Sandip Biswal, MD

All Publications

• Cyclotron produced radio-manganese as a potential radiotracer for identifying neuroinflammation in inflammatory pain Barrett, K., Biswal, S., Lennertz, R., Jeffery, J., Becker, K., Aluicio-Sarduy, E., Barnhart, T., Engle, J. SOC NUCLEAR MEDICINE INC. 2022

  View details for Web of Science ID 000893739700038

• A robust 3D fast spin-echo technique for fast examination of the brachial plexus. Skeletal radiology Yoon, D., Antil, N., Biswal, S., Lutz, A. M. 2022

  Abstract

  To introduce a 3D fast spin-echo (FSE) sequence technique that may replace conventional clinical 2D FSE sequences for examining the brachial plexus.A 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.The 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).Our 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.

  View details for DOI 10.1007/s00256-022-04021-9

  View details for PubMedID 35347408

• Machine Learning Approach to Differentiation of Peripheral Schwannomas and Neurofibromas: A Multi-Center Study. Neuro-oncology Zhang, M., Tong, E., Wong, S., Hamrick, F., Mohammadzadeh, M., Rao, V., Pendleton, C., Smith, B. W., Hug, N. F., Biswal, S., Seekins, J., Napel, S., Spinner, R. J., Mahan, M. A., Yeom, K. W., Wilson, T. J. 2021

  Abstract

  BACKGROUND: Non-invasive differentiation between schwannomas and neurofibromas is important for appropriate management, preoperative counseling, and surgical planning, but has proven difficult using conventional imaging. The objective of this study was to develop and evaluate machine learning approaches for differentiating peripheral schwannomas from neurofibromas.METHODS: We assembled a cohort of schwannomas and neurofibromas from 3 independent institutions and extracted high-dimensional radiomic features from gadolinium-enhanced, T1-weighted MRI using the PyRadiomics package on Quantitative Imaging Feature Pipeline. Age, sex, neurogenetic syndrome, spontaneous pain, and motor deficit were recorded. We evaluated the performance of 6 radiomics-based classifier models with and without clinical features and compared model performance against human expert evaluators.RESULTS: 107 schwannomas and 59 neurofibroma were included. The primary models included both clinical and imaging data. The accuracy of the human evaluators (0.765) did not significantly exceed the no-information rate (NIR), whereas the Support Vector Machine (0.929), Logistic Regression (0.929), and Random Forest (0.905) classifiers exceeded the NIR. Using the method of DeLong, the AUC for the Logistic Regression (AUC=0.923) and K Nearest Neighbor (AUC=0.923) classifiers was significantly greater than the human evaluators (AUC=0.766; p = 0.041).CONCLUSIONS: The radiomics-based classifiers developed here proved to be more accurate and had a higher AUC on the ROC curve than expert human evaluators. This demonstrates that radiomics using routine MRI sequences and clinical features can aid in differentiation of peripheral schwannomas and neurofibromas.

  View details for DOI 10.1093/neuonc/noab211

  View details for PubMedID 34487172

• Machine-learning Approach to Differentiation of Benign and Malignant Peripheral Nerve Sheath Tumors: A Multicenter Study Zhang, M., Tong, E., Hamrick, F., Pendleton, C., Smith, B., Hug, N., Mattonen, S., Napel, S., Spinner, R., Yeom, K., Wilson, T., Mahan, M. AMER ASSOC NEUROLOGICAL SURGEONS. 2021

  View details for Web of Science ID 000680654900137

• Machine-Learning Approach to Differentiation of Benign and Malignant Peripheral Nerve Sheath Tumors: A Multicenter Study. Neurosurgery Zhang, M., Tong, E., Hamrick, F., Lee, E. H., Tam, L. T., Pendleton, C., Smith, B. W., Hug, N. F., Biswal, S., Seekins, J., Mattonen, S. A., Napel, S., Campen, C. J., Spinner, R. J., Yeom, K. W., Wilson, T. J., Mahan, M. A. 2021

  Abstract

  BACKGROUND: Clinicoradiologic differentiation between benign and malignant peripheral nerve sheath tumors (PNSTs) has important management implications.OBJECTIVE: To develop and evaluate machine-learning approaches to differentiate benign from malignant PNSTs.METHODS: We identified PNSTs treated at 3 institutions and extracted high-dimensional radiomics features from gadolinium-enhanced, T1-weighted magnetic resonance imaging (MRI) sequences. Training and test sets were selected randomly in a 70:30 ratio. A total of 900 image features were automatically extracted using the PyRadiomics package from Quantitative Imaging Feature Pipeline. Clinical data including age, sex, neurogenetic syndrome presence, spontaneous pain, and motor deficit were also incorporated. Features were selected using sparse regression analysis and retained features were further refined by gradient boost modeling to optimize the area under the curve (AUC) for diagnosis. We evaluated the performance of radiomics-based classifiers with and without clinical features and compared performance against human readers.RESULTS: A total of 95 malignant and 171 benign PNSTs were included. The final classifier model included 21 imaging and clinical features. Sensitivity, specificity, and AUC of 0.676, 0.882, and 0.845, respectively, were achieved on the test set. Using imaging and clinical features, human experts collectively achieved sensitivity, specificity, and AUC of 0.786, 0.431, and 0.624, respectively. The AUC of the classifier was statistically better than expert humans (P=.002). Expert humans were not statistically better than the no-information rate, whereas the classifier was (P=.001).CONCLUSION: Radiomics-based machine learning using routine MRI sequences and clinical features can aid in evaluation of PNSTs. Further improvement may be achieved by incorporating additional imaging sequences and clinical variables into future models.

  View details for DOI 10.1093/neuros/nyab212

  View details for PubMedID 34131749

• S1R PET/MRI of patients with chronic knee pain reveals potential pain generators not otherwise identified with standard care: Early experience Yoon, L., Yoon, P., Yoon, D., Cipriano, P., Castillo, J., Shen, B., Biswal, S. SOC NUCLEAR MEDICINE INC. 2021

  View details for Web of Science ID 000713713600142

• Increased sigma-1 receptor binding observed in the pain matrix of patients suffering from chronic pain Pajouhesh, P., Fan, A., Castillo, J., Shen, B., Cipriano, P., Yoon, D., Biswal, S. SOC NUCLEAR MEDICINE INC. 2021

  View details for Web of Science ID 000713713600248

• Neurovascular, muscle, and skin changes on [18F]FDG PET/MRI in complex regional pain syndrome of the foot: A Prospective Clinical Study. Pain medicine (Malden, Mass.) Yoon, D., Xu, Y., Cipriano, P. W., Alam, I. S., Mari Aparici, C. A., Tawfik, V. L., Curtin, C. M., Carroll, I. R., Biswal, S. 2021

  Abstract

  The goal of this study is to demonstrate the feasibility of simultaneous [18F]-fluorodeoxyglucose (FDG) positron emission tomography (PET) and magnetic resonance imaging (MRI) for non-invasive visualization of muscular, neurovascular, and skin changes secondary to complex regional pain syndrome (CRPS).Seven adult patients with CRPS of the foot and seven healthy adult controls participated in our [18F]FDG PET/MRI study.All participants received whole-body PET/MRI scans one hour after the injection of 370MBq [18F]FDG. Resulting PET/MRI images were reviewed by two radiologists. Metabolic and anatomic abnormalities identified, were grouped into muscular, neurovascular, and skin lesions. The [18F]FDG uptake of each lesion was compared with that of corresponding areas in controls using a Mann-Whitney U-test.On PET images, muscular abnormalities were found in five patients, neurovascular abnormalities in four patients, and skin abnormalities in two patients. However, on MRI images, no muscular abnormalities were detected. Neurovascular abnormalities and skin abnormalities in the affected limb were identified on MRI in one and two patients, respectively. The difference in [18F]FDG uptake between the patients and the controls was significant in muscle (p = 0.018) and neurovascular bundle (p = 0.0005).The increased uptake of [18F]FDG in the symptomatic areas likely reflects the increased metabolism due to the inflammatory response causing pain. Therefore, our approach combining metabolic [18F]FDG PET and anatomic MR imaging may offer non-invasive monitoring of the distribution and progression of inflammatory changes associated with CRPS.

  View details for DOI 10.1093/pm/pnab315

  View details for PubMedID 34718774

• Abnormal [18F]FDG PET/MRI findings in paraspinal structures of patients with suspected cerebrospinal fluid leak. Scientific reports Yoon, D., Cipriano, P. W., Penticuff, R., Castillo, J. B., Xu, Y., Carroll, I. R., Biswal, S. 2021; 11 (1): 15926

  Abstract

  A combination of magnetic resonance imaging (MRI), computed tomography (CT), and radionuclide cisternography are typically used to locate a cerebrospinal fluid (CSF) leak. However, the site of leakage cannot be determined, making treatment more difficult. Therefore, more sensitive imaging tools are needed. A whole-body [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/MRI was conducted on six patients with suspected CSF leak and the resulting images were reviewed in comparison with those from six healthy controls. Paraspinal regions of focally increased uptake of [18F]FDG were quantified using maximum standardized uptake values (SUVmax) and compared to the SUVmax of corresponding regions in the healthy controls. All six patients with suspected CSF leak showed paraspinal regions of significantly greater [18F]FDG uptake compared to the corresponding areas in controls (P < 0.05). Two patients treated with local injections (epidural blood patches and/or epidural fibrin patches) on the site of abnormal PET/MRI findings reported temporary but significant improvement in symptoms. Our results suggest [18F]FDG PET/MRI is sensitive to abnormalities potentially due to suspected CSF leak, which are not necessarily visible on conventional MRI alone or by the standard-of-care imaging methods.

  View details for DOI 10.1038/s41598-021-95056-w

  View details for PubMedID 34354104

• Sigma-1 Receptor Changes Observed in Chronic Pelvic Pain Patients: A Pilot PET/MRI Study. Frontiers in pain research (Lausanne, Switzerland) Yoon, D., Fast, A. M., Cipriano, P., Shen, B., Castillo, J. B., McCurdy, C. R., Mari Aparici, C., Lum, D., Biswal, S. 2021; 2: 711748

  Abstract

  Introduction: Chronic pelvic pain is a highly prevalent pain condition among women, but identifying the exact cause of pelvic pain remains a significant diagnostic challenge. In this study, we explored a new diagnostic approach with PET/MRI of the sigma-1 receptor, a chaperone protein modulating ion channels for activating nociceptive processes. Methods: Our approach is implemented by a simultaneous PET/MRI scan with a novel radioligand [18F]FTC-146, which is highly specific to the sigma-1 receptor. We recruited 5 chronic pelvic pain patients and 5 healthy volunteers and compared our PET/MRI findings between these two groups. Results: All five patients showed abnormally increased radioligand uptake on PET compared to healthy controls at various organs, including the uterus, vagina, pelvic bowel, gluteus maximus muscle, and liver. However, on MRI, only 2 patients showed abnormalities that could be potentially associated with the pain symptoms. For a subset of patients, the association of pain and the abnormally increased radioligand uptake was further validated by successful pain relief outcomes following surgery or trigger point injections to the identified abnormalities. Conclusion: In this preliminary study, sigma-1 receptor PET/MRI demonstrated potential for identifying abnormalities associated with chronic pelvic pain. Future studies will need to correlate samples with imaging findings to further validate the correlation between S1R distribution and pathologies of chronic pelvic pain. Trial Registration: The clinical trial registration date is June 2, 2018, and the registration number of the study is NCT03195270 (https://clinicaltrials.gov/ct2/show/NCT03556137).

  View details for DOI 10.3389/fpain.2021.711748

  View details for PubMedID 35295458

• Characteristics of Patients With Complex Limb Pain Evaluated Through an Interdisciplinary Approach Utilizing Magnetic Resonance Neurography Frontiers in Pain Research Johnson, E. M., Yoon, D., Biswal, S., Curtin, C., Fox, P., Wilson, T. J., Carroll, I., Lutz, A., Tawfik, V. 2021

  View details for DOI 10.3389/fpain.2021.689402

• Abnormal [18F]FDG PET/MRI Findings In Paraspinal Muscles of Patients with Suspected Cerebrospinal Fluid Leak. Cipriano, P., Yoon, D., Xu, Y., Carroll, I., Biswal, S. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290501468

• Sigma-1 receptor PET/MRI for identifying nociceptive sources of radiating low back pain Yoon, D., Cipriano, P., Carroll, I., Curtin, C., Roh, E., Wilson, T., Biswal, S. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290500159

• PET/MR imaging of sigma-1 receptor pinpoints previously undetectable abnormalities in chronic pelvic pain Yoon, D., Fast, A., Shen, B., James, M. L., Lum, D., Biswal, S. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290500161

• 18F-FDG PET/MRI of patients with chronic pain alters management. Cipriano, P., Yoon, D., Carroll, I., Curtin, C., Tawfik, V., Xu, Y., Biswal, S. SOC NUCLEAR MEDICINE INC. 2020

  View details for Web of Science ID 000568290500352

• Imaging of Damaged Nerves. Clinics in plastic surgery Purger, D. A., Sakamuri, S., Hug, N. F., Biswal, S., Wilson, T. J. 2020; 47 (2): 245–59

  Abstract

  Nerve imaging is an important component in the assessment of patients presenting with suspected peripheral nerve pathology. Although magnetic resonance neurography and ultrasound are the most commonly utilized techniques, several promising new modalities are on the horizon. Nerve imaging is useful in localizing the nerve injury, determining the severity, providing prognostic information, helping establish the diagnosis, and helping guide surgical decision making. The focus of this article is imaging of damaged nerves, focusing on nerve injuries and entrapment neuropathies.

  View details for DOI 10.1016/j.cps.2019.12.003

  View details for PubMedID 32115050

• Identifying Musculoskeletal Pain Generators Using Clinical PET. Seminars in musculoskeletal radiology Yoon, D. n., Kogan, F. n., Gold, G. E., Biswal, S. n. 2020; 24 (4): 441–50

  Abstract

  Identifying the source of a person's pain is a significant clinical challenge because the physical sensation of pain is believed to be subjective and difficult to quantify. The experience of pain is not only modulated by the individual's threshold to painful stimuli but also a product of the person's affective contributions, such as fear, anxiety, and previous experiences. Perhaps then to quantify pain is to examine the degree of nociception and pro-nociceptive inflammation, that is, the extent of cellular, chemical, and molecular changes that occur in pain-generating processes. Measuring changes in the local density of receptors, ion channels, mediators, and inflammatory/immune cells that are involved in the painful phenotype using targeted, highly sensitive, and specific positron emission tomography (PET) radiotracers is therefore a promising approach toward objectively identifying peripheral pain generators. Although several preclinical radiotracer candidates are being developed, a growing number of ongoing clinical PET imaging approaches can measure the degree of target concentration and thus serve as a readout for sites of pain generation. Further, when PET is combined with the spatial and contrast resolution afforded by magnetic resonance imaging, nuclear medicine physicians and radiologists can potentially identify pain drivers with greater accuracy and confidence. Clinical PET imaging approaches with fluorine-18 fluorodeoxyglucose, fluorine-18 sodium fluoride, and sigma-1 receptor PET radioligand and translocator protein radioligands to isolate the source of pain are described here.

  View details for DOI 10.1055/s-0040-1713607

  View details for PubMedID 32992371

• Diagnosis and Successful Management of an Unusual Presentation of Chronic Foot Pain Using Positron Emission Tomography/Magnetic Resonance Imaging and a Simple Surgical Procedure CLINICAL JOURNAL OF SPORT MEDICINE Cipriano, P., Yoon, D., Holley, D., Hargreaves, B., Carroll, I., Curtin, C., Biswal, S. 2020; 30 (1): E11–E14

  View details for DOI 10.1097/JSM.0000000000000651

  View details for Web of Science ID 000524358800006

• 18F-FDG PET/MRI of patients with chronic pain alters management. Cipriano, P., Yoon, D., Carroll, I., Curtin, C., Tawfik, V., Xu, Y., Biswal, S. SOC NUCLEAR MEDICINE INC. 2019

  View details for Web of Science ID 000473116800093

• Abnormal [18F]FDG PET MRI Findings in Paraspmal Muscles of Patients with Suspected Cerebrospinal Fluid Leak Cipriano, P., Yoon, D., Carroll, I., Penticuff, R., Xu, Y., Biswal, S. SOC NUCLEAR MEDICINE INC. 2019

  View details for Web of Science ID 000473116800095

• Musculoskeletal changes on [18F]FDG PET/MRI from complex regional pain syndrome in foot Yoon, D., Xu, Y., Cipriano, P., Tawfik, V., Curtin, C., Carroll, I., Biswal, S. SOC NUCLEAR MEDICINE INC. 2019

  View details for Web of Science ID 000473116800094

• Diagnosis and Successful Management of an Unusual Presentation of Chronic Foot Pain Using Positron Emission Tomography/Magnetic Resonance Imaging and a Simple Surgical Procedure. Clinical journal of sport medicine : official journal of the Canadian Academy of Sport Medicine Cipriano, P. W., Yoon, D., Holley, D., Hargreaves, B. A., Carroll, I. R., Curtin, C. M., Biswal, S. 2019

  Abstract

  A 61-year-old man presented with chronic dorsal foot pain of 9 years that worsened with ambulation. Conventional diagnostic imaging and medical workup were unrevealing, and ankle arthrodesis had been recommended by an orthopedic surgeon for pain relief. Instead, the patient participated in a clinical imaging trial designed for identifying pain generators using whole-body fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI). The scan revealed not only high 18F-FDG uptake at the site of pain, but also a hematoma and an inflamed, fibrotic, ruptured plantaris muscle. The fibrotic plantaris likely altered biomechanics with walking, explaining why symptoms worsened with activity. A simple tenotomy of the plantaris tendon was performed to decouple ankle movement from the plantaris injury, resulting in pain relief. This case illustrates the potential of whole-body 18F-FDG PET/MRI to better localize pain generators.

  View details for PubMedID 30908328

• [F-18] FSPG-PET reveals increased cystine/glutamate antiporter (xc-) activity in a mouse model of multiple sclerosis JOURNAL OF NEUROINFLAMMATION Hoehne, A., James, M. L., Alam, I. S., Ronald, J. A., Schneider, B., D'Souza, A., Witney, T. H., Andrews, L. E., Cropper, H. C., Behera, D., Gowrishankar, G., Ding, Z., Wyss-Coray, T., Chin, F. T., Biswal, S., Gambhir, S. S. 2018; 15

  View details for DOI 10.1186/s12974-018-1080-1

  View details for Web of Science ID 000425975200001

• [18F]FSPG-PET reveals increased cystine/glutamate antiporter (xc-) activity in a mouse model of multiple sclerosis. Journal of neuroinflammation Hoehne, A., James, M. L., Alam, I. S., Ronald, J. A., Schneider, B., D'Souza, A., Witney, T. H., Andrews, L. E., Cropper, H. C., Behera, D., Gowrishankar, G., Ding, Z., Wyss-Coray, T., Chin, F. T., Biswal, S., Gambhir, S. S. 2018; 15 (1): 55

  Abstract

  The cystine/glutamate antiporter (xc-) has been implicated in several neurological disorders and, specifically, in multiple sclerosis (MS) as a mediator of glutamate excitotoxicity and proinflammatory immune responses. We aimed to evaluate an xc-specific positron emission tomography (PET) radiotracer, (4S)-4-(3-[18F]fluoropropyl)-L-glutamate ([18F]FSPG), for its ability to allow non-invasive monitoring of xc- activity in a mouse model of MS.Experimental autoimmune encephalomyelitis (EAE) was induced in C57BL/6 mice by subcutaneous injection of myelin oligodendrocyte glycoprotein (MOG35-55) peptide in complete Freund's adjuvant (CFA) followed by pertussis toxin. Control mice received CFA emulsion and pertussis toxin without MOG peptide, while a separate cohort of naïve mice received no treatment. PET studies were performed to investigate the kinetics and distribution of [18F]FSPG in naïve, control, pre-symptomatic, and symptomatic EAE mice, compared to 18F-fluorodeoxyglucose ([18F]FDG). After final PET scans, each mouse was perfused and radioactivity in dissected tissues was measured using a gamma counter. Central nervous system (CNS) tissues were further analyzed using ex vivo autoradiography or western blot. [18F]FSPG uptake in human monocytes, and T cells pre- and post-activation was investigated in vitro.[18F]FSPG was found to be more sensitive than [18F]FDG at detecting pathological changes in the spinal cord and brain of EAE mice. Even before clinical signs of disease, a small but significant increase in [18F]FSPG signal was observed in the spinal cord of EAE mice compared to controls. This increase in PET signal became more pronounced in symptomatic EAE mice and was confirmed by ex vivo biodistribution and autoradiography. Likewise, in the brain of symptomatic EAE mice, [18F]FSPG uptake was significantly higher than controls, with the largest changes observed in the cerebellum. Western blot analyses of CNS tissues revealed a significant correlation between light chain of xc- (xCT) protein levels, the subunit of xc- credited with its transporter activity, and [18F]FSPG-PET signal. In vitro [18F]FSPG uptake studies suggest that both activated monocytes and T cells contribute to the observed in vivo PET signal.These data highlight the promise of [18F]FSPG-PET as a technique to provide insights into neuroimmune interactions in MS and the in vivo role of xc- in the development and progression of this disease, thus warranting further investigation.

  View details for DOI 10.1186/s12974-018-1080-1

  View details for PubMedID 29471880

  View details for PubMedCentralID PMC5822551

• Combined PET/MRI: Global Warming-Summary Report of the 6th International Workshop on PET/MRI, March 27-29, 2017, Tübingen, Germany. Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging Bailey, D. L., Pichler, B. J., Gückel, B., Antoch, G., Barthel, H., Bhujwalla, Z. M., Biskup, S., Biswal, S., Bitzer, M., Boellaard, R., Braren, R. F., Brendle, C., Brindle, K., Chiti, A., la Fougère, C., Gillies, R., Goh, V., Goyen, M., Hacker, M., Heukamp, L., Knudsen, G. M., Krackhardt, A. M., Law, I., Morris, J. C., Nikolaou, K., Nuyts, J., Ordonez, A. A., Pantel, K., Quick, H. H., Riklund, K., Sabri, O., Sattler, B., Troost, E. G., Zaiss, M., Zender, L., Beyer, T. 2018; 20 (1): 4-20

  Abstract

  The 6th annual meeting to address key issues in positron emission tomography (PET)/magnetic resonance imaging (MRI) was held again in Tübingen, Germany, from March 27 to 29, 2017. Over three days of invited plenary lectures, round table discussions and dialogue board deliberations, participants critically assessed the current state of PET/MRI, both clinically and as a research tool, and attempted to chart future directions. The meeting addressed the use of PET/MRI and workflows in oncology, neurosciences, infection, inflammation and chronic pain syndromes, as well as deeper discussions about how best to characterise the tumour microenvironment, optimise the complementary information available from PET and MRI, and how advanced data mining and bioinformatics, as well as information from liquid biomarkers (circulating tumour cells and nucleic acids) and pathology, can be integrated to give a more complete characterisation of disease phenotype. Some issues that have dominated previous meetings, such as the accuracy of MR-based attenuation correction (AC) of the PET scan, were finally put to rest as having been adequately addressed for the majority of clinical situations. Likewise, the ability to standardise PET systems for use in multicentre trials was confirmed, thus removing a perceived barrier to larger clinical imaging trials. The meeting openly questioned whether PET/MRI should, in all cases, be used as a whole-body imaging modality or whether in many circumstances it would best be employed to give an in-depth study of previously identified disease in a single organ or region. The meeting concluded that there is still much work to be done in the integration of data from different fields and in developing a common language for all stakeholders involved. In addition, the participants advocated joint training and education for individuals who engage in routine PET/MRI. It was agreed that PET/MRI can enhance our understanding of normal and disrupted biology, and we are in a position to describe the in vivo nature of disease processes, metabolism, evolution of cancer and the monitoring of response to pharmacological interventions and therapies. As such, PET/MRI is a key to advancing medicine and patient care.

  View details for DOI 10.1007/s11307-017-1123-5

  View details for PubMedID 28971346

• Successful treatment of chronic knee pain following localization by a sigma-1 receptor radioligand and PET/MRI: a case report JOURNAL OF PAIN RESEARCH Cipriano, P., Lee, S., Yoon, D., Shen, B., Tawfik, V., Curtin, C., Dragoo, J. L., James, M., Mccurdy, C., Chin, F., Biswal, S. 2018; 11: 2353–56

  Abstract

  The ability to accurately diagnose and objectively localize pain generators in chronic pain sufferers remains a major clinical challenge since assessment relies on subjective patient complaints and relatively non-specific diagnostic tools. Developments in clinical molecular imaging, including advances in imaging technology and radiotracer design, have afforded the opportunity to identify tissues involved in pain generation based on their pro-nociceptive condition. The sigma-1 receptor (S1R) is a pro-nociceptive receptor upregulated in painful, inflamed tissues, and it can be imaged using the highly specific radioligand 18F-FTC-146 with PET.A 50-year-old woman with a 7-year history of refractory, left-knee pain of unknown origin was referred to our pain management team. Over the past several years, she had undergone multiple treatments, including a lateral retinacular release, radiofrequency ablation of a peripheral nerve, and physical therapy. While certain treatments provided partial relief, her pain would inevitably return to its original state. Using simultaneous positron emission tomography/magnetic resonance imaging (PET/MRI) with the novel radiotracer 18F-FTC-146, imaging showed increased focal uptake of 18F-FTC-146 in the intercondylar notch, corresponding to an irregular but equivocal lesion identified in the simultaneously acquired MRI. These imaging results prompted surgical removal of the lesion, which upon resection was identified as an inflamed, intraarticular synovial lipoma. Removal of the lesion relieved the patient's pain, and to date the pain has not recurred.We present a case of chronic, debilitating knee pain that resolved with surgery following identification of the pathology with a novel clinical molecular imaging approach that detects chronic pain generators at the molecular and cellular level. This approach has the potential to identify and localize pain-associated pathology in a variety of chronic pain syndromes.

  View details for PubMedID 30349360

• F-FTC-146 in humans. Journal of nuclear medicine Hjørnevik, T., Cipriano, P. W., Shen, B., Hyung Park, J., Gulaka, P., Holley, D., Gandhi, H., Yoon, D., Mittra, E. S., Zaharchuk, G., Gambhir, S. S., McCurdy, C. R., Chin, F. T., Biswal, S. 2017

  Abstract

  The purpose of this study is to assess safety, biodistribution and radiation dosimetry in humans for the highly selective sigma-1 receptor (S1R) positron emission tomography (PET) agent (18)F-6-(3-fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one ((18)F-FTC-146). Methods: Ten healthy volunteers (HV; five female, five male; age: 34.3 ± 6.5 years) were recruited, and written informed consent was obtained from all participants. Series of whole-body PET/magnetic resonance imaging (PET/MRI) examinations were acquired for up to three hours after injection (357.2 ± 48.8 MBq). Blood samples were collected and standard vital signs (heart rate, pulse oximetry, and body temperature) were monitored at regular intervals. Regions-of-interest were delineated, time-activity curves were calculated, and organ uptake and dosimetry was estimated using PMOD 3.7 and Organ Linear Internal Dose Assessment (OLINDA). Results: All subjects tolerated the PET/MRI examination well, and no adverse reactions to (18)F-FTC-146 were reported. High accumulation of (18)F-FTC-146 was observed in S1R dense organs such as the pancreas and spleen, moderate uptake in the brain and myocardium, and low uptake in bone and muscle. High uptake was also observed in the kidneys and bladder, indicating renal tracer clearance. The effective dose (ED) of (18)F-FTC-146 was 0.0259 ± 0.0034 mSv/MBq (range: 0.0215-0.0301 mSv/MBq). Conclusion: First-in-human studies with clinical-grade (18)F-FTC-146 were successful. Injection of (18)F-FTC-146 is safe, and absorbed doses are acceptable. The potential of (18)F-FTC-146 as an imaging agent for a variety of neuroinflammatory diseases is currently under investigation.

  View details for DOI 10.2967/jnumed.117.192641

  View details for PubMedID 28572487

• F]FTC-146. Molecular imaging and biology Shen, B., Park, J. H., Hjørnevik, T., Cipriano, P. W., Yoon, D., Gulaka, P. K., Holly, D., Behera, D., Avery, B. A., Gambhir, S. S., McCurdy, C. R., Biswal, S., Chin, F. T. 2017

  Abstract

  Sigma-1 receptors (S1Rs) play an important role in many neurological disorders. Simultaneous positron emission tomography (PET)/magnetic resonance imaging (MRI) with S1R radioligands may provide valuable information for diagnosing and guiding treatment for these diseases. Our previously reported S1R radioligand, [(18)F]FTC-146, demonstrated high affinity for the S1R (K i = 0.0025 nM) and excellent selectivity for the S1R over the sigma-2 receptor (S2Rs; K i = 364 nM) across several species (from mouse to non-human primate). Herein, we report the clinical-grade radiochemistry filed with exploratory Investigational New Drug (eIND) and first-in-human PET/MRI evaluation of [(18)F]FTC-146.[(18)F]FTC-146 is prepared via a direct [(18)F] fluoride nucleophilic radiolabeling reaction and formulated in 0.9 % NaCl containing no more than 10 % ethanol through sterile filtration. Quality control (QC) was performed based on USP 823 before doses were released for clinical use. The safety and whole body biodistribution of [(18)F]FTC-146 were evaluated using a simultaneous PET/MR scanner in two representative healthy human subjects.[(18)F]FTC-146 was synthesized with a radiochemical yield of 3.3 ± 0.7 % and specific radioactivity of 8.3 ± 3.3 Ci/μmol (n = 10, decay corrected to EOB). Both radiochemical and chemical purities were >95 %; the prepared doses were stable for 4 h at ambient temperature. All QC test results met specified clinical criteria. The in vivo PET/MRI investigations showed that [(18)F]FTC-146 rapidly crossed the blood brain barrier and accumulated in S1R-rich regions of the brain. There were also radioactivity distributed in the peripheral organs, i.e., the lungs, spleen, pancreas, and thyroid. Furthermore, insignificant uptake of [(18)F]FTC-146 was observed in cortical bone and muscle.A reliable and automated radiosynthesis for providing routine clinical-grade [(18)F]FTC-146 for human studies was established in a modified GE TRACERlab FXFN. PET/MRI demonstrated the initial tracer biodistribution in humans, and clinical studies investigating different S1R-related diseases are in progress.

  View details for DOI 10.1007/s11307-017-1064-z

  View details for PubMedID 28280965

• 18F-FDG PET/MRI in Chronic Sciatica: Early Results Revealing Spinal and Non-spinal Abnormalities. Journal of nuclear medicine : official publication, Society of Nuclear Medicine Cipriano, P. n., Yoon, D. n., Gandhi, H. n., Holley, D. n., Thakur, D. n., Ith, M. n., Hargreaves, B. n., Kennedy, D. n., Smuck, M. n., Cheng, I. n., Biswal, S. n. 2017

  Abstract

  Chronic sciatica is a major cause of disability worldwide, but accurate diagnosis of the offending pathology remains challenging. In this report, the feasibility of a fluorodeoxyglucose (18F-FDG) positron emission tomography/magnetic resonance imaging (PET/MRI) approach for improved diagnosis of chronic sciatica is presented. Methods:18F-FDG PET/MRI was performed on 9 chronic sciatica patients and 5 healthy volunteers. Region-of-interest analysis using maximum standardized uptake values (SUVmax) was performed, and 18F-FDG uptake in lesions was compared with the corresponding areas in healthy controls. Results: Significantly increased 18F-FDG uptake was observed in detected lesions of all patients, which was correlated with pain symptoms. 18F-FDG-avid lesions were not only found in impinged spinal nerves, but were also associated with non-spinal causes, such as a facet joint degeneration, pars defect, or a presumed scar neuroma. Conclusion: The feasibility of 18F-FDG PET/MRI for diagnosing pain generators in chronic sciatica has been demonstrated, revealing various possible etiologies.

  View details for PubMedID 29097408

• Feasibility of 7T MRI for Imaging Fascicular Structures of Peripheral Nerves. Muscle & nerve Yoon, D. n., Biswal, S. n., Rutt, B. n., Lutz, A. n., Hargreaves, B. n. 2017

  Abstract

  Evaluation of the nerve fascicular structure can be useful in diagnosing nerve damage, but it is a very challenging task with 3T MRI due to limited resolution. In this pilot study, we present the feasibility of high-resolution 7T MRI for examining the nerve fascicular structure.A 3D gradient-spoiled sequence was used for imaging peripheral nerves in extremities. Images acquired with different in-plane resolutions (0.42 x 0.42mm vs. 0.12 x 0.12mm), and different main field strengths (7T vs. 3T) were compared.The individual nerve fascicles were identified at 0.12 x 0.12mm resolution in both field strengths, but not at 0.42 x 0.42mm resolution. The fascicular structure was more sharply depicted in 7T images than in 3T images.High-resolution 3D imaging with 7T MRI demonstrated feasibility in imaging nerve fascicular structures. This article is protected by copyright. All rights reserved.

  View details for PubMedID 29211916

• Visualizing Nerve Injury in a Neuropathic Pain Model with [(18)F]FTC-146 PET/MRI. Theranostics Shen, B. n., Behera, D. n., James, M. L., Reyes, S. T., Andrews, L. n., Cipriano, P. W., Klukinov, M. n., Lutz, A. B., Mavlyutov, T. n., Rosenberg, J. n., Ruoho, A. E., McCurdy, C. R., Gambhir, S. S., Yeomans, D. C., Biswal, S. n., Chin, F. T. 2017; 7 (11): 2794–2805

  Abstract

  The ability to locate nerve injury and ensuing neuroinflammation would have tremendous clinical value for improving both the diagnosis and subsequent management of patients suffering from pain, weakness, and other neurologic phenomena associated with peripheral nerve injury. Although several non-invasive techniques exist for assessing the clinical manifestations and morphological aspects of nerve injury, they often fail to provide accurate diagnoses due to limited specificity and/or sensitivity. Herein, we describe a new imaging strategy for visualizing a molecular biomarker of nerve injury/neuroinflammation, i.e., the sigma-1 receptor (S1R), in a rat model of nerve injury and neuropathic pain. The two-fold higher increase of S1Rs was shown in the injured compared to the uninjured nerve by Western blotting analyses. With our novel S1R-selective radioligand, [(18)F]FTC-146 (6-(3-[(18)F]fluoropropyl)-3-(2-(azepan-1-yl)ethyl)benzo[d]thiazol-2(3H)-one), and positron emission tomography-magnetic resonance imaging (PET/MRI), we could accurately locate the site of nerve injury created in the rat model. We verified the accuracy of this technique by ex vivo autoradiography and immunostaining, which demonstrated a strong correlation between accumulation of [(18)F]FTC-146 and S1R staining. Finally, pain relief could also be achieved by blocking S1Rs in the neuroma with local administration of non-radioactive [(19)F]FTC-146. In summary, [(18)F]FTC-146 S1R PET/MR imaging has the potential to impact how we diagnose, manage and treat patients with nerve injury, and thus warrants further investigation.

  View details for PubMedID 28824716

• Detection of nociceptive-related metabolic activity in the spinal cord of low back pain patients using (18)F-FDG PET/CT. Scandinavian journal of pain Zhou, X. n., Cipriano, P. n., Kim, B. n., Dhatt, H. n., Rosenberg, J. n., Mittra, E. n., Do, B. n., Graves, E. n., Biswal, S. n. 2017; 15: 53–57

  Abstract

  Over the past couple of decades, a number of centers in the brain have been identified as important sites of nociceptive processing and are collectively known as the 'pain matrix.' Imaging tools such as functional magnetic resonance imaging (MRI) and (18)F-fluorodeoxyglucose ((18)F-FDG) positron emission tomography (PET) have played roles in defining these pain-relevant, physiologically active brain regions. Similarly, certain segments of the spinal cord are likely more metabolically active in the setting of pain conditions, the location of which is dependent upon location of symptoms. However, little is known about the physiologic changes in the spinal cord in the context of pain. This study aimed to determine whether uptake of (18)F-FDG in the spinal cord on positron emission tomography/computed tomography (PET/CT) of patients with low back pain (LBP) differs from that of patients without LBP.We conducted a retrospective review of (18)F-FDG PET/CT scans of 26 patients with non-central nervous system cancers, 13 of whom had reported LBP and 13 of whom were free of LBP (controls). No patients had spinal stenosis or significant (18)F-FDG contribution of degenerative changes of the spine into the spinal canal. Circular regions of interests were drawn within the spinal canal on transaxial images, excluding bony or discal elements of the spine, and the maximum standardized uptake value (SUVmax) of every slice from spinal nerves C1 to S1 was obtained. SUVmax were normalized by subtracting the SUVmax of spinal nerve L5, as minimal neural tissue is present at this level. Normalized SUVmax of LBP patients were compared to those of LBP-free patients at each vertebral level.We found the normalized SUVmax of patients with LBP to be significantly greater than those of control patients when jointly tested at spinal nerves of T7, T8, T9 and T10 (p<0.001). No significant difference was found between the two groups at other levels of the spinal cord. Within the two groups, normalized SUVmax generally decreased cephalocaudally.Patients with LBP show increased uptake of (18)F-FDG in the caudal aspect of the thoracic spinal cord, compared to patients without LBP.This paper demonstrates the potential of (18)F-FDG PET/CT as a biomarker of increased metabolic activity in the spinal cord related to LBP. As such, it could potentially aid in the treatment of LBP by localizing physiologically active spinal cord regions and guiding minimally invasive delivery of analgesics or stimulators to relevant levels of the spinal cord.

  View details for PubMedID 28850345

• [18F]FDG PET/MRI of patients with chronic pain alters management: early experience. EJNMMI physics Biswal, S., Behera, D., Yoon, D. H., Holley, D., Ith, M. A., Carroll, I., Smuck, M., Hargreaves, B. 2015; 2: A84-?

  View details for DOI 10.1186/2197-7364-2-S1-A84

  View details for PubMedID 26956346

  View details for PubMedCentralID PMC4798651

• Novel Noxipoint Therapy versus Conventional Physical Therapy for Chronic Neck and Shoulder Pain: Multicentre Randomised Controlled Trials SCIENTIFIC REPORTS Koo, C. C., Lin, R. S., Wang, T., Tsauo, J., Yang, P., Yen, C., Biswal, S. 2015; 5

  Abstract

  As chronic pain affects 115 million people and costs $600B annually in the US alone, effective noninvasive nonpharmacological remedies are desirable. The purpose of this study was to determine the efficacy and the generalisability of Noxipoint therapy (NT), a novel electrotherapy characterised by site-specific stimulation, intensity-and-submodality-specific settings and a immobilization period, for chronic neck and shoulder pain. Ninety-seven heavily pretreated severe chronic neck/shoulder pain patients were recruited; 34 and 44 patients were randomly allocated to different treatment arms in two patient-and-assessor-blinded, randomised controlled studies. The participants received NT or conventional physical therapy including transcutaneous electrical nerve stimulation (PT-TENS) for three to six 90-minute sessions. In Study One, NT improved chronic pain (-89.6%, Brief Pain Inventory, p < 0.0001, 95% confidence interval), function (+77.4%, range of motion) and quality of life (+88.1%) at follow-up (from 4 weeks to 5 months), whereas PT-TENS resulted in no significant changes in these parameters. Study Two demonstrated similar advantages of NT over PT-TENS and the generalisability of NT. NT-like treatments in a randomised rat study showed a similar reduction in chronic hypersensitivity (-81%, p < 0.01) compared with sham treatments. NT substantially reduces chronic neck and shoulder pain, restores function, and improves quality of life in a sustained manner.

  View details for DOI 10.1038/srep16342

  View details for Web of Science ID 000364449100001

  View details for PubMedID 26552835

  View details for PubMedCentralID PMC4639784

• Combined F-18-NaF and F-18-FDG PET/CT in the Evaluation of Sarcoma Patients CLINICAL NUCLEAR MEDICINE Jackson, T., Mosci, C., von Eyben, R., Mittra, E., Ganjoo, K., Biswal, S., Gambhir, S. S., Iagaru, A. 2015; 40 (9): 720-724

  Abstract

  The combined administration of F-NaF and F-FDG in a single PET/CT scan has the potential to improve patient convenience and cancer detection. Here we report the use of this approach for patients with sarcomas.This is a retrospective review of 21 patients (12 men, 9 women; age, 19-66 years) with biopsy-proven sarcomas who had separate F-NaF PET/CT, F-FDG PET/CT, and combined F-NaF/F-FDG PET/CT scans for evaluation of malignancy. Two board-certified nuclear medicine physicians and 1 board-certified musculoskeletal radiologist were randomly assigned to review the scans. Results were analyzed for sensitivity and specificity, using linear regression and receiver operating characteristics.A total of 13 patients had metastatic disease on F-NaF PET/CT, F-FDG PET/CT, and combined F-NaF/F-FDG PET/CT. Skeletal disease was more extensive on the F-NaF PET/CT scan than on the F-FDG PET/CT in 3 patients, whereas in 1 patient, F-FDG PET/CT showed skeletal disease and the F-NaF PET/CT was negative. Extraskeletal lesions were detected on both F-FDG and combined F-NaF/F-FDG PET/CT in 20 patients, with 1 discordant finding in the lung.The combined F-NaF/F-FDG PET/CT scan allows for accurate evaluation of sarcoma patients. Further evaluation of this proposed imaging modality is warranted to identify the most suitable clinical scenarios, including initial treatment strategy and evaluation of response to therapy.

  View details for DOI 10.1097/RLU.0000000000000845

  View details for Web of Science ID 000359668600005

  View details for PubMedID 26053718

• Fracture Healing Effects of Locally-Administered Adipose Tissue-Derived Cells YONSEI MEDICAL JOURNAL Lee, S., Jeon, T. J., Biswal, S. 2015; 56 (4): 1106-1113

  Abstract

  Although the applications of adipose tissue-derived cells (ADCs) in regenerative medicine have been investigated, the role of ADCs in fracture healing remains unclear. In this study, we examined the fracture-healing effects and survival of transplanted ADCs using micro-computed tomography (CT) and bioluminescence imaging (BLI).Luciferase-expressing ADCs were suspended in solubilized basement membrane preparation (SBMP) and xenografted on defects in the right femur of nude mice (n=5). SBMP alone was grafted on a defect in the contralateral femur. Serial in vivo micro-CT and BLI were performed for 20 days. Ex vivo BLI images of both femurs were obtained. Differences in the Hounsfield unit (HU), HU(ratio), and luciferase activities were compared using Wilcoxon signed-rank tests and non-parametric longitudinal analyses (p<0.05).In vivo BLI revealed a signal drop on day 2, reconstitution on day 5, and continuous decrement thereafter. Ex vivo BLI revealed residual activity in the ADC-implanted and adjacent areas. No activity was detected in the contralateral femur. The overall increment rate of normalized HUs was higher for ADC-treated femurs than for SBMP-treated femurs. Cell migration to distant injury sites was not detected.Enhanced bone density in the implant area suggests that ADCs have fracture-healing effects.

  View details for DOI 10.3349/ymj.2015.56.4.1106

  View details for Web of Science ID 000356902800030

  View details for PubMedID 26069136

  View details for PubMedCentralID PMC4479841

• Neuropathic Pain Mechanisms and Imaging SEMINARS IN MUSCULOSKELETAL RADIOLOGY Tung, K., Behera, D., Biswal, S. 2015; 19 (2): 103-111

  Abstract

  Molecular and cellular imaging of neuropathic pain, utilizing the myriad of receptors and inflammatory mediators involved in nociceptive activity, is a promising approach toward objectively identifying peripheral pain generators. Neuropathic conditions arise from injured and inflamed nerves, which have been shown to elaborate several molecular and cellular elements that give rise to the neuropathic phenotype and can be exploited for imaging purposes. As such, in vivo approaches to image neuropathic pain mechanisms include imaging voltage-gated sodium channels with radiolabeled saxitoxin, calcium signaling with manganese-enhanced magnetic resonance imaging, and inflammatory changes and nerve metabolism with (18)F-fluorodeoxyglucose. Imaging approaches exploiting other mediators of nociceptive activity, such as substance P (neurokinin-1) receptor, sigma-1 receptor, and macrophages, have shown promising early advances in animal models. By combining the sensitivity and specificity of molecular imaging with the high anatomical, spatial and contrast resolution afforded by computed tomography and MRI, radiologists can potentially identify sites of nerve injury or neuroinflammation that are implicated as peripheral pain drivers with greater accuracy and confidence. In addition to guiding therapy, these approaches will aid in new drug designs for analgesia and more individualized treatment options.

  View details for DOI 10.1055/s-0035-1547371

  View details for Web of Science ID 000350977600005

  View details for PubMedID 25764234

• Effect of local treatment with adipose tissue-derived mesenchymal stem cells in the early tumorigenesis of osteosarcoma. Oncology reports Lee, S., Jeon, T. J., Biswal, S. 2015; 33 (3): 1381-1387

  Abstract

  There are conflicting data describing the effect of mesenchymal stem cells (MSCs) on tumorigenesis. The present study aimed to determine the survival rate and effect of adipose tissue-derived MSCs (ADMSCs) in tumor growth using bioluminescence imaging (BLI) and ultrasound (US) in an osteosarcoma xenograft model. Firefly luciferase-expressing ADMSCs combined with the osteosarcoma cell line UMR-106 in 4 different proportions (5, 10, 15 and 25%, named G1-G4, respectively) were xenografted into the right flanks of nude mice. The same number of UMR-106 cells was inoculated into the contralateral side of each mouse. Serial bioluminescence images were captured over 16 days to monitor the presence of ADMSCs in each group of 5 animals. The tumor volume was measured by ultra-high resolution US, and the tumor volume ratio (AMDSC mixed xenograft/control xenograft) was obtained to evaluate the effect of AMDSCs on tumor growth. Immunohistochemistry was performed to confirm the distribution of residual AMDSCs in the tumor. In G1, G2 and G3, the suppression of tumor growth by AMDSCs was noted in 2/5, 4/5 and 4/5 mice, respectively. However, accelerated tumor growth was noted in G4, which had the highest proportion of ADMSCs. The tumor volume ratio was significantly lower in G2 and G3 compared to G4, by Mann-Whitney U test (P=0.0159). Bioluminescence images demonstrated a serial decrement of the reporter gene for ADMSCs in the tumor mass without evidence of proliferation. Immunohistochemistry staining revealed minimal residual ADMSCs in the tumor periphery. Taken together, our data revealed that direct inoculation of ADMSCs into a tumor xenograft caused the death of the majority of ADMSCs in the tumor mass. Furthermore, relatively low proportions of ADMSCs suppressed the growth of osteosarcoma, while higher proportions showed a tumor-promoting effect.

  View details for DOI 10.3892/or.2015.3711

  View details for PubMedID 25572125

• Factors associated with repetitive strain, and strategies to reduce injury among breast-imaging radiologists. Journal of the American College of Radiology Thompson, A. C., Kremer Prill, M. J., Biswal, S., Rebner, M., Rebner, R. E., Thomas, W. R., Edwards, S. D., Thompson, M. O., Ikeda, D. M. 2014; 11 (11): 1074-1079

  Abstract

  To investigate the prevalence of repetitive strain injury (RSI) among breast-imaging radiologists, the factors associated with such symptoms, and strategies to reduce injury.In 2012, an anonymous survey regarding RSI and work habits was administered to 2,618 physician members of the Society of Breast Imaging via e-mail. Analysis of 727 (27.8%) de-identified responses was completed using STATA 12.1. Pain levels before and after implementation of digital imaging were compared with the Wilcoxon signed-rank test. The associations between RSI symptoms and work habits were assessed with logistic regression and test for trend.In the survey 438 of 727 (60.2%) respondents reported RSI symptoms, and 242 of 727 (33.3%) reported prior diagnosis/treatment. Results showed a statistically significant trend for the odds of RSI symptoms to increase with decreasing age (P = .0004) or increasing number of daily hours spent working (P = .0006), especially in an awkward position (P < .0001). Respondents recalled a significant increase in pain level after implementation of PACS, and a decrease in pain after ergonomic training or initiating use of an ergonomic mouse, adjustable chair, or adjustable table (P < .001, all comparisons). Only 17.7% (129 of 727) used an ergonomic mouse and 13.3% (97 of 727) had attended ergonomic training. Those with RSI symptoms or prior diagnosis of a Repetitive Strain Syndrome (RSS) were more likely to desire future ergonomic training compared with those without symptoms or injury (odds ratio 5.36, P < .001; odds ratio 2.63, P = .001, respectively).RSI is highly prevalent among breast-imaging radiologists nationwide and may worsen after implementation of PACS or with longer work hours. Ergonomic training and ergonomic devices may diminish or prevent painful RSI among radiologists.

  View details for DOI 10.1016/j.jacr.2014.07.009

  View details for PubMedID 25156201

• Evaluation of s-1 Receptor Radioligand 18F-FTC-146 in Rats and Squirrel Monkeys Using PET. Journal of nuclear medicine : official publication, Society of Nuclear Medicine James, M. L., Shen, B., Nielsen, C. H., Behera, D., Buckmaster, C. L., Mesangeau, C., Zavaleta, C., Vuppala, P. K., Jamalapuram, S., Avery, B. A., Lyons, D. M., McCurdy, C. R., Biswal, S., Gambhir, S. S., Chin, F. T. 2014; 55 (1): 147-153

  Abstract

  The noninvasive imaging of σ-1 receptors (S1Rs) could provide insight into their role in different diseases and lead to novel diagnostic/treatment strategies. The main objective of this study was to assess the S1R radiotracer (18)F-FTC-146 in rats. Preliminary squirrel monkey imaging and human serum/liver microsome studies were performed to gain information about the potential of (18)F-FTC-146 for eventual clinical translation.The distribution and stability of (18)F-FTC-146 in rats were assessed via PET/CT, autoradiography, γ counting, and high-performance liquid chromatography (HPLC). Preliminary PET/MRI of squirrel monkey brain was conducted along with HPLC assessment of (18)F-FTC-146 stability in monkey plasma and human serum.Biodistribution studies showed that (18)F-FTC-146 accumulated in S1R-rich rat organs, including the lungs, pancreas, spleen, and brain. Pretreatment with known S1R compounds, haloperidol, or BD1047, before radioligand administration, significantly attenuated (18)F-FTC-146 accumulation in all rat brain regions by approximately 85% (P < 0.001), suggesting radiotracer specificity for S1Rs. Similarly, PET/CT and autoradiography results demonstrated accumulation of (18)F-FTC-146 in rat brain regions known to contain S1Rs and that this uptake could be blocked by BD1047 pretreatment. Ex vivo analysis of (18)F-FTC-146 in the brain showed that only intact radiotracer was present at 15, 30, and 60 min, whereas rapid metabolism of residual (18)F-FTC-146 was observed in rat plasma. Preliminary monkey PET/MRI studies demonstrated specific accumulation of (18)F-FTC-146 in the brain (mainly in cortical structures, cerebellum, and vermis) that could be attenuated by pretreatment with haloperidol. HPLC of monkey plasma suggested radioligand metabolism, whereas (18)F-FTC-146 appeared to be stable in human serum. Finally, liver microsome studies revealed that (18)F-FTC-146 has a longer half-life in human microsomes, compared with rodents.Together, these results indicate that (18)F-FTC-146 is a promising tool for visualizing S1Rs in preclinical studies and that it has potential for mapping these sites in the human brain.

  View details for DOI 10.2967/jnumed.113.120261

  View details for PubMedID 24337599

• A F-18-Labeled Saxitoxin Derivative for in Vivo PET-MR Imaging of Voltage-Gated Sodium Channel Expression Following Nerve Injury JOURNAL OF THE AMERICAN CHEMICAL SOCIETY Hoehne, A., Behera, D., Parsons, W. H., James, M. L., Shen, B., Borgohain, P., Bodapati, D., Prabhakar, A., Gambhir, S. S., Yeomans, D. C., Biswal, S., Chin, F. T., Du Bois, J. 2013; 135 (48): 18012-18015

  Abstract

  Both chronic and neuropathic pain conditions are associated with increased expression of certain voltage-gated sodium ion channel (NaV) isoforms in peripheral sensory neurons. A method for noninvasive imaging of these channels could represent a powerful tool for investigating aberrant expression of NaV and its role in pain pathogenesis. Herein, we describe the synthesis and evaluation of a positron emission tomography (PET) radiotracer targeting NaVs, the design of which is based on the potent, NaV-selective inhibitor saxitoxin. Both autoradiography analysis of sciatic nerves excised from injured rats as well as whole animal PET-MR imaging demonstrate that a systemically administered [(18)F]-labeled saxitoxin derivative concentrates at the site of nerve injury, consistent with upregulated sodium channel expression following axotomy. This type of PET agent has potential use for serial monitoring of channel expression levels at injured nerves throughout wound healing and/or following drug treatment. Such information may be correlated with pain behavioral analyses to help shed light on the complex molecular processes that underlie pain sensation.

  View details for DOI 10.1021/ja408300e

  View details for Web of Science ID 000328100000002

  View details for PubMedID 24261833

• A (18)F-Labeled Saxitoxin Derivative for in Vivo PET-MR Imaging of Voltage-Gated Sodium Channel Expression Following Nerve Injury. Journal of the American Chemical Society Hoehne, A., Behera, D., Parsons, W. H., James, M. L., Shen, B., Borgohain, P., Bodapati, D., Prabhakar, A., Gambhir, S. S., Yeomans, D. C., Biswal, S., Chin, F. T., Bois, J. D. 2013; 135 (48): 18012-18015

  Abstract

  Both chronic and neuropathic pain conditions are associated with increased expression of certain voltage-gated sodium ion channel (NaV) isoforms in peripheral sensory neurons. A method for noninvasive imaging of these channels could represent a powerful tool for investigating aberrant expression of NaV and its role in pain pathogenesis. Herein, we describe the synthesis and evaluation of a positron emission tomography (PET) radiotracer targeting NaVs, the design of which is based on the potent, NaV-selective inhibitor saxitoxin. Both autoradiography analysis of sciatic nerves excised from injured rats as well as whole animal PET-MR imaging demonstrate that a systemically administered [(18)F]-labeled saxitoxin derivative concentrates at the site of nerve injury, consistent with upregulated sodium channel expression following axotomy. This type of PET agent has potential use for serial monitoring of channel expression levels at injured nerves throughout wound healing and/or following drug treatment. Such information may be correlated with pain behavioral analyses to help shed light on the complex molecular processes that underlie pain sensation.

  View details for DOI 10.1021/ja408300e

  View details for PubMedID 24261833

• Molecular Imaging: An Innovative Force in Musculoskeletal Radiology AMERICAN JOURNAL OF ROENTGENOLOGY Wilmot, A., Gieschler, S., Behera, D., Gade, T. P., Reumann, M. K., Biswal, S., Mayer-Kuckuk, P. 2013; 201 (2): 264-277

  Abstract

  OBJECTIVE. A review of the innovative role molecular imaging plays in musculoskeletal radiology is provided. Musculoskeletal molecular imaging is under development in four key areas: imaging the activity of osteoblasts and osteoclasts, imaging of molecular and cellular biomarkers of arthritic joint destruction, cellular imaging of osteomyelitis, and imaging generators of musculoskeletal pain. CONCLUSION. Together, these applications suggest that next-generation musculoskeletal radiology will facilitate quantitative visualization of molecular and cellular biomarkers, an advancement that appeared futuristic just a decade ago.

  View details for DOI 10.2214/AJR.13.10713

  View details for Web of Science ID 000322225400040

  View details for PubMedID 23795682

• Automatic Retrieval of Bone Fracture Knowledge Using Natural Language Processing JOURNAL OF DIGITAL IMAGING Do, B. H., Wu, A. S., Maley, J., Biswal, S. 2013; 26 (4): 709-713

  Abstract

  Natural language processing (NLP) techniques to extract data from unstructured text into formal computer representations are valuable for creating robust, scalable methods to mine data in medical documents and radiology reports. As voice recognition (VR) becomes more prevalent in radiology practice, there is opportunity for implementing NLP in real time for decision-support applications such as context-aware information retrieval. For example, as the radiologist dictates a report, an NLP algorithm can extract concepts from the text and retrieve relevant classification or diagnosis criteria or calculate disease probability. NLP can work in parallel with VR to potentially facilitate evidence-based reporting (for example, automatically retrieving the Bosniak classification when the radiologist describes a kidney cyst). For these reasons, we developed and validated an NLP system which extracts fracture and anatomy concepts from unstructured text and retrieves relevant bone fracture knowledge. We implement our NLP in an HTML5 web application to demonstrate a proof-of-concept feedback NLP system which retrieves bone fracture knowledge in real time.

  View details for DOI 10.1007/s10278-012-9531-1

  View details for Web of Science ID 000322434700016

  View details for PubMedID 23053906

• Bilateral peripheral neural activity observed in vivo following unilateral nerve injury. American journal of nuclear medicine and molecular imaging Behera, D., Behera, S., Jacobs, K. E., Biswal, S. 2013; 3 (3): 282-290

  Abstract

  Manganese-enhanced magnetic resonance imaging (MRI) is a surrogate method to measure calcium content in nervous system since manganese physiologically follows calcium. Manganese is detectable in MRI and therefore visualizes structures and cell populations that actively regulate calcium. Since calcium is actively recruited for the transmission of action potentials, our purpose is to validate manganese-enhanced MRI for detection of changes in lumbar nerves related to nociception. A neuropathic pain model was created by chronic constrictive injury of the left sciatic nerve of Sprague-Dawley rats. Behavioral measurements, using von Frey's tests, confirmed the presence of significant allodynia in the left hind limb of animals in the injured group. T1-weighted fast spin echo images were obtained of the lumbar cord and plexus of animals with injured left sciatic nerve and uninjured animals (control) scanned in a 7 Tesla magnet after intraperitoneal manganese chloride administration four weeks after surgery. Lumbar nerve roots and sciatic nerves in the injured group show increased normalized manganese-enhanced MRI signal, representing manganese enhancement, compared to the control group. In conclusion, animals with neuropathic pain in the left hind limb show increased manganese uptake in not only the injured sciatic nerve but also in the contralateral uninjured sciatic nerve on manganese-enhanced MRI in vivo. Although poorly understood, this finding corroborates ex vivo finding of bilateral nociceptive-related molecular changes in the nervous system of unilateral pain models.

  View details for PubMedID 23638339

• Exogenous MC3T3 Preosteoblasts Migrate Systemically and Mitigate the Adverse Effects of Wear Particles TISSUE ENGINEERING PART A Fritton, K., Ren, P., Gibon, E., Rao, A. J., Ma, T., Biswal, S., Gambhir, S. S., Goodman, S. B. 2012; 18 (23-24): 2559-2567

  Abstract

  Understanding how relevant cell types respond to wear particles will reveal new avenues for treating osteolysis following joint replacements. In this study, we investigate the effects of ultrahigh molecular weight polyethylene (UHMWPE) particles on preosteoblast migration and function. We infused UHMWPE particles or saline into the left femur of mice and injected luciferase-expressing preosteoblasts (MC3T3 cells) into each left ventricle. Bioluminescence imaging (BLI) confirmed systemic administration of MC3T3 cells. BLI throughout the 28-day experiment showed greater MC3T3 migration to the site of particle infusion than to the site of saline infusion, with significant differences on days 0, 4, and 6 (p≤0.055). Immunostaining revealed a greater number of osteoblasts and osteoclasts in the particle-infused femora, indicating greater bone turnover. The bone mineralization of the particle-infused femora increased significantly when compared to saline-infused femora (an increase of 146.4±27.9 vs. 12.8±8.7 mg/mL, p=0.008). These results show that infused preosteoblasts can migrate to the site of wear particles. Additionally, as the migrated cells were associated with increased bone mineralization in spite of the presence of particles, increasing osteoblast recruitment is a potential strategy for combating bone loss due to increased osteoclast/macrophage number and decreased osteoblast function.

  View details for DOI 10.1089/ten.tea.2012.0086

  View details for PubMedID 22741555

• Rotator cuff tears: association with acromion angulation on MRI Annual Meeting of the American-Roentgen-Ray-Society (ARRS) McGinley, J. C., Agrawal, S., Biswal, S. ELSEVIER SCIENCE INC. 2012: 791–96

  Abstract

  Using magnetic resonance imaging (MRI), evaluate the correlation of acromion angulation with thickening of the coracoacromial ligament (CAL) and narrowing of the subacromial space resulting in impingement upon the rotator cuff tendons.Eighty-nine shoulder MRI studies performed on a 3T scanner were retrospectively analyzed by two blinded independent reviewers. Measurements of the acromion angle (delta angle), CAL thickness and distance between the CAL and humeral head were obtained. The data were categorized into two groups, delta angle less that and greater than 7.5°. The presence or absence of full thickness (FT) or near full thickness (NFT) rotator cuff tears was noted.In group 1, the acromion angle varied from -6.8 to 6.8° (1.7±3.5°) with a CAL thickness of 0.91±0.20 mm and a subacromial distance of 6.47±0.88 mm. Group 2 acromion angle varied from 7.6° to 46.8° (18.0°±8.1°) with a CAL of 1.77±0.51 mm and a subacromial distance of 4.52±0.82 mm. The difference in CAL thickness and subacromial distance were significantly different between the two groups (P<.001). In Group 1, 3 out of 51 patients had a FT or NFT tear of the rotator cuff compared to 20 out of 38 in Group 2 (P<.001). There was no significant interobserver variability.Steep acromion angulation is associated with CAL thickening and narrowing of the subacromial space. Patients with a steep acromion angle had a statistically increased incidence of rotator cuff tears.

  View details for DOI 10.1016/j.clinimag.2012.04.007

  View details for Web of Science ID 000311533800021

  View details for PubMedID 23154011

• Assessment of Collagen-Induced Arthritis Using Cyanine 5.5 Conjugated with Hydrophobically Modified Glycol Chitosan Nanoparticles: Correlation with F-18-Fluorodeoxyglucose Positron Emission Tomography Data KOREAN JOURNAL OF RADIOLOGY Cha, J. H., Lee, S. H., Lee, S., Park, K., Moon, D. H., Kim, K., Biswal, S. 2012; 13 (4): 450-461

  Abstract

  To evaluate the potential and correlation between near-infrared fluorescence (NIRF) imaging using cyanine 5.5 conjugated with hydrophobically modified glycol chitosan nanoparticles (HGC-Cy5.5) and (18)F-fluorodeoxyglucose-positron emission tomography ((18)F-FDG-PET) imaging of collagen-induced arthritis (CIA).We used 10 CIA and 3 normal mice. Nine days after the injecting collagen twice, microPET imaging was performed 40 minutes after the intravenous injection of 9.3 MBq (18)F-FDG in 200 µL PBS. One day later, NIRF imaging was performed two hours after the intravenous injection of HGC-cy5.5 (5 mg/kg). We assessed the correlation between these two modalities in the knees and ankles of CIA mice.The mean standardized uptake values of (18)F-FDG for knees and ankles were 1.68 ± 0.76 and 0.79 ± 0.71, respectively, for CIA mice; and 0.57 ± 0.17 and 0.54 ± 0.20 respectively for control mice. From the NIRF images, the total photon counts per 30 mm(2) for knees and ankles were 2.32 ± 1.54 × 10(5) and 2.75 ± 1.51 × 10(5), respectively, for CIA mice, and 1.22 ± 0.27 × 10(5) and 0.88 ± 0.24 × 10(5), respectively, for control mice. These two modalities showed a moderate correlation for knees (r = 0.604, p = 0.005) and ankles (r = 0.464, p = 0.039). Moreover, both HGC-Cy5.5 (p = 0.002) and (18)F-FDG-PET (p = 0.005) imaging also showed statistically significant differences between CIA and normal mice.NIRF imaging using HGC-Cy5.5 was moderately correlated with (18)F-FDG-PET imaging in the CIA model. As such, HGC-Cy5.5 imaging can be used for the early detection of rheumatoid arthritis.

  View details for DOI 10.3348/kjr.2012.13.4.450

  View details for Web of Science ID 000306396600009

  View details for PubMedID 22778567

  View details for PubMedCentralID PMC3384827

• In vivo USPIO magnetic resonance imaging shows that minocycline mitigates macrophage recruitment to a peripheral nerve injury MOLECULAR PAIN Ghanouni, P., Behera, D., Xie, J., Chen, X., Moseley, M., Biswal, S. 2012; 8

  Abstract

  Minocycline has proven anti-nociceptive effects, but the mechanism by which minocycline delays the development of allodynia and hyperalgesia after peripheral nerve injury remains unclear. Inflammatory cells, in particular macrophages, are critical components of the response to nerve injury. Using ultrasmall superparamagnetic iron oxide-magnetic resonance imaging (USPIO-MRI) to monitor macrophage trafficking, the purpose of this project is to determine whether minocycline modulates macrophage trafficking to the site of nerve injury in vivo and, in turn, results in altered pain thresholds.Animal experiments were approved by Stanford IACUC. A model of neuropathic pain was created using the Spared Nerve Injury (SNI) model that involves ligation of the left sciatic nerve in the left thigh of adult Sprague-Dawley rats. Animals with SNI and uninjured animals were then injected with/without USPIOs (300 μmol/kg i.v.) and with/without minocycline (50 mg/kg i.p.). Bilateral sciatic nerves were scanned with a volume coil in a 7 T magnet 7 days after USPIO administration. Fluid-sensitive MR images were obtained, and ROIs were placed on bilateral sciatic nerves to quantify signal intensity. Pain behavior modulation by minocycline was measured using the Von Frey filament test. Sciatic nerves were ultimately harvested at day 7, fixed in 10% buffered formalin and stained for the presence of iron oxide-laden macrophages. Behavioral measurements confirmed the presence of allodynia in the neuropathic pain model while the uninjured and minocycline-treated injured group had significantly higher paw withdrawal thresholds (p < 0.011). Decreased MR signal is observed in the SNI group that received USPIOs (3.3+/-0.5%) compared to the minocycline-treated SNI group that received USPIOs (15.2+/-4.5%) and minocycline-treated group that did not receive USPIOs (41.2+/-2.3%) (p < 0.04). Histology of harvested sciatic nerve specimens confirmed the presence USPIOs at the nerve injury site in the SNI group without minocycline treatment.Animals with neuropathic pain in the left hindpaw show increased trafficking of USPIO-laden macrophages to the site of sciatic nerve injury. Minocycline to retards the migration of macrophages to the nerve injury site, which may partly explain its anti-nociceptive effects. USPIO-MRI is an effective in vivo imaging tool to study the role of macrophages in the development of neuropathic pain.

  View details for DOI 10.1186/1744-8069-8-49

  View details for Web of Science ID 000309839300001

  View details for PubMedID 22742763

  View details for PubMedCentralID PMC3472277

• Effect of a CCR1 receptor antagonist on systemic trafficking of MSCs and polyethylene particle-associated bone loss BIOMATERIALS Gibon, E., Yao, Z., Rao, A. J., Zwingenberger, S., Batke, B., Valladares, R., Smith, R. L., Biswal, S., Gambhir, S. S., Goodman, S. B. 2012; 33 (14): 3632-3638

  Abstract

  Particle-associated periprosthetic osteolysis remains a major issue in joint replacement. Ongoing bone loss resulting from wear particle-induced inflammation is accompanied by continued attempts at bone repair. Previously we showed that mesenchymal stem cells (MSCs) are recruited systemically to bone exposed to continuous infusion of ultra high molecular weight polyethylene (UHMWPE) particles. The chemokine-receptor axis that mediates this process is unknown. We tested two hypotheses: (1) the CCR1 receptor mediates the systemic recruitment of MSCs to UHMWPE particles and (2) recruited MSCs are able to differentiate into functional mature osteoblasts and decrease particle-associated bone loss. Nude mice were allocated randomly to four groups. UHMWPE particles were continuously infused into the femoral shaft using a micro-pump. Genetically modified murine wild type reporter MSCs were injected systemically via the left ventricle. Non-invasive imaging was used to assay MSC migration and bone mineral density. Bioluminescence and immunohistochemistry confirmed the chemotaxis of reporter cells and their differentiation into mature osteoblasts in the presence of infused particles. Injection of a CCR1 antagonist decreased reporter cell recruitment to the UHMWPE particle infusion site and increased osteolysis. CCR1 appears to be a critical receptor for chemotaxis of MSCs in the presence of UHMWPE particles. Interference with CCR1 exacerbates particle-induced bone loss.

  View details for DOI 10.1016/j.biomaterials.2012.02.003

  View details for PubMedID 22364730

• MC3T3-E1 Osteoprogenitor Cells Systemically Migrate to a Bone Defect and Enhance Bone Healing TISSUE ENGINEERING PART A Gibon, E., Batke, B., Jawad, M. U., Fritton, K., Rao, A., Yao, Z., Biswal, S., Gambhir, S. S., Goodman, S. B. 2012; 18 (9-10): 968-973

  Abstract

  Although iliac crest autologous bone graft remains the gold standard for treatment of bone defects, delayed- and nonunions, and arthrodeses, several alternative strategies have been attempted, including the use of mesenchymal stem cells. Whether cells from the osteoblast lineage demonstrate systemic recruitment to an acute bone defect or fracture, and whether these cells directly participate in bone healing is controversial. This study tests two hypotheses: (1) that exogenous murine MC3T3-E1 osteoprogenitor cells with a high propensity for osteoblast differentiation are able to systemically migrate to a bone defect and (2) that the migrated MC3T3-E1 cells enhance bone healing. Two groups of nude mice were used; a bone defect was drilled in the left femoral shaft in both groups. MC3T3-E1 were used as reporter cells and injected in the left ventricle of the heart, to avoid sequestration in the lungs. Injection of saline served as a control. We used bioluminescence and microCT to assay cell recruitment and bone mineral density (BMD). Immunohistochemical staining was used to confirm the migration of reporter cells. MC3T3-E1 cells were found to systemically migrate to the bone defect. Further, BMD at the defect was significantly increased when cells were injected. Systemic cell therapy using osteoprogenitor cells may be a potential strategy to enhance bone healing.

  View details for DOI 10.1089/ten.tea.2011.0545

  View details for PubMedID 22129134

• Selective inhibition of the MCP-1-CCR2 ligand-receptor axis decreases systemic trafficking of macrophages in the presence of UHMWPE particles JOURNAL OF ORTHOPAEDIC RESEARCH Gibon, E., Ma, T., Ren, P., Fritton, K., Biswal, S., Yao, Z., Smith, L., Goodman, S. B. 2012; 30 (4): 547-553

  Abstract

  The biological mechanisms leading to periprosthetic osteolysis involve both chemokines and the monocyte/macrophage cell lineage. Whether MCP-1 plays a major role in macrophage recruitment in the presence of wear particles is unknown. We tested two hypotheses: (1) that exogenous local delivery of MCP-1 induces systematic macrophage recruitment and (2) that blockade of the MCP-1 ligand-receptor axis decreases macrophage recruitment and osteolysis in the presence of ultra high molecular weight polyethylene (UHMWPE) particles. Six groups of nude mice were used. We used non-invasive imaging to assay macrophage recruitment and osteolysis. A murine macrophage cell line and primary wild type and CCR2 knockout murine macrophages were used as the reporter cells. Particles were infused into the femoral canal. Bioluminescence and immunohistochemical staining were used to confirm the migration of reporter cells. Locally infused MCP-1 induced systemic macrophage trafficking to bone. Injection of MCP-1 receptor antagonist significantly decreased reporter cell recruitment to bone infused with UHMWPE particles and decreased osteolysis. Systemic migration of reporter cells to infused particles was decreased when the reporter cells were deficient in the CCR2 receptor. Interruption of the MCP-1 ligand-receptor axis appears to be a viable strategy to mitigate trafficking of macrophages and osteolysis due to UHMWPE particles.

  View details for DOI 10.1002/jor.21548

  View details for PubMedID 21913218

• Oral manganese as an MRI contrast agent for the detection of nociceptive activity NMR IN BIOMEDICINE Jacobs, K. E., Behera, D., Rosenberg, J., Gold, G., Moseley, M., Yeomans, D., Biswal, S. 2012; 25 (4): 563-569

  Abstract

  The ability of divalent manganese to enter neurons via calcium channels makes manganese an excellent MRI contrast agent for the imaging of nociception, the afferent neuronal encoding of pain perception. There is growing evidence that nociceptive neurons possess increased expression and activity of calcium channels, which would allow for the selective accumulation of manganese at these sites. In this study, we show that oral manganese chloride leads to increased enhancement of peripheral nerves involved in nociception on T(1)-weighted MRI. Oral rather than intravenous administration was chosen for its potentially better safety profile, making it a better candidate for clinical translation with important applications, such as pain diagnosis, therapy and research. The spared nerve injury (SNI) model of neuropathic pain was used for the purposes of this study. SNI rats were given, sequentially, increasing amounts of manganese chloride (lowest, 2.29 mg/100 g weight; highest, 20.6 mg/100 g weight) with alanine and vitamin D(3) by oral gavage. Compared with controls, SNI rats demonstrated increased signal-to-background ratios on T(1)-weighted fast spin echo MRI, which was confirmed by and correlated strongly with spectrometry measurements of nerve manganese concentration. We also found the difference between SNI and control rats to be greater at 48 h than at 24 h after dosing, indicating increased manganese retention in addition to increased manganese uptake in nociceptive nerves. This study demonstrates that oral manganese is a viable method for the imaging of nerves associated with increased nociceptive activity.

  View details for DOI 10.1002/nbm.1773

  View details for Web of Science ID 000302015500011

  View details for PubMedID 22447731

• Magnetic Resonance Reporter Gene Imaging THERANOSTICS Lee, S., Lee, S., Biswal, S. 2012; 2 (4): 403-412

  Abstract

  Molecular imaging has undergone an explosive advancement in recent years, due to the tremendous research efforts made to understand and visualize biological processes. Molecular imaging by definition assesses cellular and molecular processes in living subjects, with the targets of following metabolic, genomic, and proteomic events. Furthermore, reporter gene imaging plays a central role in this field. Many different approaches have been used to visualize genetic events in living subjects, such as, optical, radionuclide, and magnetic resonance imaging. Compared with the other techniques, magnetic resonance (MR)-based reporter gene imaging has not occupied center stage, despite its superior three-dimensional depictions of anatomical details. In this article, the authors review the principles and applications of various types of MR reporter gene imaging technologies and discuss their advantages and disadvantages.

  View details for DOI 10.7150/thno.3634

  View details for Web of Science ID 000304031200008

  View details for PubMedID 22539936

  View details for PubMedCentralID PMC3337732

• Pattern of 18F-FDG Uptake in the Spinal Cord in Patients With Non-Central Nervous System Malignancy SPINE Do, B. H., Mari, C., Tseng, J. R., Quon, A., Rosenberg, J., Biswal, S. 2011; 36 (21): E1395-E1401

  Abstract

  Retrospective review.To (1) propose a standard method to quantitate 2-deoxy-2-[18F]-fluoro-D-glucose (18F-FDG) uptake in the spinal cord and (2) use this methodology to retrospectively characterize the pattern of uptake within the entire spinal cord using whole-body positron emission tomography/computed tomography (PET/CT) imaging.A physiologic understanding of glucose metabolism within the spinal cord may provide insight regarding infectious, inflammatory, vascular, and neoplastic spinal cord diseases.Institutional review board approval was obtained. A total of 131 consecutive whole-body PET/CT studies from July to August 2004 were reviewed, and using exclusionary criteria of: (1) severe spinal arthropathy or curvature, (2) motion artifact, (3) canal hardware, (4) spinal tumor, and (5) marrow hyperplasia, 92 studies of neurologically intact patients (49 men and 43 women) were selected for a retrospective review of spinal cord 18F-FDG activity. The transaxial CT was used to define the canal and circular regions of interests were placed within the canal at the level of the vertebral body midpoint from C1 to L3. Region of interest total count, area, and maximum standardized uptake value (SUVmax) were recorded. Measurements at L5 served as an internal control. For comparative analysis, the cord-to-background (CTB) ratio was defined as spinal cord SUVmax to L5 SUVmax.Mean CTB decreased along each spinal level from cranial to caudal (P < 0.001). Significant relative increases were observed at the T11-T12 vertebral body levels (P < 0.001). Although insignificant, a relative increase was observed at C4. No significant interactions of age or sex on CTB were observed.The pattern of 18F-FDG uptake within the spinal cord, observed in patients with non-central nervous system malignancy, may be helpful in understanding glucose physiology of spinal cord diseases and warrants further research.

  View details for DOI 10.1097/BRS.0b013e31820a7df8

  View details for Web of Science ID 000295318000005

  View details for PubMedID 21311407

• F-18-FDG PET/MRI Can Be Used to Identify Injured Peripheral Nerves in a Model of Neuropathic Pain JOURNAL OF NUCLEAR MEDICINE Behera, D., Jacobs, K. E., Behera, S., Rosenberg, J., Biswal, S. 2011; 52 (8): 1308-1312

  Abstract

  We demonstrated increased (18)F-FDG uptake in injured peripheral nerves in a model of neuropathic pain using small-animal PET/MRI.A neuropathic pain model in rats was created by spared-nerve injury of the left sciatic nerve. Sham-operated rats without nerve injury were used as a control. The presence of pain was confirmed by testing for allodynia. Sequential small-animal (18)F-FDG PET and MRI scans of the thighs were obtained and coregistered. Autoradiography was performed on harvested nerves and muscle.The group with spared-nerve injury showed the development of allodynia in the operated limb (P < 0.001). Increased (18)F-FDG uptake was observed on both PET/MRI (P < 0.001) and autoradiography (P < 0.005) in the operated nerve in this group. (18)F-FDG uptake in the nerves correlated well with allodynia (ρ = -0.59; P < 0.024).Animals with neuropathic pain show increased (18)F-FDG uptake in the affected nerve. Small-animal PET/MRI can be effectively used to localize (18)F-FDG uptake in peripheral nerves.

  View details for DOI 10.2967/jnumed.110.084731

  View details for Web of Science ID 000293336000047

  View details for PubMedID 21764788

• Continuous Infusion of UHMWPE Particles Induces Increased Bone Macrophages and Osteolysis Annual Scientific Meeting of the Knee-Society Ren, P., Irani, A., Huang, Z., Ma, T., Biswal, S., Goodman, S. B. SPRINGER. 2011: 113–22

  Abstract

  Aseptic loosening and periprosthetic osteolysis resulting from wear debris are major complications of total joint arthroplasty. Monocyte/macrophages are the key cells related to osteolysis at the bone-implant interface of joint arthroplasties. Whether the monocyte/macrophages found at the implant interface in the presence of polyethylene particles are locally or systemically derived is unknown.We therefore asked (1) whether macrophages associated with polyethylene particle-induced chronic inflammation are recruited locally or systemically and (2) whether the recruited macrophages are associated with enhanced osteolysis locally.Noninvasive in vivo imaging techniques (bioluminescence and microCT) were used to investigate initial macrophage migration systemically from a remote injection site to polyethylene wear particles continuously infused into the femoral canal. We used histologic and immunohistologic staining to confirm localization of migrated macrophages to the polyethylene particle-treated femoral canals and monitor cellular markers of bone remodeling.The values for bioluminescence were increased for animals receiving UHMWPE particles compared with the group in which the carrier saline was infused. At Day 8, the ratio of bioluminescence (operated femur divided by nonoperated contralateral femur of each animal) for the UHMWPE group was 13.95 ± 5.65, whereas the ratio for the saline group was 2.60 ± 1.14. Immunohistologic analysis demonstrated the presence of reporter macrophages in the UHMWPE particle-implanted femora only. MicroCT scans showed the bone mineral density for the group with both UHMWPE particles and macrophage was lower than the control groups.Infusion of clinically relevant polyethylene particles, similar to the human scenario, stimulated systemic migration of remotely injected macrophages and local net bone resorption.

  View details for DOI 10.1007/s11999-010-1645-5

  View details for PubMedID 21042895

• Radiolabeling of a Saxitoxin derivative for PET-MRI imaging of pain Hoehne, A., Parsons, W. H., Behera, D., Shen, B., Gambhir, S. S., Du Bois, J., Biswal, S., Chin, F. T. WILEY-BLACKWELL. 2011: S2–S2

  View details for Web of Science ID 000295901600003

• Informatics in Radiology RADTF: A Semantic Search-enabled, Natural Language Processor-generated Radiology Teaching File RADIOGRAPHICS Do, B. H., Wu, A., Biswal, S., Kamaya, A., Rubin, D. L. 2010; 30 (7): 2039-2048

  Abstract

  Storing and retrieving radiology cases is an important activity for education and clinical research, but this process can be time-consuming. In the process of structuring reports and images into organized teaching files, incidental pathologic conditions not pertinent to the primary teaching point can be omitted, as when a user saves images of an aortic dissection case but disregards the incidental osteoid osteoma. An alternate strategy for identifying teaching cases is text search of reports in radiology information systems (RIS), but retrieved reports are unstructured, teaching-related content is not highlighted, and patient identifying information is not removed. Furthermore, searching unstructured reports requires sophisticated retrieval methods to achieve useful results. An open-source, RadLex(®)-compatible teaching file solution called RADTF, which uses natural language processing (NLP) methods to process radiology reports, was developed to create a searchable teaching resource from the RIS and the picture archiving and communication system (PACS). The NLP system extracts and de-identifies teaching-relevant statements from full reports to generate a stand-alone database, thus converting existing RIS archives into an on-demand source of teaching material. Using RADTF, the authors generated a semantic search-enabled, Web-based radiology archive containing over 700,000 cases with millions of images. RADTF combines a compact representation of the teaching-relevant content in radiology reports and a versatile search engine with the scale of the entire RIS-PACS collection of case material.

  View details for DOI 10.1148/rg.307105083

  View details for Web of Science ID 000284094200021

  View details for PubMedID 20801868

• Surveillance of systemic trafficking of macrophages induced by UHMWPE particles in nude mice by noninvasive imaging. Journal of biomedical materials research. Part A Ren, P., Huang, Z., Ma, T., Biswal, S., Smith, R. L., Goodman, S. B. 2010; 94 (3): 706-711

  Abstract

  Macrophages constitute a major part of the cell response to wear particles produced at articulating and nonarticulating interfaces of joint replacements. This foreign body reaction can result in periprosthetic osteolysis and implant loosening. We demonstrate that ultra-high molecular weight polyethylene (UHMWPE) particles induce systemic trafficking of macrophages by noninvasive in vivo imaging and immunohistochemistry. The distal femora of nude mice were injected with 60 mg/mL UHMWPE suspension or saline alone. Reporter RAW264.7 macrophages that stably expressed the bioluminescent reporter gene and the fluorescence reporter gene were injected intravenously. Bioluminescence imaging was performed using an in vivo imaging system immediately after macrophage injection and at 2-day intervals. Compared with the nonoperated contralateral femora, at day 4, 6, and 8, the bioluminescent signal of femora containing UHMWPE suspension increased 1.30 +/- 0.09-, 2.36 +/- 0.92-, and 10.32 +/- 7.61-fold, respectively. The values at same time points for saline-injected control group were 1.08 +/- 0.07-, 1.14 +/- 0.27-, and 1.14 +/- 0.35-fold, respectively. The relative bioluminescence of the UHMWPE group was higher at all postinjection days and significantly greater than the saline group at day 8 (p < 0.05). Histological analysis confirmed the presence of reporter macrophages within the medullary canal of mice with implanted UHMWPE particles. The presence of UHMWPE particles induced enhanced bone remodeling activity. Clinically relevant UHMWPE particles stimulated the systemic recruitment of macrophages during an early time course using the murine femoral implant model. Interference with systemic macrophage trafficking may potentially mitigate UHMWPE particle-induced periprosthetic osteolysis.

  View details for DOI 10.1002/jbm.a.32744

  View details for PubMedID 20213815

• Surveillance of systemic trafficking of macrophages induced by UHMWPE particles in nude mice by noninvasive imaging JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A Ren, P., Huang, Z., Ma, T., Biswal, S., Smith, R. L., Goodman, S. B. 2010; 94A (3): 706-711

  Abstract

  Macrophages constitute a major part of the cell response to wear particles produced at articulating and nonarticulating interfaces of joint replacements. This foreign body reaction can result in periprosthetic osteolysis and implant loosening. We demonstrate that ultra-high molecular weight polyethylene (UHMWPE) particles induce systemic trafficking of macrophages by noninvasive in vivo imaging and immunohistochemistry. The distal femora of nude mice were injected with 60 mg/mL UHMWPE suspension or saline alone. Reporter RAW264.7 macrophages that stably expressed the bioluminescent reporter gene and the fluorescence reporter gene were injected intravenously. Bioluminescence imaging was performed using an in vivo imaging system immediately after macrophage injection and at 2-day intervals. Compared with the nonoperated contralateral femora, at day 4, 6, and 8, the bioluminescent signal of femora containing UHMWPE suspension increased 1.30 +/- 0.09-, 2.36 +/- 0.92-, and 10.32 +/- 7.61-fold, respectively. The values at same time points for saline-injected control group were 1.08 +/- 0.07-, 1.14 +/- 0.27-, and 1.14 +/- 0.35-fold, respectively. The relative bioluminescence of the UHMWPE group was higher at all postinjection days and significantly greater than the saline group at day 8 (p < 0.05). Histological analysis confirmed the presence of reporter macrophages within the medullary canal of mice with implanted UHMWPE particles. The presence of UHMWPE particles induced enhanced bone remodeling activity. Clinically relevant UHMWPE particles stimulated the systemic recruitment of macrophages during an early time course using the murine femoral implant model. Interference with systemic macrophage trafficking may potentially mitigate UHMWPE particle-induced periprosthetic osteolysis.

  View details for DOI 10.1002/jbm.a.32744

  View details for Web of Science ID 000280536300006

  View details for PubMedCentralID PMC2936785

• Indirect imaging of cardiac-specific transgene expression using a bidirectional two-step transcriptional amplification strategy GENE THERAPY Chen, I. Y., Gheysens, O., Ray, S., Wang, Q., Padmanabhan, P., Paulmurugan, R., Loening, A. M., Rodriguez-Porcel, M., Willmann, J. K., Sheikh, A. Y., Nielsen, C. H., Hoyt, G., Contag, C. H., Robbins, R. C., Biswal, S., Wu, J. C., Gambhir, S. S. 2010; 17 (7): 827-838

  Abstract

  Transcriptional targeting for cardiac gene therapy is limited by the relatively weak activity of most cardiac-specific promoters. We have developed a bidirectional plasmid vector, which uses a two-step transcriptional amplification (TSTA) strategy to enhance the expression of two optical reporter genes, firefly luciferase (fluc) and Renilla luciferase (hrluc), driven by the cardiac troponin T (cTnT) promoter. The vector was characterized in vitro and in living mice using luminometry and bioluminescence imaging to assess its ability to mediate strong, correlated reporter gene expression in a cardiac cell line and the myocardium, while minimizing expression in non-cardiac cell lines and the liver. In vitro, the TSTA system significantly enhanced cTnT-mediated reporter gene expression with moderate preservation of cardiac specificity. After intramyocardial and hydrodynamic tail vein delivery of an hrluc-enhanced variant of the vector, long-term fluc expression was observed in the heart, but not in the liver. In both the cardiac cell line and the myocardium, fluc expression correlated well with hrluc expression. These results show the vector's ability to effectively amplify and couple transgene expression in a cardiac-specific manner. Further replacement of either reporter gene with a therapeutic gene should allow non-invasive imaging of targeted gene therapy in living subjects.

  View details for DOI 10.1038/gt.2010.30

  View details for Web of Science ID 000279614600002

  View details for PubMedID 20237511

  View details for PubMedCentralID PMC2900530

• Triblock copolymer coated iron oxide nanoparticle conjugate for tumor integrin targeting BIOMATERIALS Chen, K., Xie, J., Xu, H., Behera, D., Michalski, M. H., Biswal, S., Wang, A., Chen, X. 2009; 30 (36): 6912-6919

  Abstract

  A key challenge in developing nanoplatform-based molecular imaging is to achieve an optimal pharmacokinetic profile to allow sufficient targeting and to avoid rapid clearance by the reticuloendothelial system (RES). In the present study, iron oxide nanoparticles (IONPs) were coated with a PEGylated amphiphilic triblock copolymer, making them water soluble and function-extendable. These particles were then conjugated with a near-infrared fluorescent (NIRF) dye IRDye800 and cyclic Arginine-Glycine-Aspartic acid (RGD) containing peptide c(RGDyK) for integrin alpha(v)beta(3) targeting. In vitro binding assays confirmed the integrin-specific association between the RGD-particle adducts and U87MG glioblastoma cells. Successful tumor homing in vivo was perceived in a subcutaneous U87MG glioblastoma xenograft model by both magnetic resonance imaging (MRI) and NIRF imaging. Ex vivo histopathological studies also revealed low particle accumulation in the liver, which was attributed to their compact hydrodynamic size and PEGylated coating. In conclusion, we have developed a novel RGD-IONP conjugate with excellent tumor integrin targeting efficiency and specificity as well as limited RES uptake for molecular MRI.

  View details for DOI 10.1016/j.biomaterials.2009.08.045

  View details for Web of Science ID 000272071400012

  View details for PubMedID 19773081

  View details for PubMedCentralID PMC3640639

• A Novel Estrogen Receptor Intramolecular Folding-based Titratable Transgene Expression System MOLECULAR THERAPY Paulmurugan, R., Padmanabhan, P., Ahn, B., Ray, S., Willmann, J. K., Massoud, T. F., Biswal, S., Gambhir, S. S. 2009; 17 (10): 1703-1711

  Abstract

  The use of regulated gene expression systems is important for successful gene therapy applications. In this study, ligand-induced structural change in the estrogen receptor (ER) was used to develop a novel ER intramolecular folding-based transcriptional activation system. The system was studied using ER-variants of different lengths, flanked on either side by the GAL4-DNA-binding domain and the VP16-transactivation domain (GAL4(DBD)-ER-VP16). The ER ligands of different types showed efficient ligand-regulated transactivation. We also characterized a bidirectional transactivation system based on the ER and demonstrated its utility in titrating both reporter and therapeutic gene expression. The ligand-regulated transactivation system developed by using a mutant form of the ER (G521T, lacking affinity for the endogenous ligand 17beta-estradiol, whereas maintaining affinity for other ligands) showed efficient activation by the ligand raloxifene in living mice without significant interference from the circulating endogenous ligand. The ligand-regulated transactivation system was used to test the therapeutic efficiency of the tumor suppressor protein p53 in HepG2 (p53(+/+)) and SKBr3 (p53(-/-)/mutant-p53(+/+)) cells in culture and tumor xenografts in living mice. The multifunctional capabilities of this system should be useful for gene therapy applications, to study ER biology, to evaluate gene regulation, ER ligand screening, and ER ligand biocharacterization in cells and living animals.

  View details for DOI 10.1038/mt.2009.171

  View details for PubMedID 19654568

• Analysis of Bone Mineral Density and Bone Turnover in the Presence of Polymethylmethacrylate Particles JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS Zilber, S., Lee, S. W., Smith, R. L., Biswal, S., Goodman, S. B. 2009; 90B (1): 362-367

  Abstract

  Polymethylmethacrylate (PMMA) particles generated from joint arthroplasties appear to contribute to aseptic implant loosening through inflammation-induced periprosthetic osteolysis. However, osteolysis appears to be multifactorial; whether a direct link exists between PMMA particles and osteolysis in vivo is unproven. With the aim to define the relationship between PMMA particles and osteolysis, the authors analyzed the bone mineral density, using microCT scans preoperatively, the first day postoperatively and then every 7-10 days for 32 days, and bone turnover, using (18)F-fluoride positron emission tomography scanner (PET scan) at 8 weeks in four groups of mice that had undergone intramedullary femoral injection. The experimental group of five mice was injected with PMMA particles, and compared with two negative control groups (no injection and injection with the carrier, phosphate-buffered saline) and one positive control group (injection of PMMA particles contaminated with endotoxin). There was no significant change in bone mineral density with addition of PMMA particles, and no evidence of osteolysis. However, bone turnover was increased in the presence of PMMA particles. Even though a direct link between PMMA particles and osteolysis was not found in the short term, PMMA particles appear to influence the regenerative capacity of bone.

  View details for DOI 10.1002/jbm.b.31293

  View details for Web of Science ID 000267298500041

• A NEAR-INFRARED FLUORESCENT DEOXYGLUCOSE DERIVATIVE FOR OPTICAL IMAGING OF EXPERIMENTAL ARTHRITIS JOURNAL OF INNOVATIVE OPTICAL HEALTH SCIENCES Liu, X., Xiong, Z., Lee, S., Levi, J., Yaghoubi, S., Biswal, S., Gambhir, S. S., Cheng, Z. 2009; 2 (2): 179-187

  View details for DOI 10.1142/S1793545809000450

  View details for Web of Science ID 000208647200008

• Stem Cell-Mediated Accelerated Bone Healing Observed with in Vivo Molecular and Small Animal Imaging Technologies in a Model of Skeletal Injury JOURNAL OF ORTHOPAEDIC RESEARCH Lee, S., Padmanabhan, P., Ray, P., Gambhir, S. S., Doyle, T., Contag, C., Goodman, S. B., Biswal, S. 2009; 27 (3): 295-302

  Abstract

  Adult stem cells are promising therapeutic reagents for skeletal regeneration. We hope to validate by molecular imaging technologies the in vivo life cycle of adipose-derived multipotent cells (ADMCs) in an animal model of skeletal injury. Primary ADMCs were lentivirally transfected with a fusion reporter gene and injected intravenously into mice with bone injury or sham operation. Bioluminescence imaging (BLI), [(18)F]FHBG (9-(fluoro-hydroxy-methyl-butyl-guanine)-micro-PET, [(18)F]Fluoride ion micro-PET and micro-CT were performed to monitor stem cells and their effect. Bioluminescence microscopy and immunohistochemistry were done for histological confirmation. BLI showed ADMC's traffic from the lungs then to the injury site. BLI microscopy and immunohistochemistry confirmed the ADMCs in the bone defect. Micro-CT measurements showed increased bone healing in the cell-injected group compared to the noninjected group at postoperative day 7 (p < 0.05). Systemically administered ADMC's traffic to the site of skeletal injury and facilitate bone healing, as demonstrated by molecular and small animal imaging. Molecular imaging technologies can validate the usage of adult adipose tissue-derived multipotent cells to promote fracture healing. Imaging can in the future help establish therapeutic strategies including dosage and administration route.

  View details for DOI 10.1002/jor.20736

  View details for PubMedID 18752273

• Erdheim-Chester disease: case report with unique postmortem magnetic resonance imaging, high-resolution radiography, and pathologic correlation CLINICAL IMAGING de Abreu, M. R., Castro, M. O., Chung, C., Trudell, D., Biswal, S., Wesselly, M., Resnick, D. 2009; 33 (2): 150-153

  Abstract

  Erdheim-Chester disease is an infiltrative form of histiocytosis characterized by replacement of normal tissues by lipid-laden histiocytes. The disease typically infiltrates the medullary portion of the diaphysis and metaphysis of long bones, producing a characteristic radiological pattern dominated by bone sclerosis. It usually affects adults of 40 years of age with a clinical spectrum ranging from an asymptomatic focal bone lesion to multisystemic disease. This case report documents unique imaging and pathologic findings of Erdheim-Chester disease using close postmortem pathologic-imaging correlation.

  View details for DOI 10.1016/j.clinimag.2008.09.009

  View details for Web of Science ID 000264016200014

  View details for PubMedID 19237062

• Systemic trafficking of macrophages induced by bone cement particles in nude mice BIOMATERIALS Ren, P., Lee, S., Biswal, S., Goodman, S. B. 2008; 29 (36): 4760-4765

  Abstract

  Macrophages play an important role in the biological response to wear particles, which can result in periprosthetic osteolysis and implant loosening. In this study, we demonstrate that polymer particles induce systemic trafficking of macrophages by non-invasive in vivo imaging and immunohistochemistry. The distal femora of nude mice were injected with 10% (w/v) Simplex bone cement (BC) suspensions or saline (PBS). Reporter RAW264.7 macrophages which stably expressed the bioluminescent reporter gene fluc, and the fluorescence reporter gene gfp, were injected intravenously. Bioluminescence imaging was performed immediately and periodically at 2-day intervals until day 14. Compared to the non-operated contralateral femora, the bioluminescent signal of femora injected with BC suspension increased 4.7+/-1.6 and 7.8+/-2.9-fold at day 6 and 8, respectively. The same values for PBS group were 1.2+/-0.2 and 1.4+/-0.5, respectively. The increase of bioluminescence of the BC group was significantly greater than the PBS group at day 8 (p<0.05) and day 6 (p<0.1). Histological study confirmed the presence of reporter macrophages within the medullary canal of mice that received cement particles. Modulation of the signaling mechanisms that regulate systemic macrophage trafficking may provide a new strategy for mitigating the chronic inflammatory response and osteolysis associated with wear debris.

  View details for DOI 10.1016/j.biomaterials.2008.09.004

  View details for PubMedID 18824259

• Tibial aperture bone disruption after retrograde versus antegrade tibial tunnel drilling: a cadaveric study KNEE SURGERY SPORTS TRAUMATOLOGY ARTHROSCOPY McAdams, T. R., Biswal, S., Stevens, K. J., Beaulieu, C. F., Mandelbaum, B. R. 2008; 16 (9): 818-822

  Abstract

  The purpose of this study is to compare the local microfracture effects of antegrade versus retrograde drilling of the tibial tunnel in ACL reconstruction. Arthroscopic ACL excision was performed on eight matched cadaveric knees. Arthroscopic guided tibial tunnel reaming was performed in either an antegrade (four) or retrograde (four) direction. A 3 x 3 cm section of proximal tibial surrounding the tibial aperture was removed with open dissection, and each section underwent micro-computed tomography analysis. Three musculoskeletal radiologists graded the specimens for bone aperture disruption and discrete fracture lines. Tibial aperture irregularity was seen in all four of the antegrade specimens (mean, Grade 1.5), and in none of the retrograde specimens. Discrete fracture lines were present in all four antegrade specimens (mean 10.13 mm depth; 8.95 mm length). No fracture lines were seen in the retrograde group. Retrograde drilling of the tibial tunnel in ACL reconstruction results in less microfracture trauma to the surrounding aperture bone. The use of retrograde drilling in ACL reconstruction may decrease synovialization of the graft-tissue interface when compared to antegrade drilling.

  View details for DOI 10.1007/s00167-008-0554-6

  View details for PubMedID 18516594

• Early findings of small-animal MRI and small-animal computed tomography correlate with histological changes in a rat model of rheumatoid arthritis NMR IN BIOMEDICINE Lee, S., Greve, J. M., Leaffer, D., Lollini, L., Bailey, P., Gold, G. E., Biswal, S. 2008; 21 (5): 527-536

  Abstract

  With the use of a commonly utilized animal model of rheumatoid arthritis, the central goal of this work was to determine how well the small-animal imaging tools, small-animal MRI (microMRI) and small-animal X-ray computed tomography (microCT), can detect very early histological changes that occur immediately after induction of the disease. Arthritis was induced in rats by injecting complete Freund's adjuvant into the tail. Right hind paws of living rats were evaluated with 4.7 T microMRI with T1-weighted spin echo and inversion recovery sequences. Paw specimens were also evaluated with microCT and by histological examination (n = 29). MicroMR images were scored for the presence of joint effusion, soft tissue swelling, bone marrow changes, and bone erosions. MicroCT measured bone mineral density (BMD). Histology scores were obtained from representative slides from the same rats. The correlation between BMD, MRI and histology was analyzed using linear regression analysis and analysis of covariance. MRI abnormalities were detected on day 5 after induction as joint effusion and soft tissue swelling, followed by bone marrow changes on day 6 and bone erosion on day 8. BMD measured by microCT decreased, the decrease becoming significant on day 7 (P < 0.019). Soft tissue swelling, joint effusion, and bone erosion scores on microMRI correlated with histology (r2 approximately 0.7). Bone marrow changes were seen more clearly with microMRI than by histological examination. Bone loss could be detected earlier by microCT than on histological sections. In conclusion, microMRI and microCT can be used to evaluate early disease changes within 1 week of induction in the adjuvant-induced arthritis model, and have the ability to detect certain manifestations of disease earlier than histological analysis. The use of small-animal imaging techniques potentially allows earlier diagnosis, improved subject stratification, earlier drug implementation, and therefore improved drug trials in animal models of rheumatoid arthritis.

  View details for DOI 10.1002/nbm.1225

  View details for PubMedID 18023077

• Stress-related injuries around the lesser trochanter in long-distance runners AMERICAN JOURNAL OF ROENTGENOLOGY Nguyen, J. T., Peterson, J. S., Biswal, S., Beaulieu, C. F., Fredericson, M. 2008; 190 (6): 1616-1620

  Abstract

  Imaging abnormalities around the lesser trochanter are occasionally found in long-distance runners, yet little research has been conducted concerning this area of the hip. In addition, the relation between iliopsoas insertional abnormalities at the lesser trochanter and femoral neck stress injuries has not been examined, to our knowledge. We report MRI findings at the lesser trochanter in nine long-distance runners with hip or groin pain and a consistent constellation of the following findings: abnormalities associated with the iliopsoas tendon and its insertion, including marrow edema at the lesser trochanter; periostitis around the lesser trochanter; and bone marrow edema in the femoral neck. One case involved temporal progression to a cortical fracture.Long-distance runners with hip or groin pain and abnormal MRI findings involving the insertion of the iliopsoas tendon and marrow edema in the lesser trochanter may be at risk of stress injuries at the femoral neck.

  View details for DOI 10.2214/AJR.07.2513

  View details for Web of Science ID 000256064700035

  View details for PubMedID 18492915

• Synthesis and characterization of PVP-coated large core iron oxide nanoparticles as an MRI contrast agent NANOTECHNOLOGY Lee, H., Lee, S., Xu, C., Xie, J., Lee, J., Wu, B., Koh, A. L., Wang, X., Sinclair, R., Xwang, S., Nishimura, D. G., Biswal, S., Sun, S., Cho, S. H., Chen, X. 2008; 19 (16)

  Abstract

  The purpose of this study was to synthesize biocompatible polyvinylpyrrolidone (PVP)-coated iron oxide (PVP-IO) nanoparticles and to evaluate their efficacy as a magnetic resonance imaging (MRI) contrast agent. The PVP-IO nanoparticles were synthesized by a thermal decomposition method and characterized by x-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering (DLS), and a superconducting quantum interface device (SQUID). The core size of the particles is about 8-10 nm and the overall size is around 20-30 nm. The measured r(2) (reciprocal of T(2) relaxation time) and r2∗ (reciprocal of T2∗ relaxation time) are 141.2 and 338.1 (s mM)(-1), respectively. The particles are highly soluble and stable in various buffers and in serum. The macrophage uptake of PVP-IO is comparable to that of Feridex as measured by a Prussian blue iron stain and phantom study. The signal intensity of a rabbit liver was effectively reduced after intravenous administration of PVP-IO. Therefore PVP-IO nanoparticles are potentially useful for T(2)-weighted MR imaging.

  View details for DOI 10.1088/0957-4484/19/16/165101

  View details for Web of Science ID 000254174800001

  View details for PubMedCentralID PMC3050625

• Synthesis and characterization of PVP-coated large core iron oxide nanoparticles as an MRI contrast agent. Nanotechnology Lee, H. Y., Lee, S. H., Xu, C., Xie, J., Lee, J. H., Wu, B., Koh, A. L., Wang, X., Sinclair, R., Wang, S. X., Nishimura, D. G., Biswal, S., Sun, S., Cho, S. H., Chen, X. 2008; 19 (16): 165101

  Abstract

  The purpose of this study was to synthesize biocompatible polyvinylpyrrolidone (PVP)-coated iron oxide (PVP-IO) nanoparticles and to evaluate their efficacy as a magnetic resonance imaging (MRI) contrast agent. The PVP-IO nanoparticles were synthesized by a thermal decomposition method and characterized by x-ray diffraction (XRD), transmission electron microscopy (TEM), dynamic light scattering (DLS), and a superconducting quantum interface device (SQUID). The core size of the particles is about 8-10 nm and the overall size is around 20-30 nm. The measured r(2) (reciprocal of T(2) relaxation time) and r2∗ (reciprocal of T2∗ relaxation time) are 141.2 and 338.1 (s mM)(-1), respectively. The particles are highly soluble and stable in various buffers and in serum. The macrophage uptake of PVP-IO is comparable to that of Feridex as measured by a Prussian blue iron stain and phantom study. The signal intensity of a rabbit liver was effectively reduced after intravenous administration of PVP-IO. Therefore PVP-IO nanoparticles are potentially useful for T(2)-weighted MR imaging.

  View details for DOI 10.1088/0957-4484/19/16/165101

  View details for PubMedID 21394237

  View details for PubMedCentralID PMC3050625

• Mouse femoral intramedullary injection model: Technique and microCT scan validation JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART B-APPLIED BIOMATERIALS Zilber, S., Epstein, N., Lee, S., Larsen, M., Ma, T., Smith, R. L., Biswal, S., Goodman, S. B. 2008; 84B (1): 286-290

  Abstract

  The murine femoral intramedullary injection model is frequently used to examine the in vivo effects of biomaterials or cancer cells. The surgical technique includes a knee arthrotomy with patellar dislocation for intramedullary access. This study examined a less invasive surgical approach of direct injection of particles via the transpatellar tendon without patellar dislocation. By using polymethylmethacrylate injection and microCT scan, we found that, compared with the traditional technique, this new approach was more reproducible, less time consuming, and achieved identical volumes of intramedullary injections. Animal morbidity and the biomechanics of the joints were also improved as a result of the simplified procedure. Furthermore, our study suggested that an intramedullary volume in excess of 10 microL can lead to major vascular filling and so should be avoided.

  View details for DOI 10.1002/jbm.b.30872

  View details for Web of Science ID 000251802900034

• Mouse femoral intramedullary injection model: technique and microCT scan validation. Journal of biomedical materials research. Part B, Applied biomaterials Zilber, S., Epstein, N. J., Lee, S., Larsen, M., Ma, T., Smith, R. L., Biswal, S., Goodman, S. B. 2008; 84 (1): 286-290

  Abstract

  The murine femoral intramedullary injection model is frequently used to examine the in vivo effects of biomaterials or cancer cells. The surgical technique includes a knee arthrotomy with patellar dislocation for intramedullary access. This study examined a less invasive surgical approach of direct injection of particles via the transpatellar tendon without patellar dislocation. By using polymethylmethacrylate injection and microCT scan, we found that, compared with the traditional technique, this new approach was more reproducible, less time consuming, and achieved identical volumes of intramedullary injections. Animal morbidity and the biomechanics of the joints were also improved as a result of the simplified procedure. Furthermore, our study suggested that an intramedullary volume in excess of 10 microL can lead to major vascular filling and so should be avoided.

  View details for PubMedID 17563101

• Molecular imaging: Integration of molecular imaging into the musculoskeletal imaging practice RADIOLOGY Biswal, S., Resnick, D. L., Hoffman, J. M., Gambhir, S. S. 2007; 244 (3): 651-671

  Abstract

  Chronic musculoskeletal diseases such as arthritis, malignancy, and chronic injury and/or inflammation, all of which may produce chronic musculoskeletal pain, often pose challenges for current clinical imaging methods. The ability to distinguish an acute flare from chronic changes in rheumatoid arthritis, to survey early articular cartilage breakdown, to distinguish sarcomatous recurrence from posttherapeutic inflammation, and to directly identify generators of chronic pain are a few examples of current diagnostic limitations. There is hope that a growing field known as molecular imaging will provide solutions to these diagnostic puzzles. These techniques aim to depict, noninvasively, specific abnormal cellular, molecular, and physiologic events associated with these and other diseases. For example, the presence and mobilization of specific cell populations can be monitored with molecular imaging. Cellular metabolism, stress, and apoptosis can also be followed. Furthermore, disease-specific molecules can be targeted, and particular gene-related events can be assayed in living subjects. Relatively recent molecular and cellular imaging protocols confirm important advances in imaging technology, engineering, chemistry, molecular biology, and genetics that have coalesced into a multidisciplinary and multimodality effort. Molecular probes are currently being developed not only for radionuclide-based techniques but also for magnetic resonance (MR) imaging, MR spectroscopy, ultrasonography, and the emerging field of optical imaging. Furthermore, molecular imaging is facilitating the development of molecular therapies and gene therapy, because molecular imaging makes it possible to noninvasively track and monitor targeted molecular therapies. Implementation of molecular imaging procedures will be essential to a clinical imaging practice. With this in mind, the goal of the following discussion is to promote a better understanding of how such procedures may help address specific musculoskeletal issues, both now and in the years ahead.

  View details for DOI 10.1148/radiol.2443060295

  View details for Web of Science ID 000248993500006

  View details for PubMedID 17709823

• Sacral stress fractures: Magnetic resonance imaging not always definitive for early stage injuries - A report of 2 cases AMERICAN JOURNAL OF SPORTS MEDICINE Fredericson, M., Moore, W., Biswal, S. 2007; 35 (5): 835-839

  View details for DOI 10.1177/0363546506296519

  View details for Web of Science ID 000246264600019

  View details for PubMedID 17261568

• Diagnosis of aseptic deep venous thrombosis of the upper extremity in a cancer patient using fluorine-18 fluorodeoxyglucose positron emission tomography/computerized tomography (FDG PET/CT) ANNALS OF NUCLEAR MEDICINE Do, B., Mari, C., Biswal, S., Kalinyak, J., Quon, A., Gambhir, S. S. 2006; 20 (2): 151-155

  Abstract

  We describe a patient with a history of recurrent squamous cell carcinoma of the tongue and abnormal FDG uptake in the left arm during a re-staging FDG PET/CT. After revision of the patient's clinical history, tests and physical exam, the abnormal FDG uptake was found to correspond to an extensive aseptic deep venous thrombosis of the upper extremity.

  View details for Web of Science ID 000236242700010

  View details for PubMedID 16615425

• Visualization of telomerase reverse transcriptase (hTERT) promoter activity using a trimodality fusion reporter construct JOURNAL OF NUCLEAR MEDICINE Padmanabhan, P., Otero, J., Ray, P., Paulmurugan, R., Hoffman, A. R., Gambhir, S. S., Biswal, S., Ulaner, G. A. 2006; 47 (2): 270-277

  Abstract

  Our goal was to noninvasively measure chemotherapy-induced changes in the expression of critical tumor growth genes. To achieve this goal, we used radionuclide and optical methods to measure changes in human telomerase reverse transcriptase (hTERT) gene expression in tumor cells before and after 5-fluorouracil treatment.A fusion reporter construct, containing humanized Renilla luciferase (hrl, for bioluminescent imaging), monomeric red fluorescence protein 1 (mrfp1, for fluorescent imaging), and a truncated thymidine kinase (ttk, for imaging of radiolabeled acycloguanosines), was placed under the control of hTERT promoter fragments. These constructs were introduced into tumor cell lines with and without hTERT expression. Transfected cells were treated with 5-fluorouracil, a chemotherapeutic that decreases hTERT gene expression, and treatment-induced changes in hTERT promoter activity were imaged.When the fusion construct is introduced into cell lines that express hTERT, all 3 reporter systems are highly expressed and hTERT promoter activity can be visualized. Cell lines lacking hTERT transcription show no significant reporter expression. Decreases in hTERT gene expression caused by 5-fluorouracil treatment could be visualized in living 293T cells by both fluorescent microscopy and bioluminescent imaging.hTERT promoter activity can be monitored by 1 radionuclide and 2 optical reporter systems using a single reporter construct. This in vitro study provides evidence that our multimodality reporter construct can be used to study the expression of a critical tumor growth gene in living subjects.

  View details for Web of Science ID 000235283500027

  View details for PubMedID 16455633

• Erdheim-Chester disease: MR imaging, anatomic, and histopathologic correlation of orbital involvement AMERICAN JOURNAL OF NEURORADIOLOGY de Abreu, M. R., Chung, C. B., Biswal, S., Haghighi, P., Hesselink, J., Resnick, D. 2004; 25 (4): 627-630

  Abstract

  Erdheim-Chester disease (ECD) is a rare form of histiocytosis of unknown origin characterized by tissue infiltration by lipid-laden histiocytes. Typically, the diaphyseal and metaphyseal portions of the tubular bones are affected, leading to a characteristic radiographic pattern of bone sclerosis. Orbital involvement is not infrequent and is manifested by exophthalmos and periorbital xanthomatous lesions, with associated visual problems. This case report documents imaging and pathologic findings in a patient with ECD with extensive orbital involvement.

  View details for Web of Science ID 000221042900023

  View details for PubMedID 15090356

• Tetraphenylphosphonium as a novel molecular probe for Imaging tumors JOURNAL OF NUCLEAR MEDICINE Min, J. J., Biswal, S., Deroose, C., Gambhir, S. S. 2004; 45 (4): 636-643

  Abstract

  Mitochondrial membrane potential (DeltaPsim)-dependent enhanced uptake of phosphonium salts, including (3)H-tetraphenylphosphonium ((3)H-TPP), in tumor cells, suggests the potential use of phosphonium salts as tracers for tumor imaging. In this study, we characterize the tumor accumulation of (3)H-TPP and compare it with (18)F-FDG in cell culture and in xenograft, metastatic, and inflammation models in living animals.(3)H-TPP and (3)H-FDG accumulation was compared in cell culture with a variety of cell lines in different glucose concentrations. Normal biodistribution and tumor uptake were assessed using nude mice with or without subcutaneous xenograft tumors (C6). To compare the accumulation of (3)H-TPP and (18)F-FDG in a metastatic tumor, severe combined immunodeficiency mice were tail-vein injected with human melanoma cell lines (A375-FL). To characterize the accumulation of (3)H-TPP and (18)F-FDG in inflammation, an inflammatory reaction was induced by subcutaneous injection of Complete Freund's Adjuvant in the left hind paw of Sprague-Dawley rat.The DeltaPsim data from a separate study and the current (3)H-TPP uptake data showed good correlation (r(2) = 0.82, P < 0.05). (3)H-TPP accumulation was significantly greater than that of (3)H-FDG for glucose >/=100 mg/dL. The biodistribution study of (3)H-TPP showed low uptake in most tissues but high accumulation in the heart and kidneys. (3)H-TPP accumulation in xenograft or metastatic tumors was comparable with that of (18)F-FDG, whereas (3)H-TPP accumulation in inflammatory tissues was markedly lower than that of (18)F-FDG.The sensitive tumor accumulation of (3)H-TPP with less propensity for inflammatory regions warrants further investigation of radiolabeled phosphonium analogs for tumor imaging in living subjects.

  View details for Web of Science ID 000220729700023

  View details for PubMedID 15073261

• Molecular imaging of musculoskeletal diseases. Seminars in musculoskeletal radiology Biswal, S. 2003; 7 (4): 317-350

  Abstract

  Chronic musculoskeletal diseases such as arthritis, malignancy, chronic injury/ inflammation, and chronic musculoskeletal pain often pose challenges for current clinical imaging modalities. There is hope that a growing field, referred to as "molecular imaging," will shed new light on these chronic phenomenon as it aims to noninvasively detect special molecular and physiologic effects such as metabolism rate, specific proteins, cell death, and particular gene-related events. Molecular imaging represents recent advances in imaging technology, engineering, chemistry, molecular biology, and genetics that have coalesced into a multidisciplinary and multimodality effort. Molecular probes are currently being developed not only in radionuclide-based techniques but also in magnetic resonance imaging, magnetic resonance spectroscopy, ultrasound, and the emerging field of optical imaging. Furthermore, molecular imagers are fueling the development of novel molecular therapies and gene therapy, as tracking these efforts in living subjects is now possible with molecular imaging protocols.

  View details for PubMedID 14735430

• Risk factors for progressive cartilage loss in the knee: a longitudinal magnetic resonance imaging study in forty-three patients. Arthritis and rheumatism Biswal, S., Hastie, T., Andriacchi, T. P., Bergman, G. A., Dillingham, M. F., Lang, P. 2002; 46 (11): 2884-2892

  Abstract

  To evaluate the rate of progression of cartilage loss in the knee joint using magnetic resonance imaging (MRI) and to evaluate potential risk factors for more rapid cartilage loss.We evaluated baseline and followup MRIs of the knees in 43 patients (minimum time interval of 1 year, mean 1.8 years, range 52-285 weeks). Cartilage loss was graded in the anterior, central, and posterior regions of the medial and lateral knee compartments. Knee joints were also evaluated for other pathology. Data were analyzed using analysis of variance models.Patients who had sustained meniscal tears showed a higher average rate of progression of cartilage loss (22%) than that seen in those who had intact menisci (14.9%) (P

  View details for PubMedID 12428228

• Risk factors for progressive cartilage loss in the knee ARTHRITIS AND RHEUMATISM Biswal, S., Hastie, T., Andriacchi, T. P., Bergman, G. A., Dillingham, M. F., Lang, P. 2002; 46 (11): 2884-2892

  View details for DOI 10.1002/art.10573

  View details for Web of Science ID 000179239500008

• Interventional radiologic procedures: Patient anxiety, perception of pain, understanding of procedure, and satisfaction with medication - A prospective study RADIOLOGY Mueller, P. R., Biswal, S., Halpern, E. F., Kaufman, J. A., Lee, M. J. 2000; 215 (3): 684-688

  Abstract

  To prospectively assess patient anxiety, understanding of the procedure being performed, perception of pain level, and satisfaction with medication given for a variety of diagnostic and therapeutic vascular and visceral (nonvascular) interventional procedures.The authors interviewed 204 patients before and after they underwent an interventional radiologic procedure. Patients responded to a series of questions by using a visual analog scale. Patients were grouped according to (a) their level of experience with the procedure and (b) the type of procedure performed (diagnostic or therapeutic visceral procedure or diagnostic or therapeutic vascular procedure).Patients who had previous experience with a procedure, whether visceral or vascular, were less anxious, had more understanding, and anticipated less pain than did those who did not have experience with a procedure. Patients who had only local anesthesia for visceral biopsy experienced greater pain than did those who had both local and intravenous anesthesia. Satisfaction scores, however, were similar throughout all groups.Patients have a moderate amount of anxiety about interventional procedures and anticipate some discomfort. Most patients have a high level of satisfaction despite the amount of pain they experience during the procedure. Patients experienced with a procedure tend to have a greater understanding of the procedure and less anxiety.

  View details for Web of Science ID 000087247000011

  View details for PubMedID 10831684

• SPATIAL AND TEMPORAL PATTERNS OF DISTRIBUTION OF THE GAP JUNCTION PROTEIN CONNEXIN-43 DURING MOUSE GASTRULATION AND ORGANOGENESIS DEVELOPMENT YANCEY, S. B., Biswal, S., Revel, J. P. 1992; 114 (1): 203-212

  Abstract

  Connexin43 (Cx43) is a member of the family of channel-forming proteins that make up the gap junction and are believed to provide pathways for cell-cell exchange of developmental signals. We have used immunofluorescence and confocal microscopy to characterize the patterns of distribution of Cx43 in postimplantation mouse embryos representing stages of development extending through gastrulation and the major period of organogenesis [through 13.5 days post coitum (dpc)]. We find that Cx43 is expressed early after implantation by the undifferentiated, pluripotent cells of the primitive embryonic ectoderm from which all tissues of the fetus are believed to be derived. As cells become committed to particular developmental pathways, there is a progressive restriction of Cx43 to specific areas and organ systems. The patterns are complex and not limited by germ layer of origin, although there is a clear preference for expression in ectodermal and, to a lesser extent, mesodermal derivatives. Expression in lens, retina, kidney, brain, pineal and pituitary glands is initiated early in organogenesis. In heart, the first clear signal for Cx43 appears in the ventricle at about 10 dpc and is only subsequently detected in the atrium at about 13-13.5 dpc. Particularly intriguing with regard to functional implications is the high level expression observed at sites of inductive interaction; the eye lens and optic cup, the infundibulum and the apical ectodermal ridge of the limb bud.

  View details for Web of Science ID A1992HE52800020

  View details for PubMedID 1315676

• THE INFLUENCE OF DIAZIQUONE FREE-RADICALS ON THE INVITRO ACTIVITY OF DIAZIQUONE XENOBIOTICA Nguyen, B., Biswal, S., Gutierrez, P. L. 1988; 18 (5): 593-602

  Abstract

  1. The influence of the free radical of diaziquone on inhibition of cell growth in vitro was studied using P388 murine leukaemia cells and a mixture of AZQH2 + AZQ. This mixture generates the AZQ free radical by the disproportionation-comproportionation reaction AZQH2 + AZQ in equilibrium with 2AZQH. 2. Reduced AZQ (AZQH2) was produced electrochemically under anaerobic conditions. This colourless solution was added anaerobically to a solution of AZQ at a 9:1 ratio of AZQH2 to AZQ. The free radical (AZQH) generated was detected by electron spin resonance (ESR) and amounted to about 7% of the concn of AZQH2 + AZQ. The AZQ free radical was stable enough to treat cells in culture. 3. Aerobic suspensions of P388 murine leukaemia cells treated with AZQH experienced a surge of free radicals lasting approx. 30 min at concn near 10 times that of the AZQ free radicals generated by P388 cells. 4. Cell growth inhibition indicates that the concentration of AZQ required to arrest the growth of P388 cells by 50% (IC50) is twice that of the AZQ free radical generating mixture. The mechanism of action of AZQ probably does not exclusively involve AZQ free radicals, but they appear to play an important role.

  View details for Web of Science ID A1988N364600013

  View details for PubMedID 2840783

• REDUCTIVE ACTIVATION OF DIAZIQUONE AND POSSIBLE INVOLVEMENT OF FREE-RADICALS AND THE HYDROQUINONE DIANION CANCER RESEARCH Gutierrez, P. L., Biswal, S., Nardino, R., Biswal, N. 1986; 46 (11): 5779-5785

  Abstract

  To analyze the mode of action of diaziquone [AZQ] on DNA, we examined the activity of two AZQ analogues and N,N',N"-triethylenethiophosphoramide on three forms [supercoiled (Form I), open circular (Form II), and linear (Form III)] of PM-2 DNA. The AZQ analogues contained chlorine atoms which substituted either the carbethoxyamino groups or the aziridine groups of the parent compound. N,N',N"-triethylenethiophosphoramide is a triaziridine compound containing pentavalent phosphorus instead of a quinone group. We found that only when reduced with sodium borohydride did AZQ change the topology of the three forms of PM-2 DNA by introducing mainly single strand breaks. The AZQ analogue containing only aziridines (RQ2) was active in both its oxidized and its reduced forms, while the analogue containing only the carbethoxyamino groups (RQ14) or N,N',N"-triethylenethiophosphoramide were not active in either form. Under similar experimental conditions, Adriamycin alone altered the electrophoretic mobility of PM-2 DNA, while borohydride reduced Adriamycin did not. By using electron spin resonance spectroscopy, we showed that dihydrodiaziquone (AZQH2) oxidizes to the semiquinone in the presence of oxygen. Although AZQH2 was active against DNA, it was not active against cellular DNA synthesis as measured by [3H]thymidine incorporation into exponentially growing HEp-2 cells. However, AZQ alone prevented [3H]thymidine incorporation into HEp-2 cells. We found that HEp-2 cells have the ability to reduce AZQ to its free radical anion, but AZQH2 does not autoxidize to the free radical in the presence of cells. The reductive ability of HEp-2 cells may be responsible in part for preventing the oxidation of AZQH2 to the free radical. We found that under our conditions (1-h incubations) the aziridines are essential for the activity of aziridinyl quinones against PM-2 DNA and that in the case of AZQ the hydroquinone is also required.

  View details for Web of Science ID A1986E563100059

  View details for PubMedID 3019536