Comparison of synthesized and acquired high b-value diffusion-weighted MRI for detection of prostate cancer.

BACKGROUND: High b-value diffusion-weighted images (DWI) are used for detection of clinically significant prostate cancer (csPCa). This study qualitatively and quantitatively compares synthesized DWI (sDWI) to acquired (aDWI) for detection of csPCa. METHODS: One hundred fifty-one consecutive patients who underwent prostate MRI and biopsy were included in the study. Axial DWI with b = 0, 500, 1000, and 2000 s/mm2 using a 3T clinical scanner using a 32-channel phased-array body coil were acquired. We retrospectively synthesized DWI for b = 2000 s/mm2 via extrapolation based on mono-exponential decay, using b = 0 and b = 500 s/mm2 (sDWI500) and b = 0, b = 500 s/mm2, and b = 1000 s/mm2 (sDWI1000). Differences in signal intensity between sDWI and aDWI were evaluated within different regions of interest (prostate alone, prostate plus 5 mm, 30 mm and 70 mm margin and full field of view). The maximum DWI value within each ROI was evaluated for prediction of csPCa. Classification accuracy was compared to Restriction Spectrum Imaging restriction score (RSIrs), a previously validated biomarker based on multi-exponential DWI. Discrimination of csPCa was evaluated via area under the receiver operating characteristic curve (AUC). RESULTS: Within the prostate, mean ± standard deviation of percent mean differences between sDWI and aDWI signal were -46 ± 35% for sDWI1000 and -67 ± 24% for sDWI500. AUC for aDWI, sDWI500, sDWI1000, and RSIrs within the prostate 0.62[95% confidence interval: 0.53, 0.71], 0.63[0.54, 0.72], 0.65[0.56, 0.73] and 0.78[0.71, 0.86], respectively. CONCLUSION: sDWI is qualitatively comparable to aDWI within the prostate. However, hyperintense artifacts are introduced with sDWI in the surrounding pelvic tissue that interfere with quantitative cancer detection and might mask metastases. In the prostate, RSIrs yields superior quantitative csPCa detection than sDWI or aDWI.

Clinical Impact of Contouring Variability for Prostate Cancer Tumor Boost.

PURPOSE: The focal radiation therapy (RT) boost technique was shown in a phase III randomized controlled trial (RCT) to improve prostate cancer outcomes without increasing toxicity. This technique relies on the accurate delineation of prostate tumors on MRI. A recent prospective study evaluated radiation oncologists' accuracy when asked to delineate prostate tumors on MRI and demonstrated high variability in tumor contours. We sought to evaluate the impact of contour variability and inaccuracy on predicted clinical outcomes. We hypothesized that radiation oncologists' contour inaccuracies would yield meaningfully worse clinical outcomes. METHODS AND MATERIALS: Forty-five radiation oncologists and 2 expert radiologists contoured prostate tumors on 30 patient cases. Of these cases, those with CT simulation or diagnostic CT available were selected for analysis. A knowledge-based planning model was developed to generate focal RT boost plans for each contour per the RCT protocol. The probability of biochemical failure (BF) was determined using a model from the RCT. The primary metric evaluated was delta BF (DBF = Participant BF - Expert BF). An absolute increase in BF ≥5% was considered clinically meaningful. RESULTS: Eight patient cases and 394 target volumes for focal RT boost planning were included in this analysis. In general, participant plans were associated with worse predicted clinical outcomes compared to the expert plan, with an average absolute increase in BF of 4.3%. Of participant plans, 37% were noted to have an absolute increase in BF of 5% or more. CONCLUSIONS: Radiation oncologists' attempts to contour tumor targets for focal RT boost are frequently inaccurate enough to yield meaningfully inferior clinical outcomes for patients.

Agent orange exposure and prostate cancer risk in the million veteran program.

BACKGROUND: The US government considers veterans to have been exposed to Agent Orange if they served in Vietnam while the carcinogen was in use, and these veterans are often deemed at high risk of prostate cancer (PCa). Here, we assess whether presumed Agent Orange exposure is independently associated with increased risk of any metastatic or fatal PCa in a diverse Veteran cohort still alive in the modern era (at least 2011), when accounting for race/ethnicity, family history, and genetic risk. PATIENTS AND METHODS: Participants in the Million Veteran Program (MVP; enrollment began in 2011) who were on active duty during the Vietnam War era (August 1964-April 1975) were included (n = 301,470). Agent Orange exposure was determined using the US government definition. Genetic risk was assessed via a validated polygenic hazard score. Associations with age at diagnosis of any PCa, metastatic PCa, and death from PCa were assessed via Cox proportional hazards models. RESULTS AND INTERPRETATION: On univariable analysis, exposure to Agent Orange was not associated with increased PCa (hazard ratio [HR]: 1.02, 95% confidence interval [CI]: 1.00-1.04, p = 0.06), metastatic PCa (HR: 0.98, 95% CI: 0.91-1.05, p = 0.55), or fatal PCa (HR: 0.94, 95% CI: 0.79-1.09, p = 0.41). When accounting for race/ethnicity and family history, Agent Orange exposure was independently associated with slightly increased risk of PCa (HR: 1.06, 95% CI: 1.04-1.09, <10-6) but not with metastatic PCa (HR: 1.07, 95% CI: 0.98-1.15, p = 0.10) or PCa death (HR: 1.02, 95% CI: 0.83-1.23, p = 0.09). Similar results were found when accounting for genetic risk. Agent Orange exposure history may not improve modern PCa risk stratification.

Focal radiotherapy boost to MR-visible tumor for prostate cancer: a systematic review.

PURPOSE: The FLAME trial provides strong evidence that MR-guided external beam radiation therapy (EBRT) focal boost for localized prostate cancer increases biochemical disease-free survival (bDFS) without increasing toxicity. Yet, there are many barriers to implementation of focal boost. Our objectives are to systemically review clinical outcomes for MR-guided EBRT focal boost and to consider approaches to increase implementation of this technique. METHODS: We conducted literature searches in four databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guideline. We included prospective phase II/III trials of patients with localized prostate cancer underdoing definitive EBRT with MR-guided focal boost. The outcomes of interest were bDFS and acute/late gastrointestinal and genitourinary toxicity. RESULTS: Seven studies were included. All studies had a median follow-up of greater than 4 years. There were heterogeneities in fractionation, treatment planning, and delivery. Studies demonstrated effectiveness, feasibility, and tolerability of focal boost. Based on the Phoenix criteria for biochemical recurrence, the reported 5-year biochemical recurrence-free survival rates ranged 69.7-100% across included studies. All studies reported good safety profiles. The reported ranges of acute/late grade 3 + gastrointestinal toxicities were 0%/1-10%. The reported ranges of acute/late grade 3 + genitourinary toxicities were 0-13%/0-5.6%. CONCLUSIONS: There is strong evidence that it is possible to improve oncologic outcomes without substantially increasing toxicity through MR-guided focal boost, at least in the setting of a 35-fraction radiotherapy regimen. Barriers to clinical practice implementation are addressable through additional investigation and new technologies.

Use of focal radiotherapy boost for prostate cancer: radiation oncologists' perspectives and perceived barriers to implementation.

BACKGROUND: In a recent phase III randomized control trial, delivering a focal radiotherapy (RT) boost to tumors visible on MRI was shown to improve disease-free survival and regional/distant metastasis-free survival for patients with prostate cancer-without increasing toxicity. The aim of this study was to assess how widely this technique is being applied in current practice, as well as physicians' perceived barriers toward its implementation. METHODS: We invited radiation oncologists to complete an online questionnaire assessing their use of intraprostatic focal boost in December 2022 and February 2023. To include perspectives from a broad range of practice settings, the invitation was distributed to radiation oncologists worldwide via email list, group text platform, and social media. RESULTS: 263 radiation oncologist participants responded. The highest-represented countries were the United States (42%), Mexico (13%), and the United Kingdom (8%). The majority of participants worked at an academic medical center (52%) and considered their practice to be at least partially genitourinary (GU)-subspecialized (74%). Overall, 43% of participants reported routinely using intraprostatic focal boost. Complete GU-subspecialists were more likely to implement focal boost, with 61% reporting routine use. In both high-income and low-to-middle-income countries, less than half of participants routinely use focal boost. The most cited barriers were concerns about registration accuracy between MRI and CT (37%), concerns about risk of additional toxicity (35%), and challenges to accessing high-quality MRI (29%). CONCLUSIONS: Two years following publication of a randomized trial of patient benefit without increased toxicity, almost half of the radiation oncologists surveyed are now routinely offering focal RT boost. Further adoption of this technique might be aided by increased access to high-quality MRI, better registration algorithms of MRI to CT simulation images, physician education on benefit-to-harm ratio, and training on contouring prostate lesions on MRI.

Agent Orange exposure and prostate cancer risk in the Million Veteran Program.

Purpose: Exposure to Agent Orange, a known carcinogen, might increase risk of prostate cancer (PCa). We sought to investigate the association of Agent Orange exposure and PCa risk when accounting for race/ethnicity, family history, and genetic risk in a diverse population of US Vietnam War veterans. Methods & Materials: This study utilized the Million Veteran Program (MVP), a national, population-based cohort study of United States military veterans conducted 2011-2021 with 590,750 male participants available for analysis. Agent Orange exposure was obtained using records from the Department of Veterans Affairs (VA) using the US government definition of Agent Orange exposure: active service in Vietnam while Agent Orange was in use. Only veterans who were on active duty (anywhere in the world) during the Vietnam War were included in this analysis (211,180 participants). Genetic risk was assessed via a previously validated polygenic hazard score calculated from genotype data. Age at diagnosis of any PCa, diagnosis of metastatic PCa, and death from PCa were assessed via Cox proportional hazards models. Results: Exposure to Agent Orange was associated with increased PCa diagnosis (HR 1.04, 95% CI 1.01-1.06, p=0.003), primarily among Non-Hispanic White men (HR 1.09, 95% CI 1.06- 1.12, p<0.001). When accounting for race/ethnicity and family history, Agent Orange exposure remained an independent risk factor for PCa diagnosis (HR 1.06, 95% CI 1.04-1.09, p<0.05). Univariable associations of Agent Orange exposure with PCa metastasis (HR 1.08, 95% CI 0.99-1.17) and PCa death (HR 1.02, 95% CI 0.84-1.22) did not reach significance on multivariable analysis. Similar results were found when accounting for polygenic hazard score. Conclusions: Among US Vietnam War veterans, Agent Orange exposure is an independent risk factor for PCa diagnosis, though associations with PCa metastasis or death are unclear when accounting for race/ethnicity, family history, and/or polygenic risk.

ReIGNITE Radiation Therapy Boost: A Prospective, International Study of Radiation Oncologists' Accuracy in Contouring Prostate Tumors for Focal Radiation Therapy Boost on Conventional Magnetic Resonance Imaging Alone or With Assistance of Restriction Spectrum Imaging.

PURPOSE: In a phase III randomized trial, adding a radiation boost to tumor(s) visible on MRI improved prostate cancer (PCa) disease-free and metastasis-free survival without additional toxicity. Radiation oncologists' ability to identify prostate tumors is critical to widely adopting intraprostatic tumor radiotherapy boost for patients. A diffusion MRI biomarker, called the Restriction Spectrum Imaging restriction score (RSIrs), has been shown to improve radiologists' identification of clinically significant PCa. We hypothesized that (1) radiation oncologists would find accurately delineating PCa tumors on conventional MRI challenging and (2) using RSIrs maps would improve radiation oncologists' accuracy for PCa tumor delineation. METHODS AND MATERIALS: In this multi-institutional, international, prospective study, 44 radiation oncologists (participants) and 2 expert radiologists (experts) contoured prostate tumors on 39 total patient cases using conventional MRI with or without RSIrs maps. Participant volumes were compared to the consensus expert volumes. Contouring accuracy metrics included percent overlap with expert volume, Dice coefficient, conformal number, and maximum distance beyond expert volume. RESULTS: 1604 participant volumes were produced. 40 of 44 participants (91%) completely missed ≥1 expert-defined target lesion without RSIrs, compared to 13 of 44 (30%) with RSIrs maps. On conventional MRI alone, 134 of 762 contour attempts (18%) completely missed the target, compared to 18 of 842 (2%) with RSIrs maps. Use of RSIrs maps improved all contour accuracy metrics by approximately 50% or more. Mixed effects modeling confirmed that RSIrs maps were the main variable driving improvement in all metrics. System Usability Scores indicated RSIrs maps significantly improved the contouring experience (72 vs. 58, p < 0.001). CONCLUSIONS: Radiation oncologists struggle with accurately delineating visible PCa tumors on conventional MRI. RSIrs maps improve radiation oncologists' ability to target MRI-visible tumors for prostate tumor boost.

Use of focal radiotherapy boost for prostate cancer and perceived barriers toward its implementation: a survey.

Background: In a recent phase III randomized control trial (FLAME), delivering a focal radiotherapy (RT) boost to tumors visible on MRI was shown to improve outcomes for prostate cancer patients without increasing toxicity. The aim of this study was to assess how widely this technique is being applied in current practice as well as physicians' perceived barriers toward its implementation. Methods: An online survey assessing the use of intraprostatic focal boost was conducted in December 2022 and February 2023. The survey link was distributed to radiation oncologists worldwide via email list, group text platform, and social media. Results: The survey initially collected 205 responses from various countries over a two-week period in December 2022. The survey was then reopened for one week in February 2023 to allow for more participation, leading to a total of 263 responses. The highest-represented countries were the United States (42%), Mexico (13%), and the United Kingdom (8%). The majority of participants worked at an academic medical center (52%) and considered their practice to be at least partially genitourinary (GU)-subspecialized (74%). 57% of participants reported not routinely using intraprostatic focal boost. Even among complete subspecialists, a substantial proportion (39%) do not routinely use focal boost. Less than half of participants in both high-income and low-to-middle-income countries were shown to routinely use focal boost. The most commonly cited barriers were concerns about registration accuracy between MRI and CT (37%), concerns about risk of additional toxicity (35%), and challenges to accessing high-quality MRI (29%). Conclusion: Despite level 1 evidence from the FLAME trial, most radiation oncologists surveyed are not routinely offering focal RT boost. Adoption of this technique might be accelerated by increased access to high-quality MRI, better registration algorithms of MRI to CT simulation images, physician education on benefit-to-harm ratio, and training on contouring prostate lesions on MRI.

Ruptured arteriovenous malformation mortality: Incidence, risk factors, and inpatient outcome score.

BACKGROUND: Limited literature exists on the morbidity and mortality of AVM associated intracerebral hemorrhage (ICH) compared with non-AVM ICH. OBJECTIVE: We examine morbidity and mortality in cAVM in a large nationwide inpatient sample to create a prognostic inpatient ruptured AVM mortality score. METHODS: This retrospective cohort study from 2008 to 2014 compares outcomes in cAVM related hemorrhages and ICH utilizing the National Inpatient Sample database. Diagnostic codes for ICH and AVM underlying ICH were identified. We compared case fatality according to medical complications. Multivariate analysis was used to derive hazard ratios and 95% confidence intervals to assess odds of mortality. RESULTS: We identified 6496 patients with ruptured AVMs comparing them to 627,185 admitted with ICH. Mortality was lower for ruptured AVMs (11%) compared to ICH (22%) [p < 0.01]. Mortality associated factors were liver disease (OR 2.64, CI 1.81-3.85, p < .001), diabetes mellitus (OR 2.42, CI 1.38-4.22, p = 0.002), alcohol abuse (OR 1.81, CI 1.31-2.49, p = 0.001), hydrocephalus (OR 3.35 CI 2.81-4.00, p < 0.001), cerebral edema (OR 1.5, 1.25-1.85, p < 0.001), cardiac arrest (OR 15, CI 7.9-30, p < 0.001), and pneumonia (OR 1.93, CI 1.51-2.47, p < 0.001). A 0-5 ruptured AVM mortality score was developed: Cardiac arrest (=3), age >60 (=1), Black race (=1), chronic liver failure (=1) diabetes mellitus (=1), pneumonia (=1), alcohol abuse (=1) and cerebral edema (=1). Mortality increased with score. No patient with 5 or more points survived. CONCLUSION: The Ruptured AVM Mortality Score allows for risk stratification on patients with ICH due to ruptured AVM. This scale could prove useful in prognostication and patient education.

Comparison of synthesized and acquired high b -value diffusion-weighted MRI for detection of prostate cancer.

Background: High b -value diffusion-weighted images (DWI) are used for detection of clinically significant prostate cancer (csPCa). To decrease scan time and improve signal-to-noise ratio, high b -value (>1000 s/mm 2 ) images are often synthesized instead of acquired. Purpose: Qualitatively and quantitatively compare synthesized DWI (sDWI) to acquired (aDWI) for detection of csPCa. Study Type: Retrospective. Subjects: 151 consecutive patients who underwent prostate MRI and biopsy. Sequence: Axial DWI with b =0, 500, 1000, and 2000 s/mm 2 using a 3T clinical scanner using a 32-channel phased-array body coil. Assessment: We synthesized DWI for b =2000 s/mm 2 via extrapolation based on monoexponential decay, using b =0 and b =500 s/mm 2 (sDWI 500 ) and b =0, b =500, and b =1000 s/mm 2 (sDWI 1000 ). Differences between sDWI and aDWI were evaluated within regions of interest (ROIs). The maximum DWI value within each ROI was evaluated for prediction of csPCa. Classification accuracy was also compared to Restriction Spectrum Imaging restriction score (RSIrs), a previously validated biomarker based on multi-exponential DWI. Statistical Tests: Discrimination of csPCa was evaluated via area under the receiver operating characteristic curve (AUC). Statistical significance was assessed using bootstrap difference (two-sided α=0.05). Results: Within the prostate, mean ± standard deviation of percent mean differences between sDWI and aDWI signal were -46±35% for sDWI 1000 and -67±24% for sDWI 500 . AUC for aDWI, sDWI 500, sDWI 1000 , and RSIrs within the prostate 0.62[95% confidence interval: 0.53, 0.71], 0.63[0.54, 0.72], 0.65[0.56, 0.73] and 0.78[0.71, 0.86], respectively. When considering the whole field of view, classification accuracy and qualitative image quality decreased notably for sDWI compared to aDWI and RSIrs. Data Conclusion: sDWI is qualitatively comparable to aDWI within the prostate. However, hyperintense artifacts are introduced with sDWI in the surrounding pelvic tissue that interfere with quantitative cancer detection and might mask metastases. In the prostate, RSIrs yields superior quantitative csPCa detection than sDWI or aDWI.

Automated Patient-level Prostate Cancer Detection with Quantitative Diffusion Magnetic Resonance Imaging.

Background: Multiparametric magnetic resonance imaging (mpMRI) improves detection of clinically significant prostate cancer (csPCa), but the subjective Prostate Imaging Reporting and Data System (PI-RADS) system and quantitative apparent diffusion coefficient (ADC) are inconsistent. Restriction spectrum imaging (RSI) is an advanced diffusion-weighted MRI technique that yields a quantitative imaging biomarker for csPCa called the RSI restriction score (RSIrs). Objective: To evaluate RSIrs for automated patient-level detection of csPCa. Design setting and participants: We retrospectively studied all patients (n = 151) who underwent 3 T mpMRI and RSI (a 2-min sequence on a clinical scanner) for suspected prostate cancer at University of California San Diego during 2017-2019 and had prostate biopsy within 180 d of MRI. Intervention: We calculated the maximum RSIrs and minimum ADC within the prostate, and obtained PI-RADS v2.1 from medical records. Outcome measurements and statistical analysis: We compared the performance of RSIrs, ADC, and PI-RADS for the detection of csPCa (grade group ≥2) on the best available histopathology (biopsy or prostatectomy) using the area under the curve (AUC) with two-tailed α = 0.05. We also explored whether the combination of PI-RADS and RSIrs might be superior to PI-RADS alone and performed subset analyses within the peripheral and transition zones. Results and limitations: AUC values for ADC, RSIrs, and PI-RADS were 0.48 (95% confidence interval: 0.39, 0.58), 0.78 (0.70, 0.85), and 0.77 (0.70, 0.84), respectively. RSIrs and PI-RADS were each superior to ADC for patient-level detection of csPCa (p < 0.0001). RSIrs alone was comparable with PI-RADS (p = 0.8). The combination of PI-RADS and RSIrs had an AUC of 0.85 (0.78, 0.91) and was superior to either PI-RADS or RSIrs alone (p < 0.05). Similar patterns were seen in the peripheral and transition zones. Conclusions: RSIrs is a promising quantitative marker for patient-level csPCa detection, warranting a prospective study. Patient summary: We evaluated a rapid, advanced prostate magnetic resonance imaging technique called restriction spectrum imaging to see whether it could give an automated score that predicted the presence of clinically significant prostate cancer. The automated score worked about as well as expert radiologists' interpretation. The combination of the radiologists' scores and automated score might be better than either alone.

The unique role of the frontal aslant tract in speech and language processing.

The frontal aslant tract (FAT) is a recently described intralobar tract that connects the superior and inferior frontal gyri. The FAT has been implicated in various speech and language processes and disorders, including motor speech impairments, stuttering disorders, opercular syndrome, and verbal fluency, but the specific function(s) of the FAT have yet to be elucidated. In the current study, we aimed to address this knowledge gap by investigating the underlying role that the FAT plays in motor aspects of speech and language abilities in post-stroke aphasia. Our goals were three-fold: 1) To identify which specific motor speech or language abilities are impacted by FAT damage by utilizing a powerful imaging analysis method, High Angular Resolution Diffusion Imaging (HARDI) tractography; 2) To determine whether damage to the FAT is associated with functional deficits on a range of motor speech and language tasks even when accounting for cortical damage to adjacent cortical regions; and 3) To explore whether subsections of the FAT (lateral and medial segments) play distinct roles in motor speech performance. We hypothesized that damage to the FAT would be most strongly associated with motor speech performance in comparison to language tasks. We analyzed HARDI data from thirty-three people with aphasia (PWA) with a history of chronic left hemisphere stroke. FAT metrics were related to scores on several speech and language tests: the Motor Speech Evaluation (MSE), the Western Aphasia Battery (WAB) aphasia quotient and subtests, and the Boston Naming Test (BNT). Our results indicated that the integrity of the FAT was strongly associated with the MSE as predicted, and weakly negatively associated with WAB subtest scores including Naming, Comprehension, and Repetition, likely reflecting the fact that performance on these WAB subtests is associated with damage to posterior areas of the brain that are unlikely to be damaged with a frontal lesion. We also performed hierarchical stepwise regressions to predict language function based on FAT properties and lesion load to surrounding cortical areas. After accounting for the contributions of the inferior frontal gyrus, the ventral precentral gyrus, and the superior precentral gyrus of the insula, the FAT still remained a significant predictor of MSE apraxia scores. Our results further showed that the medial and lateral subsections of the FAT did not appear to play distinct roles but rather may indicate normal anatomical variations of the FAT. Overall, current results indicate that the FAT plays a specific and unique role in motor speech. These results further our understanding of the role that white matter tracts play in speech and language.

Transcarotid Access for Mechanical Thrombectomy in Acute Ischemic Stroke: A Meta-Analysis and Systematic Review.

OBJECTIVES: Despite the success of mechanical thrombectomy in large vessel acute ischemic stroke, recanalization may fail due to difficult anatomic access or peripheral arterial occlusive disease. In these cases, transcarotid access may be used as an alternative, but it has not gained prominence due to safety concerns. Our objective was to assess the efficacy and safety of transcarotid access for mechanical thrombectomy. MATERIALS AND METHODS: Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to perform a systematic review with articles published from 2010 to 2020 summarizing pre-intervention characteristics, techniques utilized, and outcomes of patients undergoing mechanical thrombectomy via trans-carotid puncture. We performed a meta-analysis of clinical outcomes, reperfusion times and overall complications rates of trans-carotid approach. RESULTS: Six studies describing 80 total attempts at carotid access, 72 of which were successful (90% success rate), were included. Direct carotid puncture was most often used as a rescue technique (87% of patients) secondary to failed femoral access. Successful recanalization was achieved in 76% of patients. 90 day modified Rankin Scale ≤ 2 was achieved in 28% of patients. Carotid puncture-reperfusion time was 32 min (CI = 24-40, p < 0.001). Cervical complications occurred at a rate of 26.5% (95% CI = 17%-38%). Only 1.3% (1/80 patients) had a fatal outcome and 96% of complications required no intervention. CONCLUSIONS: Our results on the safety and efficacy of transcarotid access suggests that this approach is a viable alternative to failed thrombectomy when transfemoral or trans-radial access may be impractical.

Correcting B0 inhomogeneity-induced distortions in whole-body diffusion MRI of bone.

Diffusion-weighted magnetic resonance imaging (DWI) of the musculoskeletal system has various applications, including visualization of bone tumors. However, DWI acquired with echo-planar imaging is susceptible to distortions due to static magnetic field inhomogeneities. This study aimed to estimate spatial displacements of bone and to examine whether distortion corrected DWI images more accurately reflect underlying anatomy. Whole-body MRI data from 127 prostate cancer patients were analyzed. The reverse polarity gradient (RPG) technique was applied to DWI data to estimate voxel-level distortions and to produce a distortion corrected DWI dataset. First, an anatomic landmark analysis was conducted, in which corresponding vertebral landmarks on DWI and anatomic T2-weighted images were annotated. Changes in distance between DWI- and T2-defined landmarks (i.e., changes in error) after distortion correction were calculated. In secondary analyses, distortion estimates from RPG were used to assess spatial displacements of bone metastases. Lastly, changes in mutual information between DWI and T2-weighted images of bone metastases after distortion correction were calculated. Distortion correction reduced anatomic error of vertebral DWI up to 29 mm. Error reductions were consistent across subjects (Wilcoxon signed-rank p < 10-20). On average (± SD), participants' largest error reduction was 11.8 mm (± 3.6). Mean (95% CI) displacement of bone lesions was 6.0 mm (95% CI 5.0-7.2); maximum displacement was 17.1 mm. Corrected diffusion images were more similar to structural MRI, as evidenced by consistent increases in mutual information (Wilcoxon signed-rank p < 10-12). These findings support the use of distortion correction techniques to improve localization of bone on DWI.

Functional Contributions of the Arcuate Fasciculus to Language Processing.

Current evidence strongly suggests that the arcuate fasciculus (AF) is critical for language, from spontaneous speech and word retrieval to repetition and comprehension abilities. However, to further pinpoint its unique and differential role in language, its anatomy needs to be explored in greater detail and its contribution to language processing beyond that of known cortical language areas must be established. We address this in a comprehensive evaluation of the specific functional role of the AF in a well-characterized cohort of individuals with chronic aphasia (n = 33) following left hemisphere stroke. To evaluate macro- and microstructural integrity of the AF, tractography based on the constrained spherical deconvolution model was performed. The AF in the left and right hemispheres were then manually reconstructed using a modified 3-segment model (Catani et al., 2005), and a modified 2-segment model (Glasser and Rilling, 2008). The normalized volume and a measure of microstructural integrity of the long and the posterior segments of the AF were significantly correlated with language indices while controlling for gender and lesion volume. Specific contributions of AF segments to language while accounting for the role of specific cortical language areas - inferior frontal, inferior parietal, and posterior temporal - were tested using multiple regression analyses. Involvement of the following tract segments in the left hemisphere in language processing beyond the contribution of cortical areas was demonstrated: the long segment of the AF contributed to naming abilities; anterior segment - to fluency and naming; the posterior segment - to comprehension. The results highlight the important contributions of the AF fiber pathways to language impairments beyond that of known cortical language areas. At the same time, no clear role of the right hemisphere AF tracts in language processing could be ascertained. In sum, our findings lend support to the broader role of the left AF in language processing, with particular emphasis on comprehension and naming, and point to the posterior segment of this tract as being most crucial for supporting residual language abilities.

Brain microstructure mediates sex-specific patterns of cognitive aging.

Normal brain aging is characterized by declining neuronal integrity, yet it remains unclear how microstructural injury influences cognitive aging and whether such mechanisms differ between sexes. Using restriction spectrum imaging (RSI), we examined sex differences in associations between brain microstructure and cognitive function in 147 community-dwelling older men and women (56-99 years). Gray and white matter microstructure correlated with global cognition, executive function, visuospatial memory, episodic memory, and logical memory, with the strongest associations for restricted, hindered and free isotropic diffusion. Associations were stronger for women than for men, a difference likely due to greater age-related variability in cognitive scores and microstructure in women. Isotropic diffusion mediated effects of age on cognition for both sexes, though distinct mediation patterns were present for women and men. For women, hippocampal and corpus callosum microstructure mediated age effects on verbal and visuospatial memory, respectively, whereas for men fiber microstructure (mainly fornix and corpus callosum) mediated age effects on executive function and visuospatial memory. These findings implicate sex-specific pathways by which changing brain cytoarchitecture contributes to cognitive aging, and suggest that RSI may be useful for evaluating risk for cognitive decline or monitoring efficacy of interventions to preserve brain health in later life.

Local delivery of hormonal therapy with silastic tubing for prevention and treatment of breast cancer.

Broad use of germline testing has identified an increasing number of women at risk for breast cancer with a need for effective chemoprevention. We report a novel method to selectively deliver various anti-estrogens at high drug levels to the breast tissue by implanting a device comprised of silastic tubing. Optimized tubing properties allow elution of otherwise poorly bioavailable anti-estrogens, such as fulvestrant, into mammary tissue in vitro and in vivo with levels sufficient to inhibit estrogen receptor activation and tumor cell proliferation. Implantable silastic tubing delivers fulvestrant selectively to mouse mammary fat tissue for one year with anti-tumor effects similar to those achieved with systemic fulvestrant exposure. Furthermore, local delivery of fulvestrant significantly decreases cell proliferation, as assessed by Ki67 expression, most effectively in tumor sections adjacent to tubing. This approach may thereby introduce a potential paradigm shift and offer a promising alternative to systemic therapy for prevention and early interception of breast cancer.

Nanodrug-Mediated Thermotherapy of Cancer Stem-Like Cells.

Cancer stem-like cells (CSCs) are rare subpopulations of cancer cells that are resistant to conventional chemotherapy and radiotherapy and contribute to cancer metastases and tumor recurrence. Therefore, it is of significance to develop an effective therapy to eliminate the CSCs. Cancer thermotherapy realized by depositing heat into tumor in a minimally invasive way is a promising alternative to the conventional therapies for cancer treatment. However, this method is limited by its inability to target CSCs, potentially allowing the CSCs to survive and re-initiate tumor growth. More recently, nanodrug-mediated thermotherapy has been explored to selectively eliminate CSCs and specifically deposit heat in tumor to spare healthy tissue. Here, we provide a brief overview of the targeting moieties and nanoplatforms used in developing nanodrug-mediated thermotherapy of cancer with particular emphasis on the CSCs, as well as the challenges and potential directions for future research in this emerging field.