Purpose To examine the potential use of BOLD (Blood Oxygenation Level Dependent) and TOLD (Tissue Oxygenation Level Dependent) contrast MRI to assess tumor oxygenation and predict radiation response. Methods BOLD and TOLD MRI were performed on Dunning R3327-AT1 rat prostate tumors during hyperoxic gas breathing challenge at 4.7 T. Animals were divided into two groups. In Group 1 (n=9), subsequent 19F MRI based on spin lattice relaxation of hexafluorobenzene reporter molecule provided quantitative oximetry for comparison. For Group 2 rats (n=13) growth delay following a single dose of 30 Gy was compared with pre-irradiation BOLD and TOLD assessments. Results Oxygen (100%O2) and carbogen (CB; 95%O2/5%CO2) challenge elicited similar BOLD, TOLD and pO2 responses. Strong correlations were observed between BOLD or R2* response and quantitative 19F pO2 measurements. TOLD response showed a general trend with weaker correlation. Irradiation caused a significant tumor growth delay and tumors with larger changes in TOLD and R1 values upon oxygen breathing exhibited significantly increased tumor growth delay. Conclusion These results provide further insight into the relationships between oxygen sensitive (BOLD/TOLD) MRI and tumor pO2. Moreover, a larger increase in R1 response to hyperoxic gas challenge coincided with greater tumor growth delay following irradiation.

No abstract

Pathological estimation of tumor necrosis after chemotherapy is essential for patients with osteosarcoma. This study reports the first fully automated tool to assess viable and necrotic tumor in osteosarcoma, employing advances in histopathology digitization and automated learning. We selected 40 digitized whole slide images representing the heterogeneity of osteosarcoma and chemotherapy response. With the goal of labeling the diverse regions of the digitized tissue into viable tumor, necrotic tumor, and non-tumor, we trained 13 machine-learning models and selected the top performing one (a Support Vector Machine) based on reported accuracy. We also developed a deep-learning architecture and trained it on the same data set. We computed the receiver-operator characteristic for discrimination of non-tumor from tumor followed by conditional discrimination of necrotic from viable tumor and found our models performing exceptionally well. We then used the trained models to identify regions of interest on image-tiles generated from test whole slide images. The classification output is visualized as a tumor-prediction map, displaying the extent of viable and necrotic tumor in the slide image. Thus, we lay the foundation for a complete tumor assessment pipeline from original histology images to tumor-prediction map generation. The proposed pipeline can also be adopted for other types of tumor.

There is intense interest in developing non-invasive prognostic biomarkers of tumor response to therapy, particularly with regard to hypoxia. It has been suggested that oxygen sensitive MRI, notably Blood Oxygen Level Dependent (BOLD) and Tissue Oxygen Level Dependent (TOLD) may provide relevant measurements. This study examined the feasibility of interleaved T2*- and T1-weighted oxygen sensitive MRI, as well as R2* and R1 maps of rat tumors to assess the relative sensitivity to changes in oxygenation.Investigations used cohorts of Dunning Prostate R3327-AT1 and -HI tumors, which are reported to exhibit distinct size-dependent levels of hypoxia and response to hyperoxic gas breathing. Proton MRI R1 and R2* maps were obtained for tumors of anesthetized rats (isoflurane/air) at 4.7 T. Then, interleaved gradient echo T2*- and T1-weighted images were acquired during air breathing and a ten minute challenge with carbogen (95% O2/5% CO2). Signals were stable during air breathing and each type of tumor showed distinct signal response to carbogen. T2* (BOLD) response preceded T1 (TOLD) responses, as expected. Smaller HI tumors (reported to be well oxygenated) showed the largest BOLD and TOLD responses. Larger AT1 tumors (reported to be hypoxic and resist modulation by gas breathing) showed the smallest response. There was a strong correlation between BOLD and TOLD signal responses, but ΔR *2 and ΔR1 were only correlated for the HI tumors. The magnitude of BOLD and TOLD signal responses to carbogen breathing reflected expected hypoxic fractions and oxygen dynamics suggesting potential value of this test as a prognostic biomarker of tumor hypoxia.

Hypoxia is reported to be a biomarker for poor prognosis in cervical cancer. However, a practical non-invasive method is needed for routine clinical evaluation of tumor hypoxia. This study examined the potential use of BOLD (Blood Oxygenation Level Dependent) contrast MRI as a non-invasive technique to assess tumor vascular oxygenation at 3 T. Following IRB-approved informed consent and in compliance with HIPAA, successful results were achieved in nine patients with locally advanced cervical cancer (FIGO stage IIA to IVA) and three normal volunteers. In the first four patients, dynamic T2*-weighted MRI was performed in the transaxial plane using a multi-shot EPI sequence while patients breathed room air followed by oxygen (15 dm3/min). Later, a multi-echo gradient echo examination was added to provide quantitative R2* measurements. Baseline T2*-weighted signal intensity was quite stable, but increased to various extents in tumors upon initiation of oxygen breathing. Signal in normal uterus increased significantly, while iliacus muscle did not change. R2* responded significantly in healthy uterus, cervix, and eight cervical tumors. This preliminary study demonstrates that BOLD MRI of cervical cancer at 3 T is feasible. However, more patients must be evaluated and followed clinically before any prognostic value can be determined.

Understanding the "normal" form and baseline distribution of asymmetry is an important anthropomorphic foundation. The authors present a method to quantify normal craniofacial form and baseline asymmetry in a large pediatric sample. The authors found that the normal pediatric craniofacial form is asymmetric, and does not change in magnitude with age, sex, or race.

BackgroundIncreased postural sway has been repeatedly documented in children with autism spectrum disorder (ASD). Characterizing the control processes underlying this deficit, including postural orientation and equilibrium, may provide key insights into neurophysiological mechanisms associated with ASD. Postural orientation refers to children’s ability to actively align their trunk and head with respect to their base of support, while postural equilibrium is an active process whereby children coordinate ankle dorsi-/plantar-flexion and hip abduction/adduction movements to stabilize their upper body. Dynamic engagement of each of these control processes is important for maintaining postural stability, though neither postural orientation nor equilibrium has been studied in ASD.MethodsTwenty-two children with ASD and 21 age and performance IQ-matched typically developing (TD) controls completed three standing tests. During static stance, participants were instructed to stand as still as possible. During dynamic stances, participants swayed at a comfortable speed and magnitude in either anterior-posterior (AP) or mediolateral (ML) directions. The center of pressure (COP) standard deviation and trajectory length were examined to determine if children with ASD showed increased postural sway. Postural orientation was assessed using a novel virtual time-to-contact (VTC) approach that characterized spatiotemporal dimensions of children’s postural sway (i.e., body alignment) relative to their postural limitation boundary, defined as the maximum extent to which each child could sway in each direction. Postural equilibrium was quantified by evaluating the amount of shared or mutual information of COP time series measured along the AP and ML directions.ResultsConsistent with prior studies, children with ASD showed increased postural sway during both static and dynamic stances relative to TD children. In regard to postural orientation processes, children with ASD demonstrated reduced spatial perception of their postural limitation boundary towards target directions and reduced time to correct this error during dynamic postural sways but not during static stance. Regarding postural equilibrium, they showed a compromised ability to decouple ankle dorsi-/plantar-flexion and hip abduction/adduction processes during dynamic stances.ConclusionsThese results suggest that deficits in both postural orientation and equilibrium processes contribute to reduced postural stability in ASD. Specifically, increased postural sway in ASD appears to reflect patients’ impaired perception of their body movement relative to their own postural limitation boundary as well as a reduced ability to decouple distinct ankle and hip movements to align their body during standing. Our findings that deficits in postural orientation and equilibrium are more pronounced during dynamic compared to static stances suggests that the increased demands of everyday activities in which children must dynamically shift their COP involve more severe postural control deficit...

Increased emphasis on personalized medicine and novel therapies require the development of non-invasive strategies for assessing biochemistry in vivo. The detection of enzyme activity and gene expression in vivo is potentially important for the characterization of diseases and gene therapy. Magnetic resonance imaging (MRI) is a particularly promising tool since it is non-invasive, and has no associated radioactivity, yet penetrates deep tissue. We now demonstrate a novel class of dual 1H/19F nuclear magnetic resonance (NMR) lacZ gene reporter molecule to specifically reveal enzyme activity in human tumor xenografts growing in mice. We report the design, synthesis, and characterization of six novel molecules and evaluation of the most effective reporter in mice in vivo. Substrates show a single 19F NMR signal and exposure to β-galactosidase induces a large 19F NMR chemical shift response. In the presence of ferric ions the liberated aglycone generates intense proton MRI T2 contrast. The dual modality approach allows both the detection of substrate and imaging of product enhancing the confidence in enzyme detection.