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The MRI community is using quantitative mapping techniques to complement qualitative imaging. For quantitative imaging to reach its full potential, it is necessary to analyze measurements across systems and longitudinally. Clinical use of quantitative imaging can be facilitated through adoption and use of a standard system phantom, a calibration/standard reference object, to assess the performance of an MRI machine. The International Society of Magnetic Resonance in Medicine AdHoc Committee on Standards for Quantitative Magnetic Resonance was established in February 2007 to facilitate the expansion of MRI as a mainstream modality for multi‐institutional measurements, including, among other things, multicenter trials. The goal of the Standards for Quantitative Magnetic Resonance committee was to provide a framework to ensure that quantitative measures derived from MR data are comparable over time, between subjects, between sites, and between vendors. This paper, written by members of the Standards for Quantitative Magnetic Resonance committee, reviews standardization attempts and then details the need, requirements, and implementation plan for a standard system phantom for quantitative MRI. In addition, application‐specific phantoms and implementation of quantitative MRI are reviewed. Magn Reson Med 79:48–61, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Abstract BACKGROUND When clinical presentation, laboratory studies, or imaging cannot diagnose cavernous sinus (CS) and/or Meckel's cave (MC) lesions, biopsy may be necessary. OBJECTIVE To review our institutional series of biopsies of indeterminate CS and MC lesions. METHODS Records from January 1994 to June 2016 were searched for biopsied indeterminate CS and MC lesions. We defined indeterminate as having an atypical imaging appearance or a broad differential and the need for tissue for definitive diagnosis. We defined primary tumors as originating from cells inherent or near the CS and MC. RESULTS Eighty-five patients were included (median age 59 [2-85] yr); 22 (28%) had a cancer history. Approaches included frontotemporal craniotomy (n = 48, 56%), endoscopic endonasal (n = 20, 24%), percutaneous transforamen ovale (n = 12, 14%), or retrosigmoid craniotomy (n = 5, 6%). Final diagnosis was metastatic in 27 (32%), primary in 21 (25%), inflammatory in 13 (15%), hematologic in 11 (13%), fungal in 5 (5%), and nondefinitive or nondiagnostic in 8 (10%) patients. Thirteen (59%) patients with a cancer history (n = 22) had a diagnosis consistent with their prior cancer; the remaining had a second pathology (n = 6, 27%) or nondiagnostic biopsy (n = 3, 14%). Two patients had surgical complications resulting in death. CONCLUSION In this patient cohort, metastatic tumors were the most likely pathology. The biopsy threshold should be lower in patients with a cancer history if clinical or radiographic diagnosis is uncertain as 27% had a second disease. However, we consider biopsy as a last resort because the risk of major morbidity/mortality, while low, is not zero.

OBJECTIVEIt has been suggested that increased body mass index (BMI) may confer a protective effect on patients who suffer from aneurysmal subarachnoid hemorrhage (aSAH). Whether the modality of aneurysm occlusion influences the effect of BMI on patient outcomes is not well understood. The authors aimed to compare the effect of BMI on outcomes for patients with aSAH treated with surgical clipping versus endovascular coiling.METHODSThe authors retrospectively reviewed the outcomes for patients admitted to their institution for the management of aSAH treated with either clipping or coiling. BMI at the time of admission was recorded and used to assign patients to a group according to low or high BMI. Cutoff values for BMI were determined by classification and regression tree analysis. Predictors of poor functional outcome (defined as modified Rankin Scale score > 2 measured ≥ 90 days after the ictus) and posttreatment cerebral hypodensities detected during admission were then determined separately for patients treated with clipping or coiling using stepwise multivariate logistic regression analysis.RESULTSOf the 469 patients admitted to the authors’ institution with aSAH who met the study’s inclusion criteria, 144 were treated with clipping and 325 were treated with coiling. In the clipping group, the frequency of poor functional outcome was higher in patients with BMI ≥ 32.3 kg/m2 (47.6% vs 19.0%; p = 0.007). In contrast, in the coiling group, patients with BMI ≥ 32.3 kg/m2 had a lower frequency of poor functional outcome at ≥ 90 days (5.8% vs 30.9%; p < 0.001). On multivariate analysis, high BMI was independently associated with an increased (OR 3.92, 95% CI 1.20–13.41; p = 0.024) and decreased (OR 0.13, 95% CI 0.03–0.40; p < 0.001) likelihood of poor functional outcome for patients treated with clipping and coiling, respectively. For patients in the surgical group, BMI ≥ 28.4 kg/m2 was independently associated with incidence of cerebral hypodensities during admission (OR 2.44, 95% CI 1.16–5.25; p = 0.018) on multivariate analysis. For patients treated with coiling, BMI ≥ 33.2 kg/m2 was independently associated with reduced odds of hypodensities (OR 0.45, 95% CI 0.21–0.89; p = 0.021).CONCLUSIONSThe results of this study suggest that BMI may differentially affect functional outcomes after aSAH, depending on treatment modality. These findings may aid in treatment selection for patients with aSAH.

Abstract Ligation of programmed cell death-1 (PD-1) in the tumor microenvironment is known to inhibit effective adaptive antitumor immunity. Blockade of PD-1 in humans has resulted in impressive, durable regression responses in select tumor types. However, durable responses have been elusive in ovarian cancer patients. PD-1 was recently shown to be expressed on and thereby impair the functions of tumor-infiltrating murine and human myeloid dendritic cells (TIDC) in ovarian cancer. In the present work, we characterize the regulation of PD-1 expression and the effects of PD-1 blockade on TIDC. Treatment of TIDC and bone marrow–derived dendritic cells (DC) with IL10 led to increased PD-1 expression. Both groups of DCs also responded to PD-1 blockade by increasing production of IL10. Similarly, treatment of ovarian tumor–bearing mice with PD-1 blocking antibody resulted in an increase in IL10 levels in both serum and ascites. While PD-1 blockade or IL10 neutralization as monotherapies were inefficient, combination of these two led to improved survival and delayed tumor growth; this was accompanied by augmented antitumor T- and B-cell responses and decreased infiltration of immunosuppressive MDSC. Taken together, our findings implicate compensatory release of IL10 as one of the adaptive resistance mechanisms that undermine the efficacy of anti–PD-1 (or anti–PD-L1) monotherapies and prompt further studies aimed at identifying such resistance mechanisms. Cancer Res; 77(23); 6667–78. ©2017 AACR.

Aging is associated with increased peripheral chemoreceptor activity, reduced nitric oxide (NO) bioavailability, and attenuation of cardiovagal baroreflex sensitivity (BRS), collectively increasing the risk of cardiovascular disease. Evidence suggests that NO may attenuate peripheral chemoreflex sensitivity and increase BRS. Exogenous inorganic nitrate ([Formula: see text]) increases NO bioavailability via the [Formula: see text]-[Formula: see text]-NO pathway. Our hypothesis was that inorganic [Formula: see text] supplementation would attenuate peripheral chemoreflex sensitivity and enhance spontaneous cardiovagal BRS in older adults. We used a randomized, placebo-controlled crossover design in which 13 older (67 ± 3 yr old) adults ingested beetroot powder containing (BRA) or devoid of (BRP) [Formula: see text] and [Formula: see text] daily over 4 wk. Spontaneous cardiovagal BRS was assessed over 15 min of rest and was quantified using the sequence method. Chemoreflex sensitivity was assessed via ~5 min of hypoxia (10% fraction of inspired O2) and reported as the slope of the relationship between O2 saturation (%[Formula: see text]) and minute ventilation (in l/min) or heart rate (in beats/min). Ventilatory responsiveness to hypoxia was reduced after BRA (from −0.14 ± 0.04 to −0.05 ± 0.02 l·min−1·%[Formula: see text]−1, P = 0.01) versus BRP (from −0.10 ± 0.05 to −0.11 ± 0.05 l·min−1·%[Formula: see text]−1, P = 0.80), with no differences in heart rate responsiveness (BRA: from −0.47 ± 0.06 to −0.33 ± 0.04 beats·min−1·%[Formula: see text]−1, BRP: from −0.48 ± 0.07 to −0.42 ± 0.06 beats·min−1·%[Formula: see text]−1) between conditions (interaction effect, P = 0.41). Spontaneous cardiovagal BRS was unchanged after BRA and BRP (interaction effects, P = 0.69, 0.94, and 0.39 for all, up, and down sequences, respectively), despite a reduction in resting systolic and mean arterial blood pressure in the experimental (BRA) group ( P < 0.01 for both). These findings illustrate that inorganic [Formula: see text] supplementation attenuates peripheral chemoreflex sensitivity without concomitant change in spontaneous cardiovagal BRS in older adults. NEW & NOTEWORTHY Exogenous inorganic nitrate supplementation attenuates ventilatory, but not heart rate, responsiveness to abbreviated hypoxic exposure in older adults. Additionally, inorganic nitrate reduces systolic and mean arterial blood pressure without affecting spontaneous cardiovagal baroreflex sensitivity. These findings suggest that inorganic nitrate may attenuate sympathetically oriented pathologies associated with aging.

AbstractMonte Carlo (MC) simulation has been used to generate commissioning data for the beam modeling of treatment planning system (TPS). We have developed a method called radial projection (RP) for postprocessing of MC‐simulation‐generated data. We used the RP method to reduce the statistical uncertainty of the lateral profile of proton pencil beams with axial symmetry. The RP method takes advantage of the axial symmetry of dose distribution to use the mean value of multiple independent scores as the representative score. Using the mean as the representative value rather than any individual score results in substantial reduction in statistical uncertainty. Herein, we present the concept and step‐by‐step implementation of the RP method, as well as show the advantage of the RP method over conventional measurement methods for generating lateral profile. Lateral profiles generated by both methods were compared to demonstrate the uncertainty reduction qualitatively, and standard error comparison was performed to demonstrate the reduction quantitatively. The comparisons showed that statistical uncertainty was reduced substantially by the RP method. Using the RP method to postprocess MC data, the corresponding MC simulation time was reduced by a factor of 10 without quality reduction in the generated result from the MC data. We concluded that the RP method is an effective technique to increase MC simulation efficiency for generating lateral profiles for axially symmetric pencil beams.

Background The angiographic evaluation of previously coiled aneurysms can be difficult yet remains critical for determining re-treatment. Objective The main objective of this study was to determine the inter-rater reliability for both the Raymond Scale and per cent embolization among a group of neurointerventionalists evaluating previously embolized aneurysms. Methods A panel of 15 neurointerventionalists examined 92 distinct cases of immediate post-coil embolization and 1 year post-embolization angiographs. Each case was presented four times throughout the study, along with alterations in demographics in order to evaluate intra-rater reliability. All respondents were asked to provide the per cent embolization (0–100%) and Raymond Scale grade (1-3) for each aneurysm. Inter-rater reliability was evaluated by computing weighted kappa values (for the Raymond Scale) and intraclass correlation coefficients (ICC) for per cent embolization. Results 10 neurosurgeons and 5 interventional neuroradiologists evaluated 368 simulated cases. The agreement among all readers employing the Raymond Scale was fair (κ=0.35) while concordance in per cent embolization was good (ICC=0.64). Clinicians with fewer than 10 years of experience demonstrated a significantly greater level of agreement than the group with greater than 10 years (κ=0.39 and ICC=0.70 vs κ=0.28 and ICC=0.58). When the same aneurysm was presented multiple times, clinicians demonstrated excellent consistency when assessing per cent embolization (ICC=0.82), but moderate agreement when employing the Raymond classification (κ=0.58). Conclusions Identifying the per cent embolization in previously coiled aneurysms resulted in good inter- and intra-rater agreement, regardless of years of experience. The strong agreement among providers employing per cent embolization may make it a valuable tool for embolization assessment in this patient population.

Abstract Androgen receptor (AR) signaling is a key driver of prostate cancer, and androgen-deprivation therapy (ADT) is a standard treatment for patients with advanced and metastatic disease. However, patients receiving ADT eventually develop incurable castration-resistant prostate cancer (CRPC). Here, we report that the chromatin modifier LSD1, an important regulator of AR transcriptional activity, undergoes epigenetic reprogramming in CRPC. LSD1 reprogramming in this setting activated a subset of cell-cycle genes, including CENPE, a centromere binding protein and mitotic kinesin. CENPE was regulated by the co-binding of LSD1 and AR to its promoter, which was associated with loss of RB1 in CRPC. Notably, genetic deletion or pharmacological inhibition of CENPE significantly decreases tumor growth. Our findings show how LSD1-mediated epigenetic reprogramming drives CRPC, and they offer a mechanistic rationale for its therapeutic targeting in this disease. Cancer Res; 77(20); 5479–90. ©2017 AACR.

Advancements in computational musculoskeletal biomechanics are constrained by a lack of experimental measurement under real-time physiological loading conditions. This paper presents the design, configuration, capabilities, accuracy, and repeatability of The University of Texas at El Paso Joint Load Simulator (UTJLS) by testing four cadaver knee specimens with 47 real-time tests including heel and toe squat maneuvers with and without musculotendon forces. The UTJLS is a musculoskeletal simulator consisting of two robotic manipulators and eight musculotendon actuators. Sensors include eight tension load cells, two force/torque systems, nine absolute encoders, and eight incremental encoders. A custom control system determines command output for position, force, and hybrid control and collects data at 2000 Hz. Controller configuration performed forward-dynamic control for all knee degrees-of-freedom (DOFs) except knee flexion. Actuator placement and specimen potting techniques uniquely replicate muscle paths. Accuracy and repeatability standard deviations across specimen during squat simulations were equal or less than 8 N and 5 N for musculotendon actuators, 30 N and 13 N for ground reaction forces (GRFs), and 4.4 N·m and 1.9 N·m for ground reaction moments. The UTJLS is the first of its design type. Controller flexibility and physical design support axis constraints to match traditional testing rigs, absolute motion, and synchronous real-time simulation of multiplanar kinematics, GRFs, and musculotendon forces. System DOFs, range of motion, and speed support future testing of faster maneuvers, various joints, and kinetic chains of two connected joints.

Significance Few patients with pancreatic cancer survive longer than 5 y, in part because most patients are identified only after their disease has progressed to an advanced stage. In this study, we show how combining mutations in circulating tumor DNA (ctDNA) with protein markers can result in a screening test with improved sensitivity while retaining specificity. The combination of the ctDNA and protein markers was superior to any single marker. Moreover, the combination detected nearly two-thirds of pancreatic cancers that had no evidence of distant metastasis at the time of surgical resection. The strategy may represent an approach to detect cancers of many types at an earlier stage.