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Quantitative three-dimensional molecular ultrasound is a promising technology for longitudinal imaging applications such as therapy monitoring; the risk profile is favorable compared to positron emission tomography and computed tomography. However, clinical translation of quantitative methods for this technology are limited in that they assume that tumor tissues are homogeneous, and often depend on contrast-destruction events that can produce unintended bioeffects. Here, we develop quantitative features (henceforth image features) that capture tumor spatial information, and that are extracted without contrast destruction. We compare these techniques with the contrast-destruction derived differential targeted enhancement parameter (dTE) in predicting response to therapy. We found thirty-three reproducible image features that predict response to antiangiogenic therapy, without the need for a contrast agent disruption pulse. Multiparametric analysis shows that several of these image features can differentiate treated versus control animals with comparable performance to post-destruction measurements, suggesting that these can potentially replace parameters such as the dTE. The highest performing pre-destruction image features showed strong linear correlations with conventional dTE parameters with less overall variance. Thus, our study suggests that image features obtained during the wash in of the molecular agent, pre-destruction, may replace conventional post-destruction image features or the dTE parameter.

Due to spatial tumor heterogeneity and consecutive sampling errors, it is critically important to assess treatment response following antiangiogenic therapy in three dimensions as two-dimensional assessment has been shown to substantially over- and underestimate treatment response. In this study, we evaluated whether three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) imaging allows assessing early changes in tumor perfusion following antiangiogenic treatment (bevacizumab administered at a dose of 10 mg/kg b.w.), and whether these changes could predict treatment response in colon cancer tumors that either are responsive (LS174T tumors) or none responsive (CT26) to the proposed treatment. Our results showed that the perfusion parameters of 3D DCE-US including peak enhancement (PE) and area under curve (AUC) significantly decreased by up to 69 and 77%, respectively, in LS174T tumors within 1 day after antiangiogenic treatment ( P  = 0.005), but not in CT26 tumors ( P  > 0.05). Similarly, the percentage area of neovasculature significantly decreased in treated versus control LS174T tumors ( P  < 0.001), but not in treated versus control CT26 tumors (P  = 0.796). Early decrease in both PE and AUC by 45–50% was predictive of treatment response in 100% (95% CI 69.2, 100%) of responding tumors, and in 100% (95% CI 88.4, 100%) and 86.7% (95% CI 69.3, 96.2%), respectively, of nonresponding tumors. In conclusion, 3D DCE-US provides clinically relevant information on the variability of tumor response to antiangiogenic therapy and may be further developed as biomarker for predicting treatment outcomes.

Increasing efforts and financial resources are being invested in early cancer detection research. Blood assays detecting tumor biomarkers promise noninvasive and financially reasonable screening for early cancer with high potential of positive impact on patients' survival and quality of life. For novel tumor biomarkers, the actual tumor detection limits are usually unknown and there have been no studies exploring the tumor burden detection limits of blood tumor biomarkers using mathematical models. Therefore, the purpose of this study was to develop a mathematical model relating blood biomarker levels to tumor burden. Using a linear one-compartment model, the steady state between tumor biomarker secretion into and removal out of the intravascular space was calculated. Two conditions were assumed: (1) the compartment (plasma) is well-mixed and kinetically homogenous; (2) the tumor biomarker consists of a protein that is secreted by tumor cells into the extracellular fluid compartment, and a certain percentage of the secreted protein enters the intravascular space at a continuous rate. The model was applied to two pathophysiologic conditions: tumor biomarker is secreted (1) exclusively by the tumor cells or (2) by both tumor cells and healthy normal cells. To test the model, a sensitivity analysis was performed assuming variable conditions of the model parameters. The model parameters were primed on the basis of literature data for two established and well-studied tumor biomarkers (CA125 and prostate-specific antigen [PSA]). Assuming biomarker secretion by tumor cells only and 10% of the secreted tumor biomarker reaching the plasma, the calculated minimally detectable tumor sizes ranged between 0.11 mm(3) and 3,610.14 mm(3) for CA125 and between 0.21 mm(3) and 131.51 mm(3) for PSA. When biomarker secretion by healthy cells and tumor cells was assumed, the calculated tumor sizes leading to positive test results ranged between 116.7 mm(3) and 1.52 x 10(6) mm(3) for CA125 and between 27 mm(3) and 3.45 x 10(5) mm(3) for PSA. One of the limitations of the study is the absence of quantitative data available in the literature on the secreted tumor biomarker amount per cancer cell in intact whole body animal tumor models or in cancer patients. Additionally, the fraction of secreted tumor biomarkers actually reaching the plasma is unknown. Therefore, we used data from published cell culture experiments to estimate tumor cell biomarker secretion rates and assumed a wide range of secretion rates to account for their potential changes due to field effects of the tumor environment. This study introduced a linear one-compartment mathematical model that allows estimation of minimal detectable tumor sizes based on blood tumor biomarker assays. Assuming physiological data on CA125 and PSA from the literature, the model predicted detection limits of tumors that were in qualitative agreement with the actual clinical performance of both biomarkers. The model may be helpful in future estimation of minimal detectable tumor sizes for novel proteomic biomarker assays if sufficient physiologic data for the biomarker are available. The model may address the potential and limitations of tumor biomarkers, help prioritize biomarkers, and guide investments into early cancer detection research efforts.

Abstract ObjectiveTo introduce a 3D fast spin-echo (FSE) sequence technique that may replace conventional clinical 2D FSE sequences for examining the brachial plexus.Materials and methodsA 3D FSE sequence with motion-sensitized driven equilibrium magnitude preparation, triple-echo Dixon, and outer-volume suppression techniques, dubbed as MSDE-CUBE-fTED, was compared with clinical 2D T2-weighted and T1-weighted FSE sequences on the conventional brachial plexus exam of 14 volunteers. The resulting images were evaluated by two radiologists for fat suppression, blood flow suppression, nerve visualization, scalene muscle shape, surrounding fat planes, and diagnostic confidence. The inter-rater agreement of the reviewers was also measured. In addition, the signal magnitude ratios and contrast-to-noise ratios between nerve-to-vessel, nerve-to-muscle, and fat-to-muscle were compared.ResultsThe MSDE-CUBE-fTED sequence scored significantly higher than the T2-weighed FSE sequence in all visualization categories (P < 0.05). Its score was not significantly different from that of the T1-weighted FSE in muscle and fat visualization (P ≥ 0.5). The inter-rater agreements were substantial (Gwet’s agreement coefficient ≥ 0.7). The signal magnitude and contrast ratios were significantly higher in the MSDE-CUBE-fTED sequence (P < 0.05).ConclusionOur results suggest that the MSDE-CUBE-fTED sequence can make a potential alternative to standard T2- and T1-weighted FSE sequences for examining the brachial plexus.

A standardized guideline and scoring system should be used for the MR imaging diagnosis of peripheral neuropathy. The MR imaging-based Neuropathy Score Reporting and Data System (NS-RADS) is a newly devised classification system (in press in AJR) that can be used to communicate both type and severity of peripheral neuropathy in the light of clinical history and examination findings. The spectrum of neuropathic conditions and peripheral nerve disorders covered in this system includes nerve injury, entrapment, neoplasm, diffuse neuropathy, and post-interventional states. This classification system also describes the temporal MR imaging appearances of regional muscle denervation changes. This review article is based on the multicenter validation study pre-published in American journal of Roentgenology and discusses technical considerations of optimal MR imaging for peripheral nerve evaluation and discusses the NS-RADS classification and its severity scales with illustration of conditions that fall under each classification. The readers can gain knowledge of the NS-RADS classification system and learn to apply it in their practices for improved inter-disciplinary communications and timely patient management.

ObjectivesTo investigate the purported relationship between sciatic nerve variant anatomy and piriformis syndrome.MethodsOver 49 months, 1039 consecutive noncontrast adult hip MRIs were completed for various clinical indications. Repeat and technically insufficient studies were excluded. Radiologists categorized sciatic nerve anatomy into Beaton and Anson anatomical types. Chart review using our institution’s cohort search and navigation tool determined the prevalence of the explicit clinical diagnosis of piriformis syndrome (primary endpoint) and sciatica and buttock pain (secondary endpoints). A Z-test compared the prevalence of each diagnosis in the variant anatomy and normal groups.ResultsSeven hundred eighty-three studies were included, with sciatic nerve variants present in 150 hips (19.2%). None of the diagnoses had a statistically significant difference in prevalence between the variant and normal hip groups. Specifically, piriformis syndrome was present in 11.3% of variant hips compared with 9.0% of normal hips (p = 0.39).ConclusionsThere were no significant differences in the prevalence of piriformis syndrome, buttock pain, or sciatica between normal and variant sciatic nerve anatomy. This large-scale correlative radiologic study into the relationship between sciatic nerve variants and piriformis syndrome calls into question this purported relationship.Key Points• Large retrospective study relating variant sciatic nerve anatomy, present in 19.2% of hip MRIs, and piriformis syndrome• While sciatic nerve variant anatomy has previously been implicated in piriformis syndrome in small studies, no relationship was identified between sciatic nerve variants and piriformis syndrome

Objectives Most of the shoulder magnetic resonance imaging (MRI) examination focuses on internal joint structures but disregarding other structures like the distal brachial plexus, which may miss important findings. Hereby, we attempt to evaluate the prevalence of distal brachial plexus abnormalities and/or muscular denervation changes seen on routine shoulder MRI examinations and discuss common pathologies affecting the distal brachial plexus. Material and methods A total of 701 routine shoulder MRI studies were evaluated. The evaluation of each exam was focused on the visualized brachial plexus elements and musculature abnormalities in each case. If any abnormalities of plexus and/or musculature were found, potential underlying etiologies such as paralabral or spinoglenoid notch cysts, infiltrative/primary masses on imaging, history of prior viral illness, and radiation therapy were searched. It was then confirmed whether the abnormal findings were mentioned in the exam reports or not. Results Thirty-four cases (4.85%) demonstrated abnormal findings of the visualized brachial plexus cords or branches and/or musculature. It was observed that in 35.3% of exam reports these findings were not mentioned, mainly missing subtle nerve abnormalities, but correctly reporting and interpreting the encountered muscle abnormalities. Conclusion The distal brachial plexus and its branches should be included in the search pattern for shoulder MRI examinations. Key Points • Normal T2 signal of the brachial plexus is iso- to slightly hyperintense to muscle but less signal intense than fluid. • Diffuse, geographic muscle edema is an indirect sign of brachial plexus pathology. • Increased T2-weighted nerve signal with or without caliber or course change should be reported and followed up to find the underlying etiology.

ObjectiveThis study aimed to evaluate injury patterns associated with Stieda avulsion fractures of the medial femoral condyle at the attachment of the proximal MCL.Materials and methodsKnee radiographs and MRI scans of 11 patients with Stieda fractures were evaluated by two fellowship-trained MSK radiologists for fracture origin, integrity of the deep and superficial components of the MCL, medial retinacular structures, posterior oblique ligament, other ligamentous injuries, meniscal tears, and osteochondral injuries. The mechanism of injury and subsequent clinical management were recorded.ResultsEight Stieda fractures only involved the meniscofemoral fibers of the deep MCL, two larger Stieda fractures related to both superficial and deep layers, and one fracture only involved the superficial layer. Posteromedial retinacular structures and posterior oblique ligament were injured in all cases. Eight had high-grade ACL injuries, but none had high-grade PCL nor FCL injuries. The proximal anterolateral ligament was injured in seven, including two with associated Segond fractures. Other injuries included posterolateral corner injuries in six, meniscal injuries in seven, and additional fractures in nine, most commonly ACL-associated impaction fractures in the lateral tibiofemoral compartment. None had high-grade chondral injury. None of the Stieda fractures were treated surgically, but four underwent subsequent ACL reconstruction.ConclusionStieda fractures most commonly involved the deep fibers of the MCL and were accompanied by moderate-to-high-grade injury of other MCL components. There was a high association with other ligamentous injuries, particularly the posterior medial retinacular structures, posterior oblique ligament, and ACL, and many were associated with additional fractures.

Objective To determine whether known variant anatomical relationships between the sciatic nerve and piriformis muscle can be identified on routine MRI studies of the hip and to establish their imaging prevalence. Methods Hip MRI studies acquired over a period of 4 years at two medical centers underwent retrospective interpretation. Anatomical relationship between the sciatic nerve and the piriformis muscle was categorized according to the Beaton and Anson classification system. The presence of a split sciatic nerve at the level of the ischial tuberosity was also recorded. Results A total of 755 consecutive scans were reviewed. Conventional anatomy (type I), in which an undivided sciatic nerve passes below the piriformis muscle, was identified in 87% of cases. The remaining 13% of cases demonstrated a type II pattern in which one division of the sciatic nerve passes through the piriformis whereas the second passes below. Only two other instances of variant anatomy were identified (both type III). Most variant cases were associated with a split sciatic nerve at the level of the ischial tuberosity (73 out of 111, 65.8%). By contrast, only 6% of cases demonstrated a split sciatic nerve at this level in the context of otherwise conventional anatomy. Conclusion Anatomical variations of the sciatic nerve course in relation to the piriformis muscle are frequently identified on routine MRI of the hips, occurring in 12–20% of scans reviewed. Almost all variants identified were type II. The ability to recognize variant sciatic nerve courses on MRI may prove useful in optimal treatment planning.

Targeted contrast-enhanced ultrasound imaging is increasingly being recognized as a powerful imaging tool for the detection and quantification of tumor angiogenesis at the molecular level. The purpose of this study was to develop and test a new class of targeting ligands for targeted contrast-enhanced ultrasound imaging of tumor angiogenesis with small, conformationally constrained peptides that can be coupled to the surface of ultrasound contrast agents. Directed evolution was used to engineer a small, disulfide-constrained cystine knot (knottin) peptide that bound to alpha(v)beta(3) integrins with a low nanomolar affinity (Knottin(Integrin)). A targeted contrast-enhanced ultrasound imaging contrast agent was created by attaching Knottin(Integrin) to the shell of perfluorocarbon-filled microbubbles (MB-Knottin(Integrin)). A knottin peptide with a scrambled sequence was used to create control microbubbles (MB-Knottin(Scrambled)). The binding of MB-Knottin(Integrin) and MB-Knottin(Scrambled) to alpha(v)beta(3) integrin-positive cells and control cells was assessed in cell culture binding experiments and compared with that of microbubbles coupled to an anti-alpha(v)beta(3) integrin monoclonal antibody (MB(alphavbeta3)) and microbubbles coupled to the peptidomimetic agent c(RGDfK) (MB(cRGD)). The in vivo imaging signals of contrast-enhanced ultrasound with the different types of microbubbles were quantified in 42 mice bearing human ovarian adenocarcinoma xenograft tumors by use of a high-resolution 40-MHz ultrasound system. MB-Knottin(Integrin) attached significantly more to alpha(v)beta(3) integrin-positive cells (1.76 +/- 0.49 [mean +/- SD] microbubbles per cell) than to control cells (0.07 +/- 0.006). Control MB-Knottin(Scrambled) adhered less to alpha(v)beta(3) integrin-positive cells (0.15 +/- 0.12) than MB-Knottin(Integrin). After blocking of integrins, the attachment of MB-Knottin(Integrin) to alpha(v)beta(3) integrin-positive cells decreased significantly. The in vivo ultrasound imaging signal was significantly higher after the administration of MB-Knottin(Integrin) than after the administration of MB(alphavbeta3) or control MB-Knottin(Scrambled). After in vivo blocking of integrin receptors, the imaging signal after the administration of MB-Knottin(Integrin) decreased significantly (by 64%). The imaging signals after the administration of MB-Knottin(Integrin) were not significantly different in the groups of tumor-bearing mice imaged with MB-Knottin(Integrin) and with MB(cRGD). Ex vivo immunofluorescence confirmed integrin expression on endothelial cells of human ovarian adenocarcinoma xenograft tumors. Integrin-binding knottin peptides can be conjugated to the surface of microbubbles and used for in vivo targeted contrast-enhanced ultrasound imaging of tumor angiogenesis. Our results demonstrate that microbubbles conjugated to small peptide-targeting ligands provide imaging signals higher than those provided by a large antibody molecule.