS), 18 secondary progressive multiple sclerosis (SPMS)) and 29 healthy controls (HCs) were studied at baseline and 12 months. SC-CSA was measured using the three-dimensional (3D) fast field echo sequences acquired at 3T and the active surface model. Multiple linear regressions were used to investigate changes in imaging measurements. RESULTS: PPMS patients had shorter disease duration, lower Expanded Disability Status Scale (EDSS) and larger SC-CSA than SPMS patients. All patients together showed a significantly greater decrease in percentage SC-CSA change than HCs, which was driven by the PPMS. All patients deteriorated over 1 year, but no association was found between percentage SC-CSA change and clinical changes. The sample size per arm required to detect a 50% treatment effect over 1 year, at 80% power, was 57 for PPMS and 546 for SPMS. CONCLUSION: SC-CSA may become an outcome measure in trials of PPMS patients, when they are at an early stage of the disease, have moderate disability and modest SC atrophy.

Evidence for early neurodegeneration in the cervical cord of patients with primary progressive multiple sclerosis.

Spinal neurodegeneration is an important determinant of disability progression in patients with primary progressive multiple sclerosis. Advanced imaging techniques, such as single-voxel (1)H-magnetic resonance spectroscopy and q-space imaging, have increased pathological specificity for neurodegeneration, but are challenging to implement in the spinal cord and have yet to be applied in early primary progressive multiple sclerosis. By combining these imaging techniques with new clinical measures, which reflect spinal cord pathology more closely than conventional clinical tests, we explored the potential for spinal magnetic resonance spectroscopy and q-space imaging to detect early spinal neurodegeneration that may be responsible for clinical disability. Data from 21 patients with primary progressive multiple sclerosis within 6 years of disease onset, and 24 control subjects were analysed. Patients were clinically assessed on grip strength, vibration perception thresholds and postural stability, in addition to the Expanded Disability Status Scale, Nine Hole Peg Test, Timed 25-Foot Walk Test, Multiple Sclerosis Walking Scale-12, and Modified Ashworth Scale. All subjects underwent magnetic resonance spectroscopy and q-space imaging of the cervical cord and conventional brain and spinal magnetic resonance imaging at 3 T. Multivariate analyses and multiple regression models were used to assess the differences in imaging measures between groups and the relationship between magnetic resonance imaging measures and clinical scores, correcting for age, gender, spinal cord cross-sectional area, brain T2 lesion volume, and brain white matter and grey matter volume fractions. Although patients did not show significant cord atrophy when compared with healthy controls, they had significantly lower total N-acetyl-aspartate (mean 4.01 versus 5.31 mmol/l, P = 0.020) and glutamate-glutamine (mean 4.65 versus 5.93 mmol/l, P = 0.043) than controls. Patients showed an increase in q-space imaging-derived indices of perpendicular diffusivity in both the whole cord and major columns compared with controls (P < 0.05 for all indices). Lower total N-acetyl-aspartate was associated with higher disability, as assessed by the Expanded Disability Status Scale (coefficient = -0.41, 0.01 < P < 0.05), Modified Ashworth Scale (coefficient = -3.78, 0.01 < P < 0.05), vibration perception thresholds (coefficient = -4.37, P = 0.021) and postural sway (P < 0.001). Lower glutamate-glutamine predicted increased postural sway (P = 0.017). Increased perpendicular diffusivity in the whole cord and columns was associated with increased scores on the Modified Ashworth Scale, vibration perception thresholds and postural sway (P < 0.05 in all cases). These imaging findings indicate reduced structural integrity of neurons, demyelination, and abnormalities in the glutamatergic pathways in the cervical cord of early primary progressive multiple sclerosis, in the absence of extensive spinal cord atrophy. The observed relationship between imaging measures and disability suggests that early spinal neurodegeneration may underlie clinical impairment, and should be targeted in future clinical trials with neuroprotective agents to prevent the development of progressive disability.

Twist1 suppresses senescence programs and thereby accelerates and maintains mutant Kras-induced lung tumorigenesis.

KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with Kras(G12D) to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy.

Functional correlates of cognitive dysfunction in multiple sclerosis: A multicenter fMRI Study.

In this multicenter study, we applied functional magnetic resonance imaging (fMRI) to define the functional correlates of cognitive dysfunction in patients with multiple sclerosis (MS). fMRI scans during the performance of the N-back task were acquired from 42 right-handed relapsing remitting (RR) MS patients and 52 sex-matched right-handed healthy controls, studied at six European sites using 3.0 Tesla scanners. Patients with at least two abnormal (<2 standard deviations from the normative values) neuropsychological tests at a standardized evaluation were considered cognitively impaired (CI). FMRI data were analyzed using the SPM8 software, modeling regions showing load-dependent activations/deactivations with increasing task difficulty. Twenty (47%) MS patients were CI. During the N-back load condition, compared to controls and CI patients, cognitively preserved (CP) patients had increased recruitment of the right dorsolateral prefrontal cortex. As a function of increasing task difficulty, CI MS patients had reduced activations of several areas located in the fronto-parieto-temporal lobes as well as reduced deactivations of regions which are part of the default mode network compared to the other two groups. Significant correlations were found between abnormal fMRI patterns of activations and deactivations and behavioral measures, cognitive performance, and brain T2 and T1 lesion volumes. This multicenter study supports the theory that a preserved fMRI activity of the frontal lobe is associated with a better cognitive profile in MS patients. It also indicates the feasibility of fMRI to monitor disease evolution and treatment effects in future studies.

Improved MRI quantification of spinal cord atrophy in multiple sclerosis.

PURPOSE: To identify an improved method for measuring spinal cord cross-sectional area (CSA) using magnetic resonance imaging (MRI) in multiple sclerosis (MS). MATERIALS AND METHODS: MRI was performed on 15 controls and 15 MS patients and repeated in nine controls and nine patients after 6 months. At this timepoint, an additional scan was acquired to evaluate scan-rescan reproducibility. Two sequences were acquired in the cervical cord: 3D phase sensitive inversion recovery (PSIR) and 3D magnetization prepared rapid acquisition T1-weighted gradient echo. CSA was outlined at C2-C3 using two methods: a semiautomated edge detection method and active surface model (ASM). We evaluated reproducibility for all combinations of sequences and analysis methods using coefficient of variation (COV) and intraclass correlation coefficient and performed sample size calculations for clinical trials to reduce longitudinal cord atrophy. RESULTS: PSIR/ASM combination provided the lowest values of COV for intrarater, interrater, scan-rescan reproducibility (0.002%, 0.03%, and 0.1% respectively). At 6-month follow-up no significant changes were seen in CSA of controls, and a trend towards significance was observed in patients. CONCLUSION: PSIR/ASM proved more reproducible than established methods of evaluating CSA in MS and also provides the lowest number of subjects per arm for 6-month and 1-year clinical trials.

Rare dorsal ossified meningioma in an elderly female: a case report and comprehensive review of literature.

Meningiomas, typically benign neoplasms originating in the central nervous system, display a predilection for female patients. Although they predominantly manifest within the cranial vault, ~25% of primary spinal neoplasms are attributed to these tumors. The occurrence of ossification in spinal meningiomas is an uncommon phenomenon, with scant documentation in medical literature. In this report, we detail the clinical journey of an octogenarian female patient afflicted with an ossified spinal meningioma, which was associated with left lower extremity weakness and reduced sensation. Diagnostic imaging, specifically magnetic resonance imaging, identified a mass exerting pressure on the spinal cord, necessitating its surgical removal. Subsequent histopathological examinations corroborated the initial diagnosis. Postoperative magnetic resonance imaging scans confirmed the absence of residual tumor tissue and ruled out recurrence. A comprehensive review of existing literature yielded 47 analogous cases, with a majority involving elderly female patients and the thoracic region of the spine being the most common site. The standard therapeutic approach is surgical intervention, which is often complicated by the tumor's tenacious adherence to surrounding structures and the potential for ensuing operative complications. This case highlights the exceptional nature of ossified spinal meningiomas and emphasizes the critical need for meticulous surgical management.

Movement disorder Deep brain stimulation Hybridization: Patient and caregiver outcomes.

Background and Objectives: Deep brain stimulation (DBS) is a well-established surgical treatment for certain movement disorders and involves the implantation of brain electrodes connected to implantable pulse generators (IPGs). As more device manufacturers have entered the market, some IPG technology has been designed to be compatible with brain electrodes from other manufacturers, which has facilitated the hybridization of implant technology. The aim of this study was to assess the benefits of hybridization of non-rechargeable, constant voltage IPGs to rechargeable, constant current IPGs. Methods: A list of DBS movement disorder patients who had their non-rechargeable, constant voltage IPGs replaced with rechargeable, constant current IPGs from a different manufacturer was compiled. Structured surveys of these patients, and their caregivers when applicable, were undertaken to determine both patient and caregiver satisfaction in this DBS hybridization strategy. Results: Eighteen patients met inclusion criteria and twelve patients or their caregivers completed the structured survey (67% response rate). Nine patients had Parkinson's disease (75%), three had essential tremor (25%). Nine (75%) were converted from bilateral single-channel IPGs, and three (25%) were converted from a unilateral dual-channel IPGs. Overall, 92% of patients and caregivers surveyed reported improvement or no change in their symptoms, 92% reported a decrease or no change in their medication requirements, and 92% report they are satisfied or very satisfied with their IPG hybridization and would recommend the surgery to similar patients. There were no immediate surgical complications. Conclusion: In this series of movement disorder DBS patients, surgery was safe and patient and caregiver satisfaction were high with a hybridization of non-rechargeable, constant voltage IPGs to rechargeable, constant current IPGs.

Radiosurgery Society Case-Based Guide to Stereotactic Body Radiation Therapy for Challenging Cases of Spinal Metastases.

PURPOSE: Spinal stereotactic body radiation therapy (SBRT) has become the standard of care in management of patients with limited sites of metastatic disease, radioresistant histologies, painful vertebral metastases with long life expectancy and cases of reirradiation. Our case-based guidelines aim to assist radiation oncologists in the appropriate utilization of SBRT for common, yet challenging, cases of spinal metastases. METHODS AND MATERIALS: Cases were selected to include scenarios of large volume sacral disease with nerve entrapment, medically inoperable disease abutting the thecal sac, and local failure after prior SBRT. Relevant literature was reviewed, and areas requiring further investigation were discussed to offer a framework for evidence-based clinical practice. RESULTS: Spinal SBRT can be effectively delivered in challenging cases following multidisciplinary discussion by using a methodical approach to patient selection, appropriate dose selection, and adherence to evidence-based dose constraints. CONCLUSIONS: The Radiosurgery Society's case-based practice review offers guidance to practicing physicians treating technically challenging SBRT candidate patients with spinal metastases.

In vivo magnetic resonance spectroscopy detection of combined glutamate-glutamine in healthy upper cervical cord at 3 T.

The possibility of quantifying the superimposed signal of glutamate and glutamine (Glx) and its components by ¹H magnetic resonance spectroscopy (MRS) in the spinal cord is an exciting challenge with important clinical applications in neurological conditions. The spinal cord is a particularly difficult region of interest due to its small volume, magnetic field inhomogeneities and physiological motion. In this study, we investigated for the first time the feasibility of obtaining quantitative measurements of Glx in healthy cervical spinal cord by ¹H MRS at 3 T. The aim of this study was to compare two commercially available MRS sequences by spectral simulations and in vivo. A short echo time (TE) point resolved spectroscopy (PRESS) with TE = 30 ms and a stimulated echo acquisition mode (STEAM) with TE = 11 ms and mixing time (TM) = 17 ms were compared for reliability of Glx fit. Data allowed us to determine sample size estimates for future clinical studies for the first time. Results showed that PRESS provided a reliable fit for Glx in all cases (Cramér Rao lower bounds < 20%) whereas no reliable Glx fits were achieved using STEAM. Neither protocol provided reliable Glu quantification. The power calculations showed that a minimum sample size of 17 subjects per group was needed to detect Glx changes of > 20% using the PRESS sequence. This study proposed a clinically feasible MRS method for Glx detection in the human cervical cord in vivo including sample sizes needed for conclusive clinical studies.

Complicated Management of Left-Sided Loculated Empyema Secondary to Streptococcus intermedius and Prevotella in a 53-Year-Old Male.

We present the case of a 53-year-old male with complicated left-sided parapneumonic effusion due to Streptococcus intermedius and Prevotella buccae. Management required video-assisted thoracoscopic surgery and partial decortication of the left lung. Complications during the hospital stay were extensive, including sepsis, acute hypoxic respiratory failure, alcohol withdrawal, and transient ischemic attack.

Foraminal stenosis and radiculopathy secondary to tophaceous gout: illustrative case.

BACKGROUND: Tophaceous gout is a severe form of gout that results in the formation of large nodules, or tophi, in the affected joints and surrounding tissues. Gouty tophi in the spine have a constellation of presentations that often mimic other pathologies and may not be easily discernable from more common pathologic processes. OBSERVATIONS: A 47-year-old female with a history of chronic renal disease, obesity, gout, inflammatory polyarthritis, and multiple sclerosis presented with 6 months of low-back pain and lumbar radiculopathy affecting the right lower extremity. A lumbar magnetic resonance imaging study revealed right foraminal stenosis and spondylolisthesis at levels L4-5. An intraspinal extradural mass was noted adjacent to the traversing right L5 and exiting right L4 nerve roots. A bilateral decompressive laminectomy, facetectomy, and foraminotomy of L4-5 was performed. A calcific, chalky-white mass was discovered in the foramen, and pathology determined the specimen to be a gout tophus. Postoperatively, the patient endorsed the resolution of her preoperative symptoms, which have not returned on follow-up. LESSONS: Reports of gouty depositions compressing the spinal cord in the current literature are relatively rare. Although the diagnosis of gouty tophi can only be confirmed histologically, patient history may serve as a helpful diagnostic tool.

Outcomes of Proton Beam Therapy Compared With Intensity-Modulated Radiation Therapy for Uterine Cancer.

Purpose: To compare Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in patients with endometrial cancer receiving adjuvant pelvic radiation therapy with proton beam therapy (PT) versus intensity-modulated radiation therapy (IMRT). Materials and Methods: Patients with uterine cancer treated with curative intent who received either adjuvant PT or IMRT between 2014 and 2020 were identified. Patients were enrolled into a prospective registry using a gynecologic-specific subset of PRO-CTCAE designed to assess symptom impact on daily living. Questions included gastrointestinal (GI) symptoms of diarrhea, flatulence, bowel incontinence, and constipation in addition to other pertinent gynecologic, urinary, and other general symptoms. Symptom-based questions were on a 0- to 4-point scale, with grade 3+ symptoms occurring frequently or almost always. Patient-reported toxicity was analyzed at baseline, end of treatment (EOT), and at 3, 6, 9, and 12 months after treatment. Unequal variance t tests were used to determine if treatment type was a significant factor in baseline-adjusted PRO-CTCAE. Results: Sixty-seven patients met inclusion criteria. Twenty-two received PT and 45 patients received IMRT. Brachytherapy boost was delivered in 73% of patients. Median external beam dose was 45 Gy for both PT and IMRT (range, 45-58.8 Gy). When comparing PRO-CTCAE, PT was associated with less diarrhea at EOT (P = .01) and at 12 months (P = .24) than IMRT. Loss of bowel control at 12 months was more common in patients receiving IMRT (P = .15). Any patient reporting grade 3+ GI toxicity was noted more frequently with IMRT (31% versus 9%, P = .09). Discussion: Adjuvant PT is a promising treatment for patients with uterine cancer and may reduce patient-reported GI toxicity as compared with IMRT.

Study of linear energy transfer effect on rib fracture in breast patients receiving pencil-beamscanning proton therapy.

Purpose: To study the effect of proton linear energy transfer (LET) on rib fracture in breast cancer patients treated with pencil-beam scanning proton therapy (PBS) using a novel tool of dose-LET volume histogram (DLVH). Methods: From a prospective registry of patients treated with post-mastectomy proton therapy to the chest wall and regional lymph nodes for breast cancer between 2015 and 2020, we retrospectively identified rib fracture cases detected after completing treatment. Contemporaneously treated control patients that did not develop rib fracture were matched to patients 2:1 considering prescription dose, boost location, reconstruction status, laterality, chest wall thickness, and treatment year.The DLVH index, V(d, l), defined as volume(V) of the structure with at least dose(d) and LET(l), was calculated. DLVH plots between the fracture and control group were compared. Conditional logistic regression (CLR) model was used to establish the relation of V(d, l) and the observed fracture at each combination of d and l. The p-value derived from CLR model shows the statistical difference between fracture patients and the matched control group. Using the 2D p-value map derived from CLR model, the DLVH features associated with the patient outcomes were extracted. Results: Seven rib fracture patients were identified, and fourteen matched patients were selected for the control group. The median time from the completion of proton therapy to rib fracture diagnosis was 12 months (range 5 to 14 months). Two patients had grade 2 symptomatic rib fracture while the remaining 5 were grade 1 incidentally detected on imaging. The derived p-value map demonstrated larger V(0-36Gy[RBE], 4.0-5.0 keV/µm) in patients experiencing fracture (p<0.1). For example, the p value for V(30 Gy[RBE], 4.0 keV/um) was 0.069. Conclusions: In breast cancer patients receiving PBS, a larger volume of chest wall receiving moderate dose and high LET may result in increased risk of rib fracture.

FLASH Effects Induced by Orthovoltage X-Rays.

PURPOSE: This work describes the first implementation and in vivo study of ultrahigh-dose-rate radiation (>37 Gy/s; FLASH) effects induced by kilovoltage (kV) x-ray from a rotating-anode x-ray source. METHODS AND MATERIALS: A high-capacity rotating-anode x-ray tube with an 80-kW generator was implemented for preclinical FLASH radiation research. A custom 3-dimensionally printed immobilization and positioning tool was developed for reproducible irradiation of a mouse hind limb. Calibrated Gafchromic (EBT3) film and thermoluminescent dosimeters (LiF:Mg,Ti) were used for in-phantom and in vivo dosimetry. Healthy FVB/N and FVBN/C57BL/6 outbred mice were irradiated on 1 hind leg to doses up to 43 Gy at FLASH (87 Gy/s) and conventional (CONV; <0.05 Gy/s) dose rates. The radiation doses were delivered using a single pulse with the widths up to 500 ms and 15 minutes at FLASH and CONV dose rates. Histologic assessment of radiation-induced skin damage was performed at 8 weeks posttreatment. Tumor growth suppression was assessed using a B16F10 flank tumor model in C57BL6J mice irradiated to 35 Gy at both FLASH and CONV dose rates. RESULTS: FLASH-irradiated mice experienced milder radiation-induced skin injuries than CONV-irradiated mice, visible by 4 weeks posttreatment. At 8 weeks posttreatment, normal tissue injury was significantly reduced in FLASH-irradiated animals compared with CONV-irradiated animals for histologic endpoints including inflammation, ulceration, hyperplasia, and fibrosis. No difference in tumor growth response was observed between FLASH and CONV irradiations at 35 Gy. The normal tissue sparing effects of FLASH irradiations were observed only for high-severity endpoint of ulceration at 43 Gy, which suggests the dependency of biologic endpoints to FLASH radiation dose. CONCLUSIONS: Rotating-anode x-ray sources can achieve FLASH dose rates in a single pulse with dosimetric properties suitable for small-animal experiments. We observed FLASH normal tissue sparing of radiation toxicities in mouse skin irradiated at 35 Gy with no sacrifice to tumor growth suppression. This study highlights an accessible new modality for laboratory study of the FLASH effect.

Postmastectomy Intensity Modulated Proton Therapy: 5-Year Oncologic and Patient-Reported Outcomes.

PURPOSE: To report oncologic, physician-assessed, and patient-reported outcomes (PROs) for a group of women homogeneously treated with modern, skin-sparing multifield optimized pencil-beam scanning proton (intensity modulated proton therapy [IMPT]) postmastectomy radiation therapy (PMRT). METHODS AND MATERIALS: We reviewed consecutive patients who received unilateral, curative-intent, conventionally fractionated IMPT PMRT between 2015 and 2019. Strict constraints were applied to limit the dose to the skin and other organs at risk. Five-year oncologic outcomes were analyzed. Patient-reported outcomes were evaluated as part of a prospective registry at baseline, completion of PMRT, and 3 and 12 months after PMRT. RESULTS: A total of 127 patients were included. One hundred nine (86%) received chemotherapy, among whom 82 (65%) received neoadjuvant chemotherapy. The median follow-up was 4.1 years. Five-year locoregional control was 98.4% (95% CI, 93.6-99.6), and overall survival was 87.9% (95% CI, 78.7-96.5). Acute grade 2 and 3 dermatitis was seen in 45% and 4% of patients, respectively. Three patients (2%) experienced acute grade 3 infection, all of whom had breast reconstruction. Three late grade 3 adverse events occurred: morphea (n = 1), infection (n = 1), and seroma (n = 1). There were no cardiac or pulmonary adverse events. Among the 73 patients at risk for PMRT-associated reconstruction complications, 7 (10%) experienced reconstruction failure. Ninety-five patients (75%) enrolled in the prospective PRO registry. The only metrics to increase by >1 point were skin color (mean change: 5) and itchiness (2) at treatment completion and tightness/pulling/stretching (2) and skin color (2) at 12 months. There was no significant change in the following PROs: bleeding/leaking fluid, blistering, telangiectasia, lifting, arm extension, or bending/straightening the arm. CONCLUSIONS: With strict dose constraints to skin and organs at risk, postmastectomy IMPT was associated with excellent oncologic outcomes and PROs. Rates of skin, chest wall, and reconstruction complications compared favorably to previous proton and photon series. Postmastectomy IMPT warrants further investigation in a multi-institutional setting with careful attention to planning techniques.

Temporal lobe perceptual predictions for speech are instantiated in motor cortex and reconciled by inferior frontal cortex.

Humans use predictions to improve speech perception, especially in noisy environments. Here we use 7-T functional MRI (fMRI) to decode brain representations of written phonological predictions and degraded speech signals in healthy humans and people with selective frontal neurodegeneration (non-fluent variant primary progressive aphasia [nfvPPA]). Multivariate analyses of item-specific patterns of neural activation indicate dissimilar representations of verified and violated predictions in left inferior frontal gyrus, suggestive of processing by distinct neural populations. In contrast, precentral gyrus represents a combination of phonological information and weighted prediction error. In the presence of intact temporal cortex, frontal neurodegeneration results in inflexible predictions. This manifests neurally as a failure to suppress incorrect predictions in anterior superior temporal gyrus and reduced stability of phonological representations in precentral gyrus. We propose a tripartite speech perception network in which inferior frontal gyrus supports prediction reconciliation in echoic memory, and precentral gyrus invokes a motor model to instantiate and refine perceptual predictions for speech.